PCSK9 Inhibitor Enhances Cholesterol-Lowering Effect Of Atorvastatin Reply

When added to low-dose atorvastatin a much-discussed new monoclonal antibody to PCSK9 significantly lowers cholesterol more effectively than atorvastatin alone, according to a phase 2 study published in the New England Journal of Medicine. Earlier this year, in March, the findings of three phase 1 trials demonstrating the cholesterol-lowering effects of the drug in healthy volunteers and in people with familial or nonfamilial hypercholesterolemia were also published in NEJM.

In the new trial, Eli Roth and colleagues studied 92 patients with LDL levels over 100 mg/dl despite taking atorvastatin 10 mg. Patients were then randomized to 8 weeks of treatment with 80 mg atorvastatin plus the PCSK9 inhibitor SAR236553, 10 mg atorvastatin plus SAR236553, or 80 mg atorvastatin alone. SAR236553 was administered as an injection once every 2 weeks. PCSK9 inhibition significantly improved LDL reduction:

Reduction in LDL cholesterol from baseline:

  • SAR236553 + atorvastatin 80 mg: 73.2% + 3.5
  • SAR236553 + atorvastatin 10 mg: 66.2% + 3.5
  • atorvastatin 80 mg: 17.3% + 3.5

The investigators reported that 100% of patients in the two groups that received SAR236553 achieved target LDL levels of less than 100 mg/dl, compared with only 52% who received atorvastatin 80 mg only.

The results, write the authors, suggest that SAR236553 “may benefit patients in whom LDL cholesterol has not been reduced to recommended levels, either because of an inadequate lipid-lowering response with high-dose statins alone or because of unacceptable side effects with high-dose statins.”

James Stein told CardioBrief:

“These results are very promising.    What we need now are larger studies of SAR236553 with a longer duration, to determine its safety and tolerability.  If it is safe and effectively lowers total and LDL cholesterol over long periods of time, it would be expected to reduce cardiovascular dissease risk, but of course outcomes studies eventually will be needed to prove that.”

In July the companies developing SAR236553, Sanofi and Regeneron, announced a large phase 3 program for the drug, including an 18,000-patient outcomes trial. Next Monday, at the American Heart Association scientific sessions, the results of two more phase 2 studies of SAR236553 will be presented, as well as a study with another PCSK9 monoclonal antibody from Pfizer, RN316 (PF-04950615).

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The Research Agrees: Smoking Is Really Bad For You Reply

Four new studies offer powerful evidence of the dangers of smoking and the health benefits of quitting or not being exposed to secondhand smoke.

Smoking in the UK– Between 1996 amd 2001 the Million Women Study started following more than one million women aged 50 to 65 years of age. In  a report published in the Lancet, trial investigators, including renowned epidemiologist Richard Peto, found that 12-year mortality was significantly higher in women with a history of smoking compared to women who never smoked (rate ratio 2.76, CI 2.71-2.81). Smokers, the authors calculated, lose 10 years of life. The good news is that stopping smoking before the age of 40 reduces the excess mortality by 90%.

Smoking in Japan– The Life Span Study, published in BMJ, was started in 1950 and has followed more than 65,000 men and women in Hiroshima and Nagasaki, Japan. The results were consistent with the Million Women Study in the UK: the rate ratio for mortality was more than doubled for smokers compared to nonsmokers both for men (2.21, CI 1.97-2.48) and for women (2.61, CI 1.98-3.44). The investigators also reported that stopping smoking before age 35 eliminated almost all of the risk associated with smoking.

Smoke-free legislation meta-analysis– Smoking is not just a personal decision that has individual health effects. A new meta-analysis published in Circulation found that smoke-free legislation results in immediate reductions in hospital admissions or deaths for coronary events (RR .848, CI .816-.881), other heart disease (RR .610, CI .440-.847), cerebrovascular accidents (RR .840, CI .753-.936) and respiratory disease (RR .760, CI .682-.846). The authors, Crystal Tan and Stanton Glatz, also report that the biggest reductions in events were associated with the most stringent smoke-free laws.

Smoke-free legislation in Minnesota– Here’s one more study to lend support to the above meta-analysis. In a paper published in Archives of Internal Medicine Richard Hurt and colleagues analyzed data before and after the implementation of a smoke-free law in Olmsted County, Minnesota and found a significant 33% reduction in the incidence of MI from 150.8 to 100.7 per 100000 people and a trend in the reduction of sudden cardiac death by 17% from 109.1 to 92.0 per 100,000 people. In an accompanying commentary, Sara Kalkhoran and Pamela Ling write that as “the evidence base documenting the positive health outcomes” of smoke-free legislation grows, “we should prioritize the enforcement of smoke-free policies, eliminating loopholes in existing policies as well as encouraging expansion of smoke-free policies to include multiunit housing, motor vehicles, casinos, and outdoor locations. Exposure to SHS should not be a condition of employment, and all workers, including those of lower income and those in the service and hospitality industries, should have equal protection from SHS exposure.”
Click here to read the press releases from the Lancet, BMJ, Circulation, and Archives…

L.A. Confidential: Preview Of AHA Scientific Sessions 2012 Reply

The American Heart Association scientific sessions, which start next weekend in Los Angeles, will be bigger than ever, with 853 separate sessions– 111 more than last year– and 27 late-breaking clinical trials– 6 more than last year. Elliott Antman, chair of the scientific sessions program committee, provided a preview of some of the highlights of this year’s late-breakers.

Two of the most interesting trials will be presented at the first late-breaking session on Sunday afternoon. Perhaps the most eagerly anticipated trial of the entire meeting is the NIH’s FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial, which will be presented by Valentin Fuster. The trial will evaluate the relative worth of CABG and PCI in patients with diabetes.

Immediately preceding FREEDOM on the program is another NIH-sponsored trial, TACT (The Trial to Assess Chelation Therapy), testing the potential value of chelation therapy, a controversial alternative therapy. “We ought to take our hat off to the NIH for doing this trial, since industry was never going to fund this trial,” said Antman. Although most physicians have a skeptical view of chelation therapy, patients often express interest in it. TACT will finally provide real data about this approach.

Directly following the first session, the second late-breaking session will focus on economic and quality-of-life studies, including a quality of life TACT substudy and a cost-effectiveness FREEDOM substudy.

On Monday, two Italian trials will look at the role of omega-3 fatty acids for recurrent atrial fibrillation (FORWARD) and for the prevention of post-operative AF (OPERA). The Physicians Health Study II will examine the effect of multivitamins for cardiovascular endpoints. The UMPIRE study will test the feasibility of giving the polypill in 2,000 patients for a period of 15 months.

The second late-breaker session on Monday will present the results of three phase 2 trials of PCSK9 inhibitors. The session will include a panel discussion and an overview of this fast-moving and much-anticipated new therapeutic area. Also at this session will be the results of the  dal-OUTCOMES phase 3 trial of the CETP inhibitor dalceptrapib. Although the drug is no longer in clinical development, many observers are eager to see if the results will have implications for other CETP inhibitors.

A Tuesday morning session will be entirely devoted to stem cell regeneration trials. Antman said this was a “promising avenue of investigation” but acknowledged that we still don’t know if this whole approach might fail.

Later on Tuesday, Arthur Moss will present the results of the MADIT Randomized Trial to Reduce Inappropriate Therapy, comparing customized programming to standard programming for the reduction of ICD-induced inappropriate shocks. At the same session the results of RELAX-AHF will be presented, testing the novel agent relaxin in acute heart failure. Finally, the CARRESS-HF  study will offer insight into the role of ultrafiltration in patients with acute decompensated heart failure and worsening renal function.

Research And Denial At St Jude Medical 2

Research and development is the cornerstone of medical progress, but sometimes R&D turns into its evil twin brother, research and denial.

Yesterday I reported on the the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial presented at the TCT meeting in Miami. The trial missed its primary endpoint, and although there were definite hints of possible benefit in the trial, most outside observers seemed to agree that the trial did not establish a firm basis for the routine clinical use of PFO closure devices in stroke. FDA approval of the device based on RESPECT seems unlikely.

This wasn’t the first we’d heard of RESPECT. Last summer, as I reported here, during an earnings call, St. Jude CEO Dan Starks gave a preview of the RESPECT results: “we are optimistic that these will be favorable results,” he said. Then, yesterday, the company doubled down on its position and issued a press release stating that the trial “provides clinical evidence of risk reduction” and offers “compelling evidence” for use of the St. Jude device “over conventional medical management alone.” A St Jude spokesman told me that the company “absolutely intends to move forward with our regulatory process and will file our PMA submission” in the fourth quarter of 2012.

Deepak Bhatt, an influential interventional cardiologist at Harvard’s Brigham and Women’s hospital, offered a very reasonable assessment of the trial in an interview with Bloomberg News: “We need a definitive trial of this approach if it’s going to be broadly used for PFO closure. Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”

The stock market provided further evidence that St. Jude’s view of the trial was not the prevailing view. Despite what the company called “compelling evidence,” St. Jude’s stock price dropped 3.6% when the news of RESPECT was released.

In contrast to St. Jude, Gore, which is conducting REDUCE, a separate study of its own device for PFO closure, said that the RESPECT data “suggest [my emphasis] closure therapy for PFO may be beneficial, but further research is required.” Gore reaffirmed its intent to complete the REDUCE trial and pursue the indication for PFO closure. Of course, by the time REDUCE is completed there’s no guarantee that Gore won’t enter its own reality distortion field. Commercial pressures can be a heavy burden on the objective assessment of reality. But for now Gore’s perspective is sensible.

Closing the Hole in Medical Progress

The mutation of research and development into research and denial has worse consequences than a drop in stock price. It can paralyze medical progress. For more than a decade the value of PFO closure in stroke has been an unanswered question. Trial enrollment has been notoriously slow and difficult. The main reason is that many interventional cardiologists don’t want to randomize their patients because they strongly believe, despite the lack of evidence, in the value of PFO closure. So expensive procedures continue to be performed, despite a lack of evidence, and despite the likelihood that good evidence will ever emerge. It’s a frustrating siutation.

Earlier this year, in an editorial in the New England Journal of Medicine, S. Claiborne Johnston wrote about the harmful effect that off-label use of PFO closure devices has on research. He recommended that reimbursement for PFO closure be limited to patients participating in a clinical trial. Seems like a good idea to me.

During the 9 years it took for the results of this trial [CLOSURE 1] to be reported, approximately 80,000 patients have had a patent foramen ovale closed with the use of a device at an average cost of $10,000 per procedure. Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $400 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved. By limiting the use of device closure to within the remaining clinical trials, such an expense could be curtailed and completion of these trials might be accelerated. In this setting, a strategy of withholding reimbursement for unproven device therapy unless such treatment is part of a randomized trial seems justified.

 

TCT: Two PFO Closure Trials Miss Primary Endpoints 1

Two trials presented today at the TCT meeting in Miami testing the benefits of PFO closure in patients with cryptogenic stroke have failed to convincingly demonstrate any significant  benefit for the controversial procedure.

The RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial randomized 980 patients  to PFO closure with the Amplatzer PFO Occluder device or medical therapy. According to the lead investigator John Carroll, the rate of recurrent stroke was low in both arms of the trial: 1.6% in the closure group and 3% in the medical group.

This difference vetween the groups did not achieve significance in the intention-to-treat (ITT) analyses:

  • ITT raw count: 46% risk reduction (p=0.157)
  • ITT Kaplan Meier: 50.8% risk reduction, (p= 0.083

However, statistical significance was achieved in the per protocol and as treated analyses:

  • Per protocol Kaplan Meier: 63.4 risk reduction (p=0.032)
  • As treated Kaplan Meier: 72.7% (p=0.007)

The investigators reported that there were very few device- or procedure-related complications. There were a similar amount of serious adverse events in the two groups (23% in the device group and 21.6% in the control group).

The investigators concluded that “for carefully selected patients with history of cryptogenic stroke and PFO, the RESPECT Trial provides evidence of benefit in stroke risk reduction from closure with the AMPLATZER PFO Occluder over medical management alone.”

“The optimal secondary prevention strategy following a cryptogenic ischemic stroke in patients who are found to have a PFO has been unknown,” said Carroll, in a TCT press release. “This need to know is particularly intense for young stroke patients who have no or minimal traditional risk factors for ischemic stroke, yet face a risk of recurrent stroke for many decades. RESPECT makes progress in both removing the ‘unknown’ or cryptogenic cause of some strokes and providing high quality data from a large, long-term randomized trial.”

A similar pattern occurred in the smaller PC (Percutaneous Closure of Patent Foramen Ovale versus Medical Treatment in Patients with Cryptogenic Embolism) Trial, in which 414 patients were randomized to PFO closure or medical therapy. The primary endpoint, the composite of death, non-fatal stroke, TIA, and peripheral embolism, occurred in 3.4% of the treatment group compared to 5.2% of the control group (relative risk reduction: 37%, p=0.34). The incidence of stroke was 0.5% versus 2.4% (relative risk reduction 80%, p=0.14).

Study investigator Stephan Windecker said that because of a lower than expected rate of events after a mean followup of 4 years the trial ended up being underpowered to detect meaningful differences. He concluded that “the observed difference in stroke… may be clinically relevant if confirmed in further studies.”

We need a definitive trial of this approach if it’s going to be broadly used for PFO closure,” said Deepak Bhatt, in an interview with Bloomberg News. “Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”

Earning Respect?

As reported here over the summer, during an earnings call St. Jude CEO Dan Starks told investors that the results of RESPECT were “favorable.” As I wrote then, the danger of this sort of statement  is that the company’s initial evaluation of the results may clash with the eventual judgement of the medical community. Companies are simply in no position to be objective about their own products or trials. Caution in this case was particularly warranted because of the sorry history of negative trials in this area, as highlighted by the failed MIST trial of the STARFlex Septal Closure System. The results of the RESPECT and PC Trials demonstrate that the communication of medical information should not be left in the hands of industry. (St. Jude stock dropped 3.5% on the announcement of the trial results.)
Click to read the TCT press releases on RESPECT and PC…

Atrial Fibrillation: Radiofrequency Catheter Ablation And Antiarrhythmic Drug Therapy Compared Reply

A trial comparing radiofrequency catheter ablation (RFA) to antiarrhythmic drug therapy (AAD) as initial therapy for atrial fibrillation (AF) found no difference in the overall burden of AF between the groups. But the trial also turned up evidence supporting the use of RFA as an initial treatment strategy in some patients.

In a paper published in the New England Journal of Medicine, European investigators report on 294 patients with paroxysmal AF with no previous use of AADs who were randomized in the MANTRA-PAF (Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) trial. Patients– under 70 years of age and with no other major heart disease– were healthier than the general AF population.

The investigators found no significant differences in the cumulative burden of AF or the burden at  3, 6, 12, or 18 months. However, at 2 years the AF burden was significantly reduced in the RFA group compared with the AAD group (90th percentile of AF burden: 9% for RFA versus 18% for AAD, p=0.007). In addition, the percentage of patients with no AF and no symptomatic AF was higher in the RFA group than in the AAD group (85% vs. 71%, p=0.004; 93% vs. 84%, p=0.01, respectively). In the RFA group, there were three cases of cardiac tamponade in addition to one death after a procedure-related stroke. In the AAD group 36% of the patients received supplementary RFA.

The overall results, write the authors, “support the current guidelines recommending antiarrhythmic drugs as first-line treatment in most patients with paroxysmal atrial fibrillation.” However, the positive findings for RFA, as well as the high number of crossovers from AAD to RFA, suggest that “a substantial minority of patients” treated with AAD “may eventually require ablation for adequate rhythm control.”

In an accompanying editorial, William Stevenson and Christine Albert mention the “substantial procedural risks” associated with RFA and warn that the results should not be extrapolated to different patient populations, since the MANTRA-PAF population was younger and healthier than the general AF population. They express hope that the much larger CABANA (Catheter Ablation versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation) trial will provide more definitive evidence about RFA. RFA, they conclude, is “a reasonable option for patients with symptomatic paroxysmal atrial fibrillation before therapy with an antiarrhythmic drug.”

TCT: Impressive Survival Benefit For TAVR In Inoperable Patients At 3 Years Reply

At the TCT meeting in Miami  Murat Tuzcu presented the latest findings from the PARTNER B trial comparing transcatheter aortic valve replacement (TAVR) with standard therapy in patients who are not considered eligible for surgical valve replacement. At three years the mortality advantage continued to grow for TAVR over standard therapy in patients who are not eligible for surgery.

All cause mortality at 3 years:

  • 80.9% in the control group versus 54.1% in the TAVR group (HR 0.53, CI 0.41-0.68, p<0.0001)

The difference between the groups has increased from from an absolute difference of 20.1% at 1 year (50.8% versus 30.7%) to 25% at 2 years (68% versus 43%) to 26.8% at 3 years. Here are the other 3 year endpoints reported by Tuzcu:

Rehospitalization at 3 years:

  • 75.7% versus 42.3% (HR0.39, CI 0.28-0.54, p<0.0001)

Mortality or reshospitalization at 3 years:

  • 93.1% versus 66.3% (HR 0.46, CI 0.36-0.58)

Mortality or stroke at 3 years:

  • 80.9% veruss 57.5% (HR 0.60, CI 0.46-0.77, p<0.0001)

The three year results, concluded Tuzcu, “continue to support the role of TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates.” As well, the results “underscore the importance of patient selection before TAVR and the need for aggressive management of illnesses after TAVR.”
Click here to read the press release from Edwards…

Setback For Trial Studying Dabigatran After Mechanical Valve Surgery 2

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 a newer oral anticoagulant has suffered a setback.

Last year Boehringer Ingelheim announced the launch of the RE-ALIGN trial, a phase 2, open-label, 12-week randomized comparison of warfarin and dabigatran (Pradaxa) in 400 patients who received a mechanical valve. There were two arms in the trial. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.

Now, following the advice of the trial’s Data Safety Monitoring Board, Boehringer Ingelheim said it had discontinued the first arm of the trial, the post-surgery arm, due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” The trial’s second arm with patients who received a valve more than 3 months before enrollment in the trial is unaffected by this decision and will continue as planned.

Boehringer-Ingelheim said that the  news about RE-ALIGN does “not affect the positive benefit/risk profile of Pradaxa 150 mg for the current labeled indication” of stroke prevention in patients with non-valvular atrial fibrillation. “RE-ALIGN is evaluating a different patient population and different doses than were studied in the RE-LY trial.”

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 Outcomesdabigatran 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.”

One clinical cardiologist who did not wish to be identified offered the following perspective:

This is similar to the case reports (with all the usual caveats) where we have seen this signal with the novel anticoagulants…. it’s not intuitively clear why this is the case.  It may be that the dose is not optimized for mechanical valves.  It is worth noting that the drug levels in patients with mechanical valves were lower than anticipated based on pharmacokinetic calculations.  Maybe patients with mechanical valves have a different metabolism of the drug versus those that don’t have mechanical valves?  There may be an interaction with von Willebrand factor in the pharmacokinetics of dabigatran. Or maybe the dose is just too low and patients with mechanical valves need higher doses, just as we use a higher INR in patients with mechanical valves?  The science keeps evolving!

Sanjay Kaul made a similar point:

The anticoagulant dose requirement for mechanical valves is higher even for warfarin (INR targeted for 2.5 to 3.5) compared with atrial fibrillation or VTE indication (Target INR of 2 to 3). It is likely that the dabigatran dose tested in RE-ALIGN was not sufficiently effective early post surgery when the thrombotic risk is the highest.

Click here to read a letter sent by Boehringer Ingelheim to members of its speakers bureau…

High Rate Of Warfarin Discontinuation Observed In Study Reply

One of the many potential problems with warfarin-based anticoagulant therapy is the poor rate of adherence and persistence among patients who are prescribed the drug. Now a new observational study published in Archives of Internal Medicine raises the possibility that the problem may be even worse than many may have previously suspected, as discontinuation rates in clinical trials appear to be much lower than in the real world.

Tara Gomes and colleagues analyzed data from more than 125,000 new users of warfarin in Ontario, Canada and found very high rates of discontinuation over time:

  • 8.9% never filled a second prescription
  • 31.8% discontinued warfarin within 1 year
  • 43.2% discontinued warfarin with 2 years
  • 61.3% discontinued warfarin within 5 years

People at higher risk for stroke, as assessed by the CHADS2 score, were more likely to continue taking warfarin over the course of the study.

In an invited commentary, Whitney Maxwell and Charles Bennett write that the results are consistent with previous observational studies but that warfarin discontinuation can be appropriate and is often initiated by the physician. “Appropriateness of anticoagulation discontinuation is perhaps a more important outcome to evaluate rather than absolute discontinuation rates,” they write. An additional plausible explanation for the study finding is that few patients in Canada were treated at anticoagulation clinics.

Maxwell and Bennett write that any potential problem with anticoagulation discontinuation is not limited to warfarin. In the RE-LY trial, they note, more patients discontinued therapy in the dabigatran arm than in the warfarin arm, and a similar trend was observed with rivaroxaban in ROCKET AF.

Jeffrey Moses Accused Of Cocaine Use And Domestic Violence (Updated) 2

Update– December 21, 2012:The New York Post has substantially disavowed significant portions of an October 22 news story about Jeffrey Moses. The story contained allegations that the well-known interventional cardiologist had tested positive for cocaine but was allowed to continue performing procedures at New York-Presbyterian Hospital. Now, the Post says, allegations of cocaine use were “subsequently proven to be conclusively false by two identical tests which were negative” and by “a court-ordered examination of Dr. Moses in May 2006 by a forensic psychiatrist who opined that he had no cocaine addiction problem.” The Post said its article gave a “false impression” about Moses and that it “regrets” any misunderstanding caused by that part of the article and “any harm it may have caused Dr. Moses personally and professionally.”

Here is the entire Editor’s Note, which was placed at the top of the story on December 20:

EDITOR’S NOTE: On October 22, 2012, The Post published an article about Dr. Jeffrey Moses, a world-renowned interventional cardiologist. Dr. Moses believes that the article gave readers the false impression that he is currently a cocaine user who is, and was for years, allowed by his hospital to operate on patients while under its influence. As the article reported, allegations of cocaine use were made by Dr. Moses’ ex-wife in their 2005 divorce case and the positive test referred to in the article was, according to Dr. Moses, a “false positive” which was subsequently proven to be conclusively false by two identical tests which were negative. The decision by New York Presbyterian Hospital not to discipline Dr. Moses and to allow him to continue to operate was made in light of the negative tests and a court-ordered examination of Dr. Moses in May 2006 by a forensic psychiatrist who opined that he had no cocaine addiction problem. Any understanding readers may have taken from the article that Dr. Moses was performing cardiovascular surgery while under the influence of cocaine was not intended. The Post regrets if any readers so misunderstood this part of the article and any harm it may have caused Dr. Moses personally and professionally.

October 22, 2012– Leading interventional cardiologist Jeffrey Moses tested positive for cocaine use but was allowed to continue his work at New York-Presbyterian Hospital, according to a news report in the New York Post. Two ex-wives of Moses accused Moses of “regularly using cocaine for years, often even before heading to work.” The accusations come from divorce records.

Reporter Dan Mangan writes that “after a court-ordered drug test came back positive for cocaine in 2005 and New York-Presbyterian Hospital was informed, he was not suspended from his busy schedule of heart procedures.”

In addition to the cocaine allegations, the two ex-wives told the court that “they suffered beatings at the hands of Moses.” The Post reports that Moses was arrested in 2004 for allegedly attacking his second wife, Laurie Levinberg, in their Park Avenue apartment. The case was dismissed after Moses “served a pretrial probationary period.”

A 2005 court-ordered drug test of Moses’ hair was positive for cocaine, which Moses reported to his hospital, but claimed that the result was a false positive. He said two subsequent tests were negative and proved that  he was drug-free. Moses told the Post that he might have taken cocaine 25 or 30 years ago. He also denied assaulting either wife.

After 22 years of marriage to Moses Levinberg sued for divorce in 2005. She claimed that Moses took cocaine constantly, “day and night, and performed his operations while high on cocaine.”

Moses’ marriage to his first wife, Carin Savel, ended in 1983 after six years years. In an affidavit filed in 2005, Savel said that Moses “was a major cocaine user, usually partaking every morning before going to the hospital.”

Moses responded to the Post story in a comment published on heartwire:

“These are old allegations that were put forth in the context of a contentious divorce that were vetted and found untrue years ago.” He added: “It is all nonsense. The allegations have been vetted by the courts and by Presbyterian and found to be baseless. That they are being repeated now is causing me a great deal of distress.”

As previously reported on CardioBrief, Moses is among the highest paid interventional cardiologists in the country. In 2010 he was reported to be earning at least $3 million a year. Long affiliated with the Cardiovascular Research Foundation and the annual TCT interventional cardiology meeting, Moses played a key role in bringing CRF leaders Martin Leon, Gregg Stone, and others to Lenox Hill from the Washington Hospital Center. The group subsequently moved to Columbia University.

NIH Trial Of Lifestyle Intervention For Type 2 Diabetes Stopped For Futility After 11 Years 2

The NIH today announced the early termination of a large randomized trial testing a lifestyle intervention approach to weight loss in type 2 diabetics.

More than 5,000 patients with type 2 diabetes were randomized to participate in an intensive lifestyle intervention program or a traditional program of diabetes support and education in Look AHEAD (Action for Health in Diabetes). In September, after 11 years of followup, the trial was stopped by the NIH after the data and safety monitoring board found no significant differences in cardiovascular events– the primary endpoint of the trial– between the two groups. According to the NIH, however, other benefits from the lifestyle intervention have been found in the course of the trial.

The NIH said that patients in the intervention group lost an average of 8% of their body weight in the first year and maintained a weight loss of nearly 5% at 4 years. By contrast, patients in the control group lost about 1% of their body weight at 1 and 4 years.

“Look AHEAD found that people who are obese and have type 2 diabetes can lose weight and maintain their weight loss with a lifestyle intervention,” said Dr. Rena Wing, chair of the study, in an NIH press release. “Although the study found weight loss had many positive health benefits for people with type 2 diabetes, the weight loss did not reduce the number of cardiovascular events.”
Click here to read the NIH press release…

FDA Approves The Sapien Transcatheter Heart Valve For High Risk Patients 2

The FDA today approved an expanded indication for Edwards Lifesciences’ Sapien transcatheter heart valve (THV). The device can now be implanted in patients who are eligible for aortic valve replacement surgery but at high risk for serious surgical complications or death. Previously the Sapien valve was approved only for use in patients who were not eligible for surgery.

The FDA also said the device could be delivered through both the transfemoral route and the transapical route. Previously the device could only be delivered through the transfemoral route.

“Any procedure to replace the aortic valve carries the risk for serious complications, but for some patients with coexisting conditions or diseases that risk may be especially high,” said the FDA’s Christy Foreman, in an FDA press release. “The THV serves as an alternative for some very high-risk patients.” The FDA requires that before being deemed eligible for the Sapien valve a patient must be evaluated by a heart team, which includes a heart surgeon.

The new approval in high risk patients was based on findings from the PARTNER A trial. The earlier approval in non-operable patients was based on findings from the PARTNER B trial.

The FDA will continue to require Edwards to evaluate the Sapien device through a national registry.

Click here to read the FDA and Edwards press releases…

FDA Panel Recommends Approval Of Mipomersen For Familial Hypercholesterolemia 1

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 Reviewers Recommend Approval For Lomitapide For Homozygous Familial Hypercholesterolemia 2

The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 13-2 to recommend approval of Aegerion Pharmaceuticals’ cholesterol-lowering drug lomitapide for use in patients with homozygous familial hypercholesterolemia (FH).

The lopsided vote does not completely reflect the views of many of the panel members, who expressed considerable concern  that the drug might be used in lower risk populations, in particular, patients with heterozygous FH. The committee also expressed concern about the use of lomitapide in children with homozygous FH, since they were not included in clinical trials, but might be considered candidates for therapy in clinical practice.

Panel members appeared to largely agree with one panel member, who explained that his yes vote was “specific for this condition” (homozygous FH) only. He said he could accept the “trade-off between a near-certain early demise versus the possibility of liver disease.”

Aegerion estimates that there are about 6,000 homozygous FH patients in the US and Europe.

The committee expressed support for the FDA’s proposed Risk Evaluation and Mitigation Strategy (REMS) that would limit access to the drug to medically appropriate patients and to provide education to prescribers about how to use lomitapide, how to prevent liver damage, and how to monitor patients during treatment. The REMS would  require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

On Thursday the same committee will meet to discuss a similar indication for Genzyme’s mipomersen injection. Following the release of a highly critical FDA review, many observers believe the mipomersen panel will be much more contentious.

FDA Review Raises Safety Concerns About Mipomersen 1

An FDA review raises a number of potentially significant safety concerns about the cholesterol-lowering drug mipomersen. The review appears ahead of a Thursday meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to evaluate Genzyme’s new drug application (NDA) for use of the drug as an adjunct to maximally tolerated lipid-lowering medications and diet to reduce LDL, apolipoprotein B, total cholesterol, non-high density lipoprotein-cholesterol and lipoprotein (a) in patients with homozygous familial hypercholesterolemia (FH). Mipomersen is an antisense oligonucleotide inhibitor which targets apoB-100. (On Wednesday the same committee will meet to discuss a similar indication for lomitapide capsules, manufactured by Aegerion.)

FDA reviewers said that mipomersen was generally effective in lowering LDL cholesterol. More than half of patients in clinical trials had more than a 20% decrease in LDL levels. In the pivotal trial with homozygous FH patients mipomersen reduced LDL by 24.7%. As expected, mipomersen also resulted in significant reductions in app B, total cholesterol, and non-HDL cholesterol.

Because of their small size the mipomersen trials were not powered to assess cardiovascular outcomes, though cardiovascular benefit is of course the ultimate intended effect of the drug. However, the numbers in the phase 3 studies ran in the wrong direction. Serious adverse events of cardiac disorders occurred in 3.8% (10/261) of patients in the mipomersen  group compared with 3.1% (4/129) in the placebo group. The reviewers concluded that “the possibility that mipomersen therapy increases the risk for cardiovascular events cannot be excluded.”

More troubling is the FDA safety review, mostly centering on liver-related problems. Mipomersen was associated with increases in serum transaminases and hepatic fat. In phase 3 trials, hepatic steatosis occurred in 7.3% (19/261) of mipomersen-treated patients compared with 1.6% (2/129)of  placebo-treated patients. ALT increased in 9.6% of mipomersen treated patients compared with 0.8% of placebo-treated patients. In a long-term extension trial one-quarter of mipomersen-treated patients had an average liver fat fraction greater than 20%. The FDA reviewers said they did not know whether long-term use of mipomersen could cause irreversible liver damage, but warned that patients could be at risk for cirrhosis and liver-related death if the observed liver changes progressed.

Other safety issues in the trials included injection site reactions and flu-like symptoms. The committee will also likely spend time discussing the cancer findings. According to the review, during clinical testing neoplasms, both benign and malignant, were detected in 3.1% (23/749) of patients who received mipomersen compared with 0.9% (2/221) of patients who received placebo. However, the FDA clinical reviewer noted that there was a diversity of malignant neoplasms and that two out of nine mipomersen patients who developed a malignancy had been on mipomersen for less than a month, “making it highly unlikely that mipomersen played a role.” The review concluded that “there are several confounding factors that make it difficult to conclude that mipomersen is playing a dominant role in this cancer imbalance.”

The FDA will also ask the panel to evaluate a proposed Risk Evaluation and Mitigation Strategies (REMS) if the drug gains approval. 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.

Given the severity and rarity of homozygous FH it is difficult to predict how the committee will vote, but the safety concerns raised by the FDA make it extremely unlikely the drug could receive an expanded indication for heterozygous FH anytime in the near future.

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

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.

Don Poldermans And The Dutch Research Scandal 4

The publication last week of the final report from the Erasmus Medical Center on the Don Poldermans research scandal in the Netherlands ends the first and most explosive chapter of an ugly episode of scientific misconduct. But there are still many important questions regarding scientific integrity and the culture of medical research raised by the case. And one key detail about the case remains– and is likely to remain– unanswered. Did Don Poldermans commit scientific fraud by fabricating data or was he only guilty of the serious but lesser sin of poor or negligent supervision of a research factory?

The final report on the Poldermans affair from his former institution and employer, Erasmus MC, accuses him of serious scientific misconduct, including:

  • “failure to preserve essential source documentation,”  so that “further verification and analysis ” is now impossible;
  • “failure to record actual medication use, in a study focusing on an intervention using medicines”; and
  • failure to obtain informed consent, or to do so improperly.

The most serious accusation is that “fictitious data” was used in one study, “a serious breach of academic integrity.” However, this accusation does not appear to be rock solid, since it is based on disparities between the study data and a database examined by the committee. However, Poldermans claims that the database examined by the committee was provided to them by the whistleblower (a fellow in his laboratory) who did not have access to the original database (which Poldermans claims was destroyed) and was not the database used in the study. It’s unlikely that the full truth about this will ever be known. Poldermans says that the committee’s conclusions were “suggestive, speculative and often even demonstrably false.”

In an hour-long interview with me during the recent ESC meeting in Munich, Poldermans talked a great deal about the case, accepted responsibility for the less serious charges but adamantly  denied the more serious charges. Poldermans, who is now working as a vascular medicine physician at a non-teaching hospital, said he has no expectation of ever regaining his former position or resuming research: “that’s something I can accept, but I can’t accept that people would think I faked patients or that patients were hurt,” he told me.
Click to continue reading…

FDA Reviewers Raise No New Red Flags Over Lomitapide 1

FDA reviewers have raised no new concerns about lomitapide ahead of a Wednesday meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.  The FDA today released briefing documents that evaluate the new drug application (NDA) for lomitapide capsules, the microsomal triglyceride transfer protein (MTP) inhibitor from  Aegerion Pharmaceuticals for use as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and triglycerides in patients with homozygous familial hypercholesterolemia. (On Thursday the same committee will meet to discuss a similar indication for Genzyme’s mipomersen injection. Briefing documents for that meeting will be released on Tuesday.)

The reviewers concluded that lomitapide was effective in lowering LDL cholesterol by about 40%. The drug also effectively reduced total cholesterol, apoB, triglyceride, non-HDL, VLDL, and Lp(a) levels. Lomitapide also lowered potentially beneficial HDL and Apo A1 levels. The reviewers said that “the clinical consequences, if any, of these changes are unknown.”

The committee will likely focus on side effects and safety issues related to lomitapide. Gastrointestinal side effects are common with the drug. More troubling are concerns about possible liver damage associated with the drug. In the pivotal trial 38% of the patients had ALT elevations greater than three times the upper limit of normal, and 24% had elevations five times the ULN. Most patients in the trials also had significant elevations in hepatic fat. The reviewers also noted that lomitapide might induce deficiencies in fat-soluble nutrients.

To address the safety issues related to lomitapide the FDA will ask the committee to evaluate a Risk Evaluation and Mitigation Strategies (REMS) that would limit access to the drug to medically appropriate patients and to provide education to prescribers about how to use lomitapide, how to prevent liver damage, and how to monitor patients during treatment. The REMS would  require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

Free Cardiac And Spine Surgery For Walmart Employees At Six Hospitals Reply

Starting next year 1.1 million US Walmart employees and their dependents will be eligible for free heart, spine, and transplant surgery at 6 highly regarded health care organizations. Walmart employees will have no out-of-pocket costs, including travel, lodging and food for the patient and a caregiver.

On Thursday the company announced that its “Centers of Excellence” program, which had previously provided free transplants to Walmart employees, would expand to include heart and spine surgeries. Here are the six health care organizations involved in the program:

  • Cleveland Clinic in Cleveland, Ohio
  • Geisinger Medical Center in Danville, Pa
  • Mayo Clinic sites in Rochester, Minn., Scottsdale/Phoenix, Ariz., and Jacksonville, Fla.
  • Mercy Hospital Springfield in Springfield, Mo
  • Scott & White Memorial Hospital in Temple, Texas
  • Virginia Mason Medical Center in Seattle, Wash

In a tweet, noted writer and surgeon Atul Gawande said, “this will change medicine.”

Walmart said that four of the hospitals– Cleveland Clinic, Geisinger Medical Center, Scott & White Memorial Hospital and Virginia Mason Medical Center– will provide the cardiac procedures, including coronary artery bypass grafting, heart valve replacement/repair, closures of heart defects, thoracic and aortic aneurysm repair and other complex cardiac surgeries. Three of the hospitals– Mercy Hospital Springfield, Scott & White Memorial Hospital and Virginia Mason Medical Center– will perform the spine procedures. Mayo Clinic will continue to provide transplants.

“We devoted extensive time developing Centers of Excellence in order to improve the quality of care our associates’ receive,” said Walmart’s senior vice president of global benefits, in a press release.  “We have identified six renowned health care systems that meet the highest quality standards for heart, spine and transplant surgery. Through these hospital systems, our associates will have no out-of-pocket expenses and a greater peace of mind knowing they are receiving exceptional care from a facility that specializes in the procedure they require. This is the first time a retailer has offered a comprehensive, nationwide program for heart, spine and transplant surgery.”

Click here to read the Walmart press release…

Chocolate And Nobel Prizes Linked In Study 1

You don’t have to be a genius to like chocolate, but geniuses are more likely to eat lots of chocolate, at least according to a new paper published in the august New England Journal of Medicine. Franz Messerli reports a highly significant correlation between a nation’s per capita chocolate consumption and the rate at which its citizens win Nobel Prizes.

Building on research raising the possibility that the flavanols in chocolate may enhance cognitive performance, Messerli “wondered whether there would be a correlation between a country’s level of chocolate consumption and its population’s cognitive function.” Using the success of a country in winning Nobel Prizes as a surrogate for “the proportion with superior cognitive function” in a country, he analyzed the relationship between the number of Nobel laureates per capita in a country with that country’s per capita chocolate consumption.

Messerli reported “a close, significant linear correlation (r=0.791, p<0.0001) between chocolate consumption per capita and the number of Nobel laureates per 10 million persons in a total of 23 countries.” The relationship was even stronger when Sweden, the home of the Nobel Prize, was removed from the calculations, as it appeared to have won more Nobel prizes than expected based on its chocolate consumption. Switzerland, on the other hand, “was the top performer in terms of both the number of Nobel Laureates and chocolate consumption.” (It should perhaps be noted at this point that Messerli, a hypertension expert who lives in New York City, was born in Switzerland and reports in his disclosure statement that he consumes chocolate daily, “mostly but not exclusively in the form of Lindt’s dark varieties.”)

Messerli duly points out that correlation does not prove causation, but, he writes, “since chocolate consumption has been documented to improve cognitive function, it seems most likely that in a dose-dependent way, chocolate intake provides the abundant fertile ground needed for the sprouting of Nobel laureates. Obviously, these findings are hypothesis-generating only and will have to be tested in a prospective, randomized trial.”

Regarding Sweden’s status as an outlier, Messerli writes that “one cannot quite escape the notion that either the Nobel Committee in Stockholm has some inherent patriotic bias when assessing the candidates for these awards or, perhaps, that the Swedes are particularly sensitive to chocolate, and even minuscule amounts greatly enhance their cognition.” Messerli also raises the possibility that reverse causation may explain the main finding, “that is, that enhanced cognitive performance could stimulate countrywide chocolate consumption.”

Sanjay Kaul provided the following comment to CardioBrief:

This article highlights, with a touch of whimsy, caveats that challenge the interpretation of findings of observational studies. From the use of surrogate endpoints (based on biological plausibility and the results of preclinical studies) to the distinction between correlation and causation, confounding (whether the effect size is too large to be explained away by confounding), and the hypothesis-generating nature of the inferential process. Careful consideration of these issues is likely to help navigate through the labyrinth of misinformation and disinformation these types of studies are particularly prone to generating.

A randomized controlled trial is warranted to validate the hypothesis raised by this study. The pressing question, in my opinion, is who would sponsor such a study – the chocolate makers or the Nobel Committee?

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

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…

PCI Utilization Lower In States With Public Reporting Of Outcomes Reply

In patients with acute MI, utilization of percutaneous coronary intervention (PCI) is lower in states that publicly report outcomes data, according to a new study published in JAMA. Despite the difference in utilization, however, there was no difference in mortality between reporting and nonreporting states.

Karen Joynt and colleagues used Medicare data to analyze PCI utilization and mortality in acute MI patients in three states with public reporting of PCI outcomes (New York, Massachusetts, and Pennsylvania) and other states in the same region without public reporting. The differences in utilization were greatest in patients at highest risk, who presented with ST-segment elevation MI (STEMI), cardiogenic shock, or cardiac arrest.

  • Overall unadjusted PCI rate: 37.7% for reporting states versus 42.7% for nonreporting states
  • Risk-adjust odds ratio: 0.82, CI 0.71-0.93, p=0.003)

Overall mortality did not differ between the reporting and nonreporting states (12.8% and 12.1%, respectively; adjusted OR 1.08 (CI 0.96-1.20], p=0.20), although there was a significant mortality difference in the STEMI subgroup (13.5% vs. 11.0%; OR 1.35, CI 1.10-1.66, p=0.004).

In Massachusetts, where outcomes reporting was initiated during the course of the study period, PCI utilization was at first no different from the other nonreporting states, but was significantly lower than nonreporting states after the change.

The authors offer two potential explanations for the findings:

…the foregone procedures were futile or unnecessary, and public reporting focused clinicians on ensuring that only the most appropriate procedures were performed. Alternatively, public reporting may have led clinicians to avoid PCI in eligible patients because of concern over the risk of poor outcomes.

The mortality findings, they write, suggest “that the foregone procedures might have been a mix of appropriate and inappropriate PCIs.”

In an accompanying editorial, Mauro Mosucci writes that the mortality finding may be due to “a conscious or unconscious ‘futility assessment’” in states with public reporting,” leading to “avoidance of PCI for patients who are less likely to benefit.” Alternatively, “public reporting might have resulted in a drive toward improved quality of care and improved outcomes in patients receiving PCI, offsetting the adverse effect of not performing PCI in high-risk patients.” Mosucci also points out that the data may be skewed because public reporting might result in “gaming” the coding of cases.

Click here to read the press release from JAMA…

Erasmus Medical Center Releases Final Report On Cardiovascular Research Scandal 2

After an extensive investigation, a large medical center in the Netherlands has confirmed earlier charges of research misconduct against a prominent cardiovascular researcher. On Tuesday, Erasmus MC in Rotterdam released a final report on the scientific integrity of trials conducted by Don Poldermans, a well-known and highly prolific Dutch cardiovascular researcher. The final report contains numerous allegations of scientific misconduct related to the conduct of several clinical trials run by Poldermans at Erasmus MC.

Poldermans admits responsibility for some instances of misconduct but also vigorously denies the most serious charges involving scientific fraud. He provided CardioBrief with detailed written responses to the charges and also presented a spirited defense during an exclusive interview conducted in August during the ESC meeting in Munich.

In a statement to the press, Erasmus MC said that the new report confirms the earlier suspicions raised in the case, which ignited a firestorm of conroversy in the Netherlands last winter. The press statement mentions”serious shortcomings” in obtaining informed consent for patients enrolled in studies and the submissions of “unreliable data” based on “scientifically inaccurate data collection.” Poldermans and Erasmus MC are in full agreement, however, that the misconduct “did not lead to health damage to patients.”

In a statement prepared for CardioBrief in response to the report, Poldermans apologizes for his “administrative carelessness” and accepts full responsibility for the missing consent forms. He accepts the “extreme consequence”–  his dismissal from Erasmus MC–  over this issue, but emphasizes that no harm occurred to any of the patients and, further, that no additional or unnecessary treatments or diagnostic procedures took place. He vigorously denies any larger scientific misconduct or fraud.

The committee report — and Poldermans defense — are often highly technical, and the report is based on incomplete and inconsistent information obtained by the investigating committee at Erasmus MC. One problem is missing data. Investigators scrutinizing Polderman’s work have been unable to find the case files and other documentation for some patients in the trials. Consequently, the report raises concerns about possible data fabrication. Poldermans strongly denies this suggestion and states that he properly stored all the files at Erasmus MC. His defense is that some records were damaged by water and some records disappeared when the hospital itself threw out boxes of documents stored in the archives.

Poldermans had been a professor of medicine and the head of perioperative cardiac care at the Erasmus Medical Center. He was widely published and active in the field, serving as a member of the European Society of Cardiology committee for practice guidelines and as the chairperson of the ESC guidelines on pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery. He was also the lead author of the influential 1999 New England Journal of Medicine DECREASE study on the use of bisoprolol during vascular surgery. Poldermans now works as a vascular medicine physician at a nonteaching hospital in the Netherlands.

CardioBrief will publish a followup story in the near future based on an interview with Poldermans conducted in Munich during the ESC.

Related Links:

Observational Study Links Common Household Chemical To Cardiovascular Disease Reply

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.”
Click to continue reading…

UK Study Casts Doubts On Value Of Type 2 Diabetes Screening Reply

The dramatic growth in type 2 diabetes has resulted in increased interest in screening programs. Now a new study published in the Lancet raises concerns that screening programs may not result in long-term improvement in outcomes.

In the ADDITION-Cambridge study, investigators in the UK randomized general practices to either screening or no screening.  The practices allocated to screening were further divided to either intensive cardiovascular risk reduction or standard care. The study population included more than 20,000 adults 40-69 years of age at high risk for undiagnosed diabetes.

3% of patients in the screening groups received a diagnosis of diabetes. After a median followup of 9.6 years, there were no significant differences between the screened population and the control group.

Rate per 1,000 person-years and hazard ratios for the no-screening and the screening group:

  • Mortality: 9.89 versus 10.50, 1.06 (CI 0.90-1.25)
  • CV mortality: 3.25 versus 3.30, 1.02 (0.75-1.38)

The authors proposed several explanations for the lack of benefit associated withs screening, including ad-hoc screening outside the practice setting in the unscreened group, patients who did not follow the screening program, and concurrent gains in identifying and managing other cardiovascular risk factors during the study period. In addition, the patient population in the study may have been a relatively healthy population with a lower prevalence of undiagnosed diabetes.

The authors concluded that “if population-based screening for diabetes is to be implemented, it should be undertaken alongside assessment and management of risk factors for diabetes and cardiovascular disease and population level preventive strategies targeting underlying determinants of these diseases.”

In a Lancet press release, senior author Simon Griffin said that “the benefits of screening might be smaller than expected and restricted to individuals with detectable disease.  However, benefits to the population could be increased by including the detection and management of cardiovascular risk factors alongside the assessment of diabetes risk, performing repeated rounds of screening, and improving strategies to maximize the uptake of screening.”

In an accompanying comment, Michael Engelgau and Edward W Gregg write that prevention programs should screen not just for diabetes but for high-risk individuals as well, though they note that this strategy “assumes that effective prevention programs are available to high-risk cases.” Further, the value of screening depends “on more than just mortality as an outcome,” and will need to include morbidity, quality of life, and costs.
Click here to read the Lancet press release…