Most recent articles are listed first within a Section (TMT reviews are included back to January, 2006 and are available in archives for earlier years). The Sections below in order are:

Click on the blue title above for any Section to go to that Section.  Clicking on the blue title for an Item within a Section will take you to a new web page with the original article (if this is still available at the original website). To search, do Ctrl+F (hit the "F" key while holding down the "Control" or "Ctrl" key) and type in the search word or phrase (e.g., "heart").

NOTE September 1, 2007: Because of the great success of our pain questionnaires (http://masterdocs.com/pain.htm - over 3,500 responders to date) and the activity of our collaborations with several academic units, we are temporarily suspending regular postings on this medical news web page,

Why we publish our Medical News: We give you the latest medical news without the hype. Our focus is "patient empowerment" -- free medical questionnaires for common symptoms and medical conditions, and unbiased, up-to-date medical news that can be understood by the public as well as physicians. We flag three of the commonest errors in interpreting clinical studies - not prespecifying a primary study endpoint, overinterpreting observational studies, and overinterpreting subgroup analyses. We normally email the first author of an article reviewed for comment and appropriate revision of our review.

 Remember to check out our free Chronic Pain Questionnaires and other Medical Questionnaires.

Latest Entries (Sections in parentheses):

July 26, 2007: Adverse cardiovascular effects with rofecoxib (Vioxx) versus placebo in patients with colorectal cancer (Heart Disease & Stroke).

July 16, 2007: Older oral hypoglycemic (metformin) gives equivalent blood sugar control in Type II diabetes, lowers LDL cholesterol, and does not increase weight (Other Chronic Disease).

July 12, 2007: As implemented, Electronic Health Records were not associated with better quality ambulatory care (Computers in Medicine).

June 29, 2007: Second-hand smoke increases levels of tobacco-specific carcinogens (Other Chronic Disease).

June 11, 2007: Randomized study suggests weight loss is greater with a reduced fat diet if more fruits and vegetables are eaten (Diet & Exercise).

June 5, 2007: Randomized acupuncture trial suggests blood pressure reduction (Heart Disease & Stroke). Out of hospital cooling of patients with cardiac arrest feasible and safe. Larger studies should be done. (Heart Disease & Stroke).

May 21, 2007: Meta-analysis suggests heart hazard with rosiglitazone (Avandia) but manufacturer's data should be released (Heart Disease & Stroke).

May 18, 2007: HPV vaccine could prevent cancer of cervix, vulva, vagina, mouth and throat (Cancer).

May 9, 2007: Senate votes new powers to FDA on drug safety (Administrative&Political).

May 2, 2007: Depressed patients may need both antidepressants and treatment for insomnia (Neurological/Psychological).

April 14, 2007: Active, electronic post-marketing drug safety surveillance system advocated by former FDA Commissioner (Computers in Medicine).

April 4, 2007: Combination of sumatriptan and naproxen useful for acute treatment of migraine (Pain).

March 27, 2007: Increasing HDL cholesterol with torcetrapib did not affect the primary endpoint (percent atheroma volume) in the ILLUSTRATE study (Heart Disease & Stroke).

March 17, 2007: Cardiac-only resuscitation by bystanders may be best for out-of-hospital cardiac arrest (Heart Disease & Stroke).

March 15, 2007: Poor warfarin compliance associated with poor INR control, and more stroke, heart attack, major bleeding, and mortality. Many high risk patients are not prescribed warfarin (Heart Disease & Stroke). Weekend hospital admission for heart attack associated with higher mortality (Heart Disease & Stroke).

March 6, 2007: Randomized study suggests slightly more weight loss with Atkins diet (Diet & Exercise).

March 5, 2007: Ibuprofen best pain killer for kids with acute traumatic musculoskeletal injuries (Pain).

March 3, 2007: Happy countries may have less high blood pressure (Neurological & Psychological).

March 1, 2007: Pain killers including acetaminophen and aspirin associated with higher risk of high blood pressure (Heart Disease & Stroke). Improvement in oral health may reduce cardiovascular risk (Heart Disease & Stroke).

FEBRUARY 2007:  US Government privacy standards for electronic health data in "early stages". TMT privacy standards fully implemented. (Computers in Medicine). Heart disease rate varies from state to state (Heart Disease & Stroke). Controlled study shows low-dose morphine can improve refractory cough (Other Chronic Disease). Weekly motivational counseling improves mood after stroke (Heart Disease & Stroke). Nasal spray better than flu shots for small children (Miscellaneous). New method more accurate for identifying cardiovascular risk in women (Heart Disease & Stroke). High dose atorvastatin (Lipitor) reduces heart failure hospitalizations (Heart Disease & Stroke). Religious people with advanced cancer get inadequate spiritual support and want aggressive measures to extend life (Cancer). Randomized trial suggests that 3 months of psychoanalysis helps patients with panic disorder (Neurological & Psychological). In preliminary study, Down's Syndrome was identified by fetal DNA test on maternal blood (Miscellaneous). Lessen burden of bereavement by spending more time with family members and giving them a bereavement brochure (Neurological & Psychological).

JANUARY 2007:  FDA announces new initiatives to assess safety of marketed drugs (Administrative & Political). ABCD2 score predicts 2-day risk of progression of TIA to stroke (Heart Disease & Stroke). Financial incentives improve hospital performance (Administrative & Political). Observational study suggests that trans fats may increase infertility but additional evaluation is required (Diet & Exercise). In observational study, dense breast tissue increased risk of breast cancer and increased difficulty of diagnosis (Cancer). Cancer deaths are down. Cancer pain is treatable. (Cancer). Arthritis and related conditions cost over $500 per year per American adult (Pain). Black tea with no milk increases ability of arteries to relax, but adding milk prevents this effect (Diet & Exercise). Food industry-funded studies of soft drinks, juice or milk tend to favor the commercial interests of the funder (Diet & Exercise). Drug prices higher in Medicare private plans than in VA system (Administrative & Political). Starbucks removing trans fats from its pastries (Diet & Exercise). Therapy with ACE inhibitors, angiotensin receptor blockers or beta-blockers associated with better outcome following hospital discharge for heart failure (Heart Disease & Stroke). Pergolide (Permax) and cabergoline (Dostinex) associated with heart valve abnormalities in Parkinson's disease patients (Heart Disease & Stroke).

DECEMBER 2006:  Evidence-based procedures reduce catheter-related blood stream infections in ICUs (Miscellaneous). Observational study suggests that proton pump inhibitors increase hip fracture risk (Other Chronic Diseases). Cognitive training helps mental function in the elderly (Neurological & Psychological). Randomized study suggests reduced fat in diet reduces breast cancer recurrence (Cancer). Breast cancer rate dropped 7% in 2003, possibly because of less female hormone therapy (Cancer). Pain gene variants can increase or eliminate pain (Pain). Observational study suggests that surgery or radiation for localized prostate cancer improves survival in elderly men (Cancer). More prolonged antiplatelet therapy recommended by some experts for patients with drug-eluting stents (Heart Disease & Stroke). More on torcetrapib: conflicting studies of relationship between CETP levels and heart disease (Heart Disease & Stroke). Physicians may defer to computer in diagnosis (Computers in Medicine). Some more possible explanations for torcetrapib safety problems (Heart Disease & Stroke). Possible explanations for torcetrapib safety problems (Heart Disease & Stroke). FDA clarifies DSMB monitoring in Pfizer's ILLUMINATE torcetrapib trial (Heart Disease & Stroke). Pfizer halts all torcetrapib trials because of increase in mortality and cardiovascular events (Heart Disease & Stroke).

NOVEMBER 2006:  Moderate alcohol consumption may reduce risk of heart failure by reducing the risk of coronary disease (Heart Disease & Stroke). Most back & sciatica patients who don't require urgent surgery improve with either medical or surgical therapy. You can always get surgery later. (Pain). Identifying serious adverse drug effects: Drug companies, Investigators, Advisory Committees, and the FDA (Administrative & Political). Naproxen increases risk of cardiovascular events in Alzheimer's trial (Heart Disease & Stroke). With resveratrol, mice can run twice as long on a treadmill (Diet & Exercise). Pain relief in fibromyalgia reported with pregabelin (Lyrica) in 6-month double-blind study (Pain). Americans are living longer but have more long-term pain (Pain). Medication blister packs and education improve medication compliance in the elderly by 36%, with lower BP & cholesterol (Miscellaneous). Stable patients after acute phase of heart attack don't need angioplasty and stent (Heart Disease & Stroke). Etoricoxib (Arcoxia) similar to diclofenac in risk of heart attack, stroke & death but causes more high blood pressure and heart failure (Heart Disease & Stroke). Heart attack patients get angioplasty too late (Heart Disease & Stroke). Diet with low carbohydrate and vegetable sources of fat and protein may reduce coronary risk (Diet & Exercise). Warts and all – trial of the tape (Miscellaneous). Primary care in US lags other developed countries in clinical information systems and quality and efficiency incentives (Computers in Medicine). Poor people in wealthy neighborhoods have higher death rate than poor people in poor neighborhoods (Administrative & Political). Open study suggests that one-year of therapy with a heart assist device combined with drug therapy can reverse severe heart failure (Heart Disease & Stroke). Restraining good hand improves movement of affected arm after stroke (Heart Disease & Stroke). Chronic constipation associated with higher mortality (Other Chronic Disease). Physically active people have less macular degeneration (Other Chronic Disease). Higher PSA velocity 10-15 years before prostate cancer diagnosis may be associated with higher prostate cancer mortality (Cancer). Study in mice shows that resveratrol, found in red wine, offsets bad effects of high calorie diet and extends lifespan (Diet & Exercise).

OCTOBER 2006:  Unblinded randomized study suggests acupuncture is effective in patients with osteoarthritis (Pain). Pneumococcal vaccine appears effective with each of various vaccination schedules (Miscellaneous). 80% of US Internet users have searched on-line for health information (Computers in Medicine). Are flu shots as effective as claimed? (Miscellaneous). CT screening detects early lung cancer (Cancer). CDC recommends routine Zostavax shingles vaccine for those 60 and over (Miscellaneous). Observational study associates higher vegetable consumption with better cognitive function in elderly (Neurological & Psychological). Observational study in healthy men shows correlation between alcohol consumption and reduced risk of heart attack (Diet & Exercise). Less than 10% of US doctors use full-fledged electronic health records for outpatients (Computers in Medicine). NIH doctors criticize Eli Lilly's promotion of sepsis drug (Administrative & Political). Noise-cancelling headphones might prevent hearing loss in noisy subway (Miscellaneous). Over 700,000 adverse drug events yearly require treatment in US Emergency Rooms, with over 100,000 hospitalizations. Elderly at higher risk. (Administrative & Political). Mortality in Medicare patients depends on the hospital (Administrative & Political). FDA approves Aricept for severe Alzheimer's Disease (Neurological & Psychological). Does daily weighing help maintain weight loss? (Diet & Exercise). Symptoms suggesting stroke occur in 18% of older people without a stroke diagnosis (Heart Disease & Stroke). Industry-sponsored meta-analyses are of poorer quality and conclusions are more favorable to the experimental drug (Miscellaneous). Get your 'flu shot - it could save your life (Miscellaneous). NIH clinical trial will compare $20-100/month drug with $2000/month drug in macular degeneration (Other Chronic Disease).Smarter breast-feeding mothers mean smarter breast-fed children  (Diet & Exercise).

SEPTEMBER 2006: Bayer did not tell FDA about preliminary safety data from Trasylol observational study (Heart Disease & Stroke). IOM report recommends more funding/staffing/enforcement tools for FDA and more emphasis on safety of marketed drugs (Administrative & Political). Test for H. Pylori before starting NSAIDs in high GI risk patients (Pain). It's OK to eat canned or frozen spinach (Diet & Exercise). Prescribing errors for seniors almost 7 times as likely as with younger patients (Administrative & Political). Meta-analyses confirm Vioxx cardiovascular toxicity but raise other questions (Heart Disease & Stroke). US divided into "Eight Americas" on basis of longevity (Administrative & Political). Difficulty understanding patient pamphlets and prescription labels is common and associated with poor health (Administrative & Political). Don't take ibuprofen less than 8 hours before or less than 30 minutes after aspirin taken for cardioprotection (Heart Disease & Stroke). Report claims Norvasc reduces risk of diabetes (Other Chronic Disease). High dose Lipitor reported to reduce heart attack risk more than medium dose Zocor (Heart Disease & Stroke). Subgroup analysis of TNT trial shows that high risk patients with coronary disease and metabolic syndrome do well on high dose (80mg) Lipitor (Heart Disease & Stroke).

AUGUST 2006: APC and PreSAP double-blind trials show that celecoxib (Celebrex) at dosage of 400 mg/day or greater reduces risk of colorectal adenomas but increases cardiovascular risk (Heart Disease & Stroke). Observational study suggests that NSAIDs may protect against development of prostate cancer only in men with the gene type associated with higher LTA levels (Cancer). Observational study suggests that NSAIDs reduce BPH risk (symptoms, prostate size, urinary flow & PSA) (Other Chronic Disease). FDA Drug/Device Advisory Committees recommend approval in 8 of 10 cases and FDA usually follows the recommendation (Administrative & Political). Could stem cells be harvested from embryos without damaging the developing embryo? (Miscellaneous). Being overweight at age 50 increases risk of death, particularly in women. Waist/hip ratio may be a better measure than BMI (Diet & Exercise). 'ReNu with MoistureLoc" is 13 times as likely to cause fungus infection in contact eye wearers (Miscellaneous). Large observational study in 52 countries shows heart attack risk with all forms of tobacco, including second-hand smoke (Heart Disease & Stroke). Computerized feedback increases short-term weight loss (Diet & Exercise). In randomized trials both COX-2 inhibitors and traditional NSAIDs increase vascular risk (Heart Disease & Stroke). Observational study suggests that aspirin may mitigate the increased cardiovascular risk with NSAIDs (Heart Disease & Stroke). High-dose Lipitor reduces risk of recurrent stroke even in people without known coronary disease (Heart Disease & Stroke). Observational study suggests all NSAIDs (Cox-2-selective and non-Cox-2-selective) modestly increase heart attack risk (Heart Disease & Stroke).

JULY 2006: Faster aging in poor people may be related to shortened telomeres (Miscellaneous). Medication errors injure 1.5 million in US/year. Patients can protect themselves. Electronic prescribing can help. (Miscellaneous). FDA approves once-a-day 3-drug combination tablet for HIV treatment (Miscellaneous). Increased energy expenditure associated with reduced mortality in high-functioning older adults (Diet & Exercise). Gene effects markedly different between males and females (Miscellaneous). Most heart attacks might be prevented by a healthy lifestyle (Heart Disease & Stroke).

JUNE 2006: New England Journal of Medicine issues "correction" on Vioxx APPROVe trial (Heart Disease & Stroke). Observational study suggests mortality risk is increased with short duration NSAID therapy in patients with previous heart attack (Heart Disease & Stroke). Fibromyalgia symptoms respond to acupuncture in controlled trial (Pain). Media stories on medical reports at scientific meetings are misleading (Administrative & Political).

MAY 2006: Dr. Scott Evans of the Harvard School of Public Health, has provided us with a Review of the issue of changing clinical trial endpoints after a trial has begun, an issue posted in our Miscellaneous section on March 26, 2006 (Miscellaneous). Please send any comments to info@masterdocs.com and we will forward them to Dr. Evans. Data from Merck report suggest fairly constant cardiovascular risk (0.2% of patients/6 months) during most of Vioxx therapy and in 1-year following therapy, with higher risk in last 6 months of 3-year Vioxx period (Heart Disease & Stroke). New analysis suggests greater, earlier and more persistent increase in cardiovascular risk with rofecoxib (Vioxx) (Heart Disease & Stroke). Node-positive breast cancer women who have more HER2 receptor activity do better with epirubicin as part of a triple therapy regimen (Cancer). Cardiovascular clinical trials report more positive results if they are industry-funded  (Miscellaneous). 21% of office-based prescriptions are off-label, usually without scientific support. Could compromise patient safety and waste medications. (Miscellaneous). Fusarium eye infections cause worldwide withdrawal of MoistureLoc. Topping up storage case or leaving bottle cap open could increase risk. (Miscellaneous). Academic researchers suggest Merck should continue to follow APPROVe study patients for long-term heart damage from Vioxx (Heart Disease & Stroke). New Merck analysis suggests increased stroke risk with rofecoxib (Vioxx); increased cardiovascular risk may persist to some extent after stopping Vioxx (Heart Disease & Stroke). New Analysis suggests that paroxetine (Paxil) may increase risk of suicide attempts in young adults (Neurological & Psychological). FDA approves varenicline (Chantix) for smoking cessation (Miscellaneous). Despite higher healthcare spending, US lags in use of health information technology (Computers in Medicine). Observational study of breast cancer in post-hysterectomy women supports safety of estrogen therapy for about 10-20 years, but breast cancer risk might increase with longer duration of estrogen therapy (Cancer). Clinical trial design in the post-Vioxx world (Administrative & Political). New prostate cancer gene may cause 8% of prostate cancers in men of European stock and 16% of those in African American men (Cancer). Update on fungus infections of eye in soft contact lens wearers (Miscellaneous). New observational study suggests increased heart attack risk during first 2 weeks of rofecoxib (Vioxx) treatment (Heart Disease & Stroke). Naltrexone (Revia) and combined behavioral intervention are effective in alcohol dependence (Neurological & Psychological). Despite less healthcare expenditure, the English are healthier than Americans (Miscellaneous). CCHIT Certification process issued for Electronic Health Records (Computers in Medicine).

APRIL 2006: JAMA article examines industry financial ties and voting patterns at FDA Advisory Committee meetings (Administrative & Political). A stroke in certain sections of the brain can also damage the heart (Neurological & Psychological). Everyone agrees we need electronic medical records. So why are we not doing it? (Computers in Medicine). Planning for pregnancy - CDC recommendations (Miscellaneous). Treasury Secretary: “The typical doctor’s office has less information technology in it than the corner drug store” (Computers in Medicine). The Challenge of Subgroup Analyses - Reporting without Distorting (Miscellaneous). Compression stockings during air travel reduce leg thrombosis, leg discomfort and swelling (Miscellaneous). Review supports routine use of antibiotics in COPD exacerbations (Other Chronic Disease). Observational study suggests Mediterranean Diet may reduce risk of Alzheimer's disease (Neurological & Psychological). New observational study suggests heart risk with COX-2 NSAIDs (Heart Disease & Stroke). Trans fats associated with coronary heart disease and sudden cardiac death (Diet & Exercise). No increase in breast cancer risk with estrogen alone (Cancer). Chemotherapy most useful in the 30% of women with ER-negative breast cancers (Cancer). Coronary patients should get ACE inhibitors (Heart Disease & Stroke). Brain Training for the Aging Brain (Neurological/Psychological). 2) Prevent Jet Lag using British Airways Jet Lag Advisor (Miscellaneous). Observational study suggests early removal of ovaries may be associated with increased risk of Alzheimer's (Neurological/Psychological). In a small controlled trial, two longevity markers (insulin & temperature) fell with 6-months calorie restriction; larger, longer studies needed to assess aging/longevity (Diet & Exercise). Study shows donepezil (Aricept) improves cognition and activities of daily living in severe Alzheimer's (Neurological/Psychological). High dose Celebrex reduces risk of new colon polyps but increases cardiovascular risk in patients with previous colon polyps (Cancer). Observational study finds less breast cancer with use of COX-2 inhibitors (Cancer)

MARCH 2006: Intercessory prayer did not reduce cardiac complications after bypass surgery; patients who knew they were receiving intercessory prayer had higher complication rate (Heart Disease & Stroke). Bird flu vaccine may protect 55-60% of those people vaccinated. FDA approves flu drug that protects against seasonal flu and bird flu (Miscellaneous). MRI study shows that highly intelligent children have more dynamically changing brains and reach peak thickness of the cerebral cortex at a later age (Neurological/Psychological). Omega 3 fats (found in fish oils and some plants) do not have a clear effect on mortality, heart disease, or cancer (Diet/Exercise). Can clinical trial endpoints be added after the clinical trial begins? (Miscellaneous). Open-label studies suggest that adding or switching antidepressants may help citalopram (Celexa) non-responders (Neurological/Psychological). Stimulants may cause hallucinations in 2-5% of children taking these drugs (Neurological/Psychological). Bird flu virus stays deep in the lungs, preventing human transmission by coughing or sneezing (Miscellaneous). Three full papers for studies already reviewed by TMT (March 14 & 15, 2006) are now available for download at no charge. These studies are: "Very High-Intensity Statin Therapy and Regression of Coronary Atherosclerosis", "Fondaparinux in Patients With Acute Myocardial Infarction" and "Abciximab in Patients With Acute Coronary Syndromes Undergoing PCI After Clopidogrel Pretreatment". Inaccuracies and stigmatizing language are common in neurology coverage by US newspapers (Neurological/Psychological). Seattle Heart Failure model predicts life expectancy and effects of different therapies (Heart Disease/Stroke). Breast asymmetry may be associated with increased risk of breast cancer (Cancer). Two separate H5N1 bird flu strains have evolved, but not yet a strain allowing human-to-human transmission (Miscellaneous). Study suggests that donepezil (Aricept) could be associated with increased death rate (Neurological/Psychological). Maintenance therapy with antidepressant drug helps after drug-assisted recovery from major depression in old age  (Neurological/Psychological). Only 55% of Americans receive quality health care. Use of electronic medical records could improve population-wide quality of care (Administrative/Political). Developmental drug torcetrapib raises HDL cholesterol but also raises blood pressure (Heart Disease & Stroke). Drug-eluting stent better for coronary restenosis of bare-metal stent than radiation (Heart Disease & Stroke). Fondaparinux (Arixtra) may reduce death and repeat heart attack in STEMI heart attacks (Heart Disease & Stroke). Candesartan treatment of pre-hypertension lowers blood pressure, but effect largely disappears on stopping therapy (Heart Disease & Stroke). Adding abciximab to clopidogrel reduces coronary events in acute coronary syndrome (Heart Disease & Stroke). Surgical trial to evaluate effect of closure of patent foramen ovale on migraine headaches (Heart Disease & Stroke). High dose Crestor may cause regression of coronary atherosclerosis (Heart Disease & Stroke). High dosage or frequent use of acetaminophen and non-selective NSAIDs may increase cardiovascular risk (Heart Disease & Stroke). Salt & water blood filter more effective than diuretics in severe heart failure (Heart Disease & Stroke). High dose Lipitor may improve kidney function in coronary disease patients (Other Chronic Disease). No cardiovascular benefit with Vitamin B (folic acid, B6, B12) in two large trials (Heart Disease & Stroke). 2) Adding Plavix to aspirin may increase risk in patients without established heart disease (Heart Disease & Stroke). Three of four older Americans skip colon cancer screening (Cancer). Withdrawn MS drug might return to market (Neurological/Psychological). "Caffeine Gene" may (or may not) indicate increased risk of heart attack (Heart Disease & Stroke). Restraining good arm may give some recovery of affected arm after stroke (Neurological/Psychological). Clinical trial result causes emphysema patients to say "no" to lung surgery (Other Chronic Disease). New publications show multiple sclerosis drug previously withdrawn from market is effective (Neurological/Psychological). New analysis of Celebrex cardiovascular safety adds little (Heart Disease & Stroke).

FEBRUARY 2006: You're never too old to exercise (Diet & Exercise). Before undergoing knee cartilage surgery, make sure the symptoms come from the cartilage damage (Pain). Optimistic people have lower cardiovascular death rates (Neurological/Psychological). Virus found in prostate cancers (Cancer). The GAIT study in osteoarthritis of the knee showed no clear benefit from glucosamine and chondroitin, but Celebrex was effective (Pain). The SUCCESS-I study showed less GI complications with Celebrex than with non-COX-2-selective NSAIDs (Pain). A study in rheumatoid arthritis reported that chronic inflammation is "probably a driving force for premature atherosclerosis" (Pain). Misdiagnosis occurs in 20% of fatal illnesses (Miscellaneous). Only 1/4 of US hospitals have electronic medical records (Computers in Medicine). AMA & Congress agree on new standards of healthcare quality (Administrative/Political). Lack of flu shots in healthcare workers increases patient risk (Miscellaneous). Poverty is associated with poor health & increased mortality (Miscellaneous). In a British study, women consulted their doctor for headache 2.6 times as often as men (Pain). No clear benefit of calcium+vitamin D on risk of fracture or colon cancer in postmenopausal women, but dosage, duration and concomitant therapy may have obscured benefit (Diet & Exercise).  FDA relabeling of whole grain foods may encourage people to take recommended daily amounts of whole grain foods ( 3 slices of bread, 3 cups of breakfast cereal, or 1 1/2 cups of cooked rice or pasta) (Diet & Exercise). For older couples, if one of the partners is hospitalized for a debilitating illness, the non-hospitalized partner is at increased risk for death (Miscellaneous). Over 80% accuracy of prognostic index for 4-year mortality in older adults (Miscellaneous). Many heart attacks go undetected (Heart Disease & Stroke).

1. DIET & EXERCISE

Randomized study suggests weight loss is greater with a reduced fat diet if more fruits and vegetables are eaten

Randomized study suggests slightly more weight loss with Atkins diet

Observational study suggests that trans fats may increase infertility but additional evaluation is required

Black tea with no milk increases ability of arteries to relax, but adding milk prevents this effect

Food industry-funded studies of soft drinks, juice or milk tend to favor the commercial interests of the funder

Starbucks removing trans fats from its pastries

With resveratrol, mice can run twice as long on a treadmill

November 17, 2006: A recent study (see TMT review of November 1 below) reported that resveratrol (RSV) prolonged life span in mice. Now a new study has reported that RSV treated mice can run twice as long on a treadmill, and were protected against diet-induced-obesity and insulin resistance. These effects "were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1α acetylation and an increase in PGC-1α activity. this mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1...".

Diet with low carbohydrate and vegetable sources of fat and protein may reduce coronary risk

November 8, 2006: A 20-year observational study in over 80,000 women in the Nurses' Health Study suggests that a low carbohydrate diet in which fat and protein come from vegetables is associated with a 30% reduction in adjusted risk of coronary heart disease. Observational studies cannot establish causality but can suggest the need for further study.

Study in mice shows that resveratrol, found in red wine, offsets bad effects of high calorie diet and extends lifespan

November 1, 2006: Resveratrol, a natural, small-molecule substance found in red wine, is known to extend lifespan in several non-mammalian species. A new study published in Nature confirms this finding in middle-aged mammals (mice) exposed to a high-calorie diet. Compared with a control group, mice receiving resveratrol lived longer and offset the adverse effects on blood glucose, insulin and the liver that occurred in the mice not receiving resveratrol. The National Institute of Aging's Dr. Richard Hodes advised people to wait for the results of safety testing of the high doses of resveratrol used in the mouse study. Dr. Ronald Kahn, president of the Joslin Diabetes Center in Boston, advised "Have another glass of pinot noir — that's as far as I'd take it right now."

Observational study in healthy men shows correlation between alcohol consumption and reduced risk of heart attack

October 24, 2006: In an observational study, a cohort of almost 9,000 men free of major illness and with favorable lifestyles for cardiovascular health were followed for 16 years. Compared with men who abstained from alcohol, a lower risk of heart attack was seen in those who took alcohol: 2%, 41%, 62% and 14% with alcohol consumption of 0.1 to 4.9 g/d, 5.0 to 14.9 g/d, 15.0 to 29.9 g/d (about 2 drinks a day), and 30.0 g/d or more, respectively. The authors conclude "Even in men already at low risk on the basis of body mass index, physical activity, smoking, and diet, moderate alcohol intake is associated with lower risk" for heart attack. Observational studies cannot establish causality but can suggest the need for further study.

Does daily weighing help maintain weight loss?

October 12, 2006: A paper in the New England Journal of Medicine examined various ways of maintaining weight loss in a group of people who had lost at least 10% of body weight through dieting. Participants were randomly assigned to a control group (105 people who received quarterly newsletters), face-to-face intervention (105 who regularly met with study staff and received a scale for daily weight measurement) and Internet-based intervention (104 who received a laptop computer and a scale for daily weight measurement). The face-to-face group did significantly (p=0.05) better in maintaining weight loss than the control group, whereas the Internet group was similar to controls. The authors performed a subgroup analysis comparing those with and without daily self-weighing; daily self-weighing was associated with significantly less risk of regaining 2.3 kg or more. The abstract concluded that "a self-regulation program based on daily weighing improved maintenance of weight loss". However, in the body of the text, the authors commented that "frequent self-weighing could be either a cause or a consequence of weight-loss maintenance". In addition, and perhaps more importantly, since patients were not randomized to daily weighing or no daily weighing, and baseline variables were not examined to show comparability of the daily weighing and no-daily weighing groups, it cannot be concluded from these data that daily weighing helps to maintain weight loss. However, daily weighing is intuitively appealing and may be worth evaluating in a properly controlled study.

Smarter breast-feeding mothers mean smarter breast-fed children

October 4, 2006: Scottish researchers analyzed a US observational study and concluded that, after adjusting for confounding factors, increased intelligence in breast-fed children may be largely related to increased intelligence in the breast-feeding mothers. The authors conclude “Breast feeding has little or no effect on intelligence in children. While breast feeding has many advantages for the child and mother, enhancement of the child's intelligence is unlikely to be among them.” The three authors were male and did not mention the potential impact of the intelligence of the fathers. Observational studies cannot establish causal relationships, although they can suggest the need for further study.

It's OK to eat canned or frozen spinach

September 25, 2006: As of September 24, 173 cases of people with E. Coli infection from spinach have been reported to FDA. Infected spinach has come from three coastal California counties (Monterey, San Benito, Santa Clara). FDA says that fresh spinach known to be grown outside the implicated counties, as well as canned and frozen spinach, is safe to eat. E. coli O157:H7 causes diarrhea, often with bloody stools. Although most healthy adults can recover completely within a week, some people can develop a form of kidney failure called HUS (hemolytic uremic syndrome). HUS is most likely to occur in young children and the elderly. The condition can lead to serious kidney damage and even death. [Added Note: October 8 - FDA has now cleared the eating of fresh spinach.]

Being overweight at age 50 increases risk of death, particularly in women. Waist/hip ratio may be a better measure than BMI.

August 23, 2006: Over half a million US adults 50-71 years old were enrolled in a prospective study to evaluate self-reported Body Mass Index (BMI). In healthy people who had never smoked moderate increase in BMI (25.0-29.9 - “overweight”) was associated with an increase in the risk of death during up to 10 years follow-up, particularly if present at age 50 (20-40% increase in death risk). However, risk increased in women at the lower levels in the “overweight” range whereas increase in risk in men occurred at higher levels in the “overweight” range. In a second study published in the same issue of the New England Journal of Medicine (Korean BMI Study), the association between BMI and risk of death was examined in a 12-year prospective study of over 1 million Koreans aged 30-95. Risk of death and risk of atherosclerotic death was increased with higher BMI. Risk of respiratory death was higher with lower BMI. The impact of BMI on risk was less with higher age. However a recent study (Weight, shape, and mortality risk in older persons: elevated waist-hip ratio, not high body mass index, is associated with a greater risk of death), as well as a number of previous studies, has shown that the waist/hip ratio may be more useful than BMI in predicting increased mortality; in this study in elderly patients (>75 years) increase in waist/hip ratio but not increase in BMI or waist size was associated with increased total and cardiovascular mortality.

Computerized feedback increases short-term weight loss

August 15, 2006: A randomized study compared weight loss using three Internet treatments in 182 overweight adults (mean BMI 32.7). All subjects had one weight loss group session, coupons for meal replacements and access to an interactive website. The human e-mail counseling and computer-automated feedback groups also had access to an electronic diary and message board. The human e-mail counseling group received weekly email feedback from a counselor, and the computer-automated feedback group received automated, tailored messages. At 3 months, weight loss with computer-automated feedback (-5.3 kg) and human email counseling (-6.1 kg) was comparable and significantly greater than with no counseling (-2.8 kg). However, at 6 months weight loss was significantly greater with human email counseling (-7.3 kg) than with computer-automated feedback (-4.9 kg) or no counseling (-2.6 kg). The authors state "Further research is needed to improve the efficacy of automated computer-tailored feedback as a population-based weight loss approach."

Increased energy expenditure associated with reduced mortality in high-functioning older adults

July 12, 2006: In an observational study in 302 high-functioning, community-dwelling older adults (70-82 years) followed for 6 years, objectively measured free-living activity energy expenditure was strongly associated with lower risk of mortality. After adjusting for various confounders, the "hazard ratio" for mortality was 0.31 for the most active third versus the least active third (12% vs. 25% mortality). According to self-reports, more active subjects were more likely to work for pay (P = .004) and climb stairs (P = .01) but self-reported high-intensity exercise, walking for exercise, walking other than for exercise, volunteering, and caregiving did not differ significantly. A major strength of this study was recruitment of high-functioning, community-dwelling individuals and the objective measurement of total energy expenditure, but a weakness is the lack of objective measurement of the relationship of peak intensity of exercise to mortality. Observational studies cannot establish causal relationships, but can suggest the need for further study.

Trans fats associated with coronary heart disease and sudden cardiac death

April 14, 2006: A New England Journal of Medicine review and meta-analysis of four prospective cohort studies with nearly 140,000 subjects showed that trans fats were associated with an increased risk of coronary heart disease (CHD; 23%), and sudden cardiac death (47%). The authors believe that long-term controlled trans fat trials would be unethical and that a "reasonable approach" is to combine short-term controlled studies of intermediate endpoints with "carefully performed observational studies". The authors write “Trans fats, unsaturated fatty acids with at least one double bond in the trans configuration, are formed during the partial hydrogenation of vegetable oils, a process that converts vegetable oils into semisolid fats .... From the perspective of the food industry, partially hydrogenated vegetable oils are attractive because of their long shelf life, their stability during deep-frying, and their semisolidity, which can be customized to enhance the palatability of baked goods and sweets…. Major sources of trans fats are deep-fried fast foods, bakery products, packaged snack foods, margarines, and crackers”. The authors conclude “Thus, given the 1.2 million annual myocardial infarctions and deaths from CHD in the United States, near-elimination of industrially produced trans fats might avert between 72,000 (6 percent) and 228,000 (19 percent) CHD events each year.”

In a small controlled trial, 2 longevity markers (insulin & temperature) fell with 6-months calorie restriction; larger, longer studies needed to assess aging/longevity

April 5, 2006: Prolonged calorie restriction increases life span in rodents and in previous uncontrolled studies in humans has been associated with significant decreases in cardiovascular risk factors, blood pressure, inflammatory markers, and fasting insulin and glucose levels. The CALEIRE 6-month randomized controlled trial in 48 healthy, sedentary, "overweight" (but not "obese") adults compared 4 groups: 1) control (weight maintenance diet); 2) calorie restriction (25% calorie restriction of baseline energy requirements); 3) calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); 4) very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet). Weight loss from baseline was 1%, 10%, 10% and 14% for groups 1, 2, 3 & 4 respectively. Compared with baseline, fasting insulin levels and DNA damage fell in the intervention groups 2, 3 & 4, but DNA damage was not significantly reduced compared with controls (group 1). Compared with baseline, core body temperature was reduced in groups 2 & 3 but not in groups 1 & 4. Compared with controls, metabolic adaptation (decrease in energy expenditure more than predicted by loss of metabolic mass) was significantly more common (p<0.05) in the intervention groups. The other primary outcome measures (DHEAS, glucose, protein carbonyls) showed no significant changes, perhaps because the study was of only 6 months duration. The authors conclude that calorie restriction reduces metabolic rate more than would be expected from the "reduced metabolic body mass" but that studies "of longer duration are required to determine if calorie restriction attenuates the aging process in humans".

Omega 3 fats (found in fish oils and some plants) do not have a clear effect on mortality, heart disease, or cancer

March 27, 2006: A review of 48 controlled clinical trials (37,000 participants) and 41 cohort observational studies showed no clear reduction in total mortality, combined cardiovascular events, or cancer from consumption of long chain and shorter chain omega 3 fats [found in fish oils (especially mackerel, lake trout, herring, sardines, albacore tuna and salmon), and some plants (such as soybeans, canola and flaxseed)]. There was a slight beneficial trend for overall mortality (13% reduction - relative risk 0.87, 95% confidence interval 0.73 to 1.03), with evidence of benefit being stronger in people with established heart disease. To determine effects in people without established heart disease, larger primary prevention studies would be needed.

You're never too old to exercise

February 28, 2006: A study in the February issue of The Journal of Aging and Health says that people are never too old to gain health benefits from exercise. An elderly group of 64 volunteers were divided into three groups: 1) exercise by walking twice a week. 2) resistance training twice a week. 3) control group who did no exercise.  The age range was 66-96 years (average age 84) and three-quarters were women. All volunteers could take care of daily tasks on their own. Some of the exercisers used canes or walkers during their exercise sessions. After 16 weeks, the exercise groups had lower systolic blood pressure, improved upper and lower body strength, improved hip and shoulder flexibility and improvements in tests of agility, balance and coordination when compared with the no-exercise group. Beneficial effects were similar in the walking and resistance exercise groups.

FDA will require better labeling of whole grains

February 16, 2006: FDA says that anything labeled as containing whole grains must contain a comparable amount of the fibrous, protein-dense and nutrient-rich portions of grains — the endosperm, germ and bran — in the same proportion normally present in the intact grain. Whole grains include barley, buckwheat, bulgur, corn, millet, rice, rye, oats, sorghum, wheat and wild rice. The FDA suggests that people eat at least 3 ounces of whole-grain cereals, breads, crackers, rice or pasta every day. One ounce is about a slice of bread, a cup of breakfast cereal, or a half cup of cooked rice or pasta.

Calcium/Vitamin D Supplement does not reduce Risk of Hip Fracture or Colon Cancer in Postmenopausal Women

February 16, 2006: As part of the WHI study, over 36,000 postmenopausal women were randomized to placebo or daily calcium + vitamin D supplementation for an average of 7 years.  There was no significant difference between the randomized groups in the frequency of hip fracture or colorectal cancer, but there was a significantly increased risk of kidney stone in the calcium+vitamin D group. However, subjects in both groups were allowed to use additional calcium, vitamin D, bisphosphonates, calcitonin and hormone therapy - which may have obscured any potential benefit. Overall, the yearly rate of hip fracture was 0.14% in the active treatment group versus 0.16% in the placebo group (a 12% reduction that was not statistically significant). However, subset analyses (which should be interpreted cautiously) showed that women who consistently took the full supplement dose had a 29% reduction in hip fracture, and in women 60 years or older there was a 21% decrease in hip fracture risk. There was also a very small (but statistically significant) overall increase in hip bone density. There was no reduction in colorectal cancer although the calcium/vitamin D dosage and 7-year duration of the study may have been insufficient to detect a benefit.

Study Finds Low-Fat Diet Won't Stop Cancer or Heart Disease

February 7, 2006: A low-fat diet did not prevent cancer or heart disease in a $415 million NIH WHI study of nearly 49,000 women aged 50 to 79 randomly assigned to a low-fat or normal diet and followed for eight years. The results were reported in the Feb. 8 issue of JAMA and showed that the women assigned to the low-fat diet did eat significantly less fat (about 25% versus about 35% of calories as fat), but they had no statistically significant differences in rates of breast cancer, colon cancer, heart disease or diabetes, and showed little or no effect on body weight, insulin or glucose blood levels. For heart disease risk factors, only LDL cholesterol was lower with the low-fat diet but this effect was small. The breast cancer data showed a 9% non-statistically-significant reduction in risk with the low fat diet and the study women will continue to be followed, and the possibility of beneficial effects in certain subgroups will be examined. This study was designed 2 decades ago and does not reflect current thinking on the possible benefits of the Mediterranean diet or exercise - life style modifications that have not yet been tested in a large randomized clinical trial. These disappointing results are similar to those shown with dietary fiber, vitamin therapy and hormone replacement therapy in which non-randomized observational studies suggested benefit, but in which subsequent randomized studies showed no benefit.

Fruits & Vegetables May Reduce Stroke Risk

January 27, 2006: Five or more daily servings of fruits and vegetables were associated with a  26% reduction in stroke risk compared with less than 3 servings daily in a meta-analysis of 8 observational studies including over 250,000 adults with average follow-up of 13 years. The risk reduction applied to both hemorrhagic and ischemic strokes. Although the results of observational studies should be regarded with some caution, these latest results certainly support many other studies (as well as your mother's admonitions to eat your vegetables).

2. PAIN

Combination of sumatriptan and naproxen useful for acute treatment of migraine

April 4, 2007: A fixed dose tablet containing sumatriptan (85mg) and naproxen (500mg) was more effective than placebo and than either agent alone for acute treatment of a moderate or severe migraine attack. 

Ibuprofen best pain killer for kids with acute traumatic musculoskeletal injuries

March 5, 2007: In a double blind study in 336 children 6-17 years old with musculoskeletal injury (to extremities, neck, and back) in the last 48 hours, ibuprofen (10 mg/kg) was better than acetaminophen (15 mg/kg) and codeine (1 mg/kg) in pain relief. 

Arthritis and related conditions cost over $500 per year per American adult

January 11, 2007: The US Government Center for Disease Control and Prevention (CDC) says that arthritis and other rheumatic conditions (46 million people) cost $128 billion in 2003, i.e., $538 per American 15 years or older. Direct costs were $81 billion, with $47 billion for indirect costs such as lost wages. The 2003 figure is an increase of almost 60% in six years and is attributed by CDC to more Americans being overweight and to the aging of the population. The government recommends lowering costs with self-management programs to teach patients how to manage their pain and continue working despite the pain. Note: Over 2,000 people with chronic pain have used TMT's chronic pain questionnaires to help them understand their pain (http://masterdocs.com/pain.htm). 

Pain gene variants can increase or eliminate pain

December 14, 2006: Variants of the SCN9A gene can cause pain hypersensitivity or total elimination of the sensation of pain. Pain signals are carried to the brain through nerve impulses generated by a SCN9A-coded voltage-gated sodium channel. Because all pain fibers depend on the SCN9A gene’s protein for amplification, all signals of pain are assumed to be muted when the gene is inactive. This finding may provide a new therapeutic target for drug development. 

Most back & sciatica patients who don't require urgent surgery improve with either medical or surgical therapy. You can always get surgery later.

November 22, 2006: JAMA today published the two SPORT trials (randomized and observational) and two editorials comparing surgical (open diskectomy) and non-surgical (standard medical care) treatment of patients with a herniated intervertebral disk and sciatica for at least 6 weeks but without evidence of an urgent need for surgery such as loss of bowel or bladder control. Medical and surgical patients improved at about the same rate with a slight but unconvincing trend in favor of surgery. There was no evidence that delaying surgery increased the risk of serious complications. Neither trial gave adequate reason for saying either that the treatments were equivalent in effectiveness or for saying that one or other was better. One trial was randomized but 30% of medical patients actually received surgery in the first 3 months of the study. The non-randomized study (patients from the same clinics who declined randomization) showed an advantage for surgery by patient self-assessment of outcome but observational studies such as this cannot establish causality and require confirmation in a randomized trial of adequate size, design and execution. It is reasonable for patients with a herniated disk with sciatica but without urgent indications for surgery to select medical or surgical therapy on the basis of personal preference and level of pain; they can always decide to have surgery later if they don’t improve. A TMT associate has suggested that any superiority of surgery might not be because of the surgery itself but because it is socially and medically acceptable to have a period of bed rest and enforced inactivity following such surgery. 

Pain relief in fibromyalgia reported with pregabelin (Lyrica) in 6-month double-blind study

November 17, 2006: Previous short-term studies with pregabelin (Lyrica) have reported pain relief in patients with fibromyalgia, a poorly understood condition that affects 2-4% of the population. In a new 6-month double-blind trial, Lyrica relieved fibromyalgia pain significantly more than placebo. This trial used a placebo-withdrawal design in which responders (at least 50% improvement in pain score) after 6 weeks of open-label Lyrica treatment (663 of 1051 patients, 63%) were assigned to continue Lyrica or to be switched to placebo. By the end of the 6-month trial, 68% of Lyrica patients had maintained their pain response versus only 39% of placebo patients. Although these findings are encouraging, a definitive assessment of this study must await full publication of the results.

Americans are living longer but have more long-term pain

November 15, 2006: The annual report for the US Government Centers for Disease Control and Prevention (CDC) says that chronic pain is common in US adults: 1) One in 10 have pain that lasts a year or more, 2) One quarter had a day-long bout of pain in the past month, 3) More than a quarter had low back pain in the past three months. 4) Fifteen per cent had migraines or severe headaches in the past three months, and 5) Almost one in twenty used a narcotic drug in the past month for pain relief. Americans are living longer, with life span at a record average of almost 80 years. At birth, life expectancy for females is just over 80 years and nearly 75 for males. The gap in life expectancy between white and black Americans also has narrowed from seven years in 1990 to five years in 2004.

Unblinded randomized study suggests acupuncture is effective in patients with osteoarthritis

October 31, 2006: In a study in over 700 patients with osteoarthritis, patients were randomly assigned to acupuncture or to a control group. Over a 6-month period, acupuncture patients improved significantly more than control patients. Neither patients nor physicians were blinded to treatment group allocation, so that bias may explain the differences between treatment groups. However, previous evaluation using sham acupuncture has supported the efficacy of acupuncture for the treatment of arthritis (see the June 19, 2006 TMT review below).

Test for H. Pylori Before Starting NSAIDs in High GI Risk Patients

September 25, 2006: The American Gastroenterology Association recommends evaluation of both gastrointestinal and cardiovascular risks when considering NSAID therapy. This should include a routine test for Helicobacter pylori (H. Pylori) infection for all such patients at high risk of GI complications. Short-term studies have shown that eradicating H. Pylori infection before starting an NSAID reduces the risk of peptic ulcers from the NSAID.

Fibromyalgia symptoms respond to acupuncture in controlled trial 

June 19, 2006: A 50-patient clinical trial from the Mayo Clinic suggests that acupuncture may ease pain, fatigue and anxiety in patient with fibromyalgia. Patients were randomly assigned to acupuncture or (in a technically interesting approach) to simulated acupuncture in which subjects were unaware whether the needle merely pricked the skin or was inserted into the muscle beneath the skin. The acupuncture group improved significantly compared to the simulated acupuncture group, as determined by serial measurements of the Fibromyalgia Impact Questionnaire (FIQ) and the Multidimensional Pain Inventory (MPI). Effects were maximal at 1 month and were somewhat attenuated by 7 months. The level of clinical benefit seen was similar to that seen with drug interventions.

Before undergoing knee cartilage surgery, make sure the symptoms come from the cartilage damage  

February 28, 2006: According to the Boston Osteoarthritis Knee Study, patients with osteoarthritis of the knee commonly have damaged cartilage (medial meniscus in 86% and lateral meniscus in 63%).  However, the lead author of the study stated that while meniscectomies are often performed to relieve pain, "all efforts should be made not to go in and remove the menisci unless they are likely to be the cause of arthritis symptoms." A previous study found that tears of the menisci, common in osteoarthritis of the knee, are often incidental findings that don’t cause symptoms. Non-surgical methods to manage osteoarthritis pain include exercise and weight loss, knee braces, motion control shoes, and analgesics and anti-inflammatory drugs. (Hunter DJ et al., Arthritis & Rheumatism. 2006; 54(3):795-801).

Celebrex effective in knee osteoarthritis. Glucosamine & chondroitin did not show clear improvement. 

February 23, 2006: The GAIT study was a 1583-patient, 24-week, double-blind study in patients with painful osteoarthritis of the knee and compared 1) glucosamine (1500 mg/day), 2) chondroitin (1200 mg/day), 3) glucosamine + chondroitin, 4) celecoxib (200 mg/day), and 5) placebo. The results for the primary efficacy measure (20 percent decrease in knee pain from baseline to week 24) showed no significant improvement versus placebo for glucosamine or chondroitin (alone or in combination), although an exploratory analysis of patients with more severe pain suggested some improvement. In the celecoxib (Celebrex) patient group, there was a statistically significant (P=0.008) increase in the primary efficacy measure (70.1% response versus 60.1% for placebo). The study was not large enough or long enough for definitive evaluation of cardiovascular safety. There were three serious adverse events judged by the investigator to be related to study treatment - one patient on combined glucosamine and chondroitin had congestive heart failure; one patient on glucosamine had chest pain; and one patient on celecoxib had a stroke. A review of all adverse events requested by the data and safety monitoring board did not suggest that celecoxib increased ischemic cardiovascular events. Most adverse events were mild, infrequent, and evenly distributed among the groups.

Fewer upper gastrointestinal complications with Celebrex than NSAIDs 

February 23, 2006: The SUCCESS-I osteoarthritis trial (March 2006 issue of American Journal of Medicine) was a 13,274 patient, double-blind, 12-week comparison of twice daily dosing with celecoxib (Celebrex 200 mg or 400 mg/day), and non-COX-2-selective NSAIDs (diclofenac 100 mg/day or naproxen 1,000 mg/day). The treatments were equally effective in treating osteoarthritis. Celebrex was associated with significantly fewer serious upper gastrointestinal events than NSAIDs. The study was not designed to look at cardiovascular safety, was not large enough to answer this question definitively, and did not provide clear definitions of cardiovascular endpoints (e.g., heart attack). Although heart failure was 4.5 times as common in the non-selective NSAID group (P=.01), this finding should be interpreted cautiously and would need to be confirmed in a further prospective clinical trial. Additional analysis comparing the effects of the high (400 mg/day) and moderate (200 mg/day) doses of Celebrex would be useful.

Inflammation may be "driving force" for atherosclerosis 

February 23, 2006: Rheumatoid arthritis (RA) patients had a threefold increase in preclinical carotid atherosclerotic plaque, independent of traditional risk factors, according to a matched cross-sectional study. The researchers recommend rigorous control of rheumatoid disease activity because chronic inflammation is "probably a driving force for premature atherosclerosis." This report supports previous work showing that chronic pain conditions associated with inflammation are associated with increased cardiovascular risk and increased mortality. This work does not establish that the inflammation causes cardiovascular disease. Additional research is required to determine if effective drug treatment of inflammation associated with chronic pain might reduce cardiac risk and mortality.

Headache more common in women 

February 18, 2006: In a British general practice study, women consulted their doctor for headache 2.6 times as often as men. Consultation rates were highest in the 15 to 24 year age group and declined with age. In one third of the consultations, drug treatment for migraine was prescribed.

Heat Therapy Proves Effective for Acute Lower Back Pain 

January 27, 2006: A Johns Hopkins study suggests that continuous low-level heat wrap therapy is an effective adjunct or alternative to painkillers in treatment of acute lower back pain (Journal of Occupational and Environmental Medicine, December 2005). In a randomized study of 43 patients, those wearing the wrap (worn under the clothes and uses a chemical reaction to deliver low-level topical heat) improved by nearly two points from baseline on a 10-point pain-intensity scale, compared with less than one point of improvement in the standard care group (P=0.0029).The heat-therapy group also rated their pain relief as "more than half better" on average at day one, compared with an average assessment of "less than half better" for the standard care group (P=0.0027). The benefits of heat therapy were maintained through two weeks of follow-up. The heat-therapy group also had significantly greater improvements in mobility. The ThermaCare HeatWrap, manufactured by Proctor & Gamble, is an FDA-approved class I medical device and can be purchased without a prescription.

3. CANCER

HPV vaccine could prevent cancer of cervix, vulva, vagina, mouth and throat.

May 18, 2007: The vaccine against the human papillomavirus (HPV) is believed to reduce the risk of cancer of the cervix (http://content.nejm.org/cgi/content/abstract/356/19/1915). Mandatory HPV vaccination of girls has been suggested but is controversial (http://content.nejm.org/cgi/content/full/356/19/1905). Recent controlled trials indicate that the HPV virus may also be implicated in oropharyngeal cancer (cancer of the mouth and throat in which HPV virus may be transmitted by oral sex; http://content.nejm.org/cgi/content/abstract/356/19/1944) and in cancer of the vulva and vagina (http://www.thelancet.com/journals/lancet/article/PIIS0140673607607776/abstract).
 

Religious people with advanced cancer get inadequate spiritual support and want aggressive measures to extend life

February 9, 2007: The “Coping with Cancer” federally-funded study examined religiousness among cancer patients and its associations with end-of-life treatment preferences and quality of life. The authors stated: “Most (88%) of the study population (N = 230) considered religion to be at least somewhat important. Nearly half (47%) reported that their spiritual needs were minimally or not at all supported by a religious community, and 72% reported that their spiritual needs were supported minimally or not at all by the medical system. Spiritual support by religious communities or the medical system was significantly associated with patient QOL (P = .0003). Religiousness was significantly associated with wanting all measures to extend life (odds ratio, 1.96; 95% CI, 1.08 to 3.57).” They concluded that “Many advanced cancer patients’ spiritual needs are not supported by religious communities or the medical system, and spiritual support is associated with better QOL. Religious individuals more frequently want aggressive measures to extend life.”

In observational study, dense breast tissue increased risk of breast cancer and increased difficulty of diagnosis

January 18, 2007:  In an observational study, women with breasts with higher "mammographic density" (more epithelium/stroma and less fat) had a higher rate of breast cancer. As compared with women with density in less than 10% of the mammogram, women with density in 75% or more had an almost 5 times increase in risk. Fat is radiographically lucent and appears dark on a mammogram. In contrast, breast epithelium (layers of cells derived from membranous tissue covering internal surfaces) and stroma (connective tissue providing a support framework) are radiographically dense and look light, an appearance referred to as "mammographic density". Cancer in breasts with higher mammographic density was also more difficult to detect. The authors conclude "Extensive mammographic density is strongly associated with the risk of breast cancer detected by screening or between screening tests. A substantial fraction of breast cancers can be attributed to this risk factor". Observational studies cannot establish causality but can suggest the need for additional study.

Cancer deaths are down. Cancer pain is treatable.

January 17, 2007: Fewer people died of cancer in 2004 than in 2003, the second consecutive year cancer deaths declined in the United States. Rates declined for most major cancers. Breast cancer death rates have been dropping steadily since 1990, attributed by the American Cancer Society (ACS) to earlier detection and better treatments. Both incidence and death rates have dropped for colorectal cancer in recent years. Lung cancer remains the top cancer killer among both men and women; rates among women have flattened in recent years, but fewer men are getting lung cancer or dying from it. African-Americans are still much more likely than any other group to develop cancer and die from it. Hispanics, Asian Americans, and Pacific Islanders have lower rates of most cancers than whites, but tend to have higher rates of cancers that may be linked to infections, such as cervical cancer and liver cancer. About 30% of cancer deaths in the US are caused by smoking. Another third are linked to nutrition and physical activity. ACS recommends keeping weight in a healthy range, getting plenty of exercise, and eating a healthy diet with lots of fruits and vegetables to reduce cancer risk. The ACS has a special section in this year's Facts & Figures focusing on cancer pain and how to treat it; cancer survivors and doctors should discuss pain at every visit, and treat it promptly. [Note: TMT has an ongoing collaboration with the MD Anderson Cancer Center evaluating bone pain in patients with bony metastases.]

Randomized study suggests reduced fat in diet reduces breast cancer recurrence

December 18, 2006: An interim analysis of data from the 2,437 subjects in the Women's Intervention Nutrition Study (WINS) found that after 5 years women with previous breast cancer who were randomized to a low fat diet (compared with those randomized to a normal diet) consumed about 20 grams less fat, weighed about 6 pounds less, and had a 24% lower risk of recurrence (9.8% versus 12.4%). A reduced fat diet is known to reduce estrogen levels and the reduction in relative risk was greater for estrogen-negative cancer (42%) than for estrogen-positive cancer (15%). Although there were possible imbalances in treatment between the two groups, randomized studies like WINS provide more persuasive evidence than can be obtained from an observational study.

Breast cancer rate dropped 7% in 2003, possibly because of less female hormone therapy

December 14, 2006: In 2003, the US breast cancer rate dropped 7%, the largest-ever recorded yearly drop. Rates have risen most years since 1945. The drop could be related to slowing, stopping or reversal of the growth of small cancers because of sudden discontinuation of female hormone therapy (~50% drop in the number of hormone users in 1 year) by millions of women following the July 2002 publication of the 26% increase in risk of breast cancer associated with hormone therapy in the WHI trial. In California, where hormone therapy had been highest, the drop was larger than in other states. The drop in estrogen-positive breast cancers (the 70% of breast cancers that are fueled by female hormones) dropped twice as much as estrogen-negative breast cancer. Women 50-69 years old (those most likely to take hormones) had a drop 3 times greater than other age groups. Yearly breast cancer rates dropped 2.5% from 2001 to 2002 and dropped 7% from 2002 to 2003 (6% in the first half of 2003 and 9% in the second half). Until 2002 about one third of American women over 50 took hormones. Other explanations for the drop are possible. Observational studies cannot establish causality but can suggest the need for further study.

Observational study suggests that surgery or radiation for localized prostate cancer improves survival in elderly men

December 12, 2006: Over 44,000 men 65-80 years old with localized and well/moderately well differentiated prostate cancer who had survived for 1 year after diagnosis were followed for up to 12 years. Mortality was 37% in the observational group and 24% in the treatment group (those who received radical prostatectomy or radiation); adjusted analysis showed a statistically significant advantage for the treatment group. Observational studies cannot establish causality but can suggest the need for further study. The authors state that “these results must be validated in randomized controlled trials of alternative management strategies in elderly men with localized prostate cancer”.

Higher PSA velocity 10-15 years before prostate cancer diagnosis may be associated with higher prostate cancer mortality

October 26, 2006: An observational study in the Journal of the National Cancer Institute suggests that the rate at which serum PSA levels change (PSA velocity) may be an indicator of the risk of prostate cancer death 25 years later. However, an accompanying Editorial suggests that definite conclusions on this issue should await completion of large randomized trials that are ongoing. Observational studies cannot establish causality but can suggest the need for further study.

CT screening detects early lung cancer

October 26, 2006: Lung cancer was detected in 1.5% of over 30,000 people at risk of lung cancer who were screened by CT. The cancer was judged to be early (Stage I) in 1.3%. The authors "estimated" 10-year survival rates at 88% for all Stage I cancer patients, and 92% for the 73% of Stage I cancer patients who had surgical resection of the cancer within one month of diagnosis. Although these results are encouraging, without a control group it is not possible to determine if survival in the screening group was improved by the early detection of the lung cancer.

Observational study suggests that NSAIDs may protect against development of prostate cancer only in men with the gene type associated with higher LTA levels

August 30, 2006: An observational (case-control) study suggests that a protective effect of NSAIDs against the development of prostate cancer may be confined to those with a particular inflammatory response gene type (the LTA +80CC genotype). Aspirin or ibuprofen reduced risk of prostate cancer by 33% overall. However, this beneficial effect appeared to be confined to men with the LTA + 80CC genotype (which is associated with increased production of lymphotoxin alpha) in whom a significant 57% reduction was seen (compared to men without this genetic variant in whom no significant reduction in risk was seen with NSAIDs). Observational studies cannot establish causality but can suggest the need for further study.

Node-positive breast cancer women who have more HER2 receptor activity do better with epirubicin as part of a triple therapy regimen

May 18, 2006: An article in the New England Journal of Medicine describes a prespecified subgroup multivariate analysis of the Mammary.5 controlled trial in women with node-positive breast cancer and concludes “Amplification of HER2 in breast-cancer cells is associated with clinical responsiveness to anthracycline-containing chemotherapy.” Amplification of the human epidermal growth factor receptor type 2 (HER2) means an increased response of breast cancer cells to this growth factor. The 710 women in the trial were followed for an average of 10 years; 363 had a recurrence and 284 died. Women who had HER2 amplification (about one-quarter of the women) had a greater risk of relapse and death respectively of 24% and 53% compared to non-HER2 amplification women. However, if the Pfizer drug epirubicin [Ellence] rather than methotrexate was given as part of a triple drug therapy regimen to the HER2 amplification women, prognosis was improved: 48% (p=0.003) better for relapse-free survival, and 35% (p=0.06) better for overall survival; the adjusted hazard ratio for the “interaction between treatment and amplification status” was 1.96 (p=0.01) for relapse-free survival and 2.04 (P=0.02) for overall survival. No clear advantage was seen for epirubicin in the non-HER2 amplification group. The authors conclude that the increase in benefit attributable to the triple therapy regimen with epirubicin "is confined almost completely to women whose tumors exhibit amplification or overexpression of HER2” and they recommend that women with non-HER2 amplified breast cancer should receive the “less toxic regimen” containing methotrexate. An accompanying Editorial expresses a few caveats about this study (women were premenopausal, topoisomerase IIa may be a better molecular predictor than HER2, trastuzumab [Herceptin] may prove superior to chemotherapy) but concludes “The time has come to divide breast cancer into clinically relevant molecular subgroups, to prioritize the clinical questions applicable to each subgroup, and to strengthen collaboration between clinicians and laboratory scientists in identifying molecular signatures that can predict the success or failure of treatment.”

Observational study of breast cancer in post-hysterectomy women supports safety of estrogen therapy for up to 15 years, but breast cancer risk might increase with longer duration of estrogen therapy 

May 9, 2006:  In an observational study, post-hysterectomy women in the Nurses Health Study were divided into six pre-specified 5-year groups depending on the duration of self-reported estrogen alone (unopposed) therapy (none, less than 5 years, 5-<10 years, 10-<15 years, 15-<20 years, 20 years or more). A significantly higher risk of invasive breast cancer was reported for women who self-reported estrogen use for 20 years or more compared with women who self-reported no estrogen use. No significant increase in overall breast cancer risk was noted for estrogen users in the other four estrogen 5-year groups. There was a significant trend (p<.001) for increased overall breast cancer risk as duration of estrogen therapy increased. There was an increased risk of hormone sensitive breast cancers - i.e., cancers positive for estrogen receptor (ER+) and progesterone receptor (PR+) - after 15 years. The paper provided limited demographic and baseline comparisons. A multivariate analysis adjusted for a number of demographic/baseline factors. The total numbers in each group was not specified because the study used "person-years, rather than individuals themselves, as the denominator" (personal communication, Wendy Chen). Observational studies cannot establish causal relationships, but can suggest the need for further study. Most authorities recommend that women and their doctors review on a regular basis whether estrogen therapy needs to be continued.

New prostate cancer gene may cause 8% of prostate cancers in men of European stock and 16% of those in African American men 

May 8, 2006:  Prostate cancer is common. A new gene (a variant on chromosome 8q24; allele -8 of the microsatellite DG8S737) is associated with an estimated population attributable risk (PAR) for prostate cancer of 8% in men of European ancestry and in 16% of cases in African American men. PAR is the portion of the incidence of a disease in the population (exposed and nonexposed) that is due to exposure to a factor. It represents the incidence of a disease in the population that would be eliminated if exposure to the factor were eliminated. The genetic variant is also associated with more rapid development of the disease in prostate cancer patients. A future diagnostic test might identify patients at high risk of developing prostate cancer, and the need for more aggressive treatment if a patient with prostate cancer has the genetic variant.

No increase in breast cancer risk with estrogen alone 

April 12, 2006: A previous report of the WHI randomized trial in postmenopausal women who had had a hysterectomy showed that estrogen plus progestin (Prempro) increased the risk of breast cancer. A new WHI report in JAMA shows no increase in the risk of breast cancer with conjugated equine estrogens (CEE) alone (Premarin). This study included 10,739 postmenopausal women randomly assigned to Premarin (0.625 mg/day) or placebo. After an average 7-year follow-up, Premarin was associated with a near-significant (p=.09) 20% reduction (0.28% vs. 0.34%) in the primary endpoint of invasive breast cancer. In exploratory analysis, somewhat greater reductions with Premarin were seen for localized breast cancer and ductal breast cancer, and in those with higher breast cancer risk on entering the trial, a history of benign breast disease, or an increased number of first degree relatives with breast cancer. The Premarin group had a higher risk of mammograms with abnormalities requiring follow-up (9.2% vs. 5.5% at 1 year, and 36% vs. 28% at the end of the trial) but this was mainly because of calcifications in the breast. The authors concluded "Treatment with CEE alone for 7.1 years does not increase breast cancer incidence in postmenopausal women with prior hysterectomy. However, treatment with CEE increases the frequency of mammography screening requiring short interval follow-up. Initiation of CEE should be based on consideration of the individual woman's potential risks and benefits." The WHI was funded by the National Heart, Lung and Blood Institute (NHLBI) which stated "The findings still support current recommendations that hormone therapy should only be used to treat menopausal symptoms and should be used at the smallest effective dose for the shortest possible time." Note that this trial was prematurely discontinued in 2004 because of an Increased Stroke Risk on Premarin, and in a separate April 10, 2006 Venous Thrombosis Report  from the WHI Premarin trial in the Archives of Internal Medicine, Premarin was associated with a statistically significant increase in deep venous thrombosis (0.23%/year vs. 0.15%/year) and a near-significant increase in total venous thromboembolism (including both deep venous thrombosis and pulmonary embolism) (0.30%/year vs. 0.22%/year).

Chemotherapy most useful in the 30% of women with ER-negative breast cancers 

April 12, 2006: A combined JAMA analysis of studies of breast cancer in 6,644 lymph node-positive patients confirmed previous work showing that chemotherapy statistically significantly reduced the risk of recurrence in patients with ER-negative (estrogen-receptor-negative) tumors (by 20-25%), compared with a non-significant decrease (by about 10%) in those with ER-positive tumors who had chemotherapy added to tamoxifen anti-estrogen drug therapy. Mortality was statistically significantly reduced (55%) in ER-negative patients, and non-significantly reduced (23%) in ER-positive patients. Five-year disease-free survival was increased 23% for ER-negative patients and 7% for ER-positive patients.

High dose Celebrex reduces risk of new colon polyps but increases cardiovascular risk in patients with previous colon polyps 

April 4, 2006: New results reported at an American Association for Cancer Research meeting from the 3-year, double-blind APC and PreSAP celecoxib (Celebrex) trials show that high dose (400-800 mg/day) celecoxib reduces by 45% the risk of new colon adenomas (pre-cancerous polyps, about 20% of which progress to colon cancer). Although this is an important finding, the cardiovascular safety of celecoxib is a more important issue for the average patient on celecoxib, and was discussed only briefly at the Pfizer website: “As reported in late 2004 based on a preliminary analysis, the final results of APC demonstrated a statistically significant increase in the Celebrex group compared to placebo for serious cardiovascular events, while PreSAP did not. A new, broader analysis of serious and other cardiovascular events, including angina, for both APC and PreSAP, found more cardiovascular events with Celebrex compared to placebo. These results are consistent with the current warnings on cardiovascular risk in the Celebrex label…. The evidence available today is that the typical arthritis dose of 200 mg of Celebrex taken daily does not increase the risk of cardiovascular events compared to other common prescription arthritis pain relievers (NSAIDs).” An article on MedPage Today gives more detail on cardiovascular risk: In the APC trial, “renal/hypertensive events” (related to high blood pressure and kidney function) showed no drug effect but “cardiovascular events” were significantly more common with celecoxib than with placebo (1% placebo; 2.3% 400 mg/day; 3.4% 800 mg/day); the total number of deaths was small (10/2035, 0.5%; 1 on placebo; 3 on 400 mg/day; 6 on 800 mg/day). In the PreSAP trial, “renal/hypertensive events” were significantly (p<0.01) more common with celecoxib 400 mg once daily (21%) than with placebo (15%); “cardiovascular events” were also significantly (p<0.05) more common with celecoxib (7.5%) than with placebo (4.8%). In summary, high dosage (400 mg/day or more) of celecoxib is associated with an increased cardiovascular risk in patients with a previous history of adenomas of the colon. It is not known if cardiovascular risk is similarly increased with high celecoxib dosage in patients with arthritis, the most common reason for prescribing celecoxib. In addition, the current evidence does not suggest any increased cardiovascular risk with celecoxib at dosage of 200 mg/day or less.

Observational study finds less breast cancer with use of COX-2 inhibitors 

In an observational study reported at the American Association for Cancer Research meeting, taking COX-2 inhibitor drugs for at least two years was associated with a 71% reduction in the risk of breast cancer. The study compared 323 breast cancer patients to 649 women without breast cancer. Since this was an observational study, it cannot be concluded that the lower risk was because of taking the COX-2 inhibitor drugs.  In a separate study from the Mayo Clinic of women with atypical hyperplasia of the breast, a higher level of COX-2 activity (which might be suppressed by COX-2 inhibitors) was associated with a higher risk of breast cancer.

Breast asymmetry may be associated with increased risk of breast cancer 

March 20, 2006: A clinical study from England suggests that asymmetry in the size of a woman's left and right breasts as measured by mammography may be a risk factor for breast cancer. Women with normal initial mammography but who developed breast cancer later were compared with age-matched women who did not develop breast cancer (252 women in each group). The volume of each breast was measured and the difference in volume between breasts calculated. Breast cancer risk increased by 50% for each 100 ml difference in volume between breasts, and breast asymmetry was found to be an independent predictor of cancer risk. The authors plan additional studies in a group of 13,000 women who were free of breast cancer on entry into a menopause study 25 years ago.

Three of four older Americans skip colon cancer screening 

March 9, 2006: Three out of four Americans aged 50-70 don't get regular screening for colon cancer, the second leading cancer killer in the US. Everyone should get a screening colonoscopy at age 50. The reasons people did not have a colonoscopy were: no discussion with their doctor (26%), no symptoms of disease (24%) and don't want a colonoscopy (28%). Recommendations for colonoscopy after 50 vary. Some experts recommend testing at age 50 and then every 3-5 years. However, Dr. David Stein, director of education for the Colon Cancer Foundation says that if a person with no family history of the disease has a colonoscopy at 50, the doctor performing the test is able to review the entire colon, and no problems are found, he or she doesn’t need to have the test again for 10 years. A new non-invasive test that screens for colon cancer by looking for cancer-related DNA in the stool is less accurate and only detects about 60% of colon cancers but a positive result usually does indicate disease. Dr. Stein recommends this test if a person refuses to have a colonoscopy.

Virus found in prostate cancer - significance unclear 

February 24, 2006: A new virus has been identified in human prostate cancer tumors using a DNA-hunting "virus chip", but the current data no not establish that the new virus actually causes the prostate cancer. Previous epidemiologic and genetic research has suggested that prostate cancer may result from chronic inflammation, perhaps as a response to a viral infection. Scientists have previously speculated that a virus may be involved in some types of prostate cancer in men that have abnormal copies of the RNASEL gene (which protects against viruses), and the new virus was found more often in human prostate tumors with two RNASEL mutations (8 of 20 tumors) than in tumors with at least one normal copy of the gene (1 of 66 tumors).

Prostate Cancer Screening may not Improve Survival 

January 10, 2006:  Men who have been screened for prostate cancer by the most commonly used tests (PSA test and rectal examination) have no greater chance of surviving the disease than those who have not been screened at all, new research has found. Dr. John Concato, the lead author on the paper, stressed that a physician was obligated to clarify all the issues for patients. "He should explain the benefits and risks, in the context of each patient's values. For example, some patients place such a high premium on avoiding incontinence and impotence that a positive PSA. test can be problematic."  The research involved nearly 72,000 men over 50 (1,425 with prostate cancer) who received outpatient care at any of 10 Veterans Affairs hospitals in New England.

Treatment Is Found to Stave Off Death from Ovarian Cancer  

January 5, 2006:  Pumping chemotherapy (paclitaxel and cisplatin) directly into the abdominal cavity can add 16 months or more to the lives of many women with advanced cases of ovarian cancer. Medical practice should change immediately, cancer experts say. The National Cancer Institute is taking the unusual step of issuing a "clinical announcement" to encourage doctors to use the abdominal treatment. Such announcements are few and far between: they are made when a readily available treatment can lead to a big increase in survival. The last time the institute took this kind of action was in 1999, to publicize a major advance in cervical cancer. In a new study, published in the New England Journal of Medicine, 415 patients were treated at 40 hospitals in the United States. Most were 41 to 70 years old, and all had had surgery to remove the cancer. About half the women, 210, were picked at random to get intravenous therapy, and 205 received both intravenous and IP treatment. Patients getting IP treatment had devices and tubing implanted in the abdomen to pipe in the chemotherapy. They received a total of six treatments, given once every three weeks. Basically, the procedure soaks the tumors in the powerful cancer-killing drugs. In the intravenous group, the median survival was 49.7 months, but it was 65.6 months in the intravenous + IP group - a difference of 15.9 months.

4. HEART DISEASE & STROKE

Pergolide (Permax) and cabergoline (Dostinex) associated with heart valve abnormalities in Parkinson's disease patients 

January 3, 2007: Observational studies reported in the New England Journal of Medicine showed that about one-quarter of patients with Parkinson’s disease receiving one of two 5-HT2B serotonin agonists, pergolide (Permax) and cabergoline (Dostinex), had valvular heart disease, compared with only 6% of controls. People who took the highest doses for the longest time were at higher risk. A number of drugs that activate the 5-HT2B type of serotonin receptor have been associated with abnormalities of the heart valves in patients and also stimulate proliferation of heart valve cells in laboratory studies. Other 5-HT2B agonists include ergot derivatives (ergotamine, methysergide, and dihydroergotamine) and amphetamine derivatives (fenfluramine and the recreational drug "ecstasy"). This page routinely includes the statement “Observational studies cannot establish causality but can suggest the need for further study”; however, the magnitude of the apparent increase in risk with these 5-HT2B agonists, the apparent increased risk with other 5-HT2B agonists, and the fact that laboratory studies show an overgrowth of heart valve cells with these agents consistent with the clinical findings, suggest that use of these drugs in the dosage used for Parkinsonism may be unwise. The heart valve effect has not been shown to occur with use of these drugs in low dosage, with non-5-HT2B serotonin agonists, or with serotonin antagonists.

More prolonged antiplatelet therapy recommended by some experts for patients with drug-eluting stents 

December 8, 2006: The consensus view of an FDA Advisory Committee was that late thrombosis may be commoner with drug-eluting stents than with bare-metal stents, and that longer duration of antiplatelet drug therapy may be required. However, the lack of randomized studies makes a definite conclusion difficult. There was no evidence that the risk of heart attack or stroke was increased overall but some evidence that thrombosis was increased after late discontinuation of antiplatelet therapy. A stent is a small, self-expanding, metal mesh tube that is placed inside a coronary artery after balloon angioplasty to prevent the artery from reclosing. A drug-eluting stent is coated with a drug (sirolimus or paclitaxel) that is intended to further reduce the chance of the artery reclosing. Interpretation of these observational studies is difficult, partly because of inclusion of the 60% of patients in whom the use of the stents is "off-label" (and in whom patients are usually sicker than those for whom the devices are approved). Late thrombosis tended to occur if post-stent antiplatelet therapy [clopidogrel (Plavix) + aspirin] was stopped, and some experts advise continuing Plavix+aspirin for at least one year after the stent, or even indefinitely. Early thrombosis is less common with the drug-eluting type of stent. One recent paper concluded that, if clopidogrel (Plavix) therapy is stopped 7-18 months after stent insertion, the risk of cardiac death and heart attack may be higher with drug-eluting stents than with bare-metal stents; however, the authors calculated that drug-eluting stents may avoid five major clinical events in the first six months in 100 patients treated but lead to three patients suffering cardiac death or nonfatal heart attack during months seven to 18, when Plavix is stopped. A recent meta-analysis of randomized clinical trials in 1,230 patients who previously had in-stent restenosis with bare-metal stents showed that drug-eluting stents reduced the risk of reclosing by over 60% compared with balloon angioplasty or vascular brachytherapy (brachytherapy is where radioactive seeds or pellets which emit radiation are implanted locally). Survival rates may be higher if patients with blockages in three or more vessels or in the left main coronary artery receive coronary artery bypass grafts (CABG) instead of angioplasty and stenting.

More on torcetrapib: conflicting studies of relationship between CETP levels and heart disease 

December 8, 2006: A Forbes article discusses one of the possible reasons for the increased mortality seen with torcetrapib in the ILLUMINATE trial.  Torcetrapib increases HDL cholesterol by lowering levels of CETP (cholesterol ester transfer protein). Most clinical studies have shown that people with low HDL cholesterol have higher rates of coronary disease.  However, the relationship between CETP levels and heart disease is unclear. Evidence that reducing CETP levels could be beneficial include: 1) a 1989 study in which a group of Japanese with a genetic mutation associated with low CETP and high HDL cholesterol were reported to be exceptionally long-lived. 2) a 2004 analysis of the large EPIC-Norfolk study  which showed increasing cardiovascular hazard with higher CETP, 3) Pfizer studies in rabbits which showed that reduction in CETP levels was associated with major reduction in atherosclerotic plaque, and 4) Pfizer studies that showed that the increased HDL cholesterol with torcetrapib was indeed functional [TMT Note: An independent 2006 publication also showed enhanced ability of HDL from CETP-deficient subjects to promote cholesterol efflux]. However, data suggesting that reducing CETP levels might be harmful include: 1) a 1996 study of a group of Japanese-Americans in which those with genetic mutations, low CETP and high HDL cholesterol had a 50% higher risk of heart attack (although a repeat study in this group did not confirm these findings), 2) a 1997 study in which one of several CETP genetic mutations (G-to-A mutation at the 5' splice donor site of intron 14) was associated with more coronary heart disease, 3) a 2000 study that showed that women (but not men) with low CETP and high HDL cholesterol had more heart disease, and 4) a report in another 2000 paper that “in vitro experiments showed that large CE-rich HDL particles in CETP deficiency are defective in cholesterol efflux” (in cholesterol efflux, cholesterol is removed from atherosclerotic plaque); the authors suggested that CETP inhibitors might produce "dysfunctional HDL particles" that would promote clogged arteries. These conflicting results should be clarified when the results of the large plaque imaging study with torcetrapib are reported in March 2007.

Some more possible explanations for torcetrapib safety problems 

December 5, 2006: A number of cardiology experts have weighed in on the possible cause of the safety problems with torcetrapib, including: 1) making the HDL cholesterol produced harmful, 2) increasing atherosclerotic plaque, 3) an effect of inhibiting the CETP enzyme, 4) increasing blood pressure or 5) some other side effect of torcetrapib. Dr. James Stein (University of Wisconsin): "The HDL particles observed in patients on torcetrapib were larger and had different chemical properties than those seen under normal biological conditions. We can't simply assume that high HDL cholesterol is good. Indeed, it is conceivable that these particles are harmful." Dr. Steven Nissen (Cleveland Clinic): The key thing to determine is whether torcetrapib increased or decreased the formation of cholesterol-containing plaques on the inside of the arteries. "If the HDL produced by giving a CETP inhibitor is 'pro-atherogenic', that is, if it promotes plaque development, then it is reasonable to expect every CETP inhibitor to do the same." Dr. Christopher Cannon (Brigham and Women's Hospital): "I think we all fear that it might be the mechanism. The increased mortality and cardiovascular events speak to a broad-based problem, rather than one occurring in patients who develop hypertension from the drug." Dr. Daniel Rader (University of Pennsylvania): "I think it is terribly important to emphasize that this development says nothing about the overall strategy of targeting HDL therapeutically. Torcetrapib itself raises blood pressure, a property of the drug, and we still don't know how much this may have contributed to adverse outcomes." Dr. Kevin Graham (Minneapolis Heart Institute): "The initial questions will focus on the mechanisms, whether this applies to all drugs of this class or whether it is particular to this drug. It is too early to say." Dr. Michael Miller (University of Maryland): "Based on studies using other drugs that raise HDL, such as niacin, that have been previously shown to reduce heart attacks, it is more likely that the problem occurred due to the side effects of this drug, rather than the result of raising HDL." Dr. Daniel Edmundowicz (University of Pittsburgh): "Just because higher HDL levels are associated with decreased coronary events … doesn't guarantee that raising HDL pharmacologically will show the same benefit." Dr. Patrick McBride (University of Wisconsin): "This does not mean that other medicines under investigation to raise HDL are not going to be beneficial — they raise different types of HDL and work by different mechanisms in the body. There is still great potential for treatments in the future to raise HDL cholesterol."

Possible explanations for torcetrapib safety problems 

December 4, 2006: Dr. Steven Nissen, President of the American College of Cardiology, has suggested that the increased mortality seen in the torcetrapib ILLUMINATE clinical trial "raises the specter of something uniquely toxic about inhibiting CETP" [cholesteryl ester transfer protein] and that torcetrapib could promote creation of "dysfunctional HDL that is proatherogenic and proinflammatory". He also said that the excess mortality reported was more than would be expected "with a rise of 3 mm of mercury over three years" [as TMT also implied in our December 3 review - see below]. In addition, he suggested that the increased mortality might be seen only in those people who "had the most significant increases in blood pressure - not the mean increase of 3 mm Hg, but an increase of 10 or 15 mm Hg." Dr. Nissen said that the DSMB was chaired by Dr. Charles Hennekens of the University of Miami. TMT's view is that other possible explanations for the findings may become apparent when the data are analyzed in detail - for example, a large sudden regression of atherosclerotic plaque in response to marked increases in HDL cholesterol might destabilize the plaque and trigger cardiovascular events; if this were the case, torcetrapib might be safe and effective if used to raise HDL cholesterol levels more gradually, rather as antihypertensive drugs are safe and effective when very high blood pressure is lowered gradually but hazardous when blood pressure is lowered suddenly and drastically.

FDA clarifies DSMB monitoring in Pfizer's ILLUMINATE torcetrapib trial 

December 4, 2006: FDA's website has provided some additional information on the ILLUMINATE trial that caused Pfizer to stop all torcetrapib clinical trials: "the DSMB was conducting a monthly analysis of mortality data and a quarterly analysis of a number of outcomes including stroke, heart attack, and revascularizations (e.g., coronary stents or bypass surgery) to ensure the ongoing safety of patients in this trial". Other reports have stated that the previous analysis did not cause the DSMB to recommend any changes in the conduct of the trial. Accordingly, it appears that the most recent analysis included both a 3-month mortality analysis and the monthly non-mortality outcome analysis. In a separate report from Kaiser, it was stated that for the ILLUMINATE trial "The safety board reviews trial data and submits a monthly torcetrapib progress review to Pfizer officials, who are not permitted to see the data in order to protect the integrity of the studies" - although the raw data was clearly not provided, it is not clear what other information this monthly report contained.

Pfizer halts all torcetrapib trials because of increase in mortality and cardiovascular events 

December 3, 2006: Pfizer has stopped all clinical trials and further development of torcetrapib because of "an imbalance of mortality and cardiovascular events" in the ILLUMINATE clinical trial, a 15,000-patient, double-blind controlled trial in subjects with coronary heart disease or risk equivalents designed to compare the risk of major cardiovascular events in two treatment groups: 1) torcetrapib 60 mg/day + atorvastatin (Lipitor), 2) atorvastatin alone. An interim analysis by the independent Data Safety Monitoring Board (DSMB) for the trial showed that more patients died in the torcetrapib+atorvastatin group (82 subjects) than in the atorvastatin group (51 subjects), an increase in mortality of about 60%. The risk of heart failure and other cardiovascular events was also increased. The 60 mg torcetrapib dose was previously shown to increase systolic blood pressure by 3-4 mmHg. In a 2005 epidemiological study the effects of systolic blood pressure and cholesterol on relative risks were more than "additive" but less than "multiplicative" (multiplicative means, for example, that if 1 factor doubles risk and another triples it, then their joint effects increase risk 6-fold); according to Dr. Franz Messerli, a New York City hypertension expert, based on this epidemiological study the systolic blood pressure increase of 3-4 mmHg might translate to a 20% increase in stroke mortality and a 12% increase in ischemic heart disease mortality. Pfizer is asking all clinical investigators conducting torcetrapib trials “to inform patient participants to stop taking the study medication immediately”.

Moderate alcohol consumption may reduce risk of heart failure by reducing the risk of coronary disease 

November 27, 2006: In the Physicians' Health Study, over 20,000 male physicians were followed for over 20 years. A new analysis of this study concludes that moderate alcohol intake may lower the risk of heart failure because of a reduction in the risk of coronary artery disease, a common cause of heart failure.

Naproxen increases risk of cardiovascular events in Alzheimer's trial 

November 17, 2006: In the double-blind, placebo-controlled ADAPT trial, over 2500 people at risk of Alzheimer's dementia were randomized to Celebrex (celecoxib 200 mg twice daily), naproxen (220 mg twice daily) or placebo for about 15 months and were then followed up for a total period of about 2 years. The percentages of subjects with cardiovascular endpoints (cardiovascular or cerebrovascular death, heart attack, stroke, heart failure, or TIA) in the celecoxib-, naproxen-, and placebo-treated groups were 5.5%, 8.3% and 5.7% respectively. Celebrex was not associated with increased risk compared to placebo, but naproxen was associated with a statistically significant increase in risk of 63%. Significantly more people on Celebrex and naproxen than on placebo required antihypertensive therapy. In an Editorial comment, the Journal stated "These data on harms provided by ADAPT provide important results that should be incorporated into future meta-analyses".

Stable patients after acute phase of heart attack don't need angioplasty and stent 

November 15, 2006: In a randomized study in over 2000 heart attack patients with total blockage of the coronary artery related to the heart attack, and who were in stable condition 3 or more days after the heart attack, angioplasty and insertion of a coronary stent at that time did not reduce the risk of death, further heart attack or heart failure during 4 years of follow-up.

Etoricoxib (Arcoxia) similar to diclofenac in risk of heart attack, stroke & death but causes more high blood pressure and heart failure 

November 13, 2006: The Lancet has published the results of the MEDAL clinical trial in almost 35,000 arthritis patients. MEDAL was a double blind, 18-month comparison of etoricoxib (Arcoxia) and diclofenac. Arcoxia is a Merck COX-2 inhibitor that is marketed in several countries but not in the US. It is in the same drug class as Vioxx, a drug that has been associated with significant risk of heart attack and stroke. Arcoxia and diclofenac had comparable rates of heart attack, stroke or death. However, US experts such as Dr. Steven Nissen of the Cleveland Clinic and Dr. David Graham of the FDA pointed out that the drug to which Arcoxia was compared (diclofenac) has itself been associated with an increased cardiovascular risk. Although Arcoxia was associated with less risk of gastrointestinal problems such as ulcers or bleeding, most of these problems did not cause problems to the patients and the risk of serious gastrointestinal problems was similar with Arcoxia and diclofenac. Arcoxia was associated with more cases of high blood pressure and heart failure than diclofenac.

Heart attack patients get angioplasty too late 

November 13, 2006: Two-thirds of heart attack patients treated in US hospitals don’t get timely coronary angioplasty. If balloon angioplasty is done within 90 minutes of hospital arrival, as guidelines recommend, mortality is 40% less.  Chances of meeting the guideline are best if: 1) Paramedics do an ECG en route to hospital, 2) ER doctor reviews ECG and alerts angioplasty team, 3) Each member of the team can be paged and arrive within 20 minutes, 4) A cardiologist is on site at all times, and 5) Hospital posts feedback on each case for the angioplasty and ER teams. Hundreds of US hospitals are now joining a project to deliver faster angioplasty.

Open study suggests that one-year of therapy with a heart assist device combined with drug therapy can reverse severe heart failure 

November 2, 2006: A 15-patient open-label design study in patients with severe, nonischemic heart failure evaluated combined treatment with a left ventricular assist device (to assist heart pumping) and intensive drug therapy. Most patients were able to have the assist device removed after about a year, with minimal evidence of cardiac failure thereafter. Objective measures of cardiac function such as ejection fraction showed marked improvement. These promising findings need to be confirmed in a controlled clinical trial.

Restraining good hand improves movement of affected arm after stroke 

November 1, 2006: The EXCITE trial was a single-blind, randomized evaluation of the effect of wearing a restraining mitt on the less-affected hand in patients with impaired function of the hand/arm following a first stroke in the previous 3-9 months (106 patients) compared to usual and customary care (116 patients). An instrumented protective safety restraining mitt was worn for about 90% of waking hours over a period of 2 weeks; during this period, shaping and task training was done for up to 6 hours/day. The speed with which a task using the arm most affected by the stroke was performed was statistically significantly greater in the mitt group (52% vs. 26% improvement; P<.001). Other measures of arm function also improved significantly. Earlier preliminary work (see March 6, 2006 review below) showed similar benefit.

Symptoms suggesting stroke occur in 18% of older people without a stroke diagnosis 

October 12, 2006: A study in 18,462 Americans (average age 66 years) without a diagnosis of stroke or TIA found a prevalence of 18% for one or more stroke symptoms: sudden one-sided weakness (5.8%), numbness (8.5%), or visual loss (3.1%); other sudden visual loss (4.6%), sudden inability to understand speech (2.7%) and sudden loss of linguistic ability (3.8%). The study included all US states, but had more African-Americans and people from the "stroke belt" than the entire US population. Stroke symptoms were associated with higher Framingham Stroke Risk Scores. Stroke symptoms were commoner in African-Americans and in those with lower income, lower education and lower self-reported health status. The authors suggest that some of those with stroke symptoms may have had undiagnosed strokes or TIAs and might benefit from aggressive steps to reduce future strokes.

Bayer did not tell FDA about preliminary safety data from Trasylol observational study 

September 29, 2006: FDA issued a September 29 statement "FOR IMMEDIATE RELEASE" that discussed "preliminary findings" from a new observational study that the antifibrinolytic drug aprotinin (Trasylol) "may increase the chance for death, serious kidney damage, congestive heart failure and strokes. FDA was not aware of these new data when it held the September 21, 2006, Advisory Committee meeting on Trasylol safety." The Advisory Committee meeting was "triggered by the results of two published research studies: one that reported an increase in the chance of kidney failure, heart attack and stroke in patients treated with Trasylol compared to those treated with other similar drugs, and the other that reported an increase in kidney dysfunction compared to another drug." One of these two published studies was a New England Journal of Medicine observational study published in January, 2006. According to the New York Times, one of the investigators involved in the new study tipped off the FDA about the existence of the study. The study was not mentioned by Bayer at the Advisory Committee meeting, and one can speculate that if these "preliminary findings" had supported Trasylol safety, Bayer might have been more likely to mention them. Observational studies cannot establish causal relationships, although they can suggest the need for further study.

Meta-analyses confirm Vioxx cardiovascular toxicity but raise other questions 

September 13, 2006: JAMA has published two meta-analyses and an Editorial on the safety of COX-2 inhibitor NSAIDs. One Harvard study was a meta-analysis of combined data (116,094 patients) from randomized controlled trials and concluded that, compared with concurrent control patients: 1) rofecoxib (Vioxx) significantly increased the risk of developing cardiac arrhythmia, hypertension, edema, or impaired kidney function, 2) celecoxib (Celebrex) significantly reduced the risk of hypertension and impaired kidney function. It is of note that life-threatening cardiac arrhythmias (ventricular fibrillation, ventricular tachycardia, cardiac arrest, sudden cardiac death) were commoner with Vioxx (10 cases versus 2 in controls) but somewhat less common with Celebrex (3 cases versus 6 in controls). This study did not examine the risks of heart attack or stroke, the major clinical events that have been associated with COX-2 inhibitors. The other study was a meta-analysis of 23 observational studies and concluded: 1) Vioxx increased the risk of heart attack at both low and high doses, an effect that was present early in therapy, 2) the traditional NSAID diclofenac (with has some COX-2 selectivity) increased the risk by 40%, 3) an increased risk was seen with indomethacin, and probably meloxicam, 4) an increased risk was noted at high doses of Celebrex (in non-arthritis patients) but not at Celebrex doses of 200 mg/day or less. Observational studies cannot establish causality but can suggest the need for further study. An accompanying Editorial by David Graham (an FDA employee writing in a private capacity) stated: "naproxen appears to be the safest NSAID choice from a cardiovascular perspective. For patients at high risk of NSAID-related gastrointestinal tract complications, naproxen plus a proton pump inhibitor is less costly and as effective, and probably safer, than low-dose celecoxib". TMT's position is that while naproxen is a reasonable treatment option, no controlled trials have established the superiority of this approach; in addition, the results of the discontinued ADAPT trial (in which initial reports suggested increased cardiovascular risk with naproxen) have not yet been published.

Don't take ibuprofen less than 8 hours before or less than 30 minutes after aspirin taken for cardioprotection 

September 12, 2006: FDA has issued a caution about using ibuprofen less than 8 hours before or less than 30 minutes after a dose of aspirin taken for cardioprotection, because this can interfere with aspirin's protective antiplatelet effect. Acetaminophen does not have this problem, but the situation is unclear for other NSAID pain killers.

High dose atorvastatin (Lipitor) reported to reduce heart attack risk more than medium dose simvastatin (Zocor) 

September 6, 2006: A presentation at the World Congress of Cardiology meeting in Spain reported that high dose (80 mg/day) atorvastatin (Lipitor), compared to medium dose (20-40 mg/day) simvastatin (Zocor), provides a greater (46%) reduction in the risk of an additional heart attack in patients who recently had a heart attack. The top recommended dose of both atorvastatin and simvastatin is 80 mg/day, and it is not known whether the results would be the same if both drugs had been given at the top recommended dose. Recent studies have shown that atorvastatin 80 mg/day reduces cardiovascular risk more than atorvastatin 10 mg/day.

Subgroup analysis of TNT trial shows that high risk patients with coronary disease and metabolic syndrome do well on high dose (80mg) Lipitor 

September 5, 2006: A subgroup analysis of the previously reported double-blind TNT trial showed that 5,584 patients with both coronary heart disease and metabolic syndrome (2005 NCEP ATP III criteria - three cardiovascular risk factors such as insulin resistance, obesity, high blood pressure, abnormal cholesterol or lipids) were at significantly higher risk of a major cardiovascular event than those with coronary heart disease alone, but that high (80mg/day) dosage with atorvastatin (Lipitor) significantly reduced this risk compared with low (10mg/day) atorvastatin dosage.

APC and PreSAP double-blind trials show that celecoxib (Celebrex) at dosage of 400 mg/day or greater reduces risk of colorectal adenomas but increases cardiovascular risk 

August 30, 2006: In the 1561-subject, double-blind, placebo-controlled PreSAP Trial, celecoxib (400 mg once daily) significantly reduced the risk of colorectal adenomas (34% vs. 49%), but significantly increased the risk of adjudicated serious cardiovascular events (2.5% vs. 1.9%). In the 2035-subject, double-blind, placebo-controlled APC Trial, celecoxib significantly reduced the risk of colorectal adenoma (43% with celecoxib 200 mg twice daily, and 38% with celecoxib 400 mg twice daily) compared to placebo (61%). Celecoxib and placebo were comparable in the overall risk of serious adverse events but celecoxib was associated with an increased risk of cardiovascular events compared to placebo (risk ratio 2.6 and 3.4 for the low and high celecoxib dosages respectively). An accompanying Editorial in the New England Journal of Medicine concludes that in the APC and PreSAP trials “…among patients with colonic adenomas …celecoxib …reduces the risk of metachronous adenoma” [but the trials] “were too small to evaluate the role of celecoxib in preventing colorectal cancer … celecoxib has no role as a chemopreventive agent either in patients with nonfamilial colonic adenomas or in the general population”.

Large observational study in 52 countries shows heart attack risk with all forms of tobacco, including second-hand smoke 

August 18, 2006: A large (27 thousand subject) observational study across 52 countries showed a significant increase in risk of heart attack with current smoking (3x risk), as well as with second-hand tobacco smoke (SHS) and chewing tobacco. The increased risk with SHS increased as the degree of exposure increased. The authors conclude "Tobacco use is one of the most important causes of [heart attack] globally, especially in men. All forms of tobacco use, including different types of smoking and chewing tobacco and inhalation of SHS, should be discouraged to prevent cardiovascular diseases." As this page routinely says, "Observational studies cannot establish causal relationships, but can suggest the need for further study." While this is true, the evidence for the harmful effects of tobacco from many studies over many years is overwhelming.

In randomized trials both COX-2 inhibitors and traditional NSAIDs increase vascular risk 

August 15, 2006: A meta-analysis of randomized clinical trials comparing the risk of serious vascular events (heart attack, stroke or vascular death) showed a significantly higher risk with COX-2 inhibitors (+42%) than short-term placebo, mainly because of increase in heart attacks. Similar increase in risk was seen overall with traditional NSAIDs. Naproxen in comparison with COX-2 inhibitors showed less cardiovascular risk but this may be a reflection of the fact that the predominant COX-2 inhibitor in this comparison was rofecoxib (Vioxx), which has been associated with particularly large increase in risk in some other studies.

Observational study suggests that aspirin may mitigate the increased cardiovascular risk with NSAIDs 

August 15, 2006: An observational case-control study using the California Medicare database identified arthritic patients treated with a COX-2 selective or nonselective NSAID. A heart attack occurred in 15,343 patients. Compared with those with no recent NSAID use, risk of heart attack was significantly increased with indomethacin (65%), meloxicam (52%), sulindac (47%), rofecoxib (31%), and celecoxib (12%). No significant increase in risk was seen with ibuprofen. In patients concurrently using both aspirin and COX-2 selective or nonselective NSAIDs, no increased heart attack risk was noted, suggesting that aspirin may mitigate the effects of NSAIDs in increasing heart attack risk; however, in clinical trials, concurrent use of aspirin has not been demonstrated to be protective. Observational studies cannot establish causal relationships, but can suggest the need for further study.

High-dose Lipitor reduces risk of recurrent stroke even in people without known coronary disease 

August 9, 2006: The August 10 New England Journal of Medicine reports the results of the SPARCL study in which patients who had a previous stroke or transient ischemic attack (TIA) but without known coronary heart disease were randomized to high-dose (80 mg/day) of atorvastatin (Lipitor) or placebo. LDL cholesterol was 43% lower with Lipitor than placebo. Over a 5-year period, a stroke occurred in 11.2% of Lipitor patients compared with 13.1% for placebo, a statistically significant difference. Lipitor also significantly reduced the risk of major cardiovascular events. Mortality was comparable in the two patient groups.

Observational study suggests all NSAIDs (COX-2-selective and non-COX-2-selective) modestly increase heart attack risk 

August 2, 2006: An observational, matched case-control study from Finland reported that, in a multivariate analysis of 33,309 patients with a first-time heart attack, non-steroidal anti-inflammatory drugs (NSAIDs) were associated with an adjusted increase in the risk of heart attack of 40% (34%, 50% and 31% for conventional, semi-COX-2-selective, and COX-2 selective NSAIDs respectively). Among COX-2 inhibitors, current use of celecoxib (Celebrex) was associated with a non-statistically-significant 6% increase in risk, whereas current use of rofecoxib (Vioxx) was associated with a statistically significant 44% increase in risk. Observational studies cannot establish causal relationships, but can suggest the need for further study.

Most heart attacks might be prevented by a healthy lifestyle 

July 4, 2006: An Early Release article in Circulation in almost 43,000 men without coronary heart disease (CHD) at baseline reports that "A majority of CHD events among US men may be preventable through adherence to healthy lifestyle practices, even among those taking medications for hypertension or hypercholesterolemia". A healthy lifestyle was determined by no smoking, normal weight, regular exercise, moderate alcohol intake, and a healthy diet. In a multivariate Cox PH analysis, it was estimated that about 60% of coronary events could have been prevented by a healthy lifestyle. Another Early Release Article in the same issue of Circulation reports that in 460 patients with peripheral arterial disease of the leg (PAD), "PAD patients with higher physical activity during daily life had reduced mortality and cardiovascular events compared with PAD patients with the lowest physical activity, independent of confounders".

New England Journal of Medicine issues correction on Vioxx APPROVe trial 

June 27, 2006: The New England Journal of Medicine has posted an online “Early Release” Correction for its original publication of the results of the rofecoxib (Vioxx) APPROVe trial. The correction relates to a statistical test (Cox proportional-hazards) as to whether the increased cardiovascular risk is different at different times during the trial. The originally reported p value was statistically significant for a difference in risk over time, supporting the paper’s suggestion that visual review of the Kaplan-Meier graph of risk over time showed an increase in risk only after 18 months of Vioxx therapy. However, the corrected p value for a significant change in risk over time is not statistically significant (p=0.07). This Early Release also includes Correspondence from Dr. Nissen and Dr. Furberg (expressing concern about an earlier and greater hazard from Vioxx in the APPROVe trial based on an intention-to-treat analysis of new data that include cardiovascular events occurring more than 14 days after study drug was stopped) and a statistical Review by Dr. Lagakos (that discusses time-to-event analyses in long-term studies such as the APPROVe trial and suggests “a plausible range of excess risk associated with a shorter (less than 18 months) course of rofecoxib”).

Observational study suggests mortality risk is increased with short duration NSAID therapy in patients with previous heart attack

June 21, 2006: A new observational study describes the effect of NSAIDs (average duration of therapy 1 month) on the risk of death or reinfarction in almost 60,000 patients with previous myocardial infarction. The authors conclude that the hazard ratios for death were significantly increased for rofecoxib (hazard ratio 2.80), celecoxib (2.57), diclofenac (2.40), ibuprofen (1.50), and other NSAIDs (1.29). There were dose-related increases in risk of death for all of the drugs. There were trends for increased risk of reinfarction for each drug group, but not for reinfarction dose-response. Observational studies cannot establish causal relationships, but can suggest the need for further study.  This observational study differs from the many prior observational studies of COX-2 drugs and other NSAIDs in that study subjects had a previous history of myocardial infarction and the focus of the study analysis was risk of death rather than of myocardial infarction or stroke. It is not stated if the data analysis was prespecified. Analysis consisted of an across-group comparison of the drug groups, a within-drug-group comparison of dose levels, and a within-patient comparison of drug therapy in the 30 days before an event with drug therapy during an earlier period. The analysis was adjusted for some possible confounders (age, gender, year of MI, concomitant medical treatment, socioeconomic status, and comorbidity). Mean age was significantly higher with rofecoxib (69) and celecoxib (69) than in the other groups (64-67); the gender distribution (% of males) was markedly different for rofecoxib & celecoxib (both 50%) versus the other groups (61-66%); these substantial discrepancies increase the likelihood of other confounders (not evaluated in the study) affecting the study conclusions. Data on concomitant aspirin use was not available but the authors “assumed that most of our patients used aspirin on a daily basis”; it is possible that aspirin use differed between the NSAID treatment groups and, for example that increased GI risk (known to be associated with increased CV risk) was associated with more frequent use of COX-2 drugs. Although a dose-response relationship for risk of death with each drug could suggest a drug-induced effect, it could also be a reflection of medical differences between the low dose and high dose populations, possibly related to differences in underlying CV risk. The fact that risk of death but not risk of reinfarction was significantly increased is surprising since increased risk with COX-2 drugs in previous studies was mainly related to myocardial infarction and stroke. The risk of death with diclofenac (known to be relatively COX-2 selective) was more similar to that with the established COX-2 drugs, rofecoxib and celecoxib, than with non-selective NSAIDs. The article was accompanied by an Editorial which expressed concern about these new findings in high cardiovascular risk patients and suggested that high-dose aspirin used with proton pump inhibitors “is probably the safest choice for post-MI patients”. The Editorial also points out that the average duration of NSAID therapy in this study was about 1 month, suggesting increased risk early in therapy. The Editorial also comments that “There is a critical need for large, simple, clinical trials to test the safety, with reasonable certainty of the quantitative risk, and the real-world effectiveness of widely used available agents and those that are under development.”

Data from Merck report suggest fairly constant cardiovascular risk (0.2% of patients/6 months) during most of Vioxx therapy and in 1-year following therapy, with higher risk in last 6 months of 3-year Vioxx period

May 22, 2006: The New York Times has published some of the data from the still-unpublished 108-page Merck report on the APPROVe rofecoxib (Vioxx) study. TMT has performed a preliminary analysis of the data in the Intent-To-Treat graph which, based on visual review of the time trend, suggests that “Confirmed Thrombotic Cardiovascular Events” related to Vioxx occur at a fairly constant rate (placebo-subtracted value about 0.2% of patients/6 months - 1 event/500 patients/6-month period) for most of the double-blind period, but rise to about 1 event/100 patients/6 months during the last 6 months of the 3-year period of double-blind therapy (mainly because of a paucity of placebo events during this 6-month period). During the 1-year post-double-blind off-drug period, the placebo-subtracted rate drops down again to around the 1 event/500 patients/6-month value. See Preliminary TMT analysis for more details.

New analysis suggests greater, earlier and more persistent increase in cardiovascular risk with rofecoxib (Vioxx)

May 21, 2006: A number of media reports have discussed a recent unpublished 108-page report on the APPROVe trial of rofecoxib (Vioxx). The new analysis suggests, but does not establish, that Vioxx increases cardiovascular risk within the first few weeks of therapy, that the increase may be greater than previously thought, and that this increased risk continues during therapy and (particularly for stroke risk) for at least one year after therapy is discontinued. Key features include an Intent-To-Treat analysis that includes all cardiovascular events during the full scheduled trial period even in patients who prematurely discontinued double-blind therapy, and evaluation of the 1-year follow-up period after each patient completed the trial. Since it has been suggested that a persistent increase in cardiovascular risk on discontinuing Vioxx may reflect persistent arterial damage, non-invasive measures of arterial structure and function should be incorporated in some NSAID clinical trials. Analysis should include separate testing of the risk of heart attacks and non-hemorrhagic strokes as well as of the composite cardiovascular endpoints analyzed to date. See the Full TMT Review for more details.

Academic researchers suggest Merck should continue to follow APPROVe study patients for long-term heart damage from rofecoxib (Vioxx) 

May 13, 2006: Two academic researchers, Steven Nissen of the Cleveland Clinic and Bruce Psaty of the University of Washington, have suggested that subjects in the rofecoxib (Vioxx) APPROVe study should be followed up for more than the current 1-year period after completion of the 3-year Vioxx/placebo comparison to evaluate whether "there was some kind of permanent or longstanding injury to the artery that makes it susceptible to those kinds of continuing events" (Dr. Nissen). Dr. Psaty commented "From the public health perspective and the point of view of duty to human subjects, following them would be appropriate. That would be an honorable thing to do." In comments to the New York Times, Merck "said it had not yet decided whether to continue tracking the patients. We have questions about whether scientifically rigorous data can be obtained in such a setting. We will discuss it with regulatory agencies and the study's steering committee before making a final decision."

New Merck analysis suggests increased stroke risk with rofecoxib (Vioxx); increased cardiovascular risk may persist to some extent after stopping rofecoxib  

May 12, 2006: Merck has reported that new analyses of the full 4-year period (3 years of Vioxx/placebo followed by 1 year follow-up off-drug) of the 2,587-subject APPROVe study of rofecoxib (Vioxx) showed a significant increase with Vioxx in the risk of ischemic strokes as well as of heart attacks and thrombotic cardiovascular events. The previously published paper on the first 3 years of the study reported the following numbers of events for Vioxx vs. placebo: confirmed serious thrombotic events 46 vs. 26 (risk ratio 1.92; p=0.008), myocardial infarction (heart attack) 21 vs. 9, ischemic stroke 11 vs. 6, transient ischemic attack (TIA - not clear if TIAs and strokes were in different subjects) 5 vs. 2, APTC composite cardiovascular endpoint 34 vs. 18. In its new analysis posted on its website, Merck reported: 1) during the 1-year off-drug period there was no statistically significantly increased risk with Vioxx of "confirmed thrombotic cardiovascular events" either in all patients in the study (28 subjects vs. 16 subjects - reported to be a 64% to 85% greater risk depending on how this was calculated) or in those "who completed approximately three years of therapy". 2) "In the prespecified primary analysis of each patient's four-year data" the risks of "confirmed thrombotic cardiovascular events", "confirmed heart attacks", and "confirmed ischemic strokes" were statistically significantly increased with Vioxx. Merck pointed out that no statistically significant increase in the risk of confirmed ischemic stroke was seen in the initial 3-year period of the APPROVe study or in other clinical trials with Vioxx. No information was provided on the time course of cardiovascular events during the 1-year follow-up period.

New observational study suggests increased heart attack risk during first 2 weeks of rofecoxib (Vioxx) treatment

May 3, 2006: A new observational study suggests that rofecoxib (Vioxx) increases the risk of myocardial infarction (heart attack) in the first two weeks of treatment. In addition, heart attack risk was increased for the first week after discontinuing Vioxx but then returned to baseline. Similar effects were not seen for celecoxib (Celebrex).  Observational studies cannot establish causal relationships, but can suggest the need for further study. In commenting on this new study, Merck has correctly pointed out that effects in such a study are less persuasive than effects seen in randomized clinical trials. However, the effect of duration of therapy on heart attack risk was inadequately evaluated in the clinical trial analyses in both the Vioxx and Celebrex Briefing Books provided to FDA for the February 2005 COX-2 Advisory Committee meeting. Both Briefing Books excluded clinical trials with duration less than 4 weeks from analysis of cardiovascular safety, and analysis of data for the initial 4 weeks of therapy from longer trials was insufficient for clear evaluation of early cardiovascular risk. Both Briefing Books focused on a composite cardiovascular endpoint (APTC index) whereas with both drugs evidence for an increase in heart attack was more persuasive than for the APTC index. Additional meta-analysis of the Vioxx and Celebrex controlled clinical trial databases to evaluate heart attack risk as a function of duration of therapy (using the Cox Proportional Hazards model) would be valuable.

New observational study suggests heart risk with COX-2 NSAIDs

April 18, 2006: A new observational study found that NSAIDs (nonsteroidal antiinflammatory drugs) with greater COX-2 selectivity were associated with greater cardiovascular risk, and that higher dosage tended to be associated with an increase in this risk. Observational studies cannot establish causal relationships, but can suggest the need for further study. The UK GPRD database for June 1, 2000 to October 30, 2004 was examined in a nested case-control observational study in almost half a million patients who had received at least 1 prescription for selective or nonselective NSAID therapy (NSAID users). Cardiovascular events (heart attack or sudden cardiac death) were identified in 5,127 patients and after further blinded screening 3,643 patients were selected (cases). Control patients who did not have these cardiovascular events (controls) were randomly selected from the NSAID users and matched with the cases for age, sex, practice and year of cohort entry (total of 13,918 controls).  Cases and controls were divided according to NSAID use in the year before the cardiovascular event (or the equivalent follow-up time for controls). Statistically significant increases in cardiovascular events (compared with non-users of NSAIDs as assessed by the multivariate risk ratio) were noted for 1) the COX-2 selective NSAIDs rofecoxib (+29%), celecoxib (+56%) and etoricoxib (+109%), and 2) diclofenac (+37%), a drug assigned by the authors to the nonselective group but which they point out has comparable COX-2 selectivity to celecoxib. No statistically significant increase was seen with 3) the nonselective NSAIDs ibuprofen (+4%) or naproxen (+15%). Too few patients received the COX-2 selective drug valdecoxib for meaningful analysis. The increased risk appeared to be present even in patients without major cardiovascular risk factors. There was a trend towards increased risk with higher dosage of "COX-2-selective NSAIDS" (unadjusted risk +25% for low dose vs. +71% for medium/high dose) as compared to +21% and +24% for diclofenac, and -5% and +5% for ibuprofen + naproxen.

Coronary patients should get ACE inhibitors

April 12, 2006:  Over the last few years, compelling evidence has accumulated for prescribing ACE inhibitors (angiotensin-converting enzyme inhibitor drugs) to virtually all patients with coronary disease. Yet studies have shown that many coronary patients are not receiving ACE inhibitors. The latest addition to the literature is a meta-analysis of 7 randomized controlled trials in a total of 33,960 patients either with coronary disease or at high risk of coronary disease (but without heart failure) treated for over 4 years. Treatment with angiotensin-converting enzyme inhibitors significantly decreased overall mortality, cardiovascular mortality, heart attack, and stroke.

Intercessory prayer did not reduce cardiac complications after bypass surgery. Patients who knew they were receiving intercessory prayer had higher complication rate

 March 31, 2006: The STEP multicenter, randomized study, reported in the March 30 American Heart Journal, evaluated the effects of intercessory (pleading on somebody’s behalf) prayer in cardiac bypass patients. Prior studies have not addressed whether prayer itself or knowledge/certainty that prayer is being provided may influence outcome. The STEP study evaluated whether (1) receiving intercessory prayer or (2) being certain of receiving intercessory prayer was associated with uncomplicated recovery after coronary artery bypass graft (CABG) surgery. Patients at 6 US hospitals were randomly assigned to 1 of 3 groups: 604 received intercessory prayer after being informed that they may or may not receive prayer; 597 did not receive intercessory prayer also after being informed that they may or may not receive prayer; and 601 received intercessory prayer after being informed they would receive prayer. Intercessory prayer was provided for 14 days, starting the night before CABG. The primary outcome was presence of any complication within 30 days of CABG. Secondary outcomes were any major event and mortality. In the 2 groups uncertain about receiving intercessory prayer, complications occurred in 52% (315/604) of patients who received intercessory prayer versus 51% (304/597) of those who did not (relative risk 1.02, 95% CI 0.92-1.15). Complications occurred in 59% (352/601) of patients who knew they were receiving intercessory prayer compared with the 52% (315/604) of those uncertain of receiving intercessory prayer (relative risk 1.14, 95% CI 1.02-1.28). Major events and 30-day mortality were similar across the 3 groups. The authors concluded that "Intercessory prayer itself had no effect on complication-free recovery from CABG, but certainty of receiving intercessory prayer was associated with a higher incidence of complications." In discussion of the findings the authors suggested that the increased complication rate might be a chance finding, or the result of "performance anxiety". An accompanying Editorial questioned some study design features: 1) constraints on the actual prayers performed and on the size and number of prayer groups, 2) the prespecified primary endpoint (30-day complication rate) and secondary endpoints (any major event; mortality) were clearly evaluated, but additional, hypothesis-generating analyses were not described (such as an analysis of whether patients could guess/detect which of the three groups they were assigned to), 3) approaching a patient to participate in a prayer study before a procedure could inadvertently alarm a patient, 4) "patient awareness that a study of prayer was ongoing might profoundly change the spiritual landscape being studied" and 5) "Even the assumption that standard clinical outcome measures are appropriate end points for studies of prayer must be carefully examined; for instance, many prayers for the sick contain the implicit objective of easing the passage of the spirit out of the body, an outcome which, by Society of Thoracic Surgeons definition, would be coded as death". The Editorial also questioned the authors' suggestion in the body of the paper that the higher complication rate was a chance finding, and asked if similar reservations would have been expressed if this prespecified primary endpoint had shown findings in favor of intercessory prayer.

Seattle Heart Failure model predicts life expectancy and effects of different therapies

 March 20, 2006: The Seattle Heart Failure Model (SHFM) was developed by top cardiologists and "is a calculator of projected survival at baseline and after interventions for patients with heart failure. SHFM is designed for use by health care providers knowledgeable in cardiac medicine. Patients should only use SHFM when their healthcare providers are present, such as at a doctor’s office." Heart failure has an annual mortality rate ranging from 5% to 75%. SHFM predicts survival using easily obtainable characteristics relating to clinical status, drug therapy (e.g., ACE inhibitors, beta blockers, angiotensin receptor blockers, diuretics, statins), medical devices (biventricular pacemakers, implantable cardio-defibrillators, biventricular implantable cardio-defibrillators, left ventricular assist devices), and laboratory measurements (e.g., cholesterol, hemoglobin). SHFM was derived from a cohort of over 1,000 heart failure patients and then validated (confirmed) in 5 separate cohorts totaling almost 10,000 heart failure patients. The model can be used to estimate the benefit of adding medications or devices to an individual patient's treatment - for example, the average heart failure patient treated with only digoxin and diuretics lives for 4 years; if an ACE inhibitor, beta blocker and an aldosterone blocker are included in the therapy the average patient lives for 6 1/2 years; if an implantable cardioverter defibrillator is also included the average patient lives for 9 1/2 years. A web-based SHFM application allows clinicians to plug in a patient's variables and receive a life expectancy prediction. It should be noted that this model shows that improved survival is associated with more extensive use of the available medications and devices used for treatment of heart failure, but does not establish that this is a causal relationship (although this causal relationship has been established in previous randomized clinical trials). The magnitude of this survival benefit in the total heart failure population can not be precisely determined, either from the clinical trials (that study a select population) or from the SHFM model (that is based on the cohort type of observational study).

Developmental drug torcetrapib raises HDL cholesterol but also raises blood pressure

 March 15, 2006: In reports at the American College of Cardiology annual meeting, torcetrapib, a Pfizer drug in development, was shown to raise HDL cholesterol and one report claimed a 2% reduction in heart attack or stroke for every 1 mg/dL increase in HDL cholesterol. Torcetrapib and atorvastatin (Lipitor) in combination increased the size of HDL and LDL lipid particles, which could reduce plaque buildup. Torcetrapib was found to be more effective when taken in the morning. One concern was a slight (2 mmHg) rise in systolic blood pressure noted with torcetrapib. Pfizer said that the rise in pressure was seen more in patients who had lower pressures before beginning torcetrapib. The company will continue to study blood pressure effects of the drug.

Drug-eluting stent better for coronary restenosis of bare-metal stent than radiation

March 15, 2006: Inserting a drug-eluting coronary stent (a tiny mesh tube coated with medication) into patients with in-stent restenosis of a bare-metal stent may be more effective than radiation therapy at preventing re-stenosis and cardiac events.

Fondaparinux (Arixtra) may reduce death and repeat heart attack in STEMI heart attacks  

March 15, 2006: Fondaparinux (Arixtra), an anticoagulant that inhibits Factor Xa, may reduce mortality and repeat heart attack in patients with STEMI heart attacks (heart attacks associated with the electrocardiographic finding of ST elevation) in the subgroup of patients who do not receive angioplasty. No increase in bleeding or strokes was seen. NOTE: In a separate study (NEJMed. 2006;354), 20,078 patients with acute coronary syndromes were randomized to fondaparinux or enoxaparin for a mean of six days. At 9 days the risk of death, heart attack or refractory ischemia was comparable with the two therapies, but major bleeding episodes were cut in half with fondaparinux.  On follow-up, fondaparinux was associated with significantly reduced mortality at 30 days (-16%) and 180 days (-10%).

Candesartan treatment of pre-hypertension reduces progression to hypertension, but effect largely disappears on stopping therapy

March 15, 2006: The TROPHY trial treated patients with "pre-hypertension" (blood pressures a few mmHg below the threshold for hypertension and averaging 134/84.5 mmHg in this study) with candesartan (Atacand) or placebo for 2 years, followed by placebo in all patients for a further 2 years. During the initial 2 years, candesartan reduced the risk of crossing the blood pressure threshold to meet the definition of "hypertension" (14% versus 40% of patients). However, by the end of the second 2 year period (while all patients were on placebo) hypertension was almost equally common regardless of the treatment during the initial 2 years (63% for placebo and 53% for candesartan).

Adding abciximab to clopidogrel reduces coronary events in acute coronary syndrome

March 15, 2006: In the 2,022-patient, placebo-controlled ISAR-REACT 2 trial in patients with non-ST-segment elevation acute coronary syndrome treated with coronary stents, adding abciximab (ReoPro), a GPIIb/IIIa inhibitor, to clopidogrel (Plavix) reduced coronary event rates by 25% in the subset of patients with raised troponin levels. Abciximab treatment did not increase the risk of bleeding or increase transfusion requirements.

Surgical trial to evaluate effect of closure of patent foramen ovale on migraine headaches

March 15, 2006: Anecdotal reports have suggested that surgical repair may reduce migraine headaches. In the 147-patient MIST trial in patients with severe migraine with aura who had patent foramen ovale (an open communication between the two upper chambers of the heart that normally closes at birth), patients were randomized to surgical repair of the foramen ovale or sham surgery. Neither patients nor those evaluating the migraine were aware of which procedure had been used. In this trial, the primary endpoint (elimination of migraine attacks) did not differ between the two groups. In a preliminary analysis, the authors reported that 42% of patients receiving surgical repair had at least a 50% reduction in the number of days with headache in the 3 months following surgery (almost twice that with sham surgery), and had more reduction in the "Headache Burden" (change from 136 hours to 86 hours, 37% reduction) compared with the sham surgery group (change from 117 hours to 96 hours, 18% reduction). This trial does not establish the utility of the procedure as a treatment for coexisting migraine and patent foramen ovale.

High dose Crestor may cause regression of coronary atherosclerosis

March 14, 2006 (Revised March 22, 2006): In ASTEROID, an open-label, 507-patient, 2-year clinical trial of high dose (40 mg/day) rosuvastatin (Crestor), LDL "bad" cholesterol fell markedly (average of 130 to 61 mg/dL), HDL "good" cholesterol rose (average of 43 to 49 mg/dL), and coronary atherosclerosis appeared to regress (in 64%-78% of patients depending on the ultrasound atherosclerosis parameter measured). The ultrasound endpoints were properly pre-specified, and the ultrasound analysis was performed by observers blinded to whether a particular ultrasound test was a baseline or end-of-therapy test. Since this was an open-label trial without a control group, interpretations of effectiveness should be cautious. However, the magnitude of the changes in LDL-cholesterol and HDL-cholesterol was impressive. The trial was not large enough to allay existing safety concerns about Crestor in high dosage for long durations, or to evaluate effects on the risk of heart attacks or other cardiac events.

High dosage or frequent use of acetaminophen and non-selective NSAIDs may increase cardiovascular risk

March 14, 2006: A cohort observational study in women from the Nurses' Health Study suggests that frequent use (22 days/month or more) or high dosage (15 tablets per week or more) of acetaminophen and non-selective nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of major cardiovascular events. The study was large (70,971 women), of long duration (12 years follow-up), and well designed. Frequent use of NSAIDs (ibuprofen in 73% and naproxen in 14%) and acetaminophen was associated with increased cardiovascular risk (44% for NSAIDs and 35% for acetaminophen for the fully adjusted analysis). At the beginning of the study, the frequent users were at elevated cardiovascular risk (older, exercised less, more hypertensive, higher body mass index, and more cardiac risk factors) compared with less frequent users, and the analysis was adjusted for these differences in underlying risk.  Increased cardiovascular risks associated with frequent use of NSAIDs were 67%, 51% and 44% (for the three separate adjusted analyses - age-adjusted, all risk factors apart from history of hypertension, all risk factors including hypertension). Corresponding figures for acetaminophen were 72%, 41% and 35%. The increase in risk with NSAIDs (but not with acetaminophen) was much greater in cigarette smokers (possibly because platelet aggregation is increased with combined NSAIDs and smoking). The presence or absence of chronic inflammatory conditions did not materially affect the results. Results were similar with high dosage as well as frequent use, and for each of the three components of increased cardiovascular risk (coronary death, heart attack, and stroke). Only limited data were available for COX-2 inhibitors; in a preliminary analysis with limited follow-up, there was a significant age-adjusted 72% increase in risk for all COX-2 inhibitor doses combined; however, the risk was attenuated (47%) and not statistically significant after full adjustment; other studies have suggested that cardiovascular risk is increased at high dosage of COX-2 inhibitors. Lower dosage/frequency of NSAIDs and acetaminophen and aspirin use (any dosage/frequency) were not associated with increased cardiovascular risk. The authors correctly point out that "we cannot completely exclude residual confounding" and "The observational design of our study does not permit us to assign causality...".

Salt & water blood filter more effective than diuretics in severe heart failure  

March 13, 2006: In the UNLOAD trial to be reported at the American College of Cardiology 2006 Annual Meeting on March 14, a new device for blood filtration of salt and water was more effective than aggressive intravenous diuretics for removing excess salt and water and in reducing re-hospitalization rates in patients with "decompensated" heart failure with fluid overload. The trial randomized 200 patients to either diuretic or ultrafiltration therapy and followed them for 3 months.

No cardiovascular benefit with Vitamin B (folic acid, B6, B12) in two large trials

March 12, 2006: Increased homocysteine blood levels are associated with increased cardiovascular disease. However, two new studies of B vitamins (folic acid, B6, B12) reported in the New England Journal of Medicine (NEJM) showed that although the treatment reduced homocysteine levels by a quarter, no reduction in cardiovascular disease occurred. The NORVIT study in 3,749 patients with a previous heart attack had 4 treatment groups: 1) folic acid + B6 + B12, 2) folic acid + B12, 3) B6, and 4) placebo. The frequency of the primary endpoint (new heart attack, stroke, sudden coronary death) was similar with treatments 2, 3 and 4 and tended to be higher with treatment 1 (triple therapy). The HOPE-2 study compared triple therapy (folic acid + B6 + B12) and placebo in 5,522 patients. Again no reduction in the primary cardiovascular endpoint was found with vitamin B therapy and the risk of one of seven secondary endpoints (hospitalization for unstable angina) was increased by 24%. In subgroup analysis (which should always be interpreted cautiously) the risk of stroke was significantly reduced by 25%. Separately, manufacturers of B vitamins suggested that these results might not apply to Vitamin B therapy of longer duration in people who did not yet have established cardiovascular disease, but Dr. Yusuf of McMaster University and Dr. Lichtenstein of Tufts University have disputed this assessment. The results show an absence of benefit in people with significant underlying cardiovascular disease who receive B vitamin therapy (in dosage that effectively reduces homocysteine levels) for a period of 3-5 years. Some experts suggested that while the higher dose levels (particularly combination therapy) might increase cardiovascular risk, lower dosage might be beneficial. In an accompanying NEJM editorial, Dr. Loscalzo of Harvard suggested that using B vitamins to reduce homocysteine levels might cause other effects (e.g., atherosclerotic cell proliferation from folic acid-induced increase in thymidine, or methylation of DNA or arginine) that could counteract a beneficial effect. He suggested that alternative methods for reducing homocysteine levels might prove to be beneficial.

Adding Plavix to aspirin may increase risk in patients without established heart disease

March 12, 2006: A study in 15,603 patients reported in the New England Journal of Medicine (NEJM) suggests that adding clopidogrel (Plavix) to aspirin may help people with established cardiovascular disease but may be inadvisable (because of an increased risk of death and of dangerous internal bleeding) in people who are only at increased risk of developing cardiovascular disease (i.e., do not have established disease).

"Caffeine Gene" may (or may not) indicate increased risk of heart attack

March 8, 2006: A case-control observational study in a Costa Rica population published in the March 8 JAMA compared the risk of heart attack in those who metabolize caffeine rapidly (55% of population) and slowly (45% of population). For those with highest coffee intake (4 or more cups/day) both rapid and slow metabolizers had a significantly increased risk of heart attack (76% and 143% risk respectively) on analysis adjusted for only age, sex and area of residence. On fully adjusted analysis (i.e., adjusting for various other measured variables), only the slow metabolizers were at increased risk (64% increase). The authors did a subgroup analysis dividing the subjects into those above and below the median age (59 years) and found a significant effect of the slow metabolism gene only in the younger group. They then did a further subgroup analysis of subjects below 50 years of age and 50 years or older and found a significant increase in risk in this younger group for both rapid and slow metabolizers. The underlying hypothesis (that slow metabolizers have higher caffeine levels and consequently are at increased cardiac risk, especially at younger ages) is intriguing but is not established by this study. As regular readers of this page will note, we frequently point out that a finding in an observational study (even if properly designed and analyzed) does not establish a cause-and-effect relationship, and that results should be interpreted with particular caution if they are derived from subgroups, if the results of the unadjusted and adjusted analyses differ, and if the odds ratio is less than 2 (i.e., less than100% increase) - see Observational Studies (Richard Platt, Harvard). In the JAMA study, other concerns include coffee intake assessed only by dietary history, no analysis of baseline comparability of slow and rapid caffeine metabolizers, the substantial percentage of participants excluded from analysis, and the extent to which results may be extended to non-Costa Rican populations. Additional studies could be done for clarification, for example evaluating the magnitude of difference in caffeine levels in slow and rapid metabolizers at different caffeine intakes and, since no generally available test is available for the “caffeine gene”, measuring blood caffeine or heart rate in response to a caffeine dose as surrogate measures. It is disturbing that of over 400 media references to the article found on a Google search at 10 PM EST on March 8 (the day of publication) none appeared to recommend appropriate caution in interpreting the results.

New analysis of Celebrex cardiovascular safety adds little 

March 1, 2006: A new meta-analysis evaluating the cardiovascular safety of celecoxib (Celebrex) and published by a New Zealand group contributes little of value and the conclusions are overstated. As with other COX-2 drugs and other NSAIDs, currently available data do not exclude the possibility of cardiovascular toxicity with celecoxib, particularly for dosage higher than 200 mg/day and for longer durations of therapy. As with other meta-analyses of celecoxib clinical trials, this report suggests the possibility of an increased risk of myocardial infarction (heart attack) with celecoxib. However, design and methodology problems make the study difficult to evaluate, and the interpretations and conclusions are misleading. Definitive conclusions on the cardiovascular safety of celecoxib must await the results of the PRECISION study in 20,000 high risk patients which will begin later this year.

Many heart attacks go undetected

February 15, 2006: A Netherlands study of 4,000 people suggested that heart attacks are undetected in about 1/3 of men and over 1/2 of women because patients do not recognize or dismiss the symptoms. The study included patients who had not had a heart attack on entry into the study. All had an examination and an electrocardiogram (ECG) and were then followed up for a median time of more than 6 years and received at least one repeat ECG to assess undiagnosed heart attacks.  Chest pain was the most common symptom but a heart attack sometimes presented with shoulder pain or as what was thought to be a severe flu that was taking a long time to recover from.

Coronary Angiography Underdiagnoses Coronary Disease in Women

February 7, 2006: Coronary angiography does not detect coronary disease in about one in every six women with chest pain. These women have coronary microvascular syndrome and their arterial disease leads to general narrowing of the arteries rather than the local blockages commonly seen on angiography. The syndrome can be detected using nuclear SPECT (single-photon emission compute tomography) tests, or provocative coronary testing (in which an adenosine injection mimics the effects of exercising on a treadmill). This study provides further evidence that heart disease in women and men is different (other recent work has shown that women with heart attacks are more likely than men to present with severe fatigue, perspiration or atypical pain locations).

Many Don't Know a Heart Attack When They Have One

Jan. 25, 2006: People who have risk factors for coronary disease and are in the coronary event age group should seek prompt medical evaluation or call 911 for persistent symptoms that seem unusual. Although most Americans are aware that chest pain can be an ominous sign, most don't realize that heart attack may present as discomfort in the neck, back or jaw. or as nausea. An online survey of 2.515 adults (including 1,370 who had a heart attack of had a friend or relative with a heart attack) was released in conjunction with "Act in Time to Heart Attack Signs", a National Heart, Lung, and Blood Institute public awareness campaign. Only 35% of those who had been diagnosed with a heart attack or who had a friend/relative diagnosed said calling 911 was their first step. Many patients waited two or more hours after symptoms started before seeking medical attention because they were unaware they were having a heart attack. Nearly half of all heart attack deaths occur before the patient reaches the hospital. Only 46% of those diagnosed with a heart attack or who had a friend or family member diagnosed said they had experienced chest discomfort.

High Dose Lipitor did not Slow Progression of Calcified Atherosclerosis over 1 Year

Jan. 17, 2006: Recent clinical trials have suggested that intensive versus standard lipid-lowering therapy provides for additional benefit. A large double blind study using electron-beam CT scans to measure progression of coronary artery calcification showed no difference between high and low dose atorvastatin (Lipitor) over a 12-month period, despite greater reduction in LDL cholesterol with the high dose.

Cardiovascular Risk Factors Undertreated in Heart Patients Worldwide

Jan. 17, 2006: Undertreatment of risk factors for patients with a history of cardiovascular disease appears to be an American and worldwide phenomenon. More than half of patients worldwide with diagnosed hypertension still had elevated blood pressure according to a Jan. 11, 2006 JAMA article. Of the more than 31,000 patients with a history of diabetes, only 86% were receiving at least one diabetes medication.

5. NEUROLOGICAL/PSYCHOLOGICAL

Depressed patients may need both antidepressants and treatment for insomnia

May 2, 2007: Patients with major depression often have insomnia and this may need to be treated also. Sleep aids do appear to work in depressed patients. "Treating the insomnia pharmacologically or behaviorally can improve outcomes in depression," said Christopher L. Drake, Ph.D., of the Henry Ford Hospital Sleep Disorders and Research Center in Detroit. In a 2006 clinical study, giving the sleep aid eszopiclone (Lunesta) in combination with fluoxetine (Prozac) was associated with an antidepressant response about two weeks earlier than patients treated with fluoxetine alone.

Happy countries may have less high blood pressure

March 3, 2007: In a cross-country survey of about 15,000 randomly sampled individuals from 16 European countries, people were asked about life satisfaction and high blood pressure problems. There was a trend (statistically significant on 1-tailed but not 2-tailed testing of unadjusted data) for countries with less high blood pressure problems to have greater life satisfaction. The best quartile of countries (less high blood pressure & more life satisfaction) were Ireland, Denmark, the Netherlands and Sweden), followed by the second quartile (Spain, France, Luxemburg, United Kingdom), the third quartile (Austria, Italy, Belgium and Greece) and the fourth (worst) quartile (East Germany, West Germany, Portugal, and Finland). Although the statistics are not compelling, the survey does suggest the value of more definitive evaluation of the relationship between blood pressure and happiness.

Randomized trial suggests that 3 months of psychoanalysis helps patients with panic disorder

February 6, 2007: In the era of evidence-based medicine, psychoanalysis has become increasingly marginalized. However, a new 49-patient, 3-month randomized trial has found that significantly more panic disorder patients receiving psychoanalytic psychotherapy improved (73%) than patients receiving relaxation training (39%). The primary outcome measure was the Panic Disorder Severity Scale, rated by blinded independent evaluators.

Lessen burden of bereavement by spending more time with family members and giving them a bereavement brochure

February 4, 2007:  Providing relatives of patients who are dying in the ICU with a brochure on bereavement and using a proactive communication strategy that includes longer conferences and more time for family members to talk may lessen the burden of bereavement.

Cognitive training helps mental function in the elderly

December 20, 2006: Ten sessions of cognitive training (memory, reasoning, mental processing speed) given to elderly people (average age 74) was associated with significantly better performance in activities of daily living (e.g., reacting to a road sign, looking up a number in a telephone book or checking the ingredients on a medicine bottle). The benefit lasted for at least 5 years after the sessions. Almost 3,000 elderly people from senior housing, community centers, and hospitals and clinics were randomized to different treatments; those performing the mental testing were unaware of the treatment assignments.

Observational study associates higher vegetable consumption with better cognitive function in elderly

October 24, 2006: A prospective cohort observational study in over 3,000 participants 65 years or older showed an association between higher self-reported vegetable dietary consumption and cognitive function (assessed by immediate memory, delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test). A multivariate analysis was used adjusted for age, sex, race, education, cardiovascular conditions and risk factors. Observational studies cannot establish causality but can suggest the need for further study. Older people who started eating more than two cups a day of vegetables showed a significant delay in mental decline; accordingly, it should be possible to test the vegetable/cognition relationship in a controlled study in which elderly subjects are randomly assigned to increased vegetable consumption or not.

FDA approves Aricept for severe Alzheimer's Disease

October 16, 2006: FDA has approved Aricept (donepezil) for the treatment of severe dementia in patients with Alzheimer's Disease. It now becomes the first product approved for all degrees of severity. Aricept was approved for mild to moderate Alzheimer's ten years ago. The additional approval for severe Alzheimer's is based on over 500 patients in two randomized, placebo-controlled, 24-week clinical trials in Sweden and Japan that showed superiority to placebo in cognitive functions (e.g., memory, language, orientation, attention) and in overall functioning (see our April 5, 2006 review). Alzheimer's affects 4.5 million Americans.

New Analysis suggests that paroxetine (Paxil) may increase risk of suicide attempts in young adults

May 11, 2006: GlaxoSmithKline (GSK) has conducted a new analysis of suicidality in adults with depression and other psychiatric disorders and has concluded "..young adults, especially those with MDD [Major Depressive Disorder] may be at increased risk for suicidal behavior during treatment with paroxetine [Paxil]" but "It is difficult to conclude a causal relationship between paroxetine and suicidality in adults.." Detailed information is available on its website. The analysis found that 11 of 3,455 people who were taking Paxil for depression reported an attempted suicide, compared with 1 in 1,978 taking placebo in the trials. Most were among adults ages 18 to 30. Overall, the analysis found no increased risk of suicidal behavior in adults over 30.

Naltrexone (Revia) and combined behavioral intervention are effective in alcohol dependence

May 3, 2006: Alcohol dependence (DSM IV criteria) is alcohol use with clinically significant impairment as shown by at least three of the following within any one-year period: tolerance; withdrawal; taken in greater amounts or over longer time course than intended; desire or unsuccessful attempts to cut down or control use; great deal of time spent obtaining, using, or recovering from use; social, occupational, or recreational activities given up or reduced; continued use despite knowledge of physical or psychological sequelae. Treatment of alcohol dependence was tested in the 1383-patient, 9-treatment group, 16-week, randomized COMBINE clinical trial. After showing 3 days of abstinence, patients were randomized to various combinations of drug therapy (naltrexone or acamprosate), placebo, and combined behavioral intervention. Reduction in drinking was seen in all treatment groups, but reduction was greater in patients receiving naltrexone (Revia), combined behavioral intervention, or both along with medical management; acamprosate (Campral) was not more effective than placebo.

A stroke in certain sections of the brain can also damage the heart

April 26, 2006: Damage to heart muscle or even a clinical heart attack has long been known to be a possible consequence of a stroke. A new study in 738 patients with acute ischemic stroke (a stroke caused by blockage in an artery that supplies blood to the brain, resulting in a deficiency in blood flow) identified 50 patients with heart damage (as measured by increased levels of cardiac troponin, a protein released by the heart). Compared with 50 randomly selected age- and sex-matched ischemic stroke controls without heart damage, the strokes in the patients with heart damage occurred most frequently when certain regions of the brain were affected by the stroke, including the right insula (an oval region of the cerebral cortex located in the sylvian fissure in the language area of the brain) and the right inferior parietal lobule (the lower part of the parietal lobe of the cerebral cortex located behind the frontal lobe).

Observational study suggests Mediterranean Diet may reduce risk of Alzheimer's disease

April 19, 2006: An observational study suggests that higher adherence to the Mediterranean Diet is associated with reduced risk of Alzheimer's disease. Observational studies cannot establish causal relationships, but can suggest the need for further study. The study included 2,258 New York subjects without dementia at baseline who were followed for an average of 4 years (range 0.2-13.9 years). Alzheimer's disease developed in 12% of subjects. Higher adherence to the Mediterranean Diet (0-9 scale) was significantly (p=0.015) associated with less risk of Alzheimer's disease, after adjustment for confounding variables (cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index). Compared to the least Mediterranean Diet adherent third of subjects (lowest tertile), subjects in the middle tertile had about 20% less risk of developing Alzheimer's disease, while those most adherent to the Mediterranean Diet (highest tertile) had about 40% less risk of developing Alzheimer's disease, with a significant dose-response relationship (p = 0.007). In other studies, the Mediterranean diet has been associated with lower risk for cardiovascular disease, several forms of cancer, and overall mortality. The Mediterranean Diet is inspired by the traditional dietary patterns of the Mediterranean basin (particularly Southern Italy, Greece, Portugal and Spain). These diets are characterized by rich full-flavored foods with high consumption of fruit, vegetables, bread, other cereals, olive oil, and fish; low saturated fat; high monounsaturated fat and fiber; and moderate consumption of red wine.

Brain Training for the Aging Brain

April 11, 2006: Quizzes, memory tests and arithmetic drills to help keep seniors sharp are very popular in Japan. PlayStation Portables (PSP) has the "Brain Trainer" based on work by Ryuta Kawashima, a professor of brain science at Tohoku University. To exercise your brain, try these tests: Picture Memory, List Recall, Word Memory.

Observational study suggests early removal of ovaries may be associated with increased risk of Alzheimer's

April 7, 2006: A Mayo Clinic observational study reported at the American Academy of Neurology meeting found a 42% increased risk of Alzheimer's disease in women who had unilateral or bilateral oophorectomy (surgical removal of the ovaries). In the subgroup with oopherectomy before age 38 the risk was higher (23 of 404 women). The study used a cohort design and compared a group of 1,466 women who had an oophorectomy with 1,421 matched women who did not have an oophorectomy. Differences between groups did not emerge until the women were in their 80s. This study has not yet been published and requires confirmation. An observational study can not establish a causal relationship. However, it may be one factor to consider for women considering elective oophorectomy.

Study shows donepezil (Aricept) improves cognition and activities of daily living in severe Alzheimer's

April 5, 2006: Donepezil (Aricept) is presently indicated in the US for mild to moderate Alzheimer's disease. A new double-blind, placebo-controlled, 6 month study in 248 patients with severe Alzheimer's disease and living in assisted care nursing homes showed significant improvement with donepezil in cognition (mental processes such as awareness, perception, reasoning, and judgment) and activities of daily living (using modified ADCS-ADL-severe scores). More donepezil patients discontinued treatment because of adverse events (16% versus 7% for placebo). Writing in the April 1-7 Lancet the authors conclude "Donepezil improves cognition and preserves function in individuals with severe Alzheimer's disease who live in nursing homes".

MRI study shows that highly intelligent children have more dynamically changing brains and reach peak thickness of the cerebral cortex at a later age

March 30, 2006: A study in 307 children in whom the thickness of the cerebral cortex was measured in a series of MRI brain scans showed that highly intelligent children have more dynamically changing brains and reach a peak cortical thickness later (around 13 years old) than children of average intelligence (around 7-8 years old).

Open-label studies suggest that adding or switching antidepressants may help citalopram (Celexa) non-responders

March 23, 2006: Two reports from the STAR*D Study Team describe the effects of switching or adding antidepressant therapy to depressed patients who do not respond to (or cannot tolerate) the selective serotonin-reuptake inhibitor (SSRI) citalopram (Celexa). The primary outcome in both studies was symptom remission, defined as a score of 7 or less on the HRSD-17 as assessed by raters blinded to the treatment given. In one open-label study, depressed patients who did not respond by symptom remission on citalopram were randomized to be switched to one of three other antidepressants for up to 14 weeks. The primary outcome was comparable with all three treatments, bupropion-SR (21%), sertraline (18%) and venlafaxine-XR (25%). The authors point out that "without a placebo group, we cannot be certain that any of the treatments was specifically effective (i.e., the results were due to the pharmacological effects of the medication)". Another open-label study tested the effect of adding a second antidepressant drug in depressed patients who did not respond to citalopram after an average of 12 weeks therapy. Patients were randomly assigned to add bupropion-SR or buspirone to their citalopram treatment. The primary outcome was comparable with bupropion-SR and buspirone (30% in each group). Bupropion-SR had a significantly lower dropout rate because of intolerance than buspirone (13% versus 21%). The authors point out that "the lack of a placebo control does not allow us to exclude spontaneous remission, the non-specific effects of treatment, or the extended use of citalopram alone as the likely explanation for the present findings". Thus these reports suggest but do not establish that adding or switching antidepressants in citalopram non-responders causes remission in about 20-30% of patients.

Stimulants may cause hallucinations in 2-5% of children taking these drugs

March 23, 2006: Stimulants such as methylphenidate (Ritalin and Concerta), atomoxetine (Strattera), and Adderall (a combination of mixed salts of amphetamine) may cause hallucinations (usually of insects, snakes or worms) in 2-5% of children who take the drugs. An FDA advisory committee recommended that a warning (rather than a "black box") regarding hallucinations as well as recently described cardiovascular side effects should be included in the labels for the drugs, and FDA suggested that it would follow this recommendation.

Inaccuracies and stigmatizing language are common in neurology coverage by US newspapers

March 21, 2006: An article in the March issue of Mayo Clinic Proceedings reports that inaccuracies such as medical errors or exaggerations (20%) and stigmatizing language (15%) were common in 1,203 stories on neurologic conditions reported in 9 newspapers with circulation greater than 200,000 during 2003. Excluding wire stories, the average for stigmatizing language among locally produced newspaper stories was higher (21%) than for the New York Times. The most common subjects of the stories were Alzheimer’s disease (33% of stories), Parkinson’s disease (15%), cerebrovascular disease (13%), and multiple sclerosis (11%). Common conditions such as migraine headaches (3%) and head trauma (2%) received little coverage. An accompanying Editorial pointed out that adults obtain much of their health information from mass media and that more research is needed in this area.

Study suggests that donepezil (Aricept) could be associated with increased death rate

March 17, 2006: Donezepil (Aricept) is approved in the US for treatment of mild and moderate Alzheimer’s disease. A recent 2-year clinical trial in a different disease (vascular dementia) randomized patients in a 2:1 ratio to Aricept (648 patients) or placebo (326 patients). Eleven deaths occurred in the Aricept patients (1.7%) versus no deaths in the placebo patients (0%). The sponsoring company, Eisai, commented that the absence of deaths in the placebo group was different from that seen in early vascular dementia trials (in which about 2% of the placebo patients died). The 2-year trial demonstrated significant improvement with Aricept in tests of cognitive function (tests measuring memory or other mental functions) but did not show significant improvement in global function (an overall test of ability to function in daily life). An increase in the death rate versus placebo was found previously with another cholinesterase inhibitor, galantamine (Razadyne, formerly Reminyl), in trials in elderly subjects with mild cognitive impairment - 13 deaths in 1,026 Razadyne subjects (1.3%), versus 1 death in 1,022 placebo subjects (0.1%). Eisai is discussing the new Aricept findings with the FDA which commented that Aricept “remains a safe option”. Other experts commented that drugs of this class may cause adverse cardiovascular effects and that Aricept use should be restricted to diseases currently US-approved for Aricept use  (mild and moderate Alzheimer’s disease).

Maintenance therapy with antidepressant drug helps after drug-assisted recovery from major depression in old age

March 16, 2006: In a double-blind study, 116 elderly patients whose major depression had responded to combined paroxetine (Paxil) and psychotherapy were randomly assigned to one of four treatments: 1) Paxil + psychotherapy, 2) Paxil + clinical-management sessions, 3) placebo + psychotherapy, 2) placebo + clinical-management sessions. Major depression recurred within 2 years significantly less frequently in the Paxil groups (35% & 37%) than in the placebo groups (68% and 58%). The effect of Paxil was greater in those with fewer and less severe coexisting medical conditions (such as hypertension or heart disease). Maintenance psychotherapy did not reduce the risk of recurrent depression. This study demonstrated that continuing Paxil therapy in patients whose previous depression had responded to Paxil substantially reduces the risk of future episodes of depression.

Withdrawn MS drug might return to market

March 9, 2006: The multiple sclerosis (MS) drug, natalizumab (Tysabri), might return to the market. An FDA Advisory Committee unanimously recommended that sales may resume. However, patients receiving the drug must be treated only at specially designated sites, must have the relapsing form of MS, must be taking no other MS medicines, and must be enrolled in a mandatory registry to track a rare brain infection, progressive multifocal leukoencephalopathy (PML), that may occur in about one in 1,000 patients receiving the drug. FDA usually follows its Advisory Committee recommendations. Recently published studies in the New England Journal of Medicine (see below) found that Tysabri was highly effective in relapsing MS. It may work by blocking the passage of immune cells from the blood to the brain, where the cells can damage nerves. The magnitude of the risk of PML (caused by activation of a common virus that usually lies dormant) with Tysabri is not precisely known at this time because only a few cases have occurred. PML risk may be substantially different from the current estimate of 1 in 1,000, and may be higher for patients who have weak immune systems.

Restraining good arm may give some recovery of affected arm after stroke

March 6, 2006: A small, preliminary study suggests that as long as five years after suffering a stroke, people may regain some limited function in a weak arm post-stroke when their strong arm is restrained during 10 days of intensive therapy to the weak arm. Some patients retained these benefits for two years. A hand splint or sling was used to immobilize the patient's good arm while intensive daily physical therapy was given to strengthen the weak one. The concept is that the "use it or lose it" therapy may rewire nerve communications between the brain and the affected arm. In the study, 21 people with mild to moderate impairment in their arms about five years after surviving a stroke received this therapy and results were compared with those in a group of 20 similar stroke survivors receiving a general exercise program.

Discontinued MS drug effective in new publications

March 2, 2006: The multiple sclerosis (MS) drug, natalizumab, was shown to be highly effective in relapsing MS in three clinical trials reported in the current New England Journal of Medicine. Natalizumab (Tysabri) was removed from the market a year ago because of 3 cases of  progressive multifocal leukoencephalopathy (PML). FDA has recently allowed resumption of clinical trials on the drug for patients who had previously received it.

The optimistic live longer

Feb. 27, 2006: More optimistic men have half the cardiovascular death rate of the less optimistic according to a study of 545 Dutch men aged 64-84 published in the Archives of Internal Medicine. This finding supports previous research that being optimistic is associated with better overall physical health and lowers mortality from all causes. Participants responded to statements such as "I do not look forward to what lies ahead for me in the years to come" and "My days seem to be passing by slowly," or "I am still full of plans." The lead researcher said "Optimism can be estimated easily and is stable over long periods".  More optimistic scores were associated with being younger, being better educated, living with others, having better health, and doing more physical activity. It has not been shown if optimism improves health or is merely associated with improved health.

FDA Advisers Recommend Black Box Warning for ADHD Drugs

Feb. 10, 2006: An FDA Advisory Committee has suggested a black-box warning on the risk of heart attacks, stroke, and sudden death in patients receiving drugs for attention-deficit/hyperactivity - e.g., methylphenidate (Ritalin & Concerta) and amphetamine-dextroamphetamine (Adderall). FDA staffers had reported 54 serious cardiovascular events on the drugs (prescribed to about two million children and one million adults each month). The recommendation passed by a 1-vote margin in a contentious meeting in which some panel members backed a conservative strategy of merely requiring more clinical studies to clarify the findings. The New York Times reported that, in a subsequent news conference, the FDA Director of the Division of Psychiatry Products stated "We think the labeling right now is adequate". All 15 members of the Advisory Committee agreed that parents of children on ADHD drugs who have preexisting heart conditions should consult their doctors. Many workers in the field believe that ADHD drugs are overused in children and underused in adults. However, any increased cardiovascular risk could argue against increased use in adults.

Large Twin Study Confirms Heritability of Alzheimer's

Feb. 8, 2006: A large twin study has confirmed the conclusions of other recent studies that genetics is important in causing Alzheimer's disease (about 60-80% of cases) as well as the age at onset. The Swedish Twin Registry identified 392 pairs 65 years or over in whom one or both had Alzheimer's. Genetics appeared to play a role in 58% of cases (95% confidence interval=19%-87%). However, when considering only twins who did not share environmental influences, genetics appeared to account for 79% of cases (95% CI=67%-88%). The genetic influence held for unlike-sex twins suggesting that the same genes cause Alzheimer's in men and women. It may be particularly advisable for people with Alzheimer's disease in the family to practice a lifestyle that minimizes the risk of Alzheimer's (e.g., regular exercise for both body and mind).

Exercise Fends Off Dementia in Older Adults

Jan. 17, 2006: A prospective cohort study suggested that even moderate exercise (at least 15 minutes per day three times per week or more) can help older people significantly delay or reduce their risks of developing Alzheimer's disease or other forms of dementia.

ECT and Drugs Still Best Options For Depression

Jan. 17, 2006: According to a recent large-scale, population-based study from Scotland in The Lancet: 1) Modern electroconvulsive therapy is safe and is the most effective treatment for depression, especially if it presents with psychotic symptoms, such as delusions and hallucinations., 2) Antidepressants drugs are not associated with an increased risk of suicide. 3) Psychotherapies are recommended as treatment of milder depression or as an adjunct to antidepressant drugs in more severe illness. 4) While transcranial magnetic stimulation appears to be an intriguing research tool, there is insufficient evidence currently to support its therapeutic use. In an accompanying editorial, The Lancet editors wrote that "over 50% of people with depression will become functionally impaired because of their illness. Sadly, for many people a diagnosis of depression is made worse by the social stigma that still clings to all mental-health diagnoses, by difficulties in accessing treatment options, and by confusion about which treatments work and which may make their problems worse."

6. OTHER CHRONIC DISEASE

Older oral hypoglycemic (metformin) gives equivalent blood sugar control in Type II diabetes, lowers LDL cholesterol, and does not increase weight 

June 29, 2007: In a review article, oral diabetes agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and -glucosidase inhibitors) were compared for the treatment of adults with type 2 diabetes mellitus. Evidence from clinical trials was inconclusive on major clinical end points, such as cardiovascular mortality. Most oral agents (thiazolidinediones, metformin, and repaglinide) improved glycemic control to the same degree as sulfonylureas (absolute decrease in hemoglobin A1c level of about 1 percentage point. Nateglinide and -glucosidase inhibitors may have slightly weaker effects, on the basis of indirect comparisons of placebo-controlled trials. Thiazolidinediones were the only class that had a beneficial effect on high-density lipoprotein cholesterol levels (mean relative increase, 0.08 to 0.13 mmol/L [3 to 5 mg/dL]) but a harmful effect on low-density lipoprotein (LDL) cholesterol levels (mean relative increase, 0.26 mmol/L [10 mg/dL]) compared with other oral agents. Metformin decreased LDL cholesterol levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents had no obvious effects on LDL cholesterol levels. Most agents other than metformin increased body weight by 1 to 5 kg. Sulfonylureas and repaglinide were associated with greater risk for hypoglycemia, thiazolidinediones with greater risk for heart failure, and metformin with greater risk for gastrointestinal problems compared with other oral agents. Lactic acidosis was no more common in metformin recipients without comorbid conditions than in recipients of other oral diabetes agents.

Second-hand smoke increases levels of tobacco-specific carcinogens 

June 29, 2007: Non-smokers who work in bars and restaurants where smoking was permitted had higher levels of a tobacco-specific carcinogen
than those who worked where the air wasn't tainted. They were six times more likely (P=0.005) to have three detectable metabolites of the tobacco-specific NNAL known chemically as 4-(methylnitrosamino)-1-(3-pryridyl)-1-butanol, in their urine, and that their mean levels were significantly higher (p<0.001).
than people with similar jobs in smoke-free establishments. The presence of the compound, known as NNAL, is specific to tobacco use or exposure.

Controlled study shows low-dose morphine can improve refractory cough 

February 16, 2007: A 4-week, double-blind crossover study in 27 patients with chronic, persistent, refractory cough for greater than three months without significant lung disease showed a rapid 40% improvement in cough with morphine (oral, slow-release, low-dose - 5 mg twice daily) compared with placebo (p<0.01).

Observational study suggests that proton pump inhibitors increase hip fracture risk 

December 27, 2006: A nested case-control study in the UK compared proton pump inhibitor users and nonusers of acid suppression drugs who were older than 50 years. There was a statistically significant 44% increased risk of hip fracture with more than 1 year of proton pump inhibitor therapy, and the risk increased as duration increased (59% increase after 4 years). Observational studies cannot establish causality but can suggest the need for further study.

Chronic constipation associated with higher mortality 

November 1, 2006: A Mayo Clinic prospective observational study in almost 4,000 people and presented at the American College of Gastroenterology Annual Meeting reported that about 15% of people had chronic constipation and that their adjusted 10-year mortality risk was about 20% greater than people without chronic constipation. The authors suggested that the constipation was probably a marker of increased mortality risk rather than a cause. Observational studies cannot establish causality but can suggest the need for further study.

Physically active people have less macular degeneration 

November 1, 2006: A prospective observational study in almost 4,000 people found that the adjusted risk of exudative age-related macular degeneration over 15 years was only one-third as likely in those who walked three times or more a week compared to sedentary people. This suggests yet one more benefit of regular physical exercise. Observational studies cannot establish causality but can suggest the need for further study.

NIH clinical trial will compare $20-100/month drug with $2000/month drug in macular degeneration 

October 6, 2006: An editorial in the New England Journal of Medicine suggests that bevacizumab (Avastin), a very similar but much less expensive drug, might be as effective as ranibizumab (Lucentis) in treating macular degeneration, the leading cause of blindness in the elderly. However, controlled trials in macular degeneration have not been done with bevacizumab, so that equal efficacy cannot be assumed. Accordingly, the NIH has announced that it will sponsor a 1200-patient clinical trial comparing the two drugs in macular degeneration. The study will take 4 years and cost $16 million. Monthly costs for treatment are about $2,000 per month for Lucentis and about $20-100 for Avastin.

Report claims Norvasc reduces risk of diabetes 

September 6, 2006: A 20,000 patient study presented on September 6 at the World Congress of Cardiology meeting in Spain was reported as showing that amlodipine (Norvasc) "reduced the risk of developing diabetes by 34%" compared with the beta-blocker atenolol. However, until additional data on this study are available, this conclusion should be interpreted with caution. Patients on Norvasc also took Coversyl (a member of the class of ACE inhibitors that have been shown to reduce the risk of diabetes) and it is not clear if the patients on atenolol also took Coversyl. In addition, beta blockers are known to increase blood glucose, and in one September 6 report beta-blockers were reported to increase the risk of developing diabetes (by 32% in older women, and 20% in men).

Observational study suggests that NSAIDs reduce BPH risk (symptoms, prostate size, urinary flow & PSA) 

August 30, 2006: An age-adjusted analysis of an observational (population-based cohort) study in 2,447 men found that daily NSAID use was associated with a 27% reduction in the risk of moderate/severe symptoms related to Benign Prostatic Hyperplasia (BPH). In a random subset of 634 men, daily NSAID use was associated with higher urinary flow rate, smaller prostate volume, and lower PSA level. Observational studies cannot establish causality but can suggest the need for further study.

Review supports routine use of antibiotics in COPD exacerbations 

April 20, 2006:  Despite their widespread use, the value of antibiotics in exacerbations (acute episodes of worsened disease) of chronic obstructive pulmonary disease (COPD) remains controversial. Eleven trials with 917 patients with moderate to severe COPD were included in this review. Use of antibiotics (regardless of the type) reduced the risk of patient deaths by 77% and the risk of the patient not responding to medical intervention by 53%. In addition, the chances of sputum remaining colored (green/yellow) were reduced by 44%. As expected with antibiotic use there was an increased risk of diarrhea. This review supports using antibiotics for patients with COPD exacerbations who are moderately or severely ill with increased cough and colored sputum.

High dose Lipitor may improve kidney function in coronary disease patients 

March 13, 2006:  TNT was a large double-blind trial comparing low dose (10 mg/day) and high dose (80 mg/day) atorvastatin (Lipitor) in coronary heart disease patients with mild to moderately raised cholesterol. The beneficial results with the high dose for the primary endpoint (heart attack, cardiac arrest, stroke) have been previously reported. A just-released additional analysis of the non-pre-specified endpoint of kidney function (as assessed by eGFR) showed  improvement of kidney function at the high dose (half of those with abnormal kidney function at the beginning of the study had normal kidney function at the end of the study). Since these encouraging findings come from an analysis that was not pre-specified in the study design, they should be interpreted with caution.

Clinical trial result causes patients to say "no" to lung surgery 

March 3, 2006:  Medicare has begun requiring its beneficiaries to participate in controlled clinical trials to measure the effectiveness of some treatments. One such trial evaluated lung volume reduction surgery for emphysema. It had been touted as a life-saving procedure but a 1,281-patient, 2-year trial that compared the results in groups with or without surgery showed disappointing results. Overall, the operative mortality was 8% and patients in the study lived no longer, whether or not they had the surgery. Patient subset analysis (which should be interpreted with caution) suggested that certain subsets of surgery patients outlived similarly ill non-surgery patients, or found it easier to walk or breathe. Although lung surgeons still recommend the treatment, referring physicians and patients made aware of the trial results have been opting for non-surgical treatment. Medicare is now enrolling patients in other trials or registries, examining the effectiveness of a wide range of expensive and popular treatments and procedures — new cancer drugs, defibrillators, PET scans to detect early Alzheimer's disease and. possibly, home oxygen therapy for emphysema.

Pfizer Wins FDA Approval for Inhaled Form of Insulin 

January 27, 2006: FDA has given marketing approval for Exubera, an inhaled form of insulin to be sold by Pfizer. Exubera could offer Type 1 (insulin-dependent) diabetics more convenience and less pain, and could prompt Type 2 diabetics who have failed oral therapy for diabetes to switch to insulin so as to control their blood sugar and reduce diabetic complications. Exubera therapy may sometimes have to be supplemented by injectable insulin, and finger pricks for blood sugar will still be needed. The inhaler is bulky compared to ordinary insulin syringes and may be less convenient for diabetics to carry around with them. It is not approved for children and is not recommended in those with underlying lung disease such as asthma, bronchitis or emphysema, or in smokers or those who quit smoking less than 6 months ago. People who use Exubera should have their lung function checked before they start on the drug and every six to 12 months afterwards. Exubera should be available by the middle of 2006.

Older Women Report High Rate of Fecal Incontinence 

January 27, 2006: Older women have a high rate of fecal incontinence according to a University of Washington study. Advanced age, obesity, history of vaginal operative deliveries, multiple childbirths, urinary incontinence, diabetes and major depression are associated with increased risk. In a postal survey of 3,536 women with a 64% response rate, the fecal incontinence prevalence was 7.2% overall, 12.5% for ages 60 to 69 said, 10.8% for ages 70 to 79, and 15% for ages 80 to 90. Fecal incontinence among younger women is likely to be due to childbirth, and in older women to age-related weakening of muscles as well as comorbid conditions. Urinary incontinence was highly associated with fecal incontinence (70%). Because fecal incontinence is embarrassing to discuss, specific questioning of patients may be helpful. However, the low (64%) response rate suggests that the true prevalence may be lower, since patients without fecal incontinence could be less likely to respond to the survey.

Gene Confers Increased Diabetes Risk - Diagnostic Test to be Developed 

January 16, 2006: A gene variant carried by 38% of Americans increases the risk of diabetes according to Decode Genetics, a company that looks for medically relevant genes in the Iceland population.  The increased risk of diabetes was found in the Iceland study and then confirmed in Danish and American populations. A diagnostic test is being developed to identify people who carry the variant gene, and perhaps give them an additional incentive to stay thin and exercise. One copy of the gene increases risk 45% and two copies in the same person increase risk 141%. The "population-attributable risk" (the % of cases attributable to the new gene) is 21 percent. The gene, designated TCF7L2, is one that controls the activity of other genes. Its role may include setting the level of a hormone that acts along with insulin to control blood sugar levels. The scientists don't yet know if the variant gene is more common in African-Americans, Latinos, American Indians and Asian-Americans (in whom diabetes is more common). New treatments in the future might target the biochemical pathways affected by the variant gene.

7. COMPUTERS IN MEDICINE

As implemented, Electronic Health Records were not associated with better quality ambulatory care

July 12, 2007: The authors of an article in the Archives of Internal Medicine assessed the association between use of Electronic Health records (EHR), as implemented, and the quality of ambulatory care in a nationally representative survey. EHR were used in 18% (95% confidence interval [CI], 15%-22%) of the estimated 1.8 billion ambulatory visits (95% CI, 1.7-2.0 billion) in the United States in 2003 and 2004. As implemented, EHR were not associated with better quality ambulatory care.
However, the investigators emphasized that the findings do not refute the value of EHR, but, rather, emphasize the need for greater commitment to quality improvement.

Active, electronic post-marketing drug safety surveillance system advocated by former FDA Commissioner

April 14, 2007: Among several articles on drug safety published by the New England Journal of Medicine on April 13, one paragraph by Dr. Mark McClellan, a former commissioner of the FDA states: "With almost all prescriptions now processed electronically, and with the availability of increasingly detailed data on health care utilization and outcomes for insured Americans, we could implement a routine, systematic approach to active population-based drug surveillance that could identify potential safety problems much more effectively and relatively inexpensively. For example, Richard Platt, a professor of ambulatory care and prevention at Harvard Medical School, has noted that with a (now feasible) data network including information on 100 million patients, a statistically significant "signal" of serious cardiovascular risk could have been detected after less than 3 months of experience with rofecoxib.5 Such an electronic surveillance network would also help in targeting follow-up clinical studies to determine causality when necessary and follow-up actions to influence prescribing."

US Government privacy standards for electronic health data in "early stages". TMT privacy standards fully implemented.

February 18, 2007: The US Government Accounting Office has issued a report on the efforts of the Department of Health and Human Services (HHS) to ensure the privacy of electronic health information. The report states that HHS "is in the early stages of its efforts" and recommends that HHS "define and implement an overall privacy approach that identifies milestones...". [NOTE: TMT has a fully established procedure for managing the privacy of health information of responders to TMT questionnaires. This includes providing a unique website address (URL) for each responder with the option of password protection, use of Secure Sockets Layer (SSL) technology to prevent interception of data transmitted over the Internet, and maintenance of databases in secure locations with limited access. The most secure process of all is for the questionnaire responder not to provide any personally identifying information. He or she can download the TMT medical report and then insert whatever personal information is required.]

Physicians may defer to computer in diagnosis

December 6, 2006: In a study of over 56,000 mammograms for diagnosis of breast cancer, computer analysis was associated with improved sensitivity of cancer detection for computer-marked visible cancers and decreased sensitivity for computer-unmarked visible masses. A computer interpretation of an absence of cancer slightly increased the radiologist’s ability to correctly determine that a woman was cancer-free. If the computer did not suggest that a mammogram was suspicious, radiologists were less likely to recommend further evaluation than when they did not receive the computer interpretation; if a mass was not marked by the computer as suspicious, the radiologists identified 37.4% of cancers in this subset without computer-assisted detection, but only 30.1% when they received the computer interpretation. This suggests that they deferred to the computer interpretation when the computer did not suggest cancer.

Primary care in US lags other developed countries in clinical information systems and quality and efficiency incentives

November 3, 2006: A survey of primary care physicians in Australia, Canada, Germany, New Zealand, the Netherlands, the United Kingdom, and the United States reveals striking differences in elements of practice systems that underpin quality and efficiency. Wide gaps exist between leading and lagging countries in clinical information systems and payment incentives. U.S. physicians are among the least likely to have extensive clinical information systems or incentives targeted on quality and the most likely to report that their patients have difficulty paying for care. Disease management capacity varies widely. Overall, findings highlight the importance of nationwide policies. Policy changes in the United States could lead to improved performance.

80% of US Internet users have searched on-line for health information

October 30, 2006: Eighty percent of American Internet users (113 million adults) have searched the Internet for information on health topics.  On a typical day about 10 million American adults (7% of Internet users) search for information on a health topic. Two-thirds of these start their search using a search engine such as Google. People feel "reassured" by the information in 74% of cases but "confused" in 18%. Three quarters don't usually check the date or source of the information. Health information seekers tend to be college educated with at least 6 years experience of the Internet and are fairly similar to the entire US Internet population. Two thirds had a broadband connection. There is no gender difference. The most common age group is 30-49. Although 17% of the US population is 65 or over, only one third of these search the Internet for health information.

Less than 10% of US doctors use full-fledged electronic health records for outpatients

October 19, 2006: When electronic health records (EHRs) are widely implemented they are expected to greatly improve standards of healthcare. However, a new study has found that, despite encouragement from the US government and medical associations, only 9% of doctors treating outpatients use full-fledged EHRs (patient demographics; computerized orders for drugs, lab tests and other procedures; clinical decision support such as reminders of recurring tests; and information about findings, including doctors’ notes and lab results). Previous studies have shown that the reasons for this slow progress are complex, but one important factor is the lack of financial return on EHR investment. One of the co-authors of this study, David Blumenthal, M.D., director, Institute for Health Policy, MGH/Partners, says "We are pitifully behind where we should be. We must find ways to get more physicians to embrace this technology if we are to make major strides in improving health care quality". Note that TMT provides a Free EHR for patients to use if their doctor has no EHR.

Despite higher healthcare spending, US lags in use of health information technology

May 10, 2006: Per capita, the US has fewer practicing physicians, practicing nurses, and acute care bed days but spends more than twice as much on health than the median OECD country (US, Canada, Europe & other industrialized nations). The US lags as much as a dozen years behind other OECD countries in adopting Health Information Technology (HIT). The HIT centerpiece is the EHR, but HIT also includes telehealth, electronic ordering systems, decision support tools, networks, and infrastructure. US physicians are reluctant to adopt HIT because of concerns about lost productivity spent during training and inadequate financial incentives. The US has a fragmented approach to HIT implementation resulting in a lack of interoperability among HIT systems, but has recently recommended the Health Level Seven (HL7) interoperability standards which have already been adopted by Canada, Germany, the UK, Norway and Australia.

CCHIT Certification process issued for Electronic Health Records

May 2, 2006: CCHIT (the Certification Commission for Healthcare Information Technology) was jointly created in 2004 by three leading HIT industry associations – the American Health Information Management Association (AHIMA), the Healthcare Information and Management Systems Society (HIMSS) and The National Alliance for Health Information Technology (Alliance). It is a voluntary, private-sector organization to certify HIT products, and has been praised by David Brailer, the outgoing Health IT czar. It held a public teleconference on May 2 to discuss certification of generic requirements for ambulatory EHR (Electronic Health Record) vendors. Certification for 2006 will evaluate security and functionality. It is hoped to include interoperability in 2007. EHR system certification can be pre-marketing or post-marketing. EHR systems can be stand-alone (meeting all criteria) or “joint products” which meet requirements by working together with outside systems. Cost is currently $28,000 for initial certification, with an additional $4,800/year for maintenance certification. CCHIT inspection is done by web conferencing.

• CCHIT certification will initially focus on generic requirements for all ambulatory EHR vendors (with a focus on products for small and medium size medical practices who are in most need of CCHIT advice – large practices usually make their own EHR-selection decisions).

• Certification will address three areas – security (the most mature set of standards), functionality (current requirements provisional and likely to evolve) and interoperability (lack of standards means that no interoperability requirements will be included in the 2006 certification).

• Any EHR system must meet all specified criteria (based on HL7 standards) before certification. However, a system can “assign” certain criteria to be met by EHR partners or other hardware/software solutions that can be documented (by demonstration or external documentation) to meet specific criteria. Thus a system can be modular, with different elements fulfilling certain requirements but with sufficient interoperability to allow the modules to work together.

• Of 264 functionality criteria identified, about half will be included in the 2006 certification. There was considerable discussion about the basis for selecting these criteria, and about concerns of vendor or specialty bias in their selection. Some criteria use the concept of “functional equivalence” in which a particular core function (e.g., tracking values over time) could be implemented in different settings (e.g., serial ejection fraction, serial intraocular pressure, pediatric growth chart).

• Of 51 security criteria, 25 are “assignable”.

• Applications may be for “premarket conditional certification” (if the system is not yet deployed in the field) or “production certification” (if it has already been deployed in routine use). A system may be a “comprehensive product” (meeting all criteria on its own) or a “joint product” (meets all criteria when combined with one or more external systems).

• Certification is version-dependent (e.g., V 1.0.3).

• Certification costs $28,000 per product for the first year, and $4,800 per year thereafter for a maintenance certificate for a further 2 years. New certification in future years will include all criteria from previous years and add new criteria that have been validated. Criteria will remain constant throughout a given certification year (e.g. “2006” could include quarterly certifications in May 2006, August 2006, November 2006 and February 2007). Projected certification costs for future years are not yet available. Certification testing will be done in order of the date of acceptance of a complete application.

• CCHIT inspection is performed using web conferencing between the vendor/deployed system and CCHIT staff. CCHIT will arrange for web conferencing for any OS (e.g., Windows, Mac, Linux). Functionality testing takes 4-8 hours and Security testing takes 2-4 hours. Arrangements can be made for supplemental testing, retesting, and appeal of a certification decision.

• Functionality criteria are evaluated by a panel of 3 “jurors” (at least 1 MD). A passing grade is 2 or more of the 3 jurors approving.

• Security criteria are tested by a single “IT/Security juror” who is monitored by a CCHIT “Proctor”. The IT/Security juror also evaluates off-line any “Self Attestation” materials (security materials or documentation submitted by the vendor).

• Some of the questions addressed in the Q&A included:

  • If a system has several modules, no one of which meets all criteria, will multiple site inspection be needed? Answer: Yes.

  • What is the definition of “functional equivalence”? Answer: Not well worked out and may depend on circumstances.

  • If a particular system is intended for a particular market segment that does not require certain functionalities (e.g., pediatric tools for a geriatric application) can it still get certification approved? Answer: Will address this in FAQ (to be published on CCHIT website).

  • As specialty-specific functionality requirements emerge, will these be added to the general requirements? Answer: Not decided. CCHIT could “suggest” desirable features for certain settings without making them mandatory for all ambulatory EHR.

  • Will separate standards emerge for small, medium and large practices, or for different specialties? Answer: This might come later.

  • Are certification standards too high for small office vendors and too low for large office vendors? Answer: Could be.

  • How should questions about the process be handled? Answer: General questions will be handled in the FAQ rather than one-on-one. Vendor-specific questions will be addressed one-on-one. All questions should be submitted to info@cchit.com.

  • Was the organization and criteria setting of CCHIT managed democratically with full involvement of stakeholders? Answer: CCHIT tried to find a balance between public involvement and speed. CCHIT is not a “populist organization”.

  • What guidance can CCHIT give to EHR vendors who want to have the best chance of meeting interoperability standards when CCHIT issues these? Answer:  There is “no answer yet” but they “hope” to have them for the 2007 certification. Cost of certification may increase when interoperability requirements are added. Dr. Leavitt is going to Washington DC tomorrow to discuss IT “harmonization” and the development of an “overarching road map” (with timeline) for interoperability requirements. TMT comment: For joint systems that combine different modules to meet the various criteria, it is not clear how CCHIT will determine if they work adequately together if no interoperability criteria are currently available.

  • Will the maintenance certificates for subsequent years require full testing of all criteria or only those that have been added since the previous year? Answer: Not decided.

Everyone agrees we need electronic medical records. So why are we not doing it?

April 25, 2006:  An article in the Washington Times points out "It may be one of the few things President Bush, Senate Majority Leader Bill Frist, and Sens. Hillary Rodham Clinton and Barack Obama all agree on: In less than 10 years, every American should have an electronic medical record that's instantly accessible. .... But many of us -- as in almost everyone -- has their records on paper right now, probably in more than one doctor's or dentist's office, and perhaps in way more than one geographic location.... a study published in the Mayo Clinic Proceedings shows that an alarming number of people being discharged from hospitals know little about their diagnoses and medications. The study found that 62 percent of patients didn't know the purpose of their medications, 86 percent didn't know the side effects of their medications and 58 percent didn't know their diagnosis." TMT Comment: The three main reasons we don't promptly set up electronic medical records (EMRs) for everybody are conversion costs, lack of standards to exchange electronic data confidentially and efficiently, and lack of economic incentives for healthcare providers. TMT provides confidential EMR software that empowers any patient in the world -- and best of all it is free. TMT Medical Questionnaires and TMT Electronic Personal Health Record.

Treasury Secretary: “The typical doctor’s office has less information technology in it than the corner drug store”

April 24, 2006:  Treasury Secretary John Snow told attendees at the World Health Care Congress meeting in Washington, D.C. that healthcare insurance now represents a large part of an employee's compensation. Among several ways to hold down healthcare costs, Snow said technology such as electronic medical records and e-prescribing would reduce medical errors and wring costs from the system. “The typical doctor’s office has less information technology in it than the corner drug store,” he said.

Only 1/4 of US hospitals have electronic medical records

February 21, 2006: Electronic medical records (EMRs) have been endorsed by the US government, supported by many academic medical groups, and widely and effectively implemented in the VA medical system. "By computerizing health records, we can avoid dangerous medical mistakes, reduce costs and improve care," President Bush said in his 2004 State of the Union address. However, the February, 2006 survey by the Health Information and Management Systems Society (HIMSS) reported that only 24% of respondents had a fully operational system ("electronically maintaining information about an individual's lifetime health status in a completely paperless fashion.") for electronic medical records in place as of February 2006 (compared with 18% in 2005 and 19% in 2004) with an additional 40% being in the process of installing (or having signed a contract for) an EMR system. Another 23 percent said they had “developed a plan” to implement an EMR. Only 12 percent of respondents reported no plans for electronic medical records. TMT’s “patient empowerment” approach (free web-based questionnaires and electronic medical records) may provide an immediately available partial solution while the medical community is implementing physician-based medical records and agreeing on interoperability standards, and. that can later be incorporated into hospital or private practice electronic systems when these become available.

Digital divide widens in medicine

February 10, 2006: An article in the Boston Globe identifies key problems in digital transformation of US healthcare data:
• Lack of financial return for medical groups, particularly small groups or solo practitioners.
• Required changes in work flow and data entry with associated training costs.
• Lack of interoperability between competing electronic systems.

8. ADMINISTRATIVE/POLITICAL

Senate votes new powers to FDA on drug safety

May 9, 2007: The US Senate voted 93 to 1 to give FDA power to monitor drug safety after marketing, to order drug label changes, and restrict the use and distribution of drugs with serious risks.

FDA announces new initiatives to assess safety of marketed drugs

January 31, 2007: FDA has announced “initial steps” for “new initiatives” in response to Institute of Medicine (IOM) recommendations on post-marketing drug safety evaluation. It is not clear how effective these steps will be. They include using new approaches to identifying drug safety problems and balancing risk, improving communication between “stakeholders”, establishing a new safety advisory committee, and endorsing initiatives in Congress that would provide more funding and resources for drug safety. A pilot program will be set up for regular review of the safety profiles of some recently approved drugs. The FDA did not endorse a number of IOM proposals, such as giving increased authority to those who evaluate drug safety after drugs go on the market.

Financial incentives improve hospital performance

January 26, 2007: Financial incentives ("pay for performance") was associated with improvement in quality of hospital care in a study of 613 US hospitals that voluntarily reported information about the quality of care, 207 of which participated in a pay-for-performance Medicare/Medicaid demonstration project. Pay-for-performance hospitals showed greater improvement in all composite measures of quality, including measures of care for heart failure, heart attack, and pneumonia and a composite of 10 measures. Adjusted analysis showed pain for performance was associated with 2.6-4.1% improvement over a 2-year period. Hospitals with the poorest performance at baseline showed the greatest improvement.

Drug prices higher in Medicare private plans than in VA system

January 10, 2007: Drug prices in Medicare Part D prescription drug plans are about 60% higher for the 20 most commonly prescribed drugs than prices paid by the U.S. Department of Veteran Affairs (VA). The VA can use its purchasing power to negotiate for lower drug prices, but under the 2003 Medicare law, Medicare does not have the right to negotiate with drug companies. Differences in price ranged from one-third higher for clopidogrel (Plavix) to 10 times higher for simvastatin (Zocor). For half of the 20 drugs, the highest price charged by a Medicare Part D plan was at least twice the lowest VA price. The report suggests that drug companies could maintain the current level of funding for Research & Development (R&D) if they shifted money from marketing, advertising and administration (32% of net sales) to R&D (14% of net sales).

Identifying serious adverse drug effects: Drug companies, Investigators, Advisory Committees, and the FDA

November 22, 2006: Tomorrow's New England Journal of Medicine has two Perspective articles, one Editorial and two letters expressing concern about adverse safety data being hidden by pharmaceutical companies. They focus on safety data for aprotinin (Trasylol) that was not revealed by Bayer for an FDA Advisory Committee meeting, but also discuss earlier issues with Vioxx and Merck. One of the Perspective articles is by Dr. Jerry Avorn, a Harvard Professor, who has an excellent summary of how carefully performed observational (non-randomized) studies can provide important signals of potential safety problems "but propensity scores and other multivariable techniques applied to epidemiologic research cannot always control for all the inevitable selection bias, making the transparency of methods and raw data even more important than in randomized trials". The other material on this subject in the Journal is from Dr. William Hiatt (the current chair of the FDA Cardiovascular and Renal Drugs Advisory Committee), Dr. Jeffrey Drazen (writing for the Journal), one of the aprotinin study investigators, and the FDA. There seems to be plenty of blame to spread around.

Poor people in wealthy neighborhoods have higher death rate than poor people in poor neighborhoods

November 2, 2006: A population-based mortality study in over 8,000 adults who were followed up for a mean of 17 years showed that low socioeconomic class people who live in high socioeconomic class neighborhoods have about 70% greater mortality than low socioeconomic class people who live in low socioeconomic class neighborhoods. The baseline risk factors that were measured were comparable in these two groups. Possible explanations suggested by the authors include: 1) less disposable income because of higher housing costs, 2) working longer hours with less time for healthy activities, 3) living farther from social services like free community clinics, or 4) "low relative standing in their communities" (the latter tying in with other data suggesting that psychosocial factors may influence health behaviors or neuroendocrine or immune functioning). Observational studies cannot establish causality but may suggest the need for further study.

NIH doctors criticize Eli Lilly's promotion of sepsis drug

October 19, 2006: Three NIH critical care specialists have published a New England Journal of Medicine "Perspective" that criticizes Eli Lilly's attempts to promote use of its Xigris drug for the treatment of sepsis. The authors comment that "bundled performance measures" to improve health outcomes "is vulnerable to manipulation for inappropriate — and possibly harmful — ends. Seeing in these bundles a potentially powerful vehicle for promoting their products, pharmaceutical and medical-device companies have begun to invest in influencing the adoption of guidelines that serve their own financial goals." Xigris costs $8,000 for a 4-day course of treatment, and FDA approved Xigris only for use in the sickest patients with sepsis. . The authors comment: "The challenges involved in producing first-rate guidelines and performance standards are only exacerbated by the intrusion of marketing strategies masquerading as evidence-based medicine."

Over 700,000 adverse drug events yearly require treatment in US Emergency Rooms, with over 100,000 hospitalizations. Elderly at higher risk.

October 18, 2006: The frequency and severity of adverse drug events in outpatients was assessed in a U.S. adverse drug event surveillance project. It was estimated that there are over 700,000 adverse drug events yearly resulting in Emergency Room treatment, with over 100,000 requiring hospitalization. Those 65 years or older were over twice as likely to have adverse drug events, and almost seven times as likely to be hospitalized as a result. Adverse effects were most common with drugs that have been used for many years. For example, with insulin, patients would forget to take meals after insulin dosing or would get confused about the correct insulin dose. With warfarin (Coumadin), causes included other medications, changes in diet, or too few coagulation blood tests. With amoxicillin, allergic reactions were a common cause.

Mortality in Medicare patients depends on the hospital

October 16, 2006: Health Grades, Inc. reviewed risk-adjusted mortality using the computerized MedPAR database in over 40 million Medicare patient hospitalizations in over 5,000 non-federal US hospitals. Each hospital was rated according to whether its mortality rate was significantly better (5-star), not significantly different (3-star) or significantly worse (1-star) than the average hospital. Compared with the 5-star hospitals, it was estimated that over 300,000 excess deaths occurred from 2003-2005 in the 1-star or 3-star hospitals. Mortality in the 5-star hospitals was 69% and 49% lower than in the 1-star and 3-star hospitals respectively. Half of the excess deaths were related to four diagnoses (heart failure, community-acquired pneumonia, sepsis, respiratory failure). For coronary bypass surgery, 5-star hospitals had a 73% lower mortality rate than 1-star hospitals. For heart attack, the mortality difference between 1-star and 5-star hospitals was 48%.

IOM report recommends more funding/staffing/enforcement tools for FDA and more emphasis on safety of marketed drugs

September 25, 2006: The Institute of Medicine (IOM) has issued "The Future of Drug Safety", a report that makes 25 recommendations to bring the strengths of the FDA preapproval process to monitoring of the safety of marketed drugs. Recommendations include a large boost in FDA funding & staffing, increased emphasis on post-marketing drug safety, additional enforcement tools for FDA, more timely and effective communication of safety concerns by industry and FDA, mandatory clinical trials registration and results reporting, reevaluation of new drugs 5 years after marketing approval, special symbol on labels of new drugs for the first 2 years of marketing, and advertising limits for new drugs. The IOM report was commissioned in the wake of the Vioxx/COX-2/NSAID safety controversy which also triggered TMT's April 2005 Recommendations for: 1) across-drug collaborative meta-trials, databases and analyses; 2) new clinical trial design, analysis and reporting standards; and 3) structured information processing/reporting from FDA Advisory Committee meetings.

Prescribing errors for seniors almost 7 times as likely as with younger patients

September 14, 2006: A report from Medco found that seniors are almost 7 times as likely as younger patients to be prescribed drugs wrongly (drug incompatible with medicines already being taken, can worsen another medical condition, or incorrect dosage). The problem is worse in those with more doctors and more prescribed drugs. Seniors treated by 2 doctors average 27 prescriptions/year with an average of 10 prescribing errors. Seniors treated by 5 doctors average 42 prescriptions/year with an average of 16 prescribing errors. Almost ¼ of seniors receive prescriptions from 5 or more doctors. The priority of the primary care physician “has to be a review of the medicines”.

US divided into "Eight Americas" on basis of longevity

September 12, 2006: A Harvard study of life expectancy divides the US into "Eight Americas" on the basis of race, location, population density, income and homicide rate. The longest-lived were Asian females and the shortest-lived were urban black males. These disparities have not changed significantly over the past two decades, and are related to chronic diseases and injuries with well-established risk factors, but not by the level of health-care utilization. Longevity in descending order (males and females combined) was: Asian Americans (85 years), Northland low-income rural White (79), Middle America, mostly White (78), Low-income White Appalachia & Mississippi Valley (75), Black Middle America (73), Western American Indians (73), Southern low-income rural Black (71), High-risk urban Black (71).

Difficulty understanding patient pamphlets and prescription labels is common and associated with poor health

September 12, 2006: According to the "Health Literacy of American Adults" report, many people find patient education pamphlets and prescription labels difficult to understand. One third could not perform tasks such as reading a chart to find what age a child should get a vaccine, or reading a prescription label to find substances that could interact with their medicine. One in 7 could not understand a patient pamphlet on who should be tested for a disease. Those with higher health literacy levels consistently reported better overall health. The authors commented "Understanding the health literacy of America's adults is important because so many aspects of finding health care and health information, and maintaining health, depend on understanding written information."

FDA Drug/Device Advisory Committees recommend approval in 8 of 10 cases and FDA usually follows the recommendation

August 30, 2006: FDA Advisory Committees recommend marketing approval for drugs and medical devices about 80% of the time. FDA follows a Committee recommendation for approval 96% of the time, but does so less frequently when the Committee recommends against approval.

Media stories on medical reports at scientific meetings misleading

June 14, 2006: 187 newspaper and TV/radio stories about research reports from scientific meetings of medical societies were reviewed. It was concluded that basic study facts and cautions were often omitted and that the public may be misled about the validity and relevance of the science presented. A quarter of meeting presentations garnering media attention (including those on page 1 of major newspapers) are never published in the medical literature.

Clinical trial design in the post-Vioxx world

May 9, 2006: An Editorial in the May 9 issue of Circulation discusses “a better way” to evaluate “drug effects in the post-Vioxx world”. It recommends that safety evaluation should be enhanced by improved post-approval drug testing. In addition, better pre-approval  testing should include a) progressive recruitment of  patients more similar in age, disease severity and safety risk factors to the expected users of the drug, b) larger numbers of short-duration patients, c) “avoiding blatant risk-obscuring aspects of trial design”, d) “better use of pharmacogenetics, biomarkers, and other basic science approaches to provide earlier warnings about drug toxicities”, and e) clinical trial designs specifically targeted to evaluate potential emerging hazards (e.g., prothrombotic effects of COX-2 inhibitors). It recommends avoiding blanket “black box warnings” for whole classes of drugs when only some such drugs have shown clear evidence of a safety problem [TMT has concern about this recommendation, since drug companies should not be penalized for good clinical designs if their competitors are able to use bad designs to avoid demonstrating a similar problem]. The Editorial concludes “Fortunately, other solutions are possible that are more scientifically rigorous, clinically appropriate, and feasible. All that is lacking is the political will to implement them.” An article in the same issue of Circulation (Clinical Trials in the Wake of Vioxx) rebuts recent suggestions to “require statistically extreme (e.g., p<0.0001) evidence of benefit” for early termination of pre-approval trials so as to increase the number of patients available for safety testing. TMT has previously suggested ways of improving pre-approval and post-approval drug testing (Recommendations). Clinical trials should improve the identification of emerging safety hazards by measuring the appropriate safety parameters at appropriate times, by safety-sensitive statistical analysis (with appropriate p value adjustment for testing of multiple parameters and for interim analyses), and by progressive increase in clinical trial sample sizes and progressive recruitment of more at-risk patients from the expected user population as the drug proceeds through the pre-approval/post-approval process.

JAMA article examines industry financial ties and voting patterns at FDA Advisory Committee meetings

April 26, 2006: An article in JAMA examines the impact of disclosed financial conflicts of interest on voting patterns at FDA drug Advisory Committee meetings. It concludes that conflicts of interest are common, that there is a “weak relationship between certain types of conflicts and voting behaviors” but that “excluding advisory committee members and voting consultants with conflicts would not have altered the overall vote outcome at any meeting studied”.  Despite these conclusions (which were based on an analysis of data from 2001-2004), the article also states that at a “2005 advisory committee meeting to evaluate the risks of 3 cyclooxygenase 2 (COX-2) inhibitor drugs, 93% of votes cast by individuals who had received consulting fees from 1 or more of the drugs' makers favored the drugs, compared with 56% of votes by individuals without conflicts. Exclusion of the members with conflicts would have resulted in recommendations to remove 2 of the 3 drugs from the market”. On March 2, 2005, TMT posted an analysis of COX-2 voting patterns on its website (http://masterdocs.com/voting.htm) and concluded 1) Both financial ties to industry and the specialty of rheumatology were associated with more favorable voting for marketing of COX-2 drugs. 2) An analysis confined to non-rheumatologists still showed a statistically significant relationship between financial ties and more favorable voting. 3) The widely disseminated figure (e.g., in the New York Times and a subsequent New England Journal of Medicine article) of ten voting members with industry ties is inaccurate. The correct figure is eight. This corrected figure was provided to the New York Times which declined to print a correction. 4) Rheumatologists (many of whom might be COX-2 investigators with appropriate financial links to Sponsors) were more in favor of keeping COX-2 drugs available for treating their patients with chronic pain. 5) In the first Bextra vote, the Committee did not support Bextra marketing. For reasons that are unclear, this vote was retaken and resulted in support for marketing. 6) “It should be noted that these findings do not imply any improprieties on the part of the industry sponsors, the Committee members or the FDA. However, the findings do show that different groupings of Committee members show differences in voting responses: Rheumatologists who have the daily task of managing patients with chronic pain tended to feel that all the drugs should remain available with appropriate restrictions on their use and with emphasis on selection of the best drug for an individual patient. Epidemiologists and statisticians tended to focus more on identifying differences in population risks between individual drugs. Members reported as having ties to industry tended to be more in favor of allowing marketing of the COX-2 drugs -- although unconscious bias cannot be excluded as a reason for this finding, the finding could also be based on sound analysis and detailed knowledge of individual drugs.” The JAMA article conclusions on this observational study are based on a univariate analysis (analysis using a single random variable and ignoring possible confounding factors) of the financial-conflict/voting relationship (whereas multivariate analysis is the standard approach for observational studies). The authors justify their univariate analysis by saying “We were unable to control for the many other potential confounding factors that could have an impact on an advisory committee's vote (secular trends in drug approval rates, forcefulness of the advisory committee chair, press coverage, and the like)”.  However, TMT’s analysis of the impact of medical specialty on voting patterns was posted in March 2005 using publicly available information that could have been incorporated in the JAMA authors’ analysis.

Only 55% of Americans receive quality health care.  Use of electronic medical records could improve population-wide quality of care

March 16, 2006: In a survey of almost 7,000 patients in 12 US communities, only 55% received recommended care (based on 439 indicators of quality of care for 30 medical conditions and for disease prevention). Quality of care was fairly similar across sociodemographic groups, being slightly better in women (57% with quality care vs. 52%; P<0.001), in those 30 years or younger versus those 65 or older ( 58% vs. 52%, P<0.001), in Blacks and Hispanics (58% each) versus Whites (54%, P<0.001 for both comparisons), and with annual household income over $50,000 versus less than $15,000 (57% vs. 53%, P<0.001). Some more detailed subgroup comparisons showed greater inequality - e.g., insured white women (57%) versus uninsured black men (51%). The authors comment that “Quality-improvement programs that focus solely on reducing disparities among sociodemographic subgroups may miss larger opportunities to improve care.”  Minorities fared worse in some areas of expensive care and suffer more from some conditions than whites, but once in treatment, their overall care was similar to that of Whites. However, since minorities go without treatment more often than whites, such people were not included in the survey, so that identifying and treating disease in minorities might reduce racial inequality in health care more than just focusing on inequality after treatment is begun. The authors comment that "To make substantial improvements in the quality of health care available to all patients, we must focus on large-scale, system-wide changes. Our previous study of the quality of care delivered in the Veterans Affairs health system illustrates some of the potential for improvement. In that system, with one of the country's most mature electronic medical-record systems, decision-support tools at the point of care, automated order entry, routine measurement of and reporting on quality, and financial incentives for performance, we found that participants received 67 percent of recommended care, a considerably better rate than the 55 percent observed in the current study."

AMA & Congress agree on performance standards for healthcare

February 21, 2006: The American Medical Association has agreed with Congress to develop more than 100 standard measures of healthcare performance, which doctors will report to the federal government in an effort to improve the quality of care.  The performance measures will focus on diagnostic tests and treatments that are known to produce better outcomes for patients — longer lives, improved quality of life and fewer complications. Examples include: the proportion of diabetic patients with blood sugar and cholesterol at the recommended levels; the percentage of surgical patients who receive medications to prevent blood clots; the proportion of patients with pneumonia who receive antibiotics within a few hours of diagnosis; and the percentage of heart attack patients who receive beta-blockers when they arrive at a hospital.

9. MISCELLANEOUS

Nasal spray better than flu shots for small children

February 15, 2007: Small children (6-59 months old) given live attenuated flu vaccine by nasal spray had 55% fewer cases of culture-confirmed influenza than those given a flu shot with inactivated vaccine given by intramuscular injection.

In preliminary study, Down's Syndrome was identified by fetal DNA test on maternal blood

February 5, 2007: The chromosomal abnormality trisomy 21, the cause of Down's syndrome, can be identified from free fetal DNA in maternal blood, according to a preliminary study in The Lancet. Maternal and fetal DNA were distinguished by measuring the ratio of alleles at the site of single nucleotide polymorphisms on different chromosomes. In 60 samples, two of three Down's fetuses were correctly identified by the test; in the 57 fetuses without Down's syndrome the test correctly gave a negative result in 56 of 57 cases. This gave the test a sensitivity of 66.7% and a specificity of 98·2%.

Evidence-based procedures reduce catheter-related blood stream infections in ICUs

December 28, 2006: In a study in over 100 Michigan ICUs, bloodstream infections were reduced by two-thirds by implementing evidence-based procedures (hand washing, using full-barrier precautions during the insertion of central venous catheters, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters). An accompanying NEJM Editorial comments “There is much to criticize about U.S. health care, including its fragmentation, high costs, impersonal delivery, and adverse events. In contrast, a focus on quality could be a unifying concept, part of a new, team-based professionalism using evidence-based systems and caring behavior that consistently lead to safety and comfort for patients.” TMT Comment: There is overwhelming evidence that evidence-based medicine improves healthcare and saves lives. Patients and doctors should realize that evidence-based medicine does not eliminate personalized care -- it just means that evidence-based standards should be used unless there is a convincing reason not to do so in an individual patient.

Medication blister packs and education improve medication compliance in the elderly by 36%, with lower BP and cholesterol

November 15, 2006: Adherence to medication in elderly on multiple medications is increased by dispensing medication in blister packs stating when to take each dose, medication education and follow-up by a pharmacist. Inn 200 patients 65 years or older taking at least four chronic medications, medication adherence increased from 61% to 97% (p<.001), blood pressure fell 3.3 mmHg (p=.02) and “bad” LDL cholesterol fell 4.9 mg/dL (p=.001).

Warts and all – trial of the tape

November 7, 2006: A 6-week clinical trial in the treatment of warts in 103 primary school children compared duct tape (reported to be effective in a previous controlled trial) to a control treatment (a corn pad protective ring). The primary outcome measure was disappearance of the wart after 6 weeks and this was achieved in 16% of the duct tape children and 6% of the control children, a non-significant difference (p=.12). Effect on a secondary measure, diameter reduction of the treated wart, was significantly greater in the duct tape group (mean 1.0 mm; P = .02). Based on the overall response rates in this and prior studies, the subjects in this study might have had more resistant warts and the study may have been underpowered.

Pneumococcal vaccine appears effective with each of various vaccination schedules

October 30, 2006: The effectiveness of seven-valent pneumococcal conjugate vaccine was evaluated in an observational study comparing 782 cases of invasive pneumococcal infection to 2512 matched controls. The authors concluded “The seven-valent pneumococcal conjugate vaccine prevents invasive disease in both healthy and chronically ill children. The vaccine is effective when used with various non-standard schedules.”  Although these findings are encouraging, the observational nature of this study raises the possibility that the cases and controls may not have been at comparable risk (see review immediately below). Observational studies cannot establish causality but can suggest the need for further study.

Are flu shots as effective as claimed?

October 27, 2006: A thoughtful review article considers the evidence for vaccination against seasonal influenza (flu). Only a small number of randomized, placebo-controlled trials have tested the value of an annual flu shot, only some showed efficacy against confirmed flu, and only in some groups of patients. There is little evidence of efficacy from randomized studies using other endpoints such as hospitalization or mortality. Observational (non-randomized) study reports claim much stronger evidence of the value of flu shots. However, apparent effects in observational studies may just represent differences in underlying risk between the treatment groups, and such differences may not be adequately accounted for by statistical adjustment for baseline factors. The author comments that “policy makers favour intervention with what is available” because "we have to make decisions and cannot wait to have perfect data". However, he believes that “placebo controlled randomised trials …. are desperately needed and we should invest in them without delay”. These trials would seem particularly appropriate for patient populations in which little evidence of efficacy has been shown.

CDC recommends routine Zostavax shingles vaccine for those 60 and over

October 19, 2006: An expert CDC committee has recommended that a recently approved vaccine against shingles (Zostavax) should be routinely given to almost all people 60 years or above. In a controlled trial in almost 40,000 subjects followed up for a median of 3 years, 642 of 19,247 placebo subjects (3.3%) developed shingles compared with only 315 of 19,254 vaccinated subjects (1.6%). Subjects who were immune compromised, on steroid therapy, or had previous shingles were excluded from the study.

Noise-cancelling headphones might prevent hearing loss in noisy subway

October 19, 2006: In a survey of noise levels in New York City, average noise levels were measured on subway platforms (average 86, maximum 106 dBA - decibel-A weighting), inside subway cars (maximum 112 dBA) and at bus stops (maximum 89 dBA) in New York City. The maximum levels exceed recommended WHO and EPA guidelines. Listening to a portable music player can increase the noise level because the volume level has to be increased over the background noise - but use of noise-cancelling microphones could cancel out the external sound and protect against hearing loss.

Industry-sponsored meta-analyses are of poorer quality and conclusions are more favorable to the experimental drug

October 9, 2006: Meta-analysis is the statistical process of combining results from previous separate but related clinical studies. In a report from the University of Copenhagen, the quality and conclusions of meta-analyses comparing two drugs were evaluated for 8 industry-supported meta-analyses and 191 meta-analyses without known industry support (175 Cochrane reviews, 9 with undeclared support, and 7 with no support or non-industry support). Quality assessment was based on such factors as control for bias (e.g., by describing excluded patients or studies, or by concealing allocation to treatment). The median quality score was 7 for the Cochrane reviews and 3 for non-Cochrane reviews. The seven industry-supported reviews with conclusions recommended the experimental drug without reservations, compared with none of the Cochrane reviews (P=0.02), although the estimated treatment effect was similar on average (z=0.46, P=0.64). Reviews with undeclared support and reviews with not-for-profit support or no support had conclusions that were similar in cautiousness to the Cochrane reviews. The authors conclude: "Industry supported reviews of drugs should be read with caution as they were less transparent, had few reservations about methodological limitations of the included trials, and had more favourable conclusions than the corresponding Cochrane reviews."

Get your 'flu shot - it could save your life

October 6, 2006: Many high risk people don't get an annual 'flu shot. About one-third of elderly people don’t get a flu shot. A 'flu shot in high risk people (e.g., those with heart disease) can save lives. To see if you are in a high risk group, answer the TMT 'flu questionnaire.

Could stem cells be harvested from embryos without damaging the developing embryo?

August 23, 2006: A fertilized egg divides into a group of cells called the blastomere. A paper in Nature describes the removal of a single cell from the blastomere and used to create a stem cell line, while the rest of the blastomere continues to develop, apparently without harm. The method is based on pre-implantation genetic diagnosis (PGD), which uses single cells taken from an 8- to 10-cell embryo to check for diseases. Minus the single cell, the embryos continue dividing normally and can be implanted into a mother's womb. About 1,500 babies have been born this way nationwide. The authors from Advanced Cell Technology conclude "The ability to create new stem cell lines and therapies without destroying embryos would address the ethical concerns of many, and allow the generation of matched tissue for children and siblings born from transferred PGD embryos." The ethical implications of this research were quickly questioned by the United States Conference of Catholic Bishops, and a spokesman said that the study "raises more ethical questions than it answers," citing concern about the long-term health of children born through fertility treatments.

ReNu with MoistureLoc 13x as likely to cause fungus infection in contact eye wearers

August 23, 2006: A report in JAMA indicates that in the recent outbreak of fungal eye infections in contact lens wearers, infection was over 13 times as likely in users of “ReNu with MoistureLoc” contact lens solution. “Topping off” lens care solutions instead of replacing them somewhat raised the risk of fungal infection, but in other respects, there was no difference between the practices of contact lens wearers who were infected and those who remained healthy.

Faster aging in poor people may be related to shortened telomeres

July 21, 2006: Telomeres lie at the end of chromosomes and progressively become shorter every time a cell such as a white blood cell (WBC) divides. Many aging-related diseases are linked to shortened telomeres and telomere attrition can be used as a biological indicator of human aging. In this study of WBC telomere length in 1552 female twins, a multivariate analysis showed that telomere length was significantly shorter in women of low socio-economic status, a group known to have shortened life expectancy compared with women of higher socio-economic status.

Medication errors injure 1.5 million in US/year. Patients can protect themselves. Electronic prescribing can help.

July 21, 2006: Medication errors are common, harm at least 1.5 million people in the US every year, and cost at least $3.5 billion a year (not taking into account lost wages and  productivity or additional health care costs). Medication mistakes happen, on average, once a day to every hospital patient. An IOM report suggests: 1) steps to increase between health care professionals and patients, 2) steps patients should take to protect themselves, 3) creation of new, consumer-friendly information resources through which patients can obtain objective, easy-to-understand drug information, 4) write all prescriptions electronically by 2010, 5) improve the naming, labeling, and packaging of drugs.

FDA approves once-a-day 3-drug combination tablet for HIV treatment

July 14, 2006: FDA has announced a "landmark achievement of three cooperating companies" - the approval of Atripla Tablets, a fixed-dose combination of three widely-used antiretroviral drugs, in a single tablet taken once a day, alone or in combination with other antiretroviral products for the treatment of HIV-1 infection in adults. Atripla combines the active ingredients of Sustiva (efavirenz), Emtriva (emtricitabine) and Viread (tenofovir disoproxil fumarate). Atripla was approved in under three months under FDA's fast track program and the drug should be available for purchase by July 15. There are more than a million people living with HIV (the virus that causes AIDS) in the United States, and 40,000 new cases are reported each year.

Gene effects markedly different between males and females

July 8, 2006: Although the "genome" (the hereditary information in DNA) is very similar between males and females of mammalian species, a new study in mice shows that "gene expression" (the way the genome is converted into the structures and functions of the body) is very different between males and females. It appears probable that similar gender differences occur in humans. Note that one of the components of TMT's 10,000-subject chronic pain study in people is evaluating gender differences in the physical locations of pain and associated symptoms. This study is currently recruiting subjects.

Review - Can Clinical Trial Endpoints be Changed after a study is begun?

May 27, 2006: Dr. Scott Evans of the Harvard School of Public Health, has provided us with a Review of the issue of changing clinical trial endpoints after a trial has begun, an issue posted for discussion in our Miscellaneous section on March 26, 2006. Please send any comments to info@masterdocs.com and we will forward them to Dr. Evans.

Cardiovascular clinical trials report more positive results if they are industry-funded

May 17, 2006: A JAMA observational study has concluded that "Recent cardiovascular trials funded by for-profit organizations are more likely to report positive findings than trials funded by not-for-profit organizations, as are trials using surrogate rather than clinical end points. Trials jointly funded by not-for-profit and for-profit organizations appear to report positive findings at a rate approximately midway between rates observed in trials supported solely by one or the other of these entities." The authors also conclude "..our observations of differential rates of positive trial reporting on the basis of end-point selection strongly reinforces the need for physician decision-making and Food and Drug Administration approval to remain on the basis of clinical rather than surrogate end points." However, no multivariate analysis was performed to adjust for confounding variables, and trials funded by device or drug manufacturers had larger sample sizes, were more likely to use clinical events rather than surrogate endpoints, and were more likely to be multicenter studies. The fact that results were more positive if the trial was funded by the drug/device manufacturer could represent what the authors describe as "author interpretation bias", "limits on publication" or "suspicion of adverse cardiovascular event suppression". However, other interpretations such as more adequate sample size estimation by the commercial sponsors, more adequate funding, or better trial design by those most knowledgeable about the effects of a drug or device are other possible explanations. Device trials were more likely to show positive results than drug trials, possibly because blinding is more difficult for device trials. The fact that surrogate endpoints were more likely to show positive results could merely reflect the fact that sample size calculations are simpler and enrollment of the required numbers of patients is easier with surrogate endpoints; for example, it is much easier to show a difference in lipid lowering than in the risk of cardiovascular clinical events. In view of the work of Chan et al it would be helpful to examine whether ambiguous protocol definitions of primary and secondary endpoints, or changes in endpoints after the study had begun, were more likely in trials that reported more positive results. Observational studies cannot establish causal relationships, but can suggest the need for further evaluation.

21% of office-based prescriptions are off-label, usually without scientific support. Could compromise patient safety and waste medications.

May 16, 2006: Office-based prescribing patterns by diagnosis were examined for 160 commonly prescribed drugs. Off-label prescriptions accounted for 21% of overall use. There was little or no scientific support for the off-label use in 73% of cases. Off-label use was commonest with cardiac medications and anticonvulsants, with gabapentin (83%) and amitriptyline (81%) having the greatest proportion of off-label use among specific medications. The authors conclude "Efforts should be made to scrutinize underevaluated off-label prescribing that compromises patient safety or represents wasteful medication use".

Fusarium eye infections cause worldwide withdrawal of MoistureLoc. Topping up storage case or leaving bottle cap open could increase risk.

May 16, 2006: Bausch & Lomb has recalled its ReNu with MoistureLoc contact lens cleaner worldwide. According to the FDA website, “Bausch & Lomb has proposed that unique characteristics of the formulation of the ReNu with MoistureLoc product in certain unusual circumstances can increase the risk of Fusarium infection….  data available do not indicate a problem with ReNu MultiPlus or ReNu Multi-Purpose or generic brands of this contact lens cleaning solution. According to the New York Times, “Bausch & Lomb said it now appeared that common, if frowned-upon, lens care practices — like topping off solution in the storage case instead of replacing it — could leave a film on lenses that shielded Fusarium from the sterilizing agent in MoistureLoc… Bausch concluded that MoistureLoc's formulation probably raised the risks of eye infections from the Fusarium fungus, if users do not carefully follow the label's directions for replacing or refilling the solution. Some MoistureLoc bottle tips can also harbor Fusarium if the caps are not regularly closed...”.

FDA approves varenicline (Chantix) for smoking cessation

May 11, 2006: In a May 12 News Release, the FDA has announced that it has approved varenicline tartrate (Chantix) tablets to help cigarette smokers stop smoking. The active ingredient in Chantix, varenicline tartrate, is a new molecular entity that acts at sites in the brain affected by nicotine and may help those who wish to give up smoking in two ways: by providing some nicotine effects to ease the withdrawal symptoms and by blocking the effects of nicotine from cigarettes if they resume smoking. "Tobacco use, particularly cigarette smoking, is the single most preventable cause of death in the United States and is responsible for a growing list of cancers as well as chronic diseases including those of the lung and heart," said an FDA spokesman. According to the Centers for Disease Control and Prevention (CDC), an estimated 44.5 million adults in the United States smoke cigarettes and more than 8.6 million of them have at least one serious illness caused by smoking. The approved course of Chantix treatment is 12 weeks. Patients who successfully quit smoking during Chantix treatment may continue with an additional 12 weeks of Chantix treatment to further increase the likelihood of long-term smoking cessation. In clinical trials, the most common adverse effects of Chantix were nausea, headache, vomiting, flatulence (gas), insomnia, abnormal dreams, and dysgeusia (change in taste perception). Chantix is manufactured and distributed by Pfizer, Inc., New York, NY.

Update on fungus infections of eye in soft contact lens wearers

May 5, 2006: Both the FDA and CDC have issued a May 5 update on cases of  Fusarium keratitis occurring in soft contact lens wearers. Bausch & Lomb’s ReNu with MoistureLoc has been associated with an increased incidence of the disease but it is too early to say that it is a causal factor in these cases. The FDA release says “We continue to confirm reported cases associated with products other than ReNu with MoistureLoc. Our interest in the MoistureLoc product is based on the disproportionate number of case of Fusarium keratitis associated with ReNu with Moisture Loc compared to the overall product market share. The trends of reported cases involving various contact lens solutions other than MoistureLoc have remained consistent throughout our investigation.” FDA also says: “…consult your doctor immediately if you experience symptoms such as redness, pain, tearing, increased light sensitivity, blurry vision, discharge or swelling.” The CDC press release says 1) “As of May 5, 2006, CDC has received reports of 102 confirmed cases, 12 possible cases and 81 cases still under investigation from 31 U.S. states and territories”, 2) of the 58 cases for which CDC has complete data “56 wear contact lenses, 32 reported using any B&L ReNu with MoistureLoc, 15 reported using any B&L ReNu MultiPlus, 7 reported using any unspecified B&L ReNu, 3 reported using any AMO product, 3 reported using any Alcon product.”, 3) “At this point, it is too early in the investigation to say whether a particular product or solution may be responsible for the outbreak. Throughout the investigation, the proportion of patients who reported using Bausch & Lomb’s ReNu with MoistureLoc has remained relatively consistent, at around 50-60 percent of confirmed cases. ReNu with MoistureLoc was used by approximately 2.3 million contact lens wearers in the United States, while MultiPlus was used by nearly 11 million contact lens wearers (branded or private label).”, 4) “The risk of getting fungal keratitis from contact lenses remains extremely low.” David M. Geiser, director of the Fusarium Research Center at Pennsylvania State University, has said that two of the Fusarium strains involved are commonly found in sinks and drains.

Despite less healthcare expenditure, the English are healthier than Americans

May 3, 2006: Evaluation of biological disease markers and self-reported disease prevalence rates for non-Hispanic whites aged 55 to 64 years in the US and England showed that, despite higher expenditures on health, persons in the United States reported more disease and had more adverse biological disease markers than persons in England at all levels of education and income.

Planning for pregnancy - CDC recommendations

April 24, 2006: The CDC (the US Government's Centers for Disease Control) has issued 10 recommendations to improve the health of women of reproductive age before they become pregnant. Goals include educating the public in optimum reproductive behavior, providing preconception care services, active intervention if there was a previous adverse pregnancy outcome, and reducing disparities in pregnancy outcomes. The 10 recommendations are: 1) Encourage men and women to have a reproductive life plan. 2) Increase public awareness about preconception health. 3) Provide risk assessment and counseling during primary-care visits.  4) Increase the number of women who receive interventions after risk screening.  5) Use the time between pregnancies to provide intensive interventions to women who have had a pregnancy that resulted in infant death, low birth weight, or premature birth. 6) Offer one pre-pregnancy visit.  7) Increase health insurance coverage among low-income women.  8) Integrate preconception health objectives into public health programs. 9) Augment research. 10) Maximize public health surveillance. Preconception/Pregnancy risks include use of isotretinoins (e.g., Accutane), alcohol misuse, anti-epileptic drugs, diabetes, folic acid deficiency, hepatitis B, HIV/AIDS, hypothyroidism, maternal phenylketonuria (PKU), rubella seronegativity (indicating need for rubella vaccination), obesity, the oral anticoagulant Coumadin (warfarin), STD (e.g., chlamydia and gonorrhea), smoking, oral health.

The Challenge of Subgroup Analyses - Reporting without Distorting

April 20, 2006: Three of the commonest errors in clinical studies are: 1) not prespecifying the primary endpoint, 2) assignment of causal relationships from observational studies, and 3) inappropriate analyses of subgroups from clinical trials. The latter problem is elegantly discussed in this week's New England Journal of Medicine by Stephen Lagakos who explains that subgroup analyses are commonly overinterpreted and that this may lead to further research that is misguided, and to suboptimal patient care. Appropriate subgroup analysis methodology has been available for many years, but is frequently ignored in publications even in the top medical journals. "Authors and medical journals have a responsibility to ensure that the reporting of subgroup analyses is transparent. Ignorance of the total number of subgroup analyses, which ones were prespecified and which were post hoc, and whether any were suggested by the data makes it very difficult to interpret the reported results. When an interaction test for a baseline variable fails to reach the appropriate threshold for significance, conclusions about a differential treatment benefit related to this variable should be avoided or presented with caution.... Overstating the results of subgroup analyses can misinform future research and lead to suboptimal clinical practice. Yet avoiding any presentation of subgroup analyses because of their history of being overinterpreted is a steep price to pay for a problem that can be remedied by more responsible analysis and reporting."

Compression stockings during air travel reduce leg thrombosis, leg discomfort and swelling

April 20, 2006: Those who wear compression stockings (sometimes called 'flight socks') during air travel reduce by 90% the risk of DVT (blood clots in the legs). The stockings are worn throughout the flight and are similar to those known to be effective in patients lying in bed after an operation. People who wore stockings also had much less discomfort and swelling in their legs (edema) than those who did not wear them. These conclusions were based on a meta-analysis of nine trials, which studied over 2800 people about half of whom were randomly assigned to wearing stockings for a flight lasting at least seven hours while the other half did not.

Prevent Jet Lag using British Airways Jet Lag Advisor

April 11, 2006: A 1,000 air passenger study by the Edinburgh Sleep Center in Scotland found that for every hour difference when you travel westwards it takes a day to recover from the effects of jet-lag (if you don't take steps to prevent jet lag). Flying eastwards results in much less jet lag. If you alter your light patterns, you can tweak your body-clock to adjust to new time zones more easily. One of the simplest methods is just to wear sunglasses at certain times, usually in the aircraft and for the first 2 hours after landing. The Jet Lag Advisor tells you when to wear them and when to be exposed to light. Eating and sleeping at the times appropriate to your new destination can also help. People flying a long distance for a business meeting should make sure it does not take place when they are at their lowest ebb - normally three hours before their normal waking up time.

Bird flu vaccine may protect 55-60% of those people vaccinated 

March 30, 2006: A study of a bird flu (H5N1 virus) in 451 healthy adults showed that about 55-60% people would be protected, as assessed by measurements of immune response (neutralization antibody titers & hemagglutination-inhibition titers). The vaccine appeared safe and fairly well tolerated. The authors of the paper suggested that H5N1 "prepriming", perhaps by including an H5 component in the annual vaccine, could increase the degree of protection from later doses of the vaccine.

FDA approves flu drug that protects against seasonal flu and bird flu 

March 30, 2006: FDA has approved zanamivir (Relenza) for the treatment and prevention of influenza (flu) in adults and children aged 5 and older. Administration is by inhaler, and it is not recommended for patients with lung disorders such as asthma or chronic obstructive pulmonary disease. It appears active against the normal seasonal influenza viruses as well as against the current strain of H5N1 bird flu virus.

Can clinical trial endpoints be added after the clinical trial begins? 

March 24, 2006: The PROactive Study Executive and Data & Safety Monitoring Committees have published a letter (to appear in the March 25, 2006 issue of The Lancet) that takes the position that “Although relatively uncommon, it is legitimate for the endpoints of a study to be amended as the study progresses, providing it is agreed and documented before any knowledge of unblinded data by the trialists. This situation is more likely when the study is of long duration and results of contemporary studies become available.” TMT's initial thinking is to disagree with the views of these distinguished Committees and Committee members. However, the arguments are fairly subtle and the views of our readers would be welcome (email comments to info@masterdocs.com). 

There are two main questions:  

Question 1: Can examination of blinded data before endpoint selection cause bias?

• Let’s assume that the Data Safety Monitoring Board (DSMB) is keeping track of a large number of safety parameters for an ongoing study of a drug versus placebo.
• Assume that patients enter the study with normal liver function tests and that 20 of these parameters define various measures of liver function that are considered to represent possible liver toxicity – say: elevation of SGOT above 100; doubling of SGOT; some specified change in SGPT, alkaline phosphatase or bilirubin; elevation of both SGOT and SGPT; elevation of SGOT, SGPT and alkaline phosphatase; etc..  
• Assume that the DSMB analyses the blinded data and selects from the 20 liver parameters, a single parameter on the basis that it shows an unexpectedly large number of events in the blinded data (and thus the event rate is likely to show a significant difference between groups if a true difference exists).
• Assume that the DSMB now includes that liver parameter as a “prespecified” endpoint of liver toxicity for the ongoing study.
• The DSMB has now selected the single parameter that is most likely to show a difference between the drug and placebo treatment groups from the 20 available parameters. However, the requirements for rejecting the null hypothesis for a single parameter are much less demanding than for rejecting the null hypothesis for one of 20 parameters. Traditionally, this problem of multiple testing is handled statistically using techniques such as Bonferroni bounds that scale the smallest p-value (representing the strongest evidence against the null hypothesis) by the number of tests under consideration (which in this case should be 20) so as to obtain an upper bound on the probability that the most extreme result does not reject the null.
• When the study is published, a significantly lower adverse liver event rate with the drug versus placebo is likely to be discarded as a statistical fluke, whereas a finding of a “significant” p value (without Bonferroni’s correction) is likely to be accepted by readers who will view the apparent increased adverse liver event rate with concern, particularly if it is reported as being a prespecified endpoint rather than the result of an exploratory post-hoc analysis.

Question 2: Can examination of data from other studies before endpoint selection cause bias?

• This is a slightly more subtle situation but, in TMT’s view, similar considerations apply.
• One can imagine a situation in which, following the report of a new finding in some outside publication, the DSMB examines the blinded database to evaluate whether enough events are occurring to provide a reasonable chance of the ongoing trial duplicating the outside finding. If so, they insert a test of this finding as a “prespecified” endpoint. If not, they don’t.

This situation is one of “cherry picking” the parameters to be statistically tested after data giving information about the probability of a significant finding have been examined. You can’t have your cake and eat it too – there is a statistical price to pay for examining a large number of parameters, and you can’t try to avoid paying that price by just ignoring the ones that don’t look significant. It is TMT’s view that prespecified endpoints should be specified (and specified unambiguously) before any data (blinded or unblinded) are examined, and ideally before data collection begins. The views of our readers would be welcome (send email comments to info@masterdocs.com).

Bird flu virus stays deep in the lungs, preventing human transmission by coughing or sneezing 

March 23, 2006: The current bird flu H5N1 virus affects cells deep in the lungs and this makes human-to-human transmission difficult. In contrast, the normal seasonal human flu virus affects cells in the upper respiratory tract making it easy to transmit the virus by coughing and sneezing. Experts differ as to the likelihood of the bird flu mutating sufficiently to cause a human pandemic.

Two separate H5N1 bird flu strains have evolved, but not yet a strain allowing human-to-human transmission 

March 20, 2006: Two genetically distinct strains of the H5N1 bird flu virus have emerged and this could complicate the development of a vaccine to prevent a human flu pandemic. However, the bird flu virus has not yet mutated to a form that facilitates human-to-human transmission (which would be required before a human flu pandemic could occur). U.S. Interior Secretary Gale Norton said that it was “increasingly likely” that bird flu would be detected in the U.S. as early as this year, but that this would not signal the start of a human pandemic.

Misdiagnosis occurs in 20% of fatal illnesses 

February 23, 2006: Autopsy studies have shown that 20% of patients with fatal illnesses are misdiagnosed. An article in the Journal of the American Medical Association suggests that this may be partly because doctors are paid according to the tests and treatment they give, rather than according to the accuracy of the diagnosis. Two approaches have been suggested to improve the situation. In one approach Medicare and some insurance companies are experimenting with pay-for-performance programs. A second approach harnesses the power of computers to increase diagnostic accuracy. Isabel Healthcare provides an award-winning diagnostic program but is expensive ($80,000 a year for a typical hospital and $750 for an individual doctor). Free questionnaires are also available on the Internet (Masterdocs.com) and generate a detailed report for review by the doctor.

Lack of flu shots in healthcare workers increases patient risk 

February 21, 2006: Although workers involved in healthcare are advised to get a flu shot each year, less than 40% do so. In a Scottish nursing home study, raising the immunization rate among health care workers to about 50 percent from 5 percent was associated with a drop of about 40 percent in deaths among patients.

Poverty associated with poor health and increased death rates 

February 21, 2006: A new 30,000 patient study reported in JAMA adds to evidence from previous studies that poverty is associated with poor health and increased mortality. Each patient had a treadmill exercise test and was allocated to a socioeconomic group based on home address. Patients in lower socioeconomic groups had poorer treadmill performance even after controlling for age, race, smoking and weight. During an average follow-up of 6 1/2 years, patients in the lowest quarter of socioeconomic status score had twice the death rate of those in the highest quarter, even though the two groups did not differ in age, sex, race or current smoking habits.

Partners of Hospitalized Spouses at Greater Risk for Early Death  

February 16, 2006:  A study in the New England Journal of Medicine reported that, for older couples,  if one of the partners is hospitalized for a debilitating illness, the non-hospitalized partner is at increased risk for death.  The risk in the first 30 days was almost as much as is associated with the death of a spouse, although for the 9 years follow-up in this study the risk increase was smaller (22% for men and 16% for women compared with those whose spouse died) . In both cases, family support and social support services are advisable. Age averaged 75 for men and 73 for women. Risk appeared greatest when hospitalization was because of a debilitating illness such as dementia, a psychiatric disease, or hip fracture.

Development and Validation of a Prognostic Index for 4-Year Mortality in Older Adults

February 15, 2006: JAMA. 2006;295:801-808. Using the 1998 wave of the Health and Retirement Study (HRS), a population-based study of community-dwelling US adults older than 50 years, a prognostic index was developed from 11 ,701 individuals and validated with 8,009. Individuals were asked about their demographic characteristics, whether they had specific diseases, and whether they had difficulty with a series of functional measures. The overall response rate was 81%. During the 4-year follow-up, there were 1361 deaths (12%) in the development cohort and 1072 deaths (13%) in the validation cohort. Twelve independent predictors of mortality were identified: 2 demographic variables (age: 60-64 years, 1 point; 65-69 years, 2 points; 70-74 years, 3 points; 75-79 years, 4 points; 80-84 years, 5 points, >85 years, 7 points and male sex, 2 points), 6 comorbid conditions (diabetes, 1 point; cancer, 2 points; lung disease, 2 points; heart failure, 2 points; current tobacco use, 2 points; and body mass index less than 25, 1 point), and difficulty with 4 functional variables (bathing, 2 points; walking several blocks, 2 points; managing money, 2 points, and pushing large objects, 1 point. Scores on the risk index were strongly associated with 4-year mortality in the validation cohort, with 0 to 5 points predicting a less than 4% risk, 6 to 9 points predicting a 15% risk, 10 to 13 points predicting a 42% risk, and 14 or more points predicting a 64% risk. The risk index showed excellent discrimination with a c-statistic of 0.84 in the development cohort and 0.82 in the validation cohort. The authors conclude: "This prognostic index, incorporating age, sex, self-reported comorbid conditions, and functional measures, accurately stratifies community-dwelling older adults into groups at varying risk of mortality".

6-Months Breast Feeding may Reduce Respiratory Infections

February 8, 2006: Breastfeeding for a full six months (the American Academy of Pediatrics' current recommendation)  may protect infants from respiratory illness during the first two years of life. Babies breastfed for only four to less than six months were more than four times as likely to develop pneumonia and during their first two years and nearly twice as likely to have otitis media (middle ear infection). Although the analysis adjusted for known risk factors such as age and exposure to cigarette smoke, it should be noted that such observational studies do not allow definitive conclusions about group differences.

Oral Vaccine for Diarrhea in Infants approved by FDA

February 7, 2006: The FDA today approved an oral liquid vaccine aimed at preventing rotavirus, which causes severe diarrhea, and fever and dehydration in infants and results in an estimated 55,000 hospitalizations in the U.S. each year. Three doses are given between 6 and 32 weeks of age.

Travelers to exotic locations face health risks    

Jan. 17, 2006: Foreign travel is on the rise (760 million people in 2004). Each year, about 8 percent of the more than 50 million travelers to developing countries become sick enough to seek health care during their trip or when they return home. Depending on the destination, up to two-thirds become sick, most with short-lived diarrhea, skin problems and respiratory infections. Malaria and dengue fever in Africa or Southeast Asia. Infections from worms and other parasites in the Caribbean and South America. In south-central Asia, respiratory illness. More than one-third of the patients became sick over a month after they got back, and one in 10 fell ill more than six months later. Many had lingering diarrhea from infections by parasites, now more common than bacterial diarrhea; dengue fever has become more prevalent than malaria in most regions; and infections from tick bites are now a big problem in sub-Saharan Africa.

This Season's Flu Virus Resistant to Two Standard Anti-Viral Drugs    

January 15, 2006: This season's flu virus is resistant to two older drugs (amantadine and rimantidine) and these should not be used for prevention or treatment of this season's flu. The newer drugs oseltamivar (Tamiflu) and zanamivir (Relenza) should be used when anti-viral drugs are required for prevention or treatment. For most people, the best way to prevent the flu is to get an annual flu shot.

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