Walking With the American Heart Association: Valerie Bertinelli and Chester Cheetah 1

A few weeks ago Chester Cheetah, the official mascot for Frito Lay’s Cheetos, played an official part in  the American Heart Association’s Dallas Heart Walk. Yoni Freedhoff, on his Weighty Matters blogpretty much says what needs to be said about this disgraceful association between Frito Lay and the AHA.

This weekend I received a press kit from Jenny Craig. The diet company was publicizing the participation of  tabloid celebrity Valerie Bertinelli, a Jenny Craig “brand ambassador,”  in the AHA’s Los Angeles Heart Walk on Saturday. At first glance, Jenny Craig’s relationship with the AHA does not appear to be as awful as Frito Lay’s. After all, whatever else you may think about the company and its methods, obesity is a major problem, and if some people can defy the odds and lose weight with Jenny Craig then all the better for them.

But the Jenny Craig relationship brings up another, more subtle harm caused by these sort of increasingly popular arrangements in which nonprofit organizations accept money from for-profit corporations. I was astonished to read the second paragraph of the Jenny Craig press release:

Bertinelli, who has lost weight on the Jenny Craig program, recognizes the importance of being in good heart health, and owes her mother’s life to Jenny Craig.  Bertinelli’s mother, Nancy, lost 54 pounds* on Jenny Craig after witnessing her daughter’s success on the program. In October of 2008, Bertinelli’s mother required emergency heart valve replacement surgery.  After the successful surgery, the cardiologist pulled Bertinelli and her brother aside and told them that if their mother hadn’t previously lost weight, she would not have survived the surgery.

Scientifically and medically, this is an entirely irresponsible statement, if in fact a cardiologist did make this statement. My source for this assertion? The AHA itself. Here’s what an AHA science advisory had to say about this exact topic:

Severe obesity has not been associated with increased mortality in patients undergoing cardiac surgery but has been associated with an increased length of hospital stay and with a greater likelihood of renal failure and prolonged assisted ventilation.

One of the most important roles of the AHA is to encourage, develop, and support the use of evidence-based medicine. Why then does the AHA agree to partner with companies that flagrantly (Frito Lay) or more subtly (Jenny Craig) undermine that effort?

Fun facts: Jenny Craig is a wholly owned subsidiary of Nestlé. Frito Lay is owned by Pepsi.

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Click here to read the Jenny Craig press release…

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Subcutaneous ICD Gains FDA Approval Reply

The FDA today approved the Subcutaneous Implantable Defibrillator (S-ICD) system from Cameron Health. The device is the first ICD that does not require a lead that connects directly to the heart and  therefore  does not need to be guided with x-ray fluoroscopy. Instead, the S-ICD lead is implanted along the bottom of the rib cage and breast bone.

The S-ICD System has been approved only for patients who do not also require a pacemaker or pacing therapy. The FDA will require Cameron Health to perform a 5-year postmarketing study with 1,616 patients to measure the long-term safety and efficacy of the device and to test whether the device is equally effective in men and women.

“The S-ICD System provides an alternative for treating patients with life-threatening heart arrhythmias for whom the routine ICD placement procedure is not ideal,” said Christy Foreman, director of the Office of Device Evaluation at FDA’s Center for Devices and Radiological Health, in a press release. “Some patients with anatomy that makes it challenging to place one of the implantable defibrillators currently on the market may especially benefit from this device.”

In April, the FDA’s Circulatory System Devices panel voted 7-1 that the benefits of the S-ICD outweigh the risks in appropriately selected patients. Approval was based on the pivotal 321-patient study in which 304 patients successfully received the S-ICD. During the six month followup period the device detected 78 arrhythmias in 21 patients. According to the FDA analysis, all the arrhythmias were terminated by the device or resolved spontaneously. Common complications of the device include inappropriate shocks, discomfort, system infection, and electrode movement.

Earlier this year Boston Scientific acquired Cameron Health for an initial payment of $150 million. Depending on future performance, the price may reach as much as $1.2 billion.

Rick Lange, who served on the FDA’s Circulatory System Devices advisory panel that reviewed the S-ICD, provided the following comment:

This will be a niche device…..it will have a limited role because it’s not suitable for patients who also need or would benefit from pacing therapy.  However, it may be particularly suitable for primary prevention of SCD in children or young adults (i.e. those with HOCM, long QT, RV dysplasia, Brugada syndrome, family history of SCD, etc) where intravascular lead placement is not attractive because of continued growth of the child or concerns about long term lead complications. The FDA panel was insistent that a post marketing study be performed to ensure that the device appropriately sensed and treated lethal arrhythmias. Early versions of the sensing algorithm needed tweaking.
Click here to read the press releases from the FDA and Boston Scientific…

FDA Sets New Decision Date For Eliquis (Apixaban) Reply

The FDA will decide the fate of apixaban (Eliquis) by March 17, 2013. The new Prescription Drug User Fee Act (PDUFA) goal date was announced yesterday by the drug’s manufacturers, Pfizer and BristolMyers Squibb.

The new drug application (NDA) for stroke prevention in atrial fibrillation has been delayed twice. Although the pivotal ARISTOTLE trial was highly praised when it was first published, the FDA first extended its review by three months and then issued a complete response letter (CRL) on June 25 requesting “additional information on data management and verification from the ARISTOTLE trial.” According to Pfizer and BristolMyers Squibb, the FDA has now accepted for evaluation their response to the CRL.

In Europe last week the Committee for Medicinal Products for Human Use (CHMP) recommended approval for apixaban for the same indication.

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

Merck Returns To Cardiome All Rights To Atrial Fibrillation Drug Vernakalant Reply

Merck and Cardiome announced today that Merck was returning to Cardiome all marketing and development rights for the atrial fibrillation (AF) drug vernakalant. An intravenous formulation of vernakalant is marketed in Europe as Brinavess. It has not been approved in the United States, though it received a positive recommendation from the FDA’s Cardiovascular and Renal Drugs Advisory Committee in 2007.

Earlier this year, as reported here, Merck announced that it was ending its involvement in the development of an oral formulation of vernakalant.

During a conference call, Dr. William Hunter, the interim CEO of Cardiome, expressed confidence that the company would go forward with vernakalant. He pointed out that “what constitutes an opportunity for Cardiome is probably very different than what constitutes one for a global corporation the size of Merck.” In a press release, Hunter stated: “Cardiome looks forward to continued advancement of the launch of BRINAVESS IV worldwide and welcomes the opportunity to continue development of vernakalant oral worldwide and vernakalant IV in North America.”

Click here to read the press release from Merck and Cardiome…

AHA Urges More Education And Support For ICD Patients 1

Despite, and perhaps sometimes because of, their life-saving benefits, ICDs are associated with a host of complex psychosocial problems, but clinicians and caregivers receive little training to deal with these problems. In response to these concerns, the American Heart Association (AHA) has published a scientific statement in Circulation to provide a “comprehensive review of what is and is not known about psychological responses and psychosocial care” for ICD patients and their families.

The authors note that many ICD patients and potential ICD patients don’t fully understand the limitations and implications of the device. For instance, they “have a tendency to believe that the device can ‘undo’ the negative consequences of their cardiac condition, overestimate benefits, and underestimate adverse aspects.”

The document provides an overview of psychological responses to ICD therapy and the quality of life issues that often come up for ICD patients and their families. The effect of ICD shocks on quality of life is discussed in detail. In addition, the impact on the intimate and sexual relationships of patients and their partners is explored.

Although they represent a small percentage of ICD patients, children are a very important subgroup. The document notes that “few data are available to fully understand the psychosocial impact of the ICD on pediatric and adolescent ICD recipients, and no longitudinal studies of psychosocial response over time are available.”

At the other end of life, the authors discuss the difficult issue of ICD deactivation “as a patient’s clinical status worsens and death is near.” Unfortunately, they note, “clinicians and patients rarely engage in discussions about deactivating ICDs, and most devices remain active until death” and “most patients are not even aware that deactivation of the shocking function is an option.”

“A shock from an ICD can be lifesaving, but it can also affect a person’s quality of life and psychological state,” said Sandra Dunbar, the  chair of the statement writing group, in an AHA press release. “It’s important to look at this issue now because 10,000 people have an ICD implanted each month. They range from older people with severe heart failure to healthy children who have a gene that increases the risk of sudden cardiac arrest.”
Click here to read the AHA press release…

Another One Bites the Dust: Diovan Patent Expires But Generic Valsartan Is MIA 1

Although the patent on valsartan (Diovan, Novartis) expired last Friday, a generic version of the popular antihypertensive drug has yet to make it to market. By contrast, a generic version of Diovan HCT, the combination of valsartan and hydrochlorothiazide, was recently launched by generic drugmaker Mylan.

As reported on Pharmalot, Ranbaxy, the embattled generic drugmaker, holds the exclusive rights to market generic valsartan for 180 days, but has so far been unable to gain FDA approval. The delay, according to Pharmalot, “only adds to the uncertainty surrounding Ranbaxy’s ability to recover from its long-standing manufacturing woes and haggling with the FDA over its ability to resume operations on regular basis in the US.”

According to the Wall Street Journal, the Diovan franchise generated $5.7 billion worldwide in 2011.
Click here to read the Mylan press release…

Novartis Announces Top Line Results For Phase 3 Trial Of New Acute Heart Failure Drug Reply

Novartis announced preliminary results from the RELAX-AHF trial, a phase 3 study of a novel drug, RLX030 (serelaxin), for patients hospitalized with acute heart failure. The company said the trial met one of its two primary endpoints in reducing dyspnea.

Novartis also reported a reduction in all cause mortality at 6 months. However, it should be noted that the predefined secondary endpoint on ClinicalTrials.Gov was mortality at 60 days, not 6 months. (CardioBrief has requested clarification from Novartis about this point.)

In the trial, 1,161 patients hospitalized with acute heart failure were randomized to placebo or an IV infusion of RLX030 for up to 48 hours.   By design, the trial had 2 primary efficacy end points measuring dyspnea,but only one of them reached statistical significance, according to the company.

The full results of RELAX-AHF are scheduled to be presented as a late-breaking clinical trial at the American Heart Association meeting in Los Angeles in November.

RLX030 is a recombinant form of the naturally occurring human hormone relaxin-2. The drug was originally developed by Corthera, Inc, which was acquired by Novartis in February 2010.
Click here to read the press release from Novartis…

“Dramatic” Increase In Bleeding Accompanies Addition Of Oral Anticoagulant Therapy In ACS Reply

The newer oral anticoagulants may help reduce ischemic events after an acute coronary syndrome (ACS), but only at the cost of a “dramatic” increase in bleeding complications, according to a new meta-analysis published in the Archives of Internal Medicine.

Hungarian researchers performed a systematic review and meta-analysis of seven trials in which 31,286 ACS patients were randomized to placebo or a new oral anticoagulant, either an anti-Xa or direct thrombin inhibitor. All patients also received antiplatelet therapy. Here are the odds ratios for bleeding events and important clinical endpoints with the newer agents:

  • TIMI major bleeding events: OR 3.03 (2.20-4.16)
  • Overall mortality: OR 0.90 (0.76-1.06)
  • Composite ischemic events: OR 0.86 (0.79-0.94)
  • Stent thrombosis (definite or probable): OR 0.73 (0.54-0.98)

“These results suggest that the unrestricted use of new-generation oral anticoagulant agents as an adjunct to dual antiplatelet therapy after an ACS cannot be recommended,” the authors concluded. However, they left open the possibility that the newer oral anticoagulants may be beneficial in the 6%-21% of ACS patients who require long-term anticoagulation for atrial fibrillation and other conditions.

In an accompanying comment, Adrian Hernandez writes that “the conclusions of the meta-analysis seem to be robust.” He points out that the large differences in the relative risk of bleeding and clinical events found in the meta-analysis translate into smaller differences in absolute risk. Nevertheless, he writes, “the benefit is largely canceled by the harm; therefore, the routine use of [novel oral anticoagulants] among patients with ACS is unwarranted.”

 

Apixaban (Eliquis) For Atrial Fibrillation Gets Positive European Recommendation 2

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…

Studies Examine Less Burdensome Dual Antiplatelet Regimens Reply

Two new studies published in the Journal of the American College of Cardiology offer hope but not, yet, compelling evidence to support less burdensome requirements for dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation.

In the first study, Spanish investigators followed 1,622 consecutive patients who received a drug-eluting stent (DES) for one year. They found that 10.6% of the DES patients interrupted at least one antiplatelet drug during the first year. Two-thirds (64.5%) of the  interruptions were temporary, lasting a median of 7 days. After discontinuation of therapy 4.1% of patients had an acute coronary syndrome (ACS), but this was not significantly different from the 5.5% rate of major cardiac events in patients who remained on DAPT.

The authors concluded that early discontinuation of DAPT “is not exceptional and is usually temporary. Although further knowledge about individual risk is desirable, our results suggest that discontinuation for a few days (median: 7 days) of DAT after the first month of DES implantation may be reasonably safe in terms of major cardiac events.”

In an accompanying editorial, Bernhard Witzenbichler points out several limitations of the study, and concludes that “the data can only suggest that a brief interruption of DAPT does not have a large impact on ischemic risk.”

In the second study, Korean investigators randomized 2,117 patients to receive either the Endeavor zotarolimus-eluting (ZES) stent plus 3 months of DAPT therapy or standard therapy, consisting of another DES with a full year of DAPT. There was no difference between the two groups in the primary endpoint (the composite of CV death, MI, stent thrombosis, TVR, or bleeding), which occurred in 4.7% of patients in each group, and there were no significant differences in any of the components of the endpoint. The authors concluded that the Endeavor ZES plus 3 month DAPT “could be safe and beneficial for the selected patients with coronary artery disease who may need to stop DAPT early after DES implantation.”
Click to continue reading…

Screening For AAA Comes Under Renewed Scrutiny And Criticism Reply

A 2007 Medicare initiative to increase AAA (abdominal aortic aneurysm) screening in appropriate patients failed to prevent AAA rupture or reduce all-cause mortality, according to a new study published in Archives of Internal Medicine. The larger implications of the study are unclear, but two accompanying papers, an invited commentary and a perspective, emphasize the darker side of AAA screening.

Jacqueline Baras Shreibati and colleagues examined the effect of the 2007 Screening Abdominal Aortic Aneurysms Very Efficiently (SAAAVE) Act which provided Medicare coverage for a one-time ultrasound screening for new Medicare patients who were men and who had a history of smoking or women with a family history of AAA. The SAAAVE Act was based on 2005 US Preventive Services Task Force recommendations.

Using Medicare data from 2004 to 2008, the investigators found a modest increase in AAA screening among eligible 65-year-old Medicare men during the study period, from 7.6% in 2004 to 9.6% in 2008. The SAAAVE Act resulted in no significant differences in the rates of AAA repair, AAA rupture, or all-cause mortality, they concluded.

In an invited commentary, Russell Harris, Stacey Sheridan, and Linda Kinsinger write that the evidence about AAA screening has changed since the 2005 USPSTF recommendations. In the past 10-15 years, they write, mortality from ruptured AAA has been cut nearly in half. AAA screening, they maintain, has had little to do with this change; rather, the change is more likely due to long term trends in the reduction of smoking prevalence and the incidence of MI.
Click to continue reading…

International Cardiology Groups Push For Aggressive Public Health Goals Reply

Cardiovascular disease is the largest cause of death in the world and accounts for almost half of all deaths from non-communicable diseases (NCDs). Earlier this year, in response to a high-level UN meeting on NCDs in 2011, the World Health Assembly set a global target  to reduce premature NCD mortality by 25% by the year 2025.

Now The Global Cardiovascular Disease Taskforce, including representatives from the World Heart Federation, the American Heart Association, the American College of Cardiology Foundation, the European Heart Network, and the European Society of Cardiology, have proposed a set of aggressive measures to help achieve the goal.

The Global Cardiovascular Disease Taskforce is urging governments and medical groups to adopt four global targets:

  • Reduce the prevalence of insufficient physical activity by 10%
  • Reduce the prevalence of hypertension by 25%
  • Reduce salt/sodium intake by 30%, with the aim of achieving the recommended level of less than 5 g/day
  • Reduce by 30% the prevalence of tobacco smoking

The Taskforce also expressed support for a halt in the increase in obesity and reductions in saturated fat intake, cholesterol, and alcohol (when excessive). The group also called for increased use of drugs to prevent MI and stroke.

“The number of people with CVD is growing and its impact is disproportionately felt by those in the developing world, where people die younger; we now have the opportunity of a lifetime to stem its rise with concerted international action that will help countries tackle the preventable causes of CVD,” said Sidney Smith, Jr, president of the WHF and chair of the writing group, in a press release.

The CVD Taskforce paper can be downloaded in the journals Global Heart, Circulation, the European Heart Journal, and the Journal of the American College of Cardiology.

Here is the press release from the AHA:

Cardiovascular disease community calls for tougher targets to curb global risk

September 17, 2012
Leaders in cardiovascular disease prevention and control publish paper calling for urgent action to reduce premature mortality by 25 per cent by 2025
 
Geneva, 18 September 2012 – Agreement by governments, by the end of 2012, on a set of ambitious global targets to curb the growing scourge of non-communicable diseases (NCDs), which includes cardiovascular disease (CVD; heart disease and stroke), is critical to avoiding the millions of premature deaths worldwide. This, according to a new paper published by the Global Cardiovascular Disease Taskforce a group of eminent experts who represent five leading heart-health organizations.
On the occasion of the first anniversary of the second ever United Nations High-Level Meeting on a health-related issue – NCDs – the Taskforce is calling on governments and the CVD community to accelerate progress on the commitments made at this landmark event by supporting 10 evidence- based targets. CVD is the leading cause of death worldwide, killing 17.3 million people a year and making up nearly half of the 36 million NCD deaths.  Around 80 per cent of these deaths are in low- and middle-income countries where human and financial resources are most limited to address them. The number of CVD deaths is expected to rise to 23.6 million by 2030.
As a first step, a global target to reduce premature deaths from NCDs, 25 per cent by 2025 was agreed at the 65th World Health Assembly in Geneva this past May. However, as the Global CVD Taskforce suggests, additional targets developed by the World Health Organization (WHO) are key to achieving this overarching goal. These include curbing physical inactivity, tobacco consumption, salt intake and hypertension.
“The number of people with CVD is growing and its impact is disproportionately felt by those in the developing world, where people die younger; we now have the opportunity of a lifetime to stem its rise with concerted international action that will help countries tackle the preventable causes of CVD,” said Dr Sidney C. Smith, Jr (World Heart Federation President and Chair of the writing group).
“Cardiovascular disease risk can be lowered by public policies that help people to make healthier choices. This set of robust targets can focus governments’ efforts on this vital task and make progress measurable,” said Dr Ralph Sacco, Past President of the American Heart Association.
“In addition to policies that aid in prevention, it is also paramount that those living with CVD and at risk of developing CVD have access to prevention and rehabilitation services, including affordable and simple medical treatments”, said Dr Hans Stam, President of the European Heart Network.
With CVD costing governments nearly US$863 billion globally, the Taskforce recommends the uptake of a set of interventions designed by the WHO and designated as “best buys” – cost-effective treatments that can be delivered regardless of the income level of a country. These include the widespread adoption of multidrug therapies that could save nearly 18 million lives over a 10-year period, at a cost of just over a dollar a day.
“The treatments are out there, and they are feasible and cost-effective; we need to make them available and affordable around the globe for a healthier outcome”, said Dr William A. Zoghbi, President of the American College of Cardiology. “The European Society of Cardiology (ESC) has recently made a call for governments to implement population-level changes, such as taxation and regulation of advertising” said Professor Robert Ferrari, ESC Past President. “Up to 50% of deaths from CVD in Europe could be avoided by making the environment healthier, in order to nudge individuals in the right direction,” added the ESC Secretary and Treasurer, Professor David Wood.
The CVD Taskforce paper is released ahead of World Heart Day on September 29, when supporters worldwide will rally for healthy homes and countries, with a particular focus on the lesser known CVD risks for women and children.
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News Flash! Company Issues Incredibly Boring Press Release 1

Last week Abiomed issued a press release (reprinted below) that was about as dull as a press release can get. The main news of the press release was that the PROTECT II study testing the company’s Impella 2.5  circulatory support device had been published online in Circulation.

The press release provides no details or information about the trial and makes no claims about the clinical benefits of the company’s device. The only remotely interesting items in the press release are  generic quotes from the principal investigator of the trial, William O’Neill, and from Michael Minogue, the chairman and CEO of Abiomed:

O’Neill: “Today marks a very significant milestone in providing new clinical insight for cardiovascular disease patients considered too risky for conventional surgery. The PROTECT II publication in Circulation underscores the importance of this study’s observations to the clinical community.”

Minogue: “PROTECT II is a landmark clinical trial and we are grateful to Dr. O’Neill and his colleagues for leading this study. The peer-reviewed publication of PROTECT II in the esteemed Circulation journal is a notable achievement for Abiomed. Most importantly, we believe that this study will advance the treatment for patients with heart failure.”

Now all this would be entirely unremarkable, except for the fact that O’Neill and Abiomed struck a very different tone earlier in the history of this trial.

In November 2010, when the trial was terminated early due to futility, the company issued a press release which contained numerous details about the results of the trial and then portrayed these results as a triumph, despite the fact that the overall trial was negative. Although the full results had not been publicly presented, much less undergone peer review or scrutiny from other physicians or regulators, the CEO said the trial would “pave the way to change the standard of care for PCI requiring prophylactic hemodynamic support.” And O’Neill told Wall Street investors that the trial was “a landmark trial that will impact practice.”

As I wrote then, the press release struck me as a perfect example of how to spin a negative result, relying on cherry picked endpoints and subgroups. (The original press release was removed from the company website but can be found in my news story.) Rick Lange and David Hillis provided their own critical perspective of the trial on CardioExchange.

The initial press release wasn’t the only problem with the rollout of PROTECT II. An additional issue became fully apparent a few months later in April 2011 when the full trial results were trial were scheduled for presentation at the American College of Cardiology meeting in New Orleans. Prior to the meeting the company issued a press release announcing that the study would be presented at a late-breaking clinical trials session, a highly prestigious and much-desired position.

But PROTECT II was not presented at a late-breaking clinical trial session. As I reported shortly before the ACC meeting,  the trial “was resoundingly shot down as an ACC late-breaking clinical trial at the selection meeting” because the company had violated the Ingelfinger Rule, which prevents publication of trial information that has been previously submitted or reported elsewhere. In other words, the earlier Abiomed press release led the ACC to disqualify the trial for presentation as a prestigious late-breaker.

Circulation is unlikely to lift the veil on its editorial process, but my guess is that the journal played a big role in the final shape of last week’s remarkably modest publication and accompanying press release. The Circulation paper concludes– properly– that “Impella 2.5 did not result in a superior outcome of the primary endpoint at 30 days.” The paper also reports the results of a more promising secondary analysis suggesting a possible benefit for the device at 90 days, but rather than hyping these results as heralding a change in the standard of care, the authors write: “Since the difference in 30 day MAE [major adverse events] did not reach statistical significance for the entire study, the analysis of 90 day events remains exploratory.”

So let’s celebrate genuine progress, in this case represented by a dull scientific paper and an even duller press release.

Click here to read the Abiomed press release from last week…

Meta-Analysis Links Stress At Work And Heart Disease Reply

A new study published in the Lancet provides the best evidence yet that work-related stress and, in particular, job strain– “the combination of high job demands and low control at work”– plays a small but important role in causing heart disease. In order to address the limitations of previous studies on this topic, including a publication bias which might exaggerate the effect, European investigators performed a large collaborative meta-analysis of published and unpublished studies.

The IPD-Work (individual-participant-data meta-analysis in working populations) consortium found that 15% of nearly 200,000 participants in the analysis reported having job strain. With a mean followup of 7.5 years, job strain was significantly associated with heart disease. The effect was higher in published studies, though it still achieved significance in the unpublished studies:

  • Overall hazard ratio (HR) for job strain: 1.23,CI 1.10–1.37
  • HR in published studies: 1.43, CI 1.15−1.77
  • HR in unpublished studies: 1.16, CI 1.02−1.32

The investigators calculated that the population attributable risk for job strain was 3.4%, which, they noted, was substantially lower than the major risk factors of smoking, obesity, and physical inactivity.

“Our findings suggest that job strain is associated with a small, but consistent, increased risk of an incident event of cardiovascular heart disease,” they concluded.

In an accompanying comment, Bo Netterstrøm writes that “job strain is a measure of only part of a psychosocially damaging work environment, which implies that prevention of workplace stress could reduce incidence of coronary heart disease to a greater extent than stated in the authors’ interpretation of the calculated population-attributable risk for job strain.”
Click here to read the press release from the Lancet…

A Manhattan Project To End The Obesity Epidemic 3

A newly launched nonprofit organization, the Nutrition Science Initiative, will try to find an answer to the question,  “What should we eat to be healthy?” NuSI is nothing if not ambitious: its goal is to seek “the end of fad diets and high obesity rates.”

The founders of the organization, called NuSI (pronounced “new see”) for short, are Gary Taubes and Peter Attia. Taubes is the science journalist who helped launch the low-carb diet resurgence with his controversial New York Times magazine articles and subsequent books, Good Calories, Bad Calories and Why We Get Fat. Attia, who is the President of NuSI, trained in surgery at Johns Hopkins and the NIH before working as a consultant at McKinsey & Company.

Taubes explains the premise of NuSI:

NuSI was founded on the premise that the reason we are beset today by epidemics  of obesity and type 2 diabetes, and the reason physicians and researchers think these diseases are so recalcitrant to dietary therapies, is because of our flawed understanding of their causes. We believe that with a concerted effort and the best possible science, this problem can be fixed.

NuSI originally started as a more modest endeavor, but has now received a significant commitment of financial support from a foundation started by billionaire hedge fund manager John Arnold. The aim of the organization is, as the following NuSI publicity slide states, to “create a Manhattan Project-like effort to solve” the problem of obesity in the US:

The NuSI scientific advisory board is composed of Alan Sniderman, a lipid researcher at McGill University, David Harlan, the former head of the Diabetes, Endocrinology, & Metabolic Diseases branch of the NIDDK and now at U Mass, Mitchel Lazar, of the University of Pennsylvania, and Kevin Schulman, of Duke University.

On his Weighty Matters blog, obesity clinician and writer Yoni Freehoff offers a perspective both critical and supportive of the NuSI agenda.

Click here to read the NuSI press release…

Study Predicts Renal Denervation Will Be Cost Effective In Resistant Hypertension 1

Renal denervation (RDN) for resistant hypertension may be cost-effective and may provide long-term clinical benefits, according to a new analysis published in the Journal of the American College of Cardiology.

Benjamin Geisler and colleagues developed a model to predict the impact of the Medtronic Symplicity RDN system in patients with resistant hypertension. Over 10 years, according to the model, RDN treatment resulted in large differences in outcomes, though the benefits were less pronounced when projected over a lifetime.

Projected 10 year Relative Risk:

  • Stroke: 0.70 (reduced from 11.6% in the control group to 8.2% in the RDN group)
  • MI: 0.68 (reduced from 9.6% to 6.5%)
  • CHD: 0.78 (reduced from 24.8% to 19.4%)
  • HF: 0.79 (reduced from 5.4% to 4.3%)
  • ESRD: 0.72 (reduced from 2.9% to 2.1%
  • CV mortality: 0.70 (reduced from 12.5% to 8.7%)
  • All-cause mortality: 0.85 (reduced from 23.0% to 19.5%)

Median survival was lengthened from 17.07 years to 18.37 years. The authors calculated an increase in quality-adjusted life-years (QALY) from 12.07 to 13.17 years, resulting in a discounted incremental cost-effectiveness ratio of $3,071/QALY. Cost-effectiveness was “markedly below the commonly accepted threshold of $50,000 per QALY [quality-adjusted life-year],” and might even be cost-saving, according to the authors.

The model assumes that RDN causes a long term reduction in blood pressure, though current data from the Symplicity HTN-2 trial only extends to 36 months. However, the authors reported that RDN remained “cost-effective across a wide range of assumptions.”

Republished with permission from CardioExchange, a NEJM group publication.

More Evidence That Omega-3 Supplements Don’t Work Reply

Once again researchers have failed to find any clinical benefit for omega-3 supplements. In a new meta-analysis and systematic review published in JAMA, Evangelos Rizos and colleagues analyzed 20 randomized controlled trials including  68,680 patients and found no significant effect on any of the endpoints:

  • all-cause mortality: relative risk (RR) 0.96, CI 0.91 – 1.02
  • cardiac death: RR 0.91, CI 0.85 – 0.98 (not significant after correction for multiple comparisons)
  • sudden death: RR 0.87, CI 0.75 – 1.01
  • MI: RR 0.89, CI 0.76 – 1.04
  • stroke: RR 1.05, CI 0.93 – 1.18

The authors reported that they found no evidence supporting a beneficial effect related to either lowering triglycerides or reducing sudden death. Regarding triglycerides, they wrote, “the proposed protective role of omega-3 PUFAs by lowering triglyceride levels is not supported by our study, because our findings do not support an advantage of higher (triglyceride-lowering) doses compared with lower doses of omega-3.” And no benefit was found in preventing sudden death, “thus rejecting a distinct antiarrhythmic mediated omega-3 PUFA effect,” though the authors acknowledged that the evidence was “underpowered to detect a small underlying effect.”

Although early studies suggested a benefit for omega-3 supplements, the accumulation of evidence has resulted in a consistent failure to confirm this benefit, according to the authors. Current evidence, they concluded, does “not justify the use of omega-3 as a structured intervention in everyday clinical practice or guidelines supporting dietary omega-3 PUFAadministration.”

Here is the press release from JAMA:

Omega-3 Fatty Acid Supplementation Not Associated With Lower Risk of Major Cardiovascular Disease Events

 

CHICAGO – In a study that included nearly 70,000 patients, supplementation with omega-3 polyunsaturated fatty acids was not associated with a lower risk of all-cause death, cardiac death, sudden death, heart attack, or stroke, according to an analysis of previous studies published in the September 12 issue of JAMA.

“Treatment with marine-derived omega-3 polyunsaturated fatty acids (PUFAs) for the prevention of major cardiovascular adverse outcomes has been supported by a number of randomized clinical trials (RCTs) and refuted by others. Although their mechanism of action is not clear, their postulated effect on cardiovascular outcomes may be due to their ability to lower triglyceride levels, prevent serious arrhythmias, or even decrease platelet aggregation and lower blood pressure. Current guidelines issued by major societies recommend their use, either as supplements or through dietary counseling, for patients after myocardial infarction [MI; heart attack], whereas the U.S. Food and Drug Administration has approved their administration only as triglyceride-lowering agents in patients with overt hypertriglyceridemia, and some (but not all) European national regulatory agencies have approved the omega-3 administration for cardiovascular risk modification. The controversy stemming from the varying labeling indications causes confusion in everyday clinical practice about whether to use these agents for cardiovascular protection,” according to background information in the article.

Evangelos C. Rizos, M.D., Ph.D., of the University Hospital of Ioannina, Ioannina, Greece, and colleagues performed a large-scale synthesis of the available randomized evidence by conducting a systematic review and meta-analysis to determine the association between omega-3 PUFAs and major cardiovascular outcomes.

Of the 3,635 citations retrieved, 20 studies with 68,680 randomized patients were included, reporting 7,044 deaths, 3,993 cardiac deaths, 1,150 sudden deaths, 1,837 heart attacks, and 1,490 strokes. Analysis indicated no statistically significant association with all-cause mortality, cardiac death, sudden death, heart attack, and stroke when all supplement studies were considered.

“In conclusion, omega-3 PUFAs are not statistically significantly associated with major cardiovascular outcomes across various patient populations. Our findings do not justify the use of omega-3 as a structured intervention in everyday clinical practice or guidelines supporting dietary omega-3 PUFA administration. Randomized evidence will continue to accumulate in the field, yet an individual patient data meta-analysis would be more appropriate to refine possible associations related to, among others, dose, adherence, baseline intake, and cardiovascular disease risk group,” the authors conclude.

(JAMA. 2012;308[10]:1024-1033.

Updated Rhythm Device Guidelines Clarify And Expand CRT Criteria Reply

A newly released update of 2008 guidelines for device-based therapy of cardiac arrhythmias contains some much-needed clarification about indications for cardiac resynchronization therapy (CRT). The document was developed jointly by the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society.

Highlights of the documents include:

  • The Class 1 recommendation for CRT for patients with systolic heart failure (HF) is now limited to patients with a QRS duration of at least 150 ms but has been expanded to include both patients with NYHA class II symptoms and LBBB patients.
  • A Class IIa recommendation for patients with a QRS duration of 120-149 who otherwise meet the criteria for a Class 1 recommendation.
  • A new Class IIB recommendation for patients with NYHA class I symptoms with LVEF < 30, ischemic HF, sinus rhythm, and LBBB with a QRS duration >150 ms.
  • Recommendations from 2008 remain in effect for hypertrophic cardiomyopathy, arrhythmogenic RV  dysplasia/cardiomyopathy, genetic arrhythmias, congenital disease, primary electrical disease, and terminal care.

The document also provides updated information about remote followup and monitoring of patients with cardiovascular implantable electronic devices.

“There is growing evidence that patients with the widest, most abnormal looking ECG potentially benefit most compared to patients whose ECG are less abnormal,” said Cynthia M. Tracy, the chair of the writing group, in a press release. She noted that patients with LBBB particularly benefit from CRT.

The authors noted that a separate document under development will define appropriate use criterial and “will help to further interpret the best science and apply it to various clinical scenarios.”

Republished with permission from CardioExchange, a NEJM group publication.

Click to continue reading…

Antihypertensive Use Among Pregnant Women on the Rise Reply

Growing numbers of pregnant women are taking antihypertensive drugs that may harm themselves or their babies, according to a new study published in Hypertension.

Brian Bateman and colleagues analyzed Medicaid data from more than 1.1 million pregnant women. Overall, 4.4% of the women received antihypertensive medications at some point during their pregnancy. From 2000 to 2007 the use of antihypertensive drugs increased from 3.5% to 4.9%. This increase, according to the authors, is “consistent with the rising rates of chronic hypertension and gestational hypertension… which in turn may reflect rising rates of obesity and advanced maternal age in US parturients.”

Exposure to antihypertensive drugs occurred in 1.9% of women during the first trimester, 1.7% during the second trimester, and 3.2% during the third trimester. ACE inhibitors, which are contraindicated in late pregnancy, were used in 4.9% of women who used antihypertensive medications in the second trimester and 1.1% in the third trimester. The authors said that automatic refills and the “prescribing physicians’ failure to ask about the possibility of pregnancy are two plausible explanations.”

About half of women who had been taking antihypertensive drugs prior to their pregnancy discontinued drug treatment during the first or second trimester. According to the authors, although antihypertensive therapy for mild-to-moderate hypertension can prevent progression to severe hypertension it is unknown whether it can reduce the risk of pregnancy complications, including placental abruption, fetal demise, superimposed preeclampsia, preterm birth, or maternal morbidity.

“While we know high blood pressure, or hypertension, occurs in about 6 percent to 8 percent of all pregnancies, we know little about how women and their doctors treat the condition,” said Bateman, in an AHA press release.

The authors pointed out that “there is virtually no data on the comparative effectiveness and safety of the different treatment options for hypertension” in pregnant women. “Research investigating the comparative safety and efficacy of antihypertensive therapy in pregnancy is urgently needed to define the optimal approach to therapy.”

Republished with permission from CardioExchange, a NEJM group publication.

Click here to read the AHA press release…

News Briefs: Cholesterol Trends, AHA Late-Breakers, FDA Updates On Rivaroxaban And Heartware HVAD Reply

Cholesterol Trends

The Centers for Disease Control issued a new report with the latest details about the prevalence of cholesterol screening and high blood cholesterol in US adults. Here is their summary of the key findings:

…cholesterol screening increased from 72.7% in 2005 to 76.0% in 2009, whereas the percentage of those screened who reported being told they had high cholesterol increased from 33.2% to 35.0%. Previously identified demographic disparities persist.

AHA Previews LBCTs

The American Heart Association has published a preview of the late-breaking clinical trials scheduled for presentation in November at the scientific sessions in Los Angeles. 28 LBCTs have been selected, including the NIH’s FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial and the controversial Trial to Assess Chelation Therapy (TACT).

J&J Provides More Information To FDA About Rivaroxaban

Johnson & Johnson said today that it had fully responded to the FDA’s request for more information about the use of rivaroxaban (Xarelto) in patients with acute coronary syndromes. The company also said it had resubmitted its supplemental New Drug Application (sNDA) for the drug to reduce the risk of stent thrombosis in ACS patients.

Heartware HVAD Close To FDA Approval

The Heartware HVAD ventricular assist system may be approved soon by the FDA, according to Wells Fargo analyst Larry Biegelsen. Robert Kormos, a cardiothoracic surgeon at the University of Pittsburgh, who also consults for Heartware,  said during a session at a Society of Thoracic Surgeons symposium that the device would be approved in the next few weeks.

Republished with permission from CardioExchange, a NEJM group publication.

Plagiarism Of Hypertension Article In Korean Journal Results In Retraction 2

In response to evidence of plagiarism in a review article in the Korean Circulation Journal, the article has now been retracted by the journal. Here is the notice:

On July 31, 2011, Korean Circulation Journal (KCJ) published a review article by Park et al.1)regarding the J-curve in hypertension and coronary artery diseases. However, a possibility of plagiarism has been raised in this article.

The Editorial Board of KCJ has examined the review article and has requested the Committee for Publication Ethics of Korean Association of Medical Journal Editors (KAMJE) to provide an adequate conclusion. After thorough investigation, the Committee for Publication Ethics of KAMJE and the Editorial Board of KCJ have concluded that the article is seriously plagiarizing from an article by Messeri et al.2)

In this regard, on May 8, 2012, the Executive Committee of the Korean Society of Cardiology has finally decided to retract the article completely. We apologize for any inconvenience this may have caused.

References

1. Park CG, Lee JY. The Significance of the J-Curve in Hypertension and Coronary Artery Diseases. Korean Circ J. 2011;41:349–353. [PMC free article] [PubMed]

2. Messerli FH, Panjrath GS. The J-Curve Between Blood Pressure and Coronary Artery Disease or Essential Hypertension. J Am Coll Cardiol. 2009;54:1827–1834. [PubMed]
By way of background, earlier this year I first reported that the KCJ article was suspiciously similar to a JACC article by Franz Messerli and Gurusher Panjrath. Shortly thereafter the editor-in-chief of the KCJ wrote me to say that an investigation into the matter had been initiated.

News of the retraction was first reported by Marilyn Mann. On the Retraction Watch blog, meanwhile, Ivan Oransky duly reported the retraction and then found another retraction in the same journalthis time for duplication of a case report of aortic dissection in an 11-year-old child.

 

Unrecognized MI: More Prevalent And Dangerous Than Previously Suspected 2

Unrecognized myocardial infarction (UMI) is more prevalent, and is associated with a worse prognosis, than may be generally understood, according to a new study published in JAMA.

Studying an elderly (67-93 years of age) population in Iceland, Erik Schelbert and colleagues used ECG and cardiac magnetic resonance (CMR) to detect UMI. CMR was more effective than ECG at detecting UMI. The study established that UMI was twice as prevalent as recognized MI (RMI):

  • No MI: 74%
  • RMI: 10%
  • Unrecognized MI by ECG: 5%
  • Unrecognized MI by CMR: 17%

Diabetics were more likely to have UMI detected by CMR than by ECG. After 6.4 years of followup, mortality was higher in the RMI and UMI groups than in the group without MI:

  • RMI: 33% (CI 23% to 43%)
  • UMI: 28% (CI 21% to 35%)
  • No MI: 17%, (CI 15% to 20%)

After adjusting for other factors, UMI by CMR, but not UMI by ECG, significantly improved risk stratification for mortality. People with UMI by CMR were less likely than people with RMI to take cardiac drugs.

According to the authors, the large percentage of UMIs has not been understood in the past due to previous reliance on ECG data; thus “a significant public health burden” has not been fully appreciated.

Click here to read the JAMA press release…

Danish Survey Finds Clopidogrel Less Effective In Diabetics Reply

A large nationwide survey of MI survivors in Denmark provides new information about the efficacy of antiplatelet therapy with clopdiogrel in patients with diabetes. In a paper published in JAMACharlotte Andersson reports on 58,851 MI patients, 12% of whom had diabetes and 60% of whom received clopidogrel.

As expected, diabetics had a worse outcome than nondiabetics: the composite endpoint of recurrent MI and all-cause mortality occurred in 25% of diabetics compared with 15% of the nondiabetics. Overall mortality was 17% in the diabetic group compared with 10% in the nondiabetic group.

Clopidogrel was less effective in diabetics than in nondiabetics in reducing all-cause mortality and CV mortality:

  • All-cause mortality risk reduction: 11%for diabetics versus 25% for nondiabetics (p value for interaction = .001)
  • CV mortality risk reduction: 7% (nonsignificant) for diabetics versus 23% for nondiabetics (p value for interaction = .01)

The results lend support to the hypothesis that “there may be a difference of effect of clopidogrel among those with diabetes compared with those without it,” wrote the authors. After acknowledging that “use of clopidogrel may still translate into a significant reduction in event rates for patients with diabetes,” they then raise the “possibility that patients with diabetes may benefit from a more potent platelet inhibitor strategy to achieve a relative risk reduction similar to patients without diabetes.”

In an accompanying editorial, Deepak Bhatt lends support to their suggestion, writing that it is plausible to suspect that there is “something about patients with diabetes that makes them less likely to respond to standard antiplatelet therapy.” Compared with nondiabetics, diabetics with coronary artery disease have increased platelet reactivity.  Bhatt writes that the newer and more potent antiplatelet agents prasugrel and ticagrelor may be more effective in diabetics, though they may also cause an increase in the risk of bleeding, and they cost more than clopidogrel, which has now gone generic.
Click here to read the press release from JAMA…

CDC: 35 Million Americans Have Uncontrolled Hypertension 2

According to the Centers for Disease Control, new data from the National Health and Nutrition Examination Survey (NHANES) shows:

  • 30.4% of US adults (about 66.9 million people) have hypertension.
  • 53.5% have uncontrolled hypertension (about 35.8 million people).
  • 39.4% with uncontrolled hypertension (about 14.1 million) are unaware that they have hypertension.
  • 89.4% with uncontrolled hypertension have a “usual source of health care and insurance, representing a missed opportunity for hypertension control.”

The CDC authors conclude: “The findings in this report can be used to target populations and refine interventions to improve hypertension control. Improved hypertension control will require an expanded effort from patients, health-care providers, and health-care systems.”

 

 

ESC Trials: The Best And The Worst Reply

Two trials presented at the ESC this year– WOEST and IABP-SHOCK II– are great examples of the way medicine is supposed to work. Another trial, FAME 2, is an example of so many of the things that can go wrong.

WOEST and IABP-SHOCK II are remarkably similar. Both trials tested conventional wisdom and found it lacking. WOEST examined the routine use of aspirin in “triple therapy” when people already taking an anticoagulant undergo PCI and then receive an additional antiplatelet drug and aspirin. IABP-SHOCK II tested the routine use of circulatory support with intraaortic balloon counterpulsation (IABP) for patients in cardiogenic shock following MI for whom early revascularization is planned.

Despite a complete lack of evidence, both of the ideas tested in these trials had received class 1 recommendations in the guidelines and were widely used in clinical practice. And both trials provided near definitive proof that the conventional wisdom was completely and utterly wrong.

This is the way science is supposed to work: an idea gets put to a fair test. Judging from the initial response to these trials, it seems likely that the cardiology community will rapidly accept the findings of the trials, and guidelines and clinical practice likely will change in short order to reflect the new evidence base.

FAME 2

FAME 2 also addressed, or claimed to address, an important question. Although the evidence base for PCI in stable angina had always been weak or nonexistent, its popularity had undergone exponential growth for many years, until COURAGE famously put the brakes on this growth. When fractional flow reserve (FFR) first came along, it was viewed with considerable suspicion in the interventional community, since in many respects it helped confirm the findings of COURAGE by appearing to demonstrate that a significant percentage of lesions intervened upon were not ischemic and therefore almost certainly didn’t benefit the patients who had undergone PCI.

Eventually, however, the interventional cardiology community found a path to renewal with FFR. Perhaps, it reasoned, instead of being used to illustrate the lack of utility of PCI, FFR could be used to guide PCI decisions, limiting interventions to ischemic lesions that would benefit from PCI.

This is where FAME 2 comes into the picture. In the trial, patients who had at least one functionally significant lesion, as defined by FFR, were randomized to FFR-guided PCI plus medical therapy or medical therapy alone. The trial was stopped early, after only about half of the intended number of patients were enrolled, because of a significant reduction in the primary endpoint (the composite of death, MI or urgent revascularization) in the PCI group compared to the medical therapy alone group.

The FAME 2 investigators, along with many members of the interventional cardiology community, have presented the results of the trial as a definitive response to the questions about PCI raised by COURAGE. In an ESC press release, FAME 2 co-ordinator Bernard De Bruyne said:

“With this new knowledge, I believe that FFR should become the standard of care for treating most patients with stable coronary artery disease and significant coronary narrowings.”

The Society for Cardiovascular Angiography and Interventions (SCAI) was so excited about the results of FAME 2 that it rushed out an e-publication of a “President’s Page” perspective on FAME 2, written by SCAI president J. Jeffrey Marshall and interventional cardiologist Ajay Kirtane, arguing that “FAME 2 offers the best data currently available to guide” treatment. The perspective of most interventional cardiologists is probably best summarized by this headline published on TCTMD: “PCI Bests Medical Therapy in Stable Patients with Proven Ischemia.”

The sad thing about these simplistic responses to FAME 2– and the reason why I use this trial as an example of a poor model for clinical trials– is that there is no acknowledgement of the extraordinary division of opinion about this trial and its meaning. The SCAI document discusses the FAME 2 publication but does not even reference, or respond to, the issues raised in an editorial accompanying the publication of FAME 2 in the New England Journal of Medicine. That editorial, by Bill Boden, the principal investigator of the COURAGE trial, delivered a trenchant attack on the view that FAME 2 represents anything like a definitive response to COURAGE.

I summarized Boden’s points in my previous news story about FAME 2:

  • There were few “hard” events in FAME 2 and urgent revascularization could be performed without objective evidence  of ischemia or positive biomarkers.
  • Since the trial was unblinded, “investigators may have had a lower threshold for recommending revascularization” for patients in the medical group.
  • Patients in the FFR group did not have noninvasive testing demonstrating ischemia, so some may have had preserved myocardial perfusion.
  • Patients in FAME II were not at very high risk.
  • The short followup period (mean followup of 7 months) did not leave enough time for the risk of restenosis in the PCI group to fully emerge.

Boden is highly critical of the early termination of the study, writing that it leaves “more questions than answers…. but the only enduring finding of the FAME 2 trial appears to be that  of a reduced short-term rate of unplanned revascularization with FFR-guided PCI, with little evidence of long-term, incremental benefit on prognostically important clinical outcomes.”

Astonishingly, the ESC press release didn’t even mention that the ESC’s own discussant of the trial, Frans Van de Werf, concluded that FAME 2 did not provide the “final answer to the question how to treat stable CHD patients.” Over on CardioExchange, Rick Lange and David Hillis provided another deeply skeptical perspective on FAME 2, and their view received endorsements from Sanjay Kaul, David Cohen, and Harlan Krumholz.

PCI supporters are acting as if the new evidence provided by FAME 2 forges a new consensus in support of FFR-guided PCI, but only by ignoring a chorus of dissent.

It is perhaps worth noting here that WOEST and IABP-SHOCK II were investigator-driven trials in which industry played no significant role. Of course, this idyllic situation may have been possible only because no significant commercial interests were at stake in the trial. With FAME 2, by contrast, the commercial stakes– for industry, for hospitals, and for interventional cardiologists– could not be higher. Perhaps these influences have helped induce a self-interested reality distortion field.