Ever wonder how safe and reliable Granny’s new pacemaker is? In most cases it turns out nobody really knows, because the quality of the evidence used by the FDA to approve these devices is poor, according to a study published in JAMA last week.

Sanket Dhruva and colleagues from UCSF drew these conclusions after examining the premarket approval process (PMA) for 78 high-risk cardiovascular devices that received FDA approval between January 2000 and December 2007.

PMA is the most stringent FDA review process for medical devices. The scientists found that 65% of the PMA applications for devices were supported by exactly one study.

And overall, the quality of the studies was abysmal. Some failed to provide details like the number of enrolled participants. Only 27% of them were randomized and even less, 14%, were blinded (blinded, randomized, controlled trials represent state-of-the-art scientific research).

The scientists concluded that in general, the FDA’s premarket approval process for cardiovascular devices lacked statistical firepower required to control for bias and hence draw valid conclusions.

The scientists understood that it is more difficult to subject medical devices to blinded studies, since there is no way to produce a “sugar pill” (that is, placebo) for medical devices.

“But we were surprised that so many devices were approved on the basis of a single study,” Dhruva told the Los Angeles Times.

The FDA started approving medical devices in 1976. Recently, there has been a marked increase in the number of cardiovascular devices implanted in Americans.  In 2008, 1.2 million people received stents in the US alone. 350,000 people received pacemakers and 140,000 received implantable cardioverter-defibrillators.

When the so-called “atypical antipsychotic” drugs hit the market 15 years ago, psychiatrists and PCPs began prescribing them like crazy for schizophrenia and bipolar disorder.

They were motivated the poor side-effect profile of previously available drugs, and encouraged by relentless and occasionally unscrupulous marketing campaigns promulgated by drug makers and paid clinical spokespeople.

Last year, the drugs generated $14.6 billion in US sales alone, according to IMS Health.

Unfortunately, the newer drugs proved to be, at best, marginally more effective than their older, cheaper brethren, and have a nasty tendency to promote weight gain and diabetes, particularly in children—for whom they are rarely indicated, according to the FDA.

Now, Christolph Correll and colleagues at Feinstein Institute for Medical Research have quantified the weight gain problem, and it’s a lot.

According to their report in JAMA, atypical antipsychotic drugs caused youths between the ages of 4-19 years old to gain up to 19 pounds on average in just 11 weeks.

“The weight gain is much larger than we thought,” Correll told the Wall Street Journal. “It’s massive, and it’s the medication” that caused it, he added.

Correll’s study involved 272 youths who were seen at semi-urban, tertiary care, academic inpatient and outpatient clinics. It included the 4 top-sellers in the space: Zyprexa (Lilly), Abilify (BMS), Risperdal (J&J) and Seroquel (AZ). Participants had not taken the drugs previously.

Of the 4, Zyprexa caused the most weight gain—nearly 19 pounds—a 15% increase over baseline. The corpulence was associated with significant increases in glucose and cholesterol levels.

The other drugs caused weight gains between 10-13 pounds on average, and had variable effects on glucose and cholesterol.

The scientists encouraged physicians to be extremely careful when prescribing these drugs to youths and to check their patients’ weight and blood tests every 3 months.

The FDA will soon decide whether to approve these drugs for use in youths. Any bets how that turns out?

The Mediterranean diet may protect against age-related cognitive decline, according to 2 studies published in JAMA.

The diet, which is long on vegetables, fruits, whole grains and fish, and short on red meat and poultry, has already been lauded for its cardio-protective and cancer preventing effects.

The first of the 2 studies, organized by Nikolaos Scarmeas and colleagues at Columbia, showed that the diet and physical activity were independently associated with a reduced risk of Alzheimer’s disease.

Scarmeas’ team enrolled 1,880 older patients with no cognitive impairment at study onset, and performed neuropsychological testing every 18 months for a mean follow-up of 5.4 years.

Alzheimer’s disease was diagnosed in 282 subjects during the study. Subjects who followed the Mediterranean diet were 40% less likely to develop Alzheimer’s than those who did not.

Similarly, a high amount of physical activity, which the scientists defined for this elderly population to be 1.3 hours of vigorous, 2.4 hours of moderate, or 4 hours of light physical activity per week, cut the risk of Alzheimer’s by 33%.

In the second study, Catherine Feart and colleagues at Universite Victor Segalen showed that the Mediterranean diet slowed cognitive decline, though it did not decrease the risk of dementia per se.

In particular, Feart’s team found that those adhering to the diet had fewer errors on the Mini Mental State Examination, but performed no better on 3 other tests of cognition.

In an accompanying editorial, the Mayo Clinic’s David Knopman said the 2 studies “provide moderately compelling evidence that adherence to the Mediterranean-type diet is linked to less late-life cognitive impairment.”

Whether these findings “should be translated into recommendations for the public is the question,” added Knopman. “For now, it is reasonable to nibble on these findings and savor them, but not to swallow them whole.”

Hospitalized Medicare beneficiaries are far less likely to be seen in house by their PCP than they were 10 years ago, according to Gulshan Sharma and his team at the University of Texas medical Branch of Galveston.

The findings raise concern about continuity of care as various payment reforms and the hospitalist movement change longstanding routines.

The scientists reported that in 1996, 51% of hospitalized Medicare patients were seen by at least one physician that had seen them as an outpatient in the preceding year.

In 2006, that number had dropped to 40%.

To reach these conclusions, the scientists utilized a retrospective cohort trial design involving 3,020,770 hospital admissions from over a 2 year period, representing a 5% national sample of Medicare beneficiaries.

The write-up is in JAMA.

Using multivariable, multilevel models, the scientists ascribed about a third of the lost continuity to the hospitalist movement. Medicare payment formulas discourage PCPs from visiting their hospitalized patients when hospitalists are on the case.

Patients admitted on weekends, or who lived in large metropolitan areas or in New England experienced greater losses in contact with their outpatient physicians during the study period.

For its study, Sharma’s team posited that continuity of care included 3 dimensions: continuity in information, continuity in management, and continuity in the patient-physician relationship.
 
The team recommends further study to determine whether the reduced continuity of care has detrimental effects on patient outcomes, and that interventions be developed which would mitigate any such untoward effects.

Outcomes data can be confounded by patient factors like burden of illness, and they are time consuming and expensive to collect.

That’s why many quality measurement programs focus on process quality and cross their fingers that the link between process and outcomes actually holds true.

Uh, guys…can we huddle up a minute?

Leslie Kernisan and colleagues at UCSF just finished a study to determine whether performance on a set of process measures known as Safe Practices for Better Healthcare could predict hospital mortality.

They couldn’t.

Hospitals with higher scores on the Safe Practices indices did not have lower inpatient mortality than those with lower scores. Progressing from the worst to the best quartile on Safe Practices, inpatient death rates bounced around from 1.97% to 2.04%, to 1.96% to 2.00%.

Data from more than 1,000 hospitals were analyzed. These data were adjusted for patient and hospital variables that could impact the results.

“It is possible that inviting hospitals to self-report on their patient safety practices and then assigning them to quartiles of score is not an effective way to assess hospital quality and safety,” stated the authors.

That may be, but it’s more likely that inpatient mortality rates are not sensitive enough as measures of quality. Before throwing in the towel on these process measures, scientists would be wise to see how well they predict other, more sensitive outcome measures like readmission rates, functional status at discharge and 6 months, and so forth.

Then again, they could be lousy process measures, or the data collection tools could have been flawed.

The Safe Practice Guidelines have been endorsed by the National Quality Forum. The write-up appears in JAMA.

That story about heartburn drugs like Nexium, Prilosec and other proton-pump inhibitors interfering with the cardio-protective effects of Plavix is growing legs.

Before Thanksgiving, Medco Health Solutions presented the results of a retrospective study of Plavix following stent placement and angioplasty.

In the study, patients taking PPIs and Plavix sustained 50% more heart attacks and other cardiac events than those just taking Plavix.

Now, Michael Ho and colleagues from the Denver VA are reporting that acute coronary syndrome patients who received both drugs had a 25% higher risk of death or readmission for the same syndrome as those receiving Plavix alone.

64% of the patients in Ho’s study were discharged on both drugs. 

Ho’s study was also retrospective. It appears in JAMA.

The authors concluded that PPIs should only be prescribed for Plavix-popping patients who have a “a clear indication for the medication” rather than using them prophylacticly, as has become common.

There are theories to explain the association. One fingers common metabolic pathways in the liver. Another proposes that the PPIs directly interfere with Plavix’ antiplatelet effects.

But it’s also possible that PPI use is nothing but a marker for sick patients who are more likely to have a lousy outcome anyway.

Issam Moussa of Weill Medical College at Cornell observed in fact that the patients who received PPIs in Ho’s study “were older, and had more comorbidities than patients who didn’t.”

The controversy moved the Brigham’s Chris Cannon to review data from his prospective CREDO study, which showed Plavix to be useful following coronary stenting.

Cannon’s review turned up “no evidence of increased risk for (the combo),” so now the whole thing is a mess.

Plavix is co-marketed by Sanofi-Aventis and Bristol-Meyers Squibb.

It did $4 plus billion in sales last year.

AZ’s Nexium came in at $5.5 billion.

A diet rich in beans and nuts has outperformed the long recommended whole-grain diet for people with Type 2 diabetes, according to a study in the Journal of the American Medical Association.

Scientists led by David Jenkins at the University of Toronto reached this conclusion after following 210 patients that had been randomly assigned to one diet or the other.

Both diets were low in trans and saturated fat. Both groups were instructed to consume 8 servings of vegetables and fruit per day (who does this?).

The bean and nut diet causes mild excursions in blood glucose after meals, and is therefore described as having a low glycemic index. It features beans, lentils, peas, pasta, rye and pumpernickel breads, as well as oatmeal and oat bran cereals.

The high-cereal high fiber diet emphasizes “brown foods” like breakfast cereal, whole-grain bread, potatoes with skin and brown rice.

The scientists found that participants consuming the bean and nut diet experienced a 0.5% decrease in mean hemoglobin A1C levels — a measure of diabetes control in recent months, as well as a rise of 1.7% in their HDL (good) cholesterol levels.

Those consuming a whole-grain diet had less than half the beneficial reduction in hemoglobin A1C and an actual drop of 0.2% in HDL cholesterol.

 “That’s…important… because there’s a double whammy for people who are diabetic,” Jenkins told the New York Times. “If they’re men, they have twice the risk of heart disease. Women have 4 times the risk. If you can hit the heart disease, you may have something useful.”

Jenkins then added, “Pharmaceuticals used to control Type 2 diabetes have not shown the expected benefits in terms of reducing cardiovascular disease.”

“We’ve been telling people to eat whole grains for a long time,” said Emmy Suhl, a nutrition and diabetes educator at the Joslin Diabetes Center in Boston.  “This study shows, it’s not enough to have whole grains. Low-glycemic carbohydrates do a better job.”

Sleep duration is correlated with risk of developing coronary artery disease, according to a study published in the Journal of the American Medical Association.

To reach this conclusion, Diane Lauderdale and colleagues at the University of Chicago implemented a prospective, observational study of 495 participants between the ages of 35 and 47 that had no coronary artery calcifications as determined by computed tomography.

The scientists assessed sleep duration and quality using motion sensing devices and questionnaires.

Overall 12.1% of study participants developed coronary artery calcifications during the 5-year study.

That number was 27% for those getting less than 5 hours of sleep per night and only 6% in those who slept 7 hours or more per night.

Thus each extra hour of rack time was associated with a 33% decline in the risk of developing coronary artery calcifications.

The findings were present in both sexes and not impacted by race or the presence of other cardiovascular risk factors.

Lauderdale told MedpageToday that “the magnitude of the observed effect was similar to sizable differences in established coronary risk factors.”

“It’s important to say that…this does not yet prove the association is causal,” Lauderdale told the New York Times. “Until we know what the mechanism is — that it’s really a direct or a causal relationship — there is no point in making recommendations based on this.”

Sanjay Patel, a sleep expert at Case Western Reserve University echoed this conclusion. “It’s possible,” he told the Times, “that people who are under more stress may be both sleeping less and at higher risk of heart disease.”
 
“If we got those people to sleep more but they still were under a lot of stress, it wouldn’t change their risk of heart disease,” he added.

In 1960, 13% of US adults were obese. Now it’s 31% and it’s looking like obesity might surpass cigarette smoking as the numero uno preventable cause of premature death.

How can we get people to get serious about losing weight?

Kevin Volpp and colleagues at the University of Pennsylvania thought why not try financial incentives and you know what? They worked like a charm.

The scientists randomized 57 obese healthy male volunteers aged 30-70 years to either of 2 incentive programs or a control group. The goal was to lose 16 pounds in 16 weeks.

In both incentive schemes, participants had to pay to play and could only win if they met weight loss targets during the study. The first involved a cash lottery. In the second, players doubled their money straight-up if they met the targets.

In both schemes, the payout came out to about the same, $300 per qualifying player. The control group received educational materials and monthly weigh-ins.

At the end of 16 weeks, only 10% of the controls achieved the weight loss target. Fully half those in each incentive group made it and the difference was significant.  The findings were not impacted by age, income or initial BMI.

At 7 months, scientists found that the weight of control group participants had returned to pre-study values. Weight of participants in the incentive groups was significantly below baseline levels, although they had packed on some pounds since the study ended.  

And almost no one in the incentive groups was lost to follow-up!

Scientists will want to study the long-term benefits of incentive programs, determine whether the findings can be generalized to women and assess program cost-effectiveness but yea, we know how get their attention all right!

Nine months after the FDA approved Genentech’s cancer-fighter Avastin for advanced breast cancer, scientists reported that it increases the risk of venous thromboembolism (VTE), a potentially serious side-effect.

Shobha Nalluri and her group at Stony Brook University combined results from 15 randomized controlled trials of 7,956 patients that were treated for advanced solid tumors. Overall, 7.3% of the patients developed VTE, and those treated with Avastin had a 33% higher risk.

The increased VTE risk was observed regardless of the site of the primary tumor and the Avastin dosing schedule.

Last year, an FDA advisory panel voted 5-4 against approving Avastin for advanced breast cancer because the drug’s beneficial effects in slowing disease progression did not, in its opinion, outweigh its potential for causing cardiovascular complications and VTE. Approval was granted anyway.

The FDA had approved Avastin for colon and lung cancer in 2004. The drug works by choking off the blood supply to a tumor rather than killing tumor cells directly. Scientists had hoped Avastin could replace traditional cancer drugs which are debilitating and increase the risk of serious infections, but this has not turned out to be the case. Avastin is typically used in conjunction with old-school cancer fighters.

Annual treatment costs for Avastin can exceed $50,000 per year. Its 2007 sales were $2.3 billion.

Previous studies were too small to detect the adverse effect found in the present study.

Avastin’s label already warns about the risk of VTE, but the Stony Brook scientists suggest in their publication that a tougher, “black box” warning should be affixed.

Honey, what should we do with the Ginkgo biloba?

How many people are asking that question after scientists at the University of Virginia proved the popular plant supplement does not reduce the risk of developing dementia of any kind nor Alzheimer’s disease specifically.

Ginkgo also did not impede progression to dementia in those having mild cognitive difficulties to begin with.

Subgroup analyses of younger patients, older patients, both sexes and those with all degrees of baseline cognitive impairment all came up dry, and there was no impact on overall mortality.

Pretty much, the stuff didn’t work.

Steven T. DeKosky and colleagues randomized 3,069 community-dwelling people who were at least 75 years of age to receive either 120 mg Ginkgo twice a day or a placebo. 482 study participants had mildly impaired cognition at study onset. Participants were evaluated twice yearly during the 6-year study.

The results were just published in the Journal of the American Medical Association. 

Annual US sales of Ginkgo products are $250 million, driven by some bench research showing neuroprotective effects that have been attributed to flavonoids contained in Ginkgo, an animal study showing mild protective effects during a stroke, and good old-fashioned hope that it could improve or at least maintain memory.

The present study did not exclude the possibilities that starting the extract at a younger age or continuing it longer than 6 years might have beneficial effects, though these seem unlikely.

A second large, randomized trial of Ginkgo biloba is nearing completion. We’ll try to remember to look for it.

Twenty years ago, we were aware that US medical school graduates tended to enter disciplines having the highest earning potential. Since then, income disparity between specialists and primary care physicians has widened, and medical student debt has ballooned to an astounding median of $140,000 per graduating senior.

So there is no reason to be surprised by the results of a recently published survey of graduating students from 11 US medical schools. Only 2% of respondents to this survey indicated that they planned to work in primary care internal medicine. That’s down from 9% in 1990. This year, 2,600 fewer US doctors enrolled in primary care training programs than did so just 6 years ago. 

The survey revealed that low income is just one reason why US medical students steer clear of general internal medicine. They are turned off by heavy workloads, continuous hassling with insurance companies and inadequate ancillary support as well.

(more…)

Still not convinced about the benefits of exercise?

The second study published this week on the subject focused on elderly denizens of Perth, Australia who reported memory loss but did not meet criteria for dementia. These people were randomized to receive either routine care or a home-based intervention consisting of moderate physical activity. The latter typically involved three 50 minute walks per week. The patients were followed for 24 weeks and then assessed for cognitive function using the Alzheimer’s Disease Assessment Scale. Assessors didn’t know which group the subjects were assigned to. 

Investigators found that patients in the treatment group improved their cognitive performance scores vs. their baseline performance, whereas those in the control group lost ground compared with their own baseline. The performance gap between groups was significant and it persisted for 18 months after the study concluded.

This study is the first randomized trial showing beneficial effects of physical activity in the population studied. Since randomized trial designs provide the most rigorous test of clinical hypotheses, a positive result here is particularly noteworthy.

Still can’t get off the couch? Two studies published this week (covered in this post and the next) might get you going, as they provide fresh evidence regarding the benefits of physical activity.

In the first one, investigators studied a group of Amish people who had particularly potent genetic versions of an obesity-producing gene known as FTO. The gene is common in people of European descent.

Was it their fate to be overweight? Actually, no.

The investigators categorized the group by activity level, and found that those who were very physically active (farmers, for example) weighed the same as those without the gene. Those in the least active category were overweight or obese most of the time. Exercise trumped the obesity gene!

The active group burned about 900 calories per day more than the sedentary group, which is the equivalent of walking 3-4 hours per day. That’s not going to be possible for many people. Nevertheless, the investigators called for more bike paths, better public transportation systems and private sector initiatives that would foster increased physical activity on a broad scale.

People who purchase Ayurvedic medicines online may want to consider buying something else.

That’s because Boston University scientists tested 200 Ayurvedic products purchased over the Internet, and found that 20% of them contained detectable levels of arsenic, lead or mercury. Sometimes the levels of these metals were dangerously high.

Ayurveda is an herbal-based health practice that began 2,000 years ago in India. Its origins are linked to the legendary Dharvarhari (pictured) who received insights directly from Brahma, the Hindu god of creation. More than 80% of Indians practice Ayurveda right now, and the practice has gained popularity in the US.

Ayurvedic medicines are categorized into herbal only and Rasa Shastra by the methods used to prepare them. To create Rasa Shastra medicines, practitioners deliberately add metals, gems and minerals to the herbs.

The BU investigators found that samples from both categories of Ayurvedic medicines contained toxic metals, but the Rasa Shastra samples were twice as likely to contain them, and they contained higher levels of the metals.

Rasa Shastra practitioners believe their medicines are safe if prepared properly. The BU researchers think otherwise. They want regulators to establish “safe levels” of these toxic metals in herbal supplements and require that manufacturers get their products tested before they are released to market.