For the second time this year, a clinical trial has shown that the cholesterol-lowering drug Zetia does not prevent heart disease.  

The first trial appeared last January. That trial compared Vytorin—a blockbuster drug that combines  the active ingredient in Zetia with a generic cholesterol-buster known as simvastatin—against simvastatin alone in patients with a genetic condition causing them to have very high levels of LDL (bad) cholesterol and premature cardiovascular disease.

In that trial, Vytorin reduced LDL cholesterol levels much more than simvastatin alone but surprisingly, atherosclerotic plaques actually grew faster in the coronary arteries of the patients taking Vytorin.

The news was greeted with a precipitous fall in prescription volume for both Zetia and Vytorin.

The second study was published last week in the New England Journal of Medicine. This study compared Zetia to Niaspan, a drug that raises blood levels of HDL (good) cholesterol.

In the second study, Allen Taylor of the Walter Reed Army Medical Center and colleagues enrolled 363 people with coronary artery disease that had been taking statins for many years. 

Taylor’s group found that Niaspan shrank carotid artery plaques by 2%, but Zetia had no such effect, even though it effectively reduced cholesterol levels (as it did in the first trial). In addition, patients who received Niaspan sustained 2 heart attacks or heart-related deaths during the study, while 9 patients receiving Zetia suffered that outcome, a significant difference.

Zetia “should be better for the arteries and it wasn’t,” Taylor told reporters covering last month’s American Heart Association meetings. “The drug wasn’t operating as you would expect.”

Officials at Merck, which co-markets Vytorin, said the study wasn’t large enough to draw firm conclusions and that larger trials of a similar nature are underway. Stay tuned.

Fourteen years ago, Harvard researchers revealed that insurance companies were big-time investors in tobacco companies. The seemingly hypocritical position prompted outrage and calls for them to divest.

But when the same scientists recently re-examined the matter, they found the industry had failed to kick the habit.

By reviewing SEC filings and news reports from 2008, J. Wesley Boyd and colleagues determined that US, UK and Canadian-based insurance companies owned at least $4.4 billion worth of stock in companies whose subsidiaries produce cigarettes, cigars, chewing tobacco and related products.

“Despite calls upon the insurance industry to get out of the tobacco business by physicians and others, insurers continue to put their profits above people’s health,” Boyd told Medical News Today. “It’s clear their top priority is making money, not safeguarding people’s well-being.”

The World Health Organization estimates that tobacco products contribute to 5.4 million deaths per year worldwide.

New Jersey-based Prudential Financial Inc., which markets life and disability insurance, has holdings in tobacco firms like Reynolds American and Philip Morris, that total $264 million.
 
These numbers are dwarfed by Toronto-based Sun Life which sells health, disability, life and long-term care insurance. It owns just north of $1 billion in tobacco company stock.

Meanwhile, London-based Prudential Plc, which offers disability, health and long-term care insurance, holds $1.38 billion in British American Tobacco and other such companies.

“Insurance firms have figured out ways to profit from both… investing in tobacco (and) selling life or health insurance. (They) exclude smokers from coverage or, more commonly, charge them higher premiums. Insurers profit -- and smokers lose -- twice over,” wrote the authors.

Boyd’s group first reported on the matter in a 1995 Lancet article.

For years, physicians have debated when to start therapy for HIV-infected patients. Starting it early might delay, perhaps indefinitely, progression from a quiescent carrier state to the full blown syndrome, but it exposes patients to unpleasant, sometimes life-threatening side effects.

A study by Mari Kitahata and colleagues may have settled the argument in favor of early drug treatment.

The scientists tracked survival in 17,517 asymptomatic HIV-infected patients who started antiretroviral therapy at different points in the course of their disease, as determined by serum CD4 cell counts.

About a quarter of the subjects began therapy when their CD4 counts were in the 351- 500 range, and the remainder started therapy only after counts dropped to 350 or less.

The mortality risk was 69% higher in the latter group. These findings were confirmed in a second, separate cohort.

The write-up appears in the New England Journal of Medicine.

“This has been one of the most important questions in the last decade: what the optimal timing is for starting therapy,” Kitahata told the New York Times.

“Our study provides evidence that patients would live longer if antiretroviral treatment was begun when their CD4 count was above 350,” added Kitahata, who is director of clinical epidemiology at the Center for AIDS and STDs at the University of Washington.

National guidelines recommend beginning therapy in asymptomatic patients when CD4 counts drop below 350.

Women who took valproate during pregnancy had children with lower IQ scores than those who used a different antiseizure medication, according to scientists at Emory University.

Valproate, available generically or under the brand name Depakote, is the second-most-popular drug for the treatment of epilepsy.

Earlier studies had shown it to cause developmental delays and malformations in the offspring of pregnant women.

To reach these conclusions, Kimford Meador and colleagues recruited 303 pregnant women that took drugs to control epilepsy from 25 medical centers in the US and the UK between 1999 and 2004.

They performed cognitive assessments on 258 2- and 3-year-olds born to these mothers, 53 of which had taken valproate.

They found that kids whose moms had taken valproate while pregnant had a mean IQ of 92. Kids that had been exposed to lamotrigine, phenytoin and carbamazepine in utero had mean IQs of 101, 99 and 98, respectively.

Overall, there was a strong correlation between the IQs of kids and their mothers, but this relation was not present in the offspring of mothers taking valproate.

The write-up appears in the New England Journal of Medicine.

Valproate is also widely prescribed for migraines, pain and psychiatric disorders although people taking the drug for these indications were not enrolled in the study.

The study authors warned against using valproate as first-line therapy for seizure control in women of childbearing age.

“If I (use another drug) and the patient has a breakthrough seizures, I can switch the patient to valproate,” said Meador reasoned for the New York Times. But “If I put the patient on valproate as a first choice and the baby has cognitive impairment or a malformation, I can’t repair that.”

Just 6 years after scientists decoded the human genome, a line of research derived from the breakthrough known as personal genomic medicine is increasingly perceived to be an expensive bear with an uncertain future, according to commentaries in the New England Journal of Medicine.

Since the heralded announcement in 2003, geneticists have undertaken hundreds of genomewide association studies designed to compare the DNA of healthy people with those of patients having specific diseases.

The hope was to pinpoint a handful of culprit genes and by association, biochemical processes that could become targets for disease-modifying drugs, immune therapy or what have you.

But the studies appear capable of explaining just a fraction of the genetic component underlying complex diseases like cancer, schizophrenia and diabetes.

The problem, it seems, has been the assumption that such conditions were promoted by variations in a small number of genes, say 10. Instead, thousands of genes appear to be involved, with multiple variations at each locus exerting myriad effects on other genes and their variants.  

The snafu represents a setback for personal genomics companies that hoped to inform customers about their risk for these diseases.

“With few exceptions, what the genomics companies are doing right now is recreational genomics,” Duke University geneticist David Goldstein told the New York Times. “The information has little or…no clinical relevance.”

In his NEJM piece, Goldstein therefore recommends a strategic shift in genomics research towards decoding the entire DNA of patients with certain diseases.

But Peter Kraft and David Hunter of the Harvard School of Public Health, publishing in the same issue, remain optimistic about genomewide association studies.

“There will be more common variants to find,” Hunter told the Times. “It would be unfortunate if we gave up now.”

Scientists have known for 3 decades that brown fat acted like a furnace in mice, burning calories, generating heat and producing weight loss when stimulated by prolonged exposure to cold temperatures.

They also knew that human infants had a pretty good stock of these mitochondria-leaden cells, but they couldn’t find it in adults, and had assumed it disappeared as a byproduct of normal human development.

Now, scientists armed with PET scanners in 3 laboratories have found the stuff in adults, raising hope we can one day turn it on and trigger weight loss as a result.

The trio of studies appears in the New England Journal of Medicine.

The studies revealed that the quantity of brown fat tended to be higher in females and those who were thin, young, and had lower fasting blood glucose levels. It was lower in those taking beta blockers.

In the first study, Aaron Cypess and colleagues at Harvard reviewed over 1,000 PET scans performed for various reasons to localize brown fat deposits in adults. It turned up in unexpected locations like the side of the neck, upper back and near the spine and collarbone.

In the second study of 24 healthy male volunteers, van Marken Lichtenbelt and colleagues at Maastricht University showed that PET scans turned up negative for brown fat until subjects were placed in a chilly room for a few hours. Retesting the chilled subjects revealed brown fat in all but one.

This phenomenon was confirmed in a third study of 5 healthy adults by Vertanin and colleagues at the University of Goteborg.

The scientists now want to lean more about how to activate brown fat, and determine whether people would respond to such a provocation by simply eating more, which would pretty much nullify any beneficial effects.

The incidence of heart failure in young African-American adults is 20 times higher than that white age-matched counterparts, according to a study in last week’s New England Journal of Medicine.

Some black adults had actually died of heart failure a decade before the chronic illness even began to affect whites.

Kirsten Bibbins-Domingo and colleagues enrolled 5,115 18-30 year olds and managed to follow them for 2 decades in an effort to understand the causes and course of cardiac disease.

Because participants were so young at the time of enrollment, the scientists didn’t expect to see much at this juncture, but it turned out that 27 participants developed heart failure and all but one was black.

The scientists estimated the incidence of heart failure in blacks under the age of 50 to be 1%.

“Blacks in our study who were in their 30s and 40s had the same rate of heart failure as whites in their 50s and 60s,” Bibbins-Domingo told the New York Times.

“These people are in the prime of their life and should be contributing in all kinds of ways,” Bibbins-Domingo added. “So this disease has a devastating effect, not just on the individual but on the family, the community and society in general.”

Afflicted individuals of all races were more likely to have diabetes, hypertension, obesity and kidney disease. They also tended to have low HDL (good) cholesterol levels.

Eric Peterson, a Duke cardiologist who wrote an accompanying editorial on racial disparities in cardiac care thought the study was “remarkably important,” especially since heart failure is largely preventable.

“This shows you where having 20 years of uncontrolled blood pressure has effects, on kidney disease — and on the heart,” Peterson said. “It wears it out.”

Adding a skosh of reason to the endless cacophony emanating from Atkins advocates, Ornish impresarios  and South Beach braggadocios, scientists at the Harvard School of Public Health have shown they all work equally well and what really matters is total caloric intake…pure, plain and simple.

Frank Sacks and colleagues randomly assigned 811 overweight or obese men and women to one of 4 heart-healthy, reduced-calorie diets that differed in the proportions of carbohydrates, fats and protein.

They followed participants for 2 years, asking that they exercise for 90 minutes per week and inviting them to attend group support sessions along the way. There was some periodic individual counseling as well.

The dieters recorded details of their food intake and tracked progress on a Web site.

Eighty percent of the subjects hung in there for the duration. By 6 months they had lost an average of 13 pounds, and they weighed-in at a minus 9 soaking wet when the study ended.

But the key was that subjects in all 4 groups had lost the same amount of weight and reduced waist girth by the same 2 inches. And all 4 groups experienced similar, modest beneficial effects on serum cholesterol and triglyceride levels and blood pressure.

The most successful dieters were those who regularly attended counseling sessions. They were good for a drop of 22 pounds on average.

“It’s just the calories that count,” Sacks underlined for the Boston Globe.

“The most important thing…to lose weight is to choose a heart-healthy diet and to keep the amounts down.”

Still basking in the glow of their study showing that financial incentives helped obese volunteers lose weight, Kevin Volpp and Co. are reporting that cash rewards help people quit smoking cigarettes too.

Volpp’s team randomized 878 GE employees who smoked a pack-a-day into 2 groups.

Controls got information regarding smoking-cessation programs while the incentive group received up to $750 in cash as well.

Payouts to the incentive group participants were pegged to milestones: completing a stop-smoking program was worth $100, stopping smoking within 6 months of the enrollment date earned an additional $250, and continued abstinence for 6 months scored $400.

Claims by participants that they had quit were verified with cotinine tests. The study is in the New England Journal of Medicine.

The scientists reported that 14.7% of people in the financial incentive group quit smoking within a year, whereas only 5% in the control group had done so. At 18 months following randomization, abstainers comprised 9.4% of the paid group and 3.6% in controls.

“It was icing for me to get a monetary reward for something I was already planning to do,” GE lighting specialist Ric Barton told the Wall Street Journal.

Meanwhile, Bob Galvin, GE’s chief medical officer and a research team member said the study’s findings convinced him to implement an incentive plan for all US-based cigarette smoking employees beginning next year.

But to its credit, Volpp’s team was a bit circumspect in their write-up. The team noted that most study participants were white, well-educated, and relatively wealthy, and cautioned against extrapolating the findings to other demographic groups.

And Kenneth Warner, the University of Michigan Tobacco Research Network director worried that high recidivism might obligate companies to continue paying ex-smokers for years.

Is it too late to add that to the stimulus?

Zoledronic acid, the intravenous biphosphonate normally used to reduce bone loss in middle-aged and elderly women, reduces by 36% the risk of recurrent or metastatic disease in some women with breast cancer.
 
To reach this conclusion, Michael Gnant and colleagues at Medical University of Vienna randomized 1,803 premenopausal women with endocrine-responsive, early-stage breast cancer to receive either standard therapy with ovarian suppression plus tamoxifen or the same regimen plus zoledronic acid.

Patients were followed for a median of 4 years.

In that time, 54 women in the treatment group and 83 women in the control group experienced a recurrence in the opposite breast or a bone metastasis.

Other studies of the matter are nearing completion, so James Ingle, the Mayo Clinic’s head of breast cancer research told the New York Times, “it’s a reason for real enthusiasm, but for now…we are not ready to make this a standard treatment.”

But Marc Lippman had a different opinion. The breast cancer specialist and chairman of medicine at the University of Miami said that many women receiving standard treatments for breast cancer already take biphosphonates to counteract the bone-depleting effects of the therapy itself.

So why not just give them zoledronic acid?  “I think you have to give it,” he told the Times.

Lab and animal studies have shown that bone-building biphosphonates have many anti-cancer effects. They suppress the activity of osteoclasts for example, and when these cells are active they stimulate cancer cell growth in bone tissue.

The bone-builders also appear to prevent malignant cells from generating their own blood supply, invading other tissues and replicating. They even kill cancer cells directly, at least in laboratory studies.

Novartis markets zoledronic acid using the brand names Zometa and Reclast.

Atypical antipsychotic drugs like Risperdal, Zyprexa and Seroquel double the risk of sudden cardiac death according to a study in the New England Journal of Medicine.

To reach this conclusion, Wayne Ray and colleagues at Vanderbilt reviewed Medicaid claims data for 276,907 people that were between 30-74 years old and had no cardiac history.

Remarkably, between 1990 and 2005 one third of that population received a prescription for antipsychotics. There were 478 sudden cardiac deaths in this group, twice the rate in controls. That’s 3 deaths per 1,000 people per year for those on the juice.

The increased risk was present in those taking the newer, atypical antipsychotics and those taking the older varieties, and it became more pronounced at higher doses. 

These days, 90% of prescriptions for schizophrenia are for an atypical antipsychotic even though government sponsored studies from 2005 suggest these drugs are not more effective than the older antipsychotics which are available in generic form and cost a tenth as much.

In 2006, scientists found that atypical antipsychotics are not effective for situational psychoses associated with Alzheimer’s disease and other forms of dementia, yet they are widely prescribed for this.

The newer drugs are also commonly used to manage emotional lability complicating psychiatric disorders of childhood such as attention deficit disorder and autism, although they are not FDA-approved for this purpose.

And then there are the side effects which include marked weight gain, metabolic abnormalities and tics. More than 1,200 children have suffered serious problems attributable to Risperdal alone, and 31 of them died.

 “Physicians need to do a careful cardiovascular evaluation prior to prescribing these drugs, especially if there are alternative treatments,” Ray told the Wall Street Journal. And “if they’re used, (use) the lowest possible dose.”

Using simple, cockpit-style checklists in operating rooms cuts mortality and complications by 40%, according to a study published in the New England Journal of Medicine.

The 19-item cheat sheets had tick-boxes for pre-operative activities including confirming the patient’s name and allergy history, and confirming equipment had been sterilized and prophylactic antibiotics had been administered.

Post-operative checks included specimen labeling and tool and equipment retrieving.

The one-year study of non-cardiac surgery involved 7,600 patients in urban and rural hospitals in 8 countries with locations including London, Seattle, Manila, New Delhi and Ifakara, Tanzania.

Hospitals using the checklists observed declines in serious complications from 11% to 7%. The highest reductions were noted in rural and underfunded hospitals.

“You take something as complex as surgery, and you think there isn’t a lot that can be done to make it better,” Atul Gawande told the Washington Post. The Brigham and Women’s hospital physician added, “a checklist seems like a no-brainer, but the size of the benefit is dramatic.”

The authors speculate that if all US operating rooms implemented the checklists, the US health system would save $15-25 billion per year by not having to treat avoidable complications.

Recent studies have shown that the average surgical complication in the US costs $12,000 to treat, and nearly half are preventable.

Worldwide, over 234 million surgical procedures are performed annually, and somewhere between 3 and 17% result in a major complication.

“We’re not great at doing the simple things all the time,” concluded Gawande. “If you miss a few percent here and a few percent there, it adds up.”

“I don’t get through a week where (the checklist) has not caught something,” he marvelled.

People who want to go to medical school take note.

A quarter of 2008 US medical school graduates have accumulated debt of $200,000 or more. And although only a third entered medical school with some degree of debt, 87% were in debt when they graduated, according a report by the Association of American Medical Colleges.

Annual medical school costs including tuition and living expenses exceed $62,000 per year. The number is $44,000 for those attending public medical schools.

Med students received $2.5 billion in financial assistance between 2006 and 2007, but only 20% was in the form of grants and scholarships, including assistance based on need and that which requires service payback, such as the National Health Service Corps and the military. 

The rest of it was in the form of loans.

Some medical schools recently bucked the trend by announcing scholarships. Yale Medical School for example no longer requires payment from students whose annual family income is less than $100,000.

But few schools have resources to support programs like this, and it hasn’t helped that the Great Economic Crisis of ’08-’09 has pummeled university endowments. 

Can the situation continue like this forever? In 2008, US medical schools enrolled over 18,000 students, which is more than ever. And twice that many applied.

But the prospect of enormous debt dissuades some from applying and more often than not it’s people from low-income families that back off.

As Robert Steinbrook noted in the New England Journal of Medicine, economic diversity in medical school is morally just and believed to improve patient care and access down the road.

But even now more than 50% of US med students come from families with incomes in the top 20%.

Putting the clamps on blood glucose did not prevent eye, nerve or kidney complications in a large cohort of patients with type 2 diabetes, according to a study in the New England Journal of Medicine. 

William Duckworth and colleagues at the Phoenix VA randomized 1,791 veterans with an average  baseline glycated hemoglobin of 9.4% to intensive or standard therapy and followed them for 6 years.

Patients had diabetes for an average of 11.5 years prior to randomization. Nearly 40% had sustained a cardiovascular event and 60% had developed microvascular complications prior to randomization.

The same oral drugs were used in both groups but they were used more aggressively in the intensive therapy group. Insulin was added when glycated hemoglobin exceeded 6% and 9% for the intensive and standard groups, respectively.

Median glycated hemoglobin levels during the study were 8.4% and 6.9% for those in the standard and intensive therapy groups, so there’s no question diabetes control was tighter in the latter group.

However, the need for photocoagulation during the study was 15.7% and 15.5% for those in standard and intensive therapy, respectively.

Similarly 4.0% and 5.7% of those in standard and intensive therapy groups experienced progression to proliferative eye disease (not a misprint). A doubling of serum creatinine was seen in 8.8% of patients in both groups.

Neuropathy developed in 43.8% and 43.5% of those in standard and intensive therapy respectively, so across the board there were no real differences.

Cardiovascular outcomes and all-cause mortality also did not differ, but hypoglycemic episodes were 4 times more frequent in those receiving intensive treatment. 

The cardiovascular results confirmed findings from other studies but left open the possibility that a longer follow-up period might reveal benefits for those receiving intensive treatment. 

Helena Rodbard, M.D., a former president of the American Association of Clinical Endocrinologists, concluded for MedpageToday that “the upshot of it is, if we catch the patients early on, they are going to benefit from intensive treatment.” 

But “if we wait too long, intensive treatment can be deleterious,” she warned.

Closing the book on another unseemly tale of tainted drug imports from China, the CDC has concluded that contaminated heparin caused an outbreak of serious, occasionally fatal allergic reactions in dialysis centers one year ago.

The CDC performed a case-control study on the matter and published its findings in the New England Journal of Medicine.

The study confirmed that oversulfated chondroitin sulfate was responsible for 152 adverse reactions in 13 states that were reported to the CDC between November, 2007 and January, 2008.

The allergic syndrome was characterized by shortness of breath, hypotension and nausea occurring within 30 minutes after administration of heparin supplied by Baxter Healthcare.

Oversulfated chondroitin sulfate has a similar molecular structure and the same molecular weight as heparin, but lacks its anticoagulant properties.

The CDC study compared 21 dialysis centers that reported reactions with 23 that did not. It also tested unopened heparin vials from affected facilities.
  
The CDC found that 98.5% of the 130 reactions for which complete information was available occurred in a facility where contaminated heparin was used. Of 54 reactions in which the heparin lot number was known, 96.3% occurred after administering contaminated heparin.

Baxter Healthcare has stated on its Web site that it “will not sell another vial of heparin until the company has helped to create a system in which the quality and safety of heparin is secured.”

At the moment, APP Pharmaceuticals is the major heparin supplier to the US. Its products were never found to have been contaminated with oversulfated chondroitin sulfate.

AstraZeneca’s drug Crestor lowers the risk of heart attacks in apparently healthy adults with no prior history of cardiac disease and normal cholesterol levels, according to the results of a trial known as Jupiter.

Participants in Jupiter did have elevated levels of C-reactive protein (CRP), a non-specific marker for inflammation that identifies people at risk for cardiac events regardless of their cholesterol levels. CRP levels are measured using a $20 dollar blood test that is covered by most insurance policies.

Jupiter was a multicenter, prospective trial involving 17,802 participants in 26 countries that had entered an age where cardiac risk is highest—men over 50 and women over 60. Participants had no signs or symptoms of cardiac disease, and their cholesterol levels were not high enough to prompt treatment using current guidelines. But their CRP levels were high—at least 2.0 milligrams/liter.

Participants were randomized to receive 20 milligrams of Crestor or a placebo. Those who took Crestor experienced a 54% reduction in the risk of heart attack and a 48% reduction in the risk of stroke. They were 46% less likely to require angioplasty or coronary bypass surgery and had 20% lower mortality from all causes. LDL (bad) cholesterol dropped 50% and CRP levels dropped 37% in the Crestor group. Serious adverse events were rare and occurred at the same rate in both groups.

Paul Ridker, a cardiologist at Brigham and Women’s Hospital, was the principal investigator of the Jupiter trial. He presented the results in New Orleans yesterday during a meeting of the American Heart Association. Ridker is listed as an inventor on several CRP assays whose patents are held by the Brigham. He and several co-authors receive grants and other income from AstraZeneca.

“The potential public health benefits are huge,” Ridker told the Washington Post. “It really changes the way we have to think about prevention of heart attack and stroke.” Ridker’s point seems well taken since nearly half of all heart attacks occur in people that have normal cholesterol levels.  JUPITER suggests a broader screening role for CRP, especially in those with normal cholesterol.

However, Stanford cardiologist Mark Hlatky expressed caution to the Wall Street Journal. “Before we expand treatment indications in any drastic way, we need to do due diligence,” he said. “The idea that everybody should get CRP measured is premature and not backed up by good data.”

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