Tag Archives: health

Unconventional Analysis Finds Threshold For LDL Reduction With Statins Reply

by • Policy & Ethics, Prevention, Epidemiology & Outcomes • Tags: , , , , ,

Using an unconventional mathematical approach, a group of Japanese researchers say there may be no good reason to reduce LDL cholesterol more than 40 mg/dl. Their research letter has been published online in JAMA Internal Medicine.

According to the authors, members of the ALICE (All-Literature Investigation of Cardiovascular Evidence) Group, most meta-analyses use linear models that assume “a constantly increasing or decreasing risk as the exposure increases or decreases.” Linear models, however, can be “misleading,” they write, because they assume a specific dose-response relationship. By contrast, their new analysis utilizes “flexible” models that can more readily uncover “threshold effects.”

Click here to read the full post on Forbes.

 

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Cuban History Offers Important Lessons For Global Health Today 1

by • Uncategorized • Tags: , , , , , , ,

A large new study from Cuba shows the impressive benefits that can be achieved with weight loss and increased exercise. Much more ominously, the same study shows the dangers associated with weight gain and less exercise.

In the study, published in BMJ, researchers took advantage of a “natural” experiment that occurred in Cuba as a result of a major economic crisis in the early 1990s. Relying on 30 years of superb health statistics available in the country, the researchers analyzed the dramatic health effects associated with the economic crisis, which last from 1991 through 1995, and the subsequent recovery.

During the economic crisis caloric intake decreased and physical activity increased, resulting in a 5.5 kg reduction in weight and a very high (80%) proportion of the population classified as physically active…

…

Click here to read the full story on Forbes.

 

 

English: A man fixing the tire of a "Bici...

 

 

Controversial PFO Closure Trials Published In NEJM Reply

by • Uncategorized • Tags: , , , , ,

Two controversial trials testing PFO closure with the Amplatzer PFO Occluder (St. Jude Medical) in patients with cryptogenic stroke, first presented last fall at the TCT meeting, have now been published in the New England Journal of Medicine. Both trials missed their primary endpoints but contained suggestions of possible benefit. The results appear unlikely to resolve the ongoing controversy over the value, or lack of value, of this procedure, but, as an accompanying editorial states, both advocates and critics of PFO closure will find source material for their arguments in these papers.

…

In the accompanying editorial, Steven Messé and David Kent write that both trials suffered from slow enrollment, “which was probably due to widespread off-label use of atrial septal closure devices.” They note that RESPECT and PC, like the only other randomized trial in the field, CLOSURE 1, did not show significant benefits in the main intention-to-treat analysis, but did present some evidence of possible benefit.

They conclude:

…we are left for the moment to make decisions under conditions of uncertainty. In such circumstances, evidentiary standards vary among decision makers — patients, clinicians, authors of practice guidelines, and regulatory authorities — depending not only on the interpretation of the results, but also on the potential consequences of their decisions. Some of them may interpret the data as supporting closure of a patent foramen ovale as a viable therapeutic option, even while conceding the failure of trials to show the superiority of closure over medical therapy. Yet given the prevalence of patent foramen ovale in the general population, the enormous potential for overuse of percutaneous closure of a patent foramen ovale, and the relatively low risk of stroke in patients who are treated medically, the routine use of this therapy seems unwise without a clearer view of who, if anyone, is likely to benefit…. Randomized studies of closure may come to an end, however, if the Amplatzer device is approved. Thus, all eyes will be on the regulatory agencies to see how they will interpret these results in light of their own evidentiary standards.

Click here to read the entire story on Forbes.

 

Amplatzer

 

 

 

High Potency Statins Linked To Increased Risk For Acute Kidney Injury Reply

by • Prevention, Epidemiology & Outcomes • Tags: , , , , , ,

Although the beneficial effects of high-potency statins have been well-characterized in clinical trials, these same trials have lacked the power to illuminate rare but potentially important adverse events. A suggestion of one such area of concern, acute kidney injury, was first raised in the JUPITER trial. Now, a new study published in BMJ provides further information about this area.

Researchers in the Canadian Network for Observational Drug Effect Studies (CNODES) performed a retrospective observational analysis of administrative databases in Canada, the UK and the US containing more than 2 million patients newly treated with statins.  59,636 of the subjects already had chronic kidney disease. One-third of the subjects received high potency statins, defined as ≥10 mg rosuvastatin, ≥20 mg atorvastatin, and ≥40 mg simvastatin.

Within 120 days of starting treatment there were 4691 hospitalizations for acute kidney injury in patients without pre-existing kidney disease and 1896 hospitalizations in patients with pre-existing disease. Patients without pre-existing disease on high potency statins were 34% more likely to be hospitalized with acute kidney injury than patients on other statin regimens. Patients with pre-existing disease did not have a significant increase in risk if they were taking high potency statins.

The authors estimated that 1,700 patients without pre-existing kidney disease would need to be treated with a high potency statin instead of a low potency statin to cause one additional acute kidney injury requiring hospitalization. The findings, according to the authors, are broadly consistent with the JUPITER trial. They write:

Given what is likely to be a small magnitude of incremental cardiovascular benefit of high potency statins over low potency statins in reality, a pressing question is how to identify patients for whom the risk-benefit balance for high potency statin treatment is unfavourable.

In an accompanying editorial, Robert Fassett and Jeff Coombes write that “clinicians should use low potency statins whenever possible to provide cardiovascular benefits without the increased risk of acute kidney injury.” Further, they note, “despite extensive experience with the use of statins over many years, optimization of doses to derive benefit but minimize risk is still evolving.”

Radiotherapy For Breast Cancer Increases Heart Disease Risk 1

by • Prevention, Epidemiology & Outcomes, Uncategorized • Tags: , , , , ,

A new study published in the New England Journal of Medicine offers the best look yet at the increased risk for heart disease produced by radiotherapy for breast cancer. Further, this increased risk may just be the tip of the iceberg of more radiation-related problems, warns a cardio-oncologist in an accompanying editorial.

The new study, based on data from Sweden and Denmark of women treated with radiotherapy for invasive breast cancer, found a linear increase in the rate of heart disease associated with the dose of radiation received by the heart. Starting 5 years after radiotherapy, and with no sign of a threshold,  the risk for major coronary events increased by 7.4% per gray. The mean dose of radiation was 4 Gy. Although the relative risk was consistent throughout the study, the increase in absolute risk was greatest in women with cardiac risk factors or established heart disease.

Findings from the study, according to the authors, “make it possible to estimate” a patient’s risk for heart disease related to radiation. “This absolute risk can be weighed against the probable absolute reduction in her risk of recurrence or death from breast cancer that would be achieved with radiotherapy.” The authors estimated that for a 50-year-old woman without preexisting risk factors and with a mean radiation exposure of 3 Gy, her risk for death from ischemic heart disease by age 80 would rise from 1.9% to 2.4% and her risk for an acute coronary event would rise from 4.5% to 5.4%. The risk for death by age 80 for an otherwise similar woman with existing risk factors would rise from 3.4% to 4.1%. Women exposed to larger doses of radiation would be exposed to even greater risks.

In the accompanying editorial, Javid Moslehi writes that results of the study suggest that “cardiac risk factors should be assessed and aggressively managed — starting at the time of radiation treatment (or even before) and continuing throughout survivorship.” To make matters worse, the findings “may represent just the tip of the iceberg.” Radiation may also cause increases in pericardial disease, peripheral vascular disease, cardiomyopathy, valvular dysfunction, and arrhythmias, according to Moslehi, and other breast cancer therapies, such as anthracyclines and hormonal therapies, may have “additional cardiotoxic effects.”

Moslehi, who is in the Cardio-Oncology Program at the Dana–Farber Cancer Institute, writes about the emerging new discipline of “cardio-oncology”:

Given the widespread use of radiation therapy in the treatment of breast cancer, and the continually expanding arsenal of novel therapies, the current study calls for greater collaboration between oncologists and cardiologists. An important lesson for the oncologist may be that the time to address concerns about cardiovascular “survivorship” is at the time of cancer diagnosis and before treatment rather than after completion of therapy. Similarly, cardiologists need to assess prior exposure to radiation therapy as a significant cardiovascular risk factor in survivors of breast cancer.

Large Study Finds Genetic Links To Aortic Valve Calcification Reply

by • Interventional Cardiology & Surgery, Prevention, Epidemiology & Outcomes • Tags: , , , , ,

A genetic component is believed to play an important role in valvular heart disease, but the specific genes involved have not been identified. Now an interntional group of researchers has identified genetic variations that increase the risk for valvular calcification.

In a paper published in the New England Journal of Medicine, members of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortium report on their search for genes associated with aortic valve calcification and mitral annular calcification in several of study cohorts. They found one SNP, in a gene previously shown to be associated with lipoprotein(a) levels and the risk of coronary artery disease, to be significantly associated with a doubling of the risk for aortic-valve calcification. This finding was replicated in additional cohorts.

Click here to read the full story on Forbes.

Becoming Your Own Doctor In The Brave New World Of Personalized Medicine Reply

by • Policy & Ethics, Prevention, Epidemiology & Outcomes • Tags: , , , , , ,

Lately there’s been a lot of talk about personalized medicine. There’s a bold idea going around that people should take control of their own healthcare and manage the flood of new data stemming from a whole bunch of new technologies, including, but hardly limited to, personal genomes, biomarkers, wireless sensors, and iPhone ECGs.

Would most should people would benefit if they took a more active role in obtaining this information (for example, by ordering a personal genome from 23andme.com), and then interpreting and acting upon the information?

It seems like a great idea, after all….

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…boutique-style healthcare is a lot like organic food, which may taste better and may help a few privileged people feel better about themselves, and may possibly yield a small individual health benefit (though there is absolutely no evidence to show this). However, there is absolutely no chance that organic food can be used to actually feed the vast majority of the 7 billion or so people currently living on this planet.

Similarly, taking control of individual health data will almost certainly allow a few privileged and obsessed people to feel they’re better off than most. It may even improve their health. But, again, more importantly, there is no possibility in the foreseeable future that this self-management of extremely complex personal health data will improve the overall public health of the planet.

Read my entire post on Forbes.

Amgen Trial Fails To Show Benefit Of Anemia Drug In Heart Failure Patients Reply

by • Heart Failure, Policy & Ethics • Tags: , , , , , , ,

Deutsch: Amgen als Sponsor der Tour of California

 

The bad news continues for Aranesp (darbepoetin alfa), Amgen’s long-acting erythropoietin-stimulating agent. The drug is intended to stimulate red cell blood production in patients with anemia. Amgen today announced the top line results of a large phase 3 heart failure trial of the drug and said  the trial had failed to meet its primary endpoint.

 

The RED-HF (Reduction of Events With Darbepoetin Alfa in Heart Failure) Trial, which started in 2006, had randomized 2,278 patients with heart failure and anemia to receive either Aranesp or placebo.

 

Click here to read the full story on Forbes.

 

Large Meta-Analysis Finds No Harm Associated With Eggs 2

by • Policy & Ethics, Prevention, Epidemiology & Outcomes • Tags: , , , , ,

No food has had more ups and downs over the last century or so than the common egg. Following a long period in which eggs were ubiquitous and highly regarded, eggs fell from favor with the rise of concerns over cholesterol. Currently the American Heart Association recommends that people restrict dietary cholesterol to 300 mg per day, which effectively limits people to 1 egg per day at most. However, the relationship of dietary cholesterol and serum cholesterol  is, at best, tenuous, and a significant number of experts now believe that egg consumption poses no risk to cardiovascular health.

In a new paper published in BMJ, a group of researchers from China and Boston performed a meta-analysis of 8 studies that included 263 938 participants for coronary heart disease (CHD) and 210 404 participants for stroke and followed them for 8 to 22 years. The authors found no evidence for an association between egg consumption and either coronary heart disease or stroke…

Click here to read the full story on Forbes.

Autopsy Studies Find Large And Dramatic Drop In Early Atherosclerosis Over 60 Years 1

by • Prevention, Epidemiology & Outcomes • Tags: , , , ,

Service members who died over the past decade were far less likely to have atherosclerosis than service members who died in Korea or Vietnam, according to a new study published in JAMA. Although it is impossible to fully understand the causes and implications of the finding, the results provide powerful new evidence pointing toward a very long term, enormous reduction in the prevalence of coronary disease, especially in younger people, though an aging population and disturbing trends in obesity and diabetes mean that cardiovascular disease will continue to be a major public health problem for the foreseeable future.

Micrograph of an artery that supplies the hear...

Bryant Webber and colleagues analyzed autopsy reports and available health data from 3,832 service members who died of combat or unintentional injuries in Afghanistan and Iraq and compared their findings to similar studies performed during the Korean and Vietnam wars. 8.5% of the newest group had evidence of coronary atherosclerosis, compared with 77% in the Korean War group and 45% in the Vietnam War group. The authors acknowledge that there are many reasons why the groups should not be directly compared but conclude that the overall trend   in the reduced prevalence of atherosclerosis is undoubtedly true.

As might be expected, service members with atherosclerosis were older and more likely to have dyslipidemia, hypertension, or obesity than service members without atherosclerosis. Surprisingly, cigarette smoking was not significantly associated with atherosclerosis in this study.

In an accompanying editorial, the Framingham Study’s Daniel Levy writes that “the main finding of this study is valid: the prevalence of atherosclerosis in young men today is much lower than the prevalence in the Korean or Vietnam War eras. If these findings are generalizable to the US population as a whole, then the cardiovascular health of the US population may have improved appreciably over the past 6 decades.”

Levy writes that the concurrent decline in mortality from cardiovascular disease is likely the result of advances in both prevention and treatment, but only advances in primary prevention can explain the trend found in the autopsy studies. Nevertheless, he notes, cardiovascular disease is still the leading cause of death in the US: “The national battle against heart disease is not over; increasing rates of obesity and diabetes signal a need to engage earlier and with greater intensity in a campaign of preemption and prevention.”
Click here to read the JAMA press release…

CHMP Recommends Against Approval For Mipomersen In Europe Reply

by • Policy & Ethics, Prevention, Epidemiology & Outcomes • Tags: , , , , , ,

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency today recommended that mipomersen (Kynamro, Isis and Genzyme) not be approved for use in Europe. The novel antisense oligonucleotide works by inhibiting the synthesis of apo-B and is under development in the United States and Europe for the treatment of familial hypercholesterolemia.

CHMP agreed that mipomersen effectively lowered LDL cholesterol in people with homozygous and severe heterozygous familial hypercholesterolemia. The negative recommendation was based on the committee’s concerns about the safety of mipomersen. Here is the CHMP discussion of the safety issue:

However, the CHMP was concerned about the medicine’s safety. The Committee noted that a high proportion of patients stopped taking the medicine within two years, even in the restricted group of patients with homozygous familial hypercholesterolemia, mainly due to side effects such as flu-like symptoms, injections site reactions and liver toxicity. This was considered important because Kynamro is intended for long-term treatment in order to maintain the cholesterol-lowering effect. The CHMP was also concerned by liver test results in patients taking Kynamro showing a build-up of fat in the liver and increased enzyme levels, and was not convinced that the company had proposed sufficient measures to prevent the risk of irreversible liver damage. Moreover, the Committee was concerned that a greater proportion of patients taking Kynamro experienced serious cardiovascular events (problems with the heart and blood vessels) than patients taking placebo. This prevented the CHMP from concluding that Kynamro’s intended cardiovascular benefit, in terms of reducing cholesterol levels, outweighed its cardiovascular risk.

In October the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee gave a weak endorsement to mipomersen, voting 9-6 in favor of an approval recommendation. Comments during the panel meeting, however, clearly indicated that committee members were concerned about both the efficacy and safety of the drug.

Another new drug under development for lowering cholesterol in FH patients is lomitapide (Aegerion). The same FDA panel in October gave lomitapide a slightly stronger approval recommendation.

The CEO of Genzyme expressed disappointment with CHMP’s recommendation. “Patients with HoFH carry extreme, ongoing cardiovascular risk with significantly elevated LDL-C levels despite use of currently available therapies. This is a rare disease patient population, with a life-threatening condition, in need of new therapies. We will work closely with the CHMP during the re-examination process to address the Committee’s concerns, with the goal of making this important medication available to HoFH patients in Europe.”
Click here to read the Genzyme press release…

Boehringer Ends Phase 2 Trial Of Dabigatran In Mechanical Valve Patients 2

by • Heart Rhythms, Interventional Cardiology & Surgery, Prevention, Epidemiology & Outcomes • Tags: , , , , , , , , , ,

Boehringer Ingelheim today announced that it had discontinued a phase 2 trial of its anticoagulant drug dabigatran (Pradaxa) in patients with mechanical heart valves. As reported here in October, the company had previously terminated one arm of the study after an interim review of the data by the trial’s Data Safety Monitoring Board

The RE-ALIGN trial was an open-label, 12-week randomized comparison of warfarin and dabigatran in 400 patients who received a mechanical valve. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.

Despite the recent advent of novel oral anticoagulants, the much-maligned warfarin remains the only current option available for patients who have received a mechanical valve. Now the first trial to explore this indication for one of the newer oral anticoagulants has been stopped.

In October Boehringer told members of its speakers bureau that the post-surgery arm of the trial had been terminated due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” At that time the company said the second arm of the trial would continue.

Dabigatran has been approved in Europe, but not in the United States, for venous thromboemoblism (VTE) prevention after knee and hip replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the United States and Europe. To date there have been no head-to-head comparisons of the newer anticoagulants.

According to a recent study in Circulation: Cardiovascular Quality and Outcomes dabigatran now has about 19% of the oral anticoagulant market, mostly for the approved treatment of AF “but increasingly for off-label indications” as well. A recent letter in the Journal of the American College of Cardiology provided information about the off-label use of dabigatran in two mechanical valve patients. Both patients developed thrombosis after switching to dabigatran from warfarin. The authors noted that “while there is a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, these data are unavailable for dabigatran.” Although newer anticoagulants “hold tremendous promise for mechanical valve anticoagulation… there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.”
Click here to read the press release from Boehringer…

Should Body Weight Influence Choice of Antihypertensive Therapy? 1

by • Heart Failure, Prevention, Epidemiology & Outcomes • Tags: , , , , , ,

The hypertension field has been troubled by repeated observations that normal weight patients have more cardiovascular (CV) events than obese patients. Now a new analysis of a large hypertension trial confirms this finding but also suggests that it may be explained by either an adverse effect of diuretics or a protective effect of calcium-channel blockers in non-obese hypertensives.

Michael Weber and colleagues analyzed data from more than 11,000 patients randomized in the ACCOMPLISH trial to shed light on this problem. In 2008 the main results of the trial showed that the combination of benazepril and amlodipine (calcium channel blocker group, CCB) was superior to the combination of benazepril and hydrochlorothiazide (diuretic group) in reducing CV events in high risk hypertensive patients.

The new analysis, published online in the Lancet, confirmed earlier observations and found significant differences in outcome based on weight. However, the differences in outcome occurred mostly in the diuretic group. In the diuretic group, the rate for the primary endpoint was significantly different between the groups (30.7 events per 1,000 patient-years in normal weight patients, 21.9 in overweight patients, and 18.2 in obese patients, p=0.0034). In the CCB group the rates were not significantly different (18.2, 16.9, and 16.5).

To explain their finding the investigators proposed that “hypertension in obese and lean patients is probably mediated by different forms of underlying pathophysiology.” Obese patients, who are more likely to have increased plasma volume and cardiac output, will be responsive to diuretics, while lean patients are more likely to have involvement of the sympathetic and renin-angiotensin systems. They concluded that “diuretic-based regimens seem to be a reasonable choice in obese patients in whom excess volume provides a rationale for this type of treatment, but thiazides are clearly less protective against cardiovascular events in patients who are lean. An alternative therapeutic regimen that includes a calcium channel blocker such as amlodipine, which works equally well across all BMI categories, provides an advantage with respect to clinical outcomes in patients who are not obese.”

In an accompanying comment, Franz Messerli and Sripal Bangalore write that the effectiveness of hydrochlorothiazide in obese people in ACCOMPLISH “has little if anything to do with obesity per se, but simply reflects the fact that among obese patients there was a preponderance of individuals at risk for heart failure who were prone to respond well to diuretic treatment.” They argue that “amlodipine-based treatment should be used irrespective of body size” for the indication of hypertension. Diuretics, on the other hand, should be used for the prevention of left-ventricular dysfunction.
Click here to read the press release from the Lancet…

Scientific Statement Examines Role Of Social Media In Fighting Childhood Obesity 1

by • Policy & Ethics, Prevention, Epidemiology & Outcomes • Tags: , , , ,

Social media may become an important weapon in the battle against childhood obesity, according to a new American Heart Association scientific statement published in Circulation. However, the statement acknowledges that the evidence so far from published social-media intervention studies has been “mixed” and that social media is also associated with troublesome drawbacks.

The statement delivers an overview of recent research in the role of social networks in health and obesity, and it reviews intervention strategies that employ various forms of social media. Because children are increasingly drawn to it, social media represents “natural points for intervention,” but the statement cautions that “identifying and measuring outcomes would be difficult.”

“Teenagers are texting and using Facebook and other social media as their primary communication with their peers, and we need to find out what factors can be incorporated into social media that will increase the effectiveness of these interventions to initiate and maintain weight loss in kids and adolescents,” said Jennifer S. Li, the chair of the writing group, in an AHA press release.

As an example of the delicate balance required in this area, the statement notes that children prefer texting over traditional paper diaries, but it also warns that social media plays a role in cyber bullying, privacy issues, sexting, and internet addiction. “Doctors need to understand digital technology better so that they can offer guidance to patients and their families on avoiding such issues, and will be aware of any such problems that occur,” said Li.

“The studies we looked at suggest that more parental involvement and more interaction with counselors and peers was associated with greater success rates for overweight children and teens who participated in an online intervention,” said Li. But the statement also acknowledges that the results of the few randomized trials of internet-based obesity interventions have been “mixed.”
Click here to read the AHA press release…

The Dangers Of Going Too Fast 5

by • Prevention, Epidemiology & Outcomes, Uncategorized • Tags: , , ,

Updated– According to an editorial published online in the BMJ journal Heart, running too hard, too fast, and for too long can be dangerous. The same holds true in publishing. The editorial was hastily released ahead of its scheduled publication time after portions of it were quoted in a Wall Street Journal article on the dangers of endurance sports. A BMJ representative told me that Heart had not yet found out how the WSJ article gained early access to the editorial, although in the article it appears that the Heart editorialists spoke at length with the WSJ reporter.

In the editorial, cardiologists James O’Keefe and Carl Lavie marshall the evidence suggesting that “extreme endurance exercise may exact a toll on cardiovascular (CV) health.” The authors acknowledge that runners have only a very small risk of dying during a marathon, but “chronic extreme exercise” can induce “adverse structural and electrical remodeling, which offsets some of the CV benefits and longevity improvements conferred by moderate physical activity.”

The authors cite data showing that “improvements from unfit to moderately fit confer dramatic reductions in morbidity and mortality” but that “fitness levels above 12 metabolic equivalents do not seem to translate into additional gains in CV health and longevity.” The authors posit a U-curve, with “couch loungers” on one side and “extreme exercise aficionados” on the other side. They recommend moderate exercise as “the safe and comfortable zone at the bottom of the U curve, which, they say, is the sweet spot for most people. They conclude with a “take home message” recommending that most people limit vigorous exercise to 30-50 minutes per day.

In the WSJ article both O’Keefe and Lavie, former elite athletes with years of intense training, discuss their current moderate exercise regimens. The article also includes an old quote from Kenneth Cooper, the sports physician who helped launch the original aerobics movement: “If you are running more than 15 miles a week, you are doing it for some reason other than health.”

Update– I asked Heart editor Adam Timmis to comment on this episode and whether he thought the Ingelfinger rule (which forbids prepublication publicity about a forthcoming paper) applied in this case. Here is the response I received:

“Embargo breaks are always regrettable, of course. But while the Ingelfinger rule is a worthy one, to apply it in this case would be like taking a mallet to a walnut.

The article in question was a review article- albeit in editorial format-not original research. And there is little or nothing in the piece that is not already in the public domain. Therefore, we think that it would be excessive to withdraw it from publication.”

FDA Panel Recommends Approval Of Mipomersen For Familial Hypercholesterolemia 1

by • People, Places & Events, Policy & Ethics, Prevention, Epidemiology & Outcomes • Tags: , , , , , , , ,

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee gave a weak endorsement to mipomersen, an antisense oligonucleotide inhibitor manufactured by Genzyme, for use in homozygous familial hypercholesterolemia (FH). With its relatively close 9-6 vote, and with its comments, the committee expressed concerns about both the efficacy and safety of the drug, but ultimately the severity of homozygous FH led the panel to recommend approval.

“We need a toolkit, we need as many options as possible for these patients,” said one panel member.

On Wednesday the same committee voted 13-2 in favor of  a similar indication for lomitapide capsules, manufactured by Aegerion. On both days, panel members strongly urged the FDA to restrict use of lomitapide and mipomersen to patients with homozygous FH and “avoid the slippery slope” of using the drugs in heterozygous FH or in patients with resistant hypercholesterolemia.

Some panel members voiced concern that the clinical trials with mipomersen excluded patients with apheresis. During the section for public comments Sidney Wolfe said that the trials were unethical for this reason, since apheresis represents the gold standard of treatment for these patients. One panelist responded that though it was an unfortunate exclusion it was not unethical. A Genzyme spokesperson reported that a trial is now underway looking at mipomersen on top of apheresis.

The panel agreed that mipomersen was effective in lowering cholesterol but felt the reduction was “modest” and that most patients would not reach LDL levels under 100. As with lopitamide, trials were not powered for clinical endpoints. Panelists wondered about the clinical effect of lowering LDL cholesterol from 400 to 300.

The committee did not appear to be greatly concerned about the possibility of a cancer signal brought up in the FDA review. Several panelists thought that the cancer signal may have reflected an ascertainment bias, and, further, that a young homozygous FH population would be less susceptible to an elevated cancer risk. Most of the cancers observed in the clinical trials occurred in elderly patients who did not have homozygous FH.

The biggest obstacle to mipomersen was the question over liver safety. Committee members wrestled with the issue without reaching a consensus, perhaps reflecting their faith (or hope) that the FDA’s proposed Risk Evaluation and Mitigation Strategies (REMS) will work as intended. The program, similar to the one proposed by the FDA for lomitapide, would ”educate prescribers about the approved indication for use of mipomersen, the potential risk of hepatotoxicity associated with the use of mipomersen, and the need to monitor patients during treatment with mipomersen as per product labeling.” The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

 

 

FDA Warns About Fungal Meningitis In Transplant Patient Who Received NECC Cardioplegia Solution Reply

by • People, Places & Events, Prevention, Epidemiology & Outcomes • Tags: , , , ,

Update (October 16): On Tuesday the FDA revised its initial report and said that only one transplant patient who had received the NECC cardioplegia solution had developed fungal meningitis. 

The FDA said on Monday that it had identified two transplant patients with Aspergillus fumigatus infection who received cardioplegia solution during surgery. The solution was manufactured by the New England Compounding Center (NECC), which has been at the center of a broad investigation after the death of several patients from fungal meningitis due to contaminated vials of methylprednisolone acetate injection.

The FDA said is had also identified a patient who may have developed meningitis from an epidural injection of another injectable steroid made by NECC, triamcinolone acetonide. The FDA said “there may be other explanations” for the infections in the transplant patients and that it has not confirmed that the three cases were caused by NECC products.

Out of “an abundance of caution” the FDA recommends that patients who received any injectable drugs manufactured by NECC “should be alerted to the potential risk of infection.” The FDA said this recommendation extends to patients who received injectable ophthalmic drugs made by NECC, although no infections have been reported with these drugs. The FDA says patients should be told about the symptoms of meningitis and instructed to immediately report if they have any of  these symptoms.

Click here to read the full FDA statement.

Danish Study Gives A Boost To Hormone Replacement Therapy Timing Hypothesis Reply

by • Prevention, Epidemiology & Outcomes • Tags: , , , ,

Hormone replacement therapy (HRT) suffered a sharp blow a decade ago when the Women’s Health Initiative failed to show any cardiovascular benefit in women taking HRT. Despite the setback, many researchers theorized that HRT might still be beneficial in women who start HRT close to menopause. Now a new study from Denmark published in BMJ lends strong support to the “timing hypothesis.”

Louise Lind Schierbeck and colleagues analyzed data from 1006 recently postmenopausal or perimenopausal women who were randomized to HRT or no treatment.

After 10 years, there were 16 primary endpoint events (the composite of death, admission to the hospital for heart failure, or MI) in the HRT group compared with 33 in the control group (hazard ratio 0.48, CI 0.26-0.87, p=0.015).

  • Mortality: 15 versus 26, HR 0.57, 0.30-1.08, p=0.084
  • HF: 1 versus 7, HR 0.14, 0.02-1.16, p=0.07
  • MI: 1 versus 40.25, HR 0.03-2.21, p=0.21.

There were no significant differences in the overall rate of cancer or of breast cancer. Women who were under 50 years of age at the start of the trial appeared to enjoy the greatest benefit from HRT.

The authors concluded:

Our findings suggest that initiation of hormone replacement therapy in women early after menopause significantly reduces the risk of the combined endpoint of mortality, myocardial infarction, or heart failure. Importantly, early initiation and prolonged hormone replacement therapy did not result in an increased risk of breast cancer or stroke.

Andrew Kaunitz told Physician’s First Watch that, when “taken together with findings from a subanalysis of younger women from the WHI, these data should reassure clinicians and women that use of hormone therapy in recently menopausal women is safe.”
Click here to read the BMJ press release…

Observational Study Links Common Household Chemical To Cardiovascular Disease Reply

by • Prevention, Epidemiology & Outcomes • Tags: , , , ,

High levels of a manmade chemical widely used in common household products and detectable in more than 98% of people may increase the risk of cardiovascular (CV) disease and peripheral arterial disease (PAD), according to a study published in Archives of Internal Medicine. (The study was published online in September and will appear in this week’s print edition of Archives.)

Anoop Shankar and colleagues measured serum levels of perfluorooctanoic acid (PFOA) in 1,216 people participating in the National Health and Nutritional Examination Survey (NHANES) and found a strong correlation between PAD and CV disease and PFOA levels. After adjusting for other risk factors, people in the highest quartile of PFOA levels had about double the risk of CV disease and PAD:

  • Odds ratio for the top quartile of PFOA: CV disease 2.01 (1.12-3.60), PAD 2.78 (1.03-3.08), CVD or PAD 2.28 (1.40-3.71)

The authors cite several studies that support the plausibility of a harmful effect of PFOA. They duly note the risk of “residual confounding and reverse causality” but write that if their findings are replicated “the population-attributable risk of PFOA exposure on CVD risk could potentially be high.”

In an invited commentary, Debabrata Mukherjee acknowledges the limitations of the study but writes that there is enough biological plausibility in the relationship so that “it would make sense to limit or to eliminate the use of PFOA and its congeners in industry through legislation and regulation while improving water purification and treatment techniques to try and remove this potentially toxic chemical from our water supply.” But, he warns concerns about PFOA “should not dissuade us from aggressively managing known existing risk factors for CVD such as dyslipidemia, smoking, hypertension, diabetes, obesity, and lack of regular physical activity.”
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Apixaban (Eliquis) For Atrial Fibrillation Gets Positive European Recommendation 2

by • Heart Rhythms, Policy & Ethics, Prevention, Epidemiology & Outcomes • Tags: , , , ,

The European Committee for Medicinal Products for Human Use (CHMP) has recommended approval for apixaban (Eliquis, Pfizer and BristolMyers Squibb) for atrial fibrillation (AF). The drug is already approved in Europe for the prevention of venous thromboembolic events (VTE) following hip or knee replacement surgery. The drug has not yet been approved in the United States.

Here is the CHMP proposed indication for the existing 2.5 mg dose and a new 5 mg dose:

“Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).”

CHMP proposed that apixaban should be contraindicated in patients at high risk for major bleeding and in patients receiving other anticoagulants.

The CHMP decision was based on data from the ARISTOTLE and AVERROES pivotal clinical trials.

Click here to download the PDF of the CHMP summary of opinion.

Click here to read the press release from Pfizer and BMS…

Many CHF Patients Not Receiving– Or Getting Benefits From– High Dose ACE Inhibitors And ARBs Reply

by • Heart Failure • Tags: , , , , ,

Although current guidelines recommend that ACE inhibitors and angiotensin-receptor blockers (ARBs) be used in high doses in patients with congestive heart failure, many CHF patients currently receive lower than recommended doses of these drugs. In a research letter published online in Archives of Internal Medicine, investigators in Montreal analyzed data from 43,405 patients with a first hospital admission for CHF in Quebec, 73% of whom received an ACE inhibitor and 27% an ARB.

Patients were classified as receiving low-, medium- or high-dose drugs. 29% received a low-dose. The groups were not evenly matched: patients in the high dose group were more likely to have hypertension and diabetes, while patients in the low dose group were more likely to have renal disease.

After adjusting for other factors, the risk of dying or being readmitted to the hospital was significantly reduced in the high dose group. Here are the hazard ratios for ACE inhibitors and ARBs (medium dose serves as the reference):
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Good Science/Bad Science: Contrasting Papers On Dietary Compositon In JAMA And BMJ 3

by • Policy & Ethics, Prevention, Epidemiology & Outcomes, Uncategorized • Tags: , , , , , , , , ,

Two studies published on Tuesday on dietary composition offer a striking contrast. One tackles the interesting question of whether different diets producing the same amount of weight loss might have different effects on energy expenditure. The investigators performed a rigorous, carefully designed experiment that advances our knowledge about diets and metabolism. The second tackled an even more important question– the long term cardiovascular (CV) impact of different diets. In this instance, however, the investigators relied on weak observational data and reached conclusions that went way beyond anything observational data can provide. One study represents good science. The other does not.

In the first study, published in JAMA, Cara Ebbeling and colleagues carefully studied 21 overweight and obese young adults. After first reaching a 10-15% weight loss during the run-in period of the study, the 21 subjects then received 3 different diets, in random order, for 4 weeks each: a high carbohydrate, low fat diet; a low-glycemic index diet with moderate percentages of carbohydrates and fats; and a very low carbohydrate diet with a high proportion of fat.

Although the subjects received the same amount of calories with each diet, there were significant differences between the groups in the amount of energy burned with the different diets. (This may be an important question, because weight loss requires energy expenditure to be greater than energy intake. If, everything else being equal, diets differ in their effect on energy expenditure, this may lead to superior weight loss strategies.) When compared to baseline, total and resting energy expenditure decreased the most with the high carbohydrate diet and the least with the very low carbohydrate diet. Further, the investigators also found that the low fat diet resulted in an increase in serum leptin levels (which could predict future weight gain) and other factors associated with metabolic syndrome. These same factors decreased with the very low-carbohydrate diet, but were perhaps offset by an incase in CRP levels– a marker of inflammation– with the very low carbohydrate diet.
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Is Chronic Kidney Disease A CHD Risk Equivalent? Reply

by • Prevention, Epidemiology & Outcomes • Tags: , , , , , ,

A new study published in the Lancet provides new data about whether chronic kidney disease (CKD) should, like diabetes, be considered a coronary heart disease (CHD) risk equivalent.

Marcello Tonelli and colleagues analyzed data from a population of 1.25 million people in Alberta, Canada. During a median followup of 4 years, 11,340 people were admitted to the hospital for MI. People with a previous MI were at higher risk for MI admission than people with either diabetes or CKD:

  • MI history: 18.5 per 1000 person-years (CI 17.4–19.8)
  • Diabetes: 5.4 per 1000 person-years (5.2–5.7)
  • CKD: 6.9 per 1000 person-years (6.6–7.2)
After adjustment for other variables, the relative rate of MI was lower in the CKD group than in the diabetes group (rate and adjusted relative rate for MI admission):
  • Previous MI: 7.7%, RR 3.8 (CI 3.5-41)
  • Diabetes and CKD: 6%, RR 2.7 (2.5-2.9)
  • CKD: 2.8%, RR 1.4 (1.3-3.5)
  • Diabetes: 2.4%, RR 2.0 (1.9-2.1)
  • No diabetes or CKD: 0.5%, RR 1 (reference)

The authors write that their “data show that diabetes alone and chronic kidney disease alone… do not increase the rate of myocardial infarction to the same extent as does a history of coronary disease, and therefore do not support the use of the term coronary heart disease risk equivalent for either disorder.” However, they concluded that CKD should “be added to the list of criteria defining people at highest risk of future coronary events.”

In an accompanying comment, Tamar Polonsky and George Bakris write that “despite negative findings for the primary outcome, compelling reasons are provided to consider lipid-lowering therapy in patients with chronic kidney disease.”
Click here to read the Lancet press release…

Real World Bleeding Risk Of Aspirin In Primary Prevention Examined Reply

by • Prevention, Epidemiology & Outcomes • Tags: , , , ,

A new study published in JAMA provides substantial new evidence about the real world effects of aspirin, including the risk of  bleeding, in a broad  population. The study also sheds important new light on the effects of aspirin in a diabetic population.

Giorgia De Berardis and colleagues analyzed data from more than 4 million people in Puglia, Italy and compared 186,425 people taking low-dose aspirin with the same number of matched controls not taking aspirin.

Major bleeding events requiring hospitalization:

  • aspirin: 5.58 (5.39-5.77) per 1000 person-years
  • controls: 3.60 ( 3.48-3.72) per 1000 person-years
  • Incidence rate ratio (IRR) 1.55 (1.48-1.63)

Diabetics overall had an increased risk of major bleeding episodes but this increased risk was not significantly associated with aspirin use:

  • Hemorrhagic events in diabetics overall (compared with non diabetics): IRR 1.36 (1.28-1.44)
  • Hemorrhagic events in diabetics taking aspirin compared with diabetics not taking aspirin: IRR 1.09 (0.97-1.22)

The authors wrote that their findings demonstrate that bleeding events occur more frequently than had been observed in clinical trials. They calculated that for individuals with a 10-year risk of cardiovascular events between 10% and 20% the risks and benefits of aspirin therapy are similar, causing 2 excess bleeds, and preventing 2 CV events, for every 1,000 people treated each year.

In an accompanying editorial, Jolanta Siller-Matula writes that the benefits of aspirin in secondary prevention are “not disputed,” since aspirin can prevent 6 major vascular events at the expense of 1 major bleeding event. But there is no such consensus for primary prevention, and Siller-Matula writes that the findings of the Italian study reinforce current European guidelines which do not recommend aspirin for primary prevention.

The JAMA study provides far more information about aspirin use in diabetics than had been previously available. Nevertheless, writes Siller-Matural, the decision whether to use aspirin for primary prevention in this population is still not clear, and will require additional data from ongoing studies.

Click here to read the JAMA press release…

Subway Meals Get American Heart Association Endorsement 2

by • People, Places & Events, Policy & Ethics • Tags: , , , , , ,

The American Heart Association (AHA) announced today that it had initiated a new program that it claims will help people choose healthy meals at restaurants. The Subway restaurant chain will be the first to display the Heart-Check Meal Certification logo next to certain selected meals.

In a press release the AHA’s president, Gordon Tomaselli, said the program would make “it easy for consumers to make smart choices that are heart-healthy when eating outside the home, knowing they often don’t have the benefit of reviewing the nutrition facts.” The meal certification program is an expansion of the AHA’s Heart-Check Food Certification program, which was established in 1995.

Tomaselli told USA Today that certification can cost companies as much as $700,000 annually. ”But it’s not pay-to-play,” he told the paper. “The money is used to make sure what we’re telling the public is correct.”

The AHA certification logo will be displayed on Subway meals that meet the AHA’s nutritional criteria for levels of sodium, calories, cholesterol, saturated fat and trans-fats. But the new program does not mean that all meals certified by the program will necessarily be heart healthy, as noted on the Heart-Check Meal Certification webpage:

Is it still heart healthy to order my meal with mayonnaise or mustard?

  • The standard SUBWAY® 6-inch sandwiches that are part of the AHA (adult) certified meal are prepared on 9-grain wheat bread and contain the following vegetables: lettuce, tomatoes, onions, green peppers and cucumbers.
  • These sandwiches were evaluated without the addition of condiments such as mustard or mayonnaise. Adding condiments containing sodium (such as mustard) or fat (such as mayonnaise) may result in the meal no longer meeting AHA meal criteria.
  • Condiments such as mayo and mustard add saturated fat, sodium and cholesterol that can easily be avoided. These small choices throughout the day can help keep eating habits on track.
  • Additions such as pickles, cheese, and olives also make the sandwich less healthy.
  • Considering the freshness of the bread and the flavor and juiciness provided by the vegetables, these sandwiches are tasty without the addition of other toppings or condiments.

Subway said that it had been an AHA supporter for 12 years. On the AHA website, Subway is listed as a member of the Industry Nutrition Advisory Panel (INAP). Here is the mission of the INAP, according to the AHA website:

The American Heart Association (AHA) Industry Nutrition Advisory Panel (INAP) is a strategic relationship between the AHA Nutrition Committee and food industry leaders. INAP provides a platform for sharing information and planning cooperative programs in the areas of diet and nutrition and cardiovascular disease.

INAP industry members pay a $10,000 yearly membership fee to participate in meetings with “science representatives” from the AHA and other industry members. Here is the AHA description of the benefits of membership:

The primary benefit of INAP is bringing together industry and science representatives to exchange dialogues on areas of mutual interest pertaining to nutrition. Benefits of this dialogue include:

  • Networking and relationship building with industry leaders
  • Education on relevant topics from the nutrition, physical activity, metabolism and obesity areas
  • Members get the latest updates on all AHA initiatives and are given the opportunity to provide input to the AHA regarding statements and positions on these topics
  • Direct access to AHA staff involved in nutrition-related issues
  • An organized relationship with the Nutrition Committee that allows for open communication on topics of interest

Members also receive one complimentary registration to attend the AHA’s spring science conference and council dinner coordinated by the Nutrition, Physical Activity and Metabolism Council (NPAM) and the Council on Epidemiology (EPI).

In addition to Subway, some of the other members of INAP are Uniliver, Coca-Cola, Dr. Pepper, Frito-Lay, Hershey, Kellog, Kraft, McDonald’s, Sara Lee, The Sugar Assocaition, Welch’s, and Yumi Brands (Taco Bell, KFC, Pizza Hut).

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