Decision on Apixaban (Eliquis) Pushed Back By Three Months 1

Update, March 1, 5 PM: Ramsay Baghadi of the RPM Report says that the Cardiorenal committee will take up the apixaban NDA on Mary 22 and the rivaroxaban supplemental NDA for the ACS indication on May 23, but this information has not been confirmed.

Confirming earlier speculation by a Wall Street analyst, Pfizer and Bristol-Myers Squibb announced on Wednesday evening that the FDA had extended by three months the action date for the new drug application (NDA) for the highly anticipated oral anticoagulant Eliquis (apixaban). The application is for their important indication of stroke prevention in atrial fibrillation. The FDA had previously granted the application a 6-month priority review, resulting in a March 28th decision date. The new decision date is June 28,2012.

Sanford Bernstein research analyst Tim Anderson first raised the idea that the decision date might be delayed back on February 10th. On Tuesday Anderson released another note with additional evidence for the delay, based on the release of the tentative FDA advisory committee calendar for 2012, suggesting that the apixaban NDA will be subject to an advisory panel meeting. According to the calendar, the Cardiovascular and Renal Drugs Advisory Committee is scheduled to meet on March 27 and May 23. The agenda for the March 27 session is already set for a discussion of Replagal for Fabry disease. Recall that yesterday the FDA granted a priority review to the NDA for rivaroxaban for ACS, resulting in a decision date of June 29. One might speculate then that another day might be added to the May 23rd meeting for consideration of the rivaroxaban and apixaban NDAs.

Anderson wonders why the FDA has suddenly put the brakes on the apixaban approval, which had heretofore seemed uncomplicated. He writes:

Our best guess remains that FDA may be seeking cover, given the safety experience following competing drug Pradaxa’s approval in 2010.  Additionally, FDA may be seeking advice on things like product labeling and what claims would be allowed.

We might also note that the approval of rivaroxaban was far more difficult than had been expected. Remember that the ROCKET AF trial had been presented and published with broad approval, but then came under heavy fire from FDA reviewers. It is possible that FDA reviewers may also raise previously unsuspected concerns about the pivotal apixaban trial, ARISTOTLE, though no serious criticisms have been publicly raised so far.
Click here to read the press release from Pfizer and Bristol-Myers Squibb…


FDA Revises the Safety Labeling of Statins 2

The FDA today announced important new changes to the safety language on the labels of statins:

Routine periodic monitoring of liver enzymes is no longer recommended. Serious liver injury associated with statins is “rare and unpredictable in individual patients” and “routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing this rare side effect,” according to the FDA.  The FDA now says that liver enzyme tests only need to be performed before starting statin therapy and “as clinically indicated thereafter.”

Memory loss and confusion will now be included in the label. But, the FDA notes, reports about the cognitive effects of statins have usually “not been serious and the patients’ symptoms were reversed by stopping the statin.” In a story published on Forbes, Matt Herper writes that the “new labeling will lead patients and doctors to take memory issues on the drugs more seriously, and it will also lead patients to link normal lapses of memory to their drugs.”

The increased risk of hyperglycemia and type 2 diabetes will be mentioned in the label. The label will now reflect data showing the small increased risk for type 2 diabetes in people taking statins.

The FDA is also making specific recommendations about lovastatin, noting that when used with some other drugs lovastatin can increase the risk of muscle injury.
Click here to read the press release from the FDA…

FDA Grants Priority Review to Rivaroxaban (Xarelto) for ACS Patients Reply

The FDA has granted a priority review for the supplemental new drug application (sNDA) for rivaroxaban (Xarelto) in combination with standard therapy to reduce the risk of cardiovascular events in acute coronary syndrome (ACS) patients. The news was announced by Bayer and Johnson & Johnson. The FDA will now be required to respond within 6 months instead of 10 months to the December 29 submission of the sNDA.

The application is based upon the results of the ATLAS ACS 2-TIMI 51 study, which was the first trial to show a benefit in ACS with an anticoagulant. Previous trials testing anticoagulants in the setting of ACS had all failed. One key difference highlighted by many experts was the low doses of rivaroxaban used in the trial. The addition of 2.5 mg bid of rivaroxaban to standard therapy resulted in a significant reduction in the combined rate of cardiovascular death, MI, or stroke, as well as a significant reduction in death from cardiovascular causes (2.7% vs. 4.1%, p=0.002) and all-cause mortality (2.9% vs. 4.5%, p=0.002). The last two benefits were not found with the higher dose of rivaroxaban (5 mg bid) also studied in the trial. Rivaroxaban also caused significant increases in bleeding complications, but not fatal bleeding.

Priority reviews are granted to treatments that offer an advance in care or that provide a treatment where no adequate therapy exists, the company said.

Click here to read the press release from Bayer…

Slow Uptake of Transcatheter Aortic Valves: Learning from History? Reply

Transcatheter aortic valve replacement (TAVR) has been one of the most exciting new developments in cardiovascular medicine in recent years. The growing enthusiasm over TAVR led to concern and even alarm in some quarters that the introduction of TAVR would ignite a stampede of uptake, mirroring the early over-enthusiasm for similarly disruptive devices like stents and ICDs, leading to repeated cycles of criticism, investigations, and pullbacks.

Early signs now indicate that history may not be repeating itself and that the careful and deliberate introduction of TAVR may result in an entirely different pattern. Remember that ACC and STS requested a National Coverage Decision (NCD)from CMS and, following the initial approval of TAVI, released a critical consensus document offering a roadmap to responsible introduction of the new procedure.

Wells Fargo medical device analyst Larry Biegelsen (email), attending the STS/ACCF Transcatheter Heart Valve (THV) Symposium in Chicago last week, reports that uptake of the Edwards Sapien device has been slow, suggesting that the measured approach advocated by the ACC and STS and others has had an impact.

He cites three reasons for the slow uptake:
Click to continue reading…

Meta-Analysis Finds No Advantages for PCI Over Medical Therapy in Stable Patients Reply

Patients with stable coronary artery disease (CAD) today do no better with stents than with medical therapy, according to a new meta-analysis published in the Archives of Internal Medicine. Kathleen Stergiopoulos and David Brown identified 8 trials with 7,229 patients comparing stents to medical therapy in which stents were used in the majority of PCI cases. ”By limiting the analysis to studies in which stent implantation was the predominant form of PCI,” they explained, their meta-analysis “compares contemporary versions of PCI and medical therapy. The exclusion of studies using balloon angioplasty as the primary form of PCI shifted the years of enrollment forward by almost a decade during which time optimal medical therapy evolved to the current regimen that includes aspirin, β-blockers, ACE-inhibitors (or angiotensin receptor blockers) and statins.”

After a mean followup of 4.3 years, there were no significant differences between the stent and medical therapy groups:

  • Death: 8.9% for PCI versus 9.1% for medical therapy (OR 0.98, CI 0.84-1.16)
  • Nonfatal MI: 8.9% versus 8.1% (OR 1.12,CI 0.93-1.34)
  • Unplanned revascularization: 21.4% versus 30.7% (OR 0.78, CI 0.57-1.06)
  • Persistent angina: 29% versus 33% (OR 0.80; CI 0.60-1.05)

The authors write that their study “suggests that up to 76% of patients with stable CAD can avoid PCI altogether if treated with optimal medical therapy, resulting in a lifetime savings of approximately $9450 per patient in health care costs.”

In an accompanying editorial, William Boden writes that “the inescapable fact is that it is increasingly harder to justify use of PCI solely for angina relief in such patients — especially as an initial approach to management, and if medical therapy has not been first instituted (or if efforts to optimize pharmacologic treatment in those treated initially medically are not undertaken).”

Boden responds to the failure of clinical trials like BARI-2D and his own COURAGE trial to effect change in clinical practice:

While physicians outwardly worship at the altar of evidence-based medicine, in reality, we more often tend to practice selective evidence-based medicine by adopting and embracing those trials and studies with results that reinforce our existing clinical practice preferences or biases, while we ignore or disdain the results of studies with results that are unpopular, conflict with our existing clinical practice beliefs, or collide with the conventional wisdom.

Archives editor Rita Redberg places the study in the journal’s “Less Is More” category and writes that, despite the evidence, “fewer than half of Americans with stable CAD who undergo stent placement have received medical therapy first.”

Here is the press release from Archives:

Study Suggests No Benefit Associated With Stent Implantation Compared to Initial Medical Therapy for Stable Coronary Disease

CHICAGO—A meta-analysis of eight previously published clinical trials suggests that initial stent implantation for patients with stable coronary artery disease is not associated with improved outcomes compared with initial medical therapy for prevention of death, nonfatal heart attacks, unplanned revascularization or angina, according to a study published in the Feb. 27 Archives of Internal Medicine, one of the JAMA/Archives journals. The article is part of the journal’s Less is More series.

While percutaneous coronary intervention (PCI) reduces death and nonfatal myocardial infarction (MI, heart attack) in acute coronary syndrome settings, its role in treating stable coronary artery disease (CAD) “remains controversial,” the authors write in their study background.

Kathleen Stergiopoulos, M.D., Ph.D, and David L. Brown, M.D., of Stony Brook University Medical Center, New York, conducted a meta-analysis of previous randomized clinical trials that compared initial coronary stent implantation and medical therapy with initial medical therapy alone. Eight trials that enrolled 7,229 patients between 1997 and 2005 were included. Of those patients, 3,617 were randomized to receive stent placement and medication therapy and 3,612 were randomized to receive medication therapy alone.

“The significant finding of this analysis is that compared with a strategy of initial medical therapy alone, coronary stent implantation in combination with medical therapy for stable CAD is not associated with a significant reduction in mortality, nonfatal MI, unplanned revascularization or angina after a mean (average) follow-up of 4.3 years,” the researchers comment.

They explain their results are in contrast to two recent meta-analyses that found reductions in mortality and angina (discomfort, tightness or heaviness in the chest) in patients assigned to initial PCI. They suggest that an aspect of the current study may explain the difference.

“By limiting the analysis to studies in which stent implantation was the predominant form of PCI, this meta-analysis, for the first time that we know of, compares contemporary versions of PCI and medical therapy. The exclusion of studies using balloon angioplasty as the primary form of PCI shifted the years of enrollment forward by almost a decade during which time optimal medical therapy evolved to the current regimen that includes aspirin, β-blockers, ACE-inhibitors (or angiotensin receptor blockers) and statins,” they note.

Of the total 649 deaths among the 7,229 patients in the trials, 322 occurred among 3,617 patients in the stent groups (8.9 percent) and 327 occurred among 3,612 patients in the medical therapy groups (9.1 percent). Nonfatal MI was reported in 323 of 3,617 patients in the stent groups (8.9 percent) compared with 291 of 3,612 patients in the medical therapy groups (8.1 percent.) Unplanned revascularization was performed in 774 of 3,617 stent patients (21.4 percent) and 1,049 of 3,420 medical therapy patients (30.7 percent).

Data on angina were available for 4,122 patients. Among the initial stent implantation patients, 597 of 2,070 experienced persistent angina (29 percent) compared with 669 of 2,052 medical therapy patients (33 percent).

“In the context of controlling rising health care costs in the United States, this study suggests that up to 76 percent of patients with stable CAD can avoid PCI altogether if treated with optimal medical therapy, resulting in a lifetime savings of approximately $9,450 per patient in health care costs,” the authors conclude.

Commentary: Mounting Evidence for Lack of Percutaneous Coronary Intervention in Stable Heart Disease

In an invited commentary, William E. Boden, M.D., of the Samuel S. Stratton VA Medical Center, Albany, N.Y., writes: “What is the practicing clinician to take away from the present study in the context of other published meta-analyses? First, the totality of evidence does not support any demonstrable clinical benefit for PCI in patients with stable CAD in terms of reducing death, nonfatal MI, hospitalization for ACS (acute coronary syndrome), need for unplanned revascularization and a durable, sustained effect on angina relief.”

He continues: “Finally, given the spiraling health care costs that we have witnessed in the United States over the past decade, and the financial burden this places on our existing health care system, businesses and health care consumers, we certainly have abundant scientific evidence to support a more selective, measured and balanced approach to the initial management of SIHD (stable ischemic heart disease) and one that promotes and embraces optimal medical therapy for the majority of patients as a proven alternative to revascularization.”
(Arch Intern Med. 2012;172[4]:312-319172[4]:319-321)

YouTube, NEJM, Whitney Houston, and Alpha Male Monkeys 3

Take a close look at this screenshot from YouTube (click to expand):

  • Jim Ware, the legendary New England Journal of Medicine biostatistician: 8 views.
  • Jerome Kassirer, Marcia Angell, and Arnold Relman, former NEJM editors: 36, 28, and 257 views.
  • Whitney Elizabeth Houston Funeral Service: 994,920 views. (And how many more Whitney Houston videos do you think are out there?)
  • Alpha Male Monkey attacks man: 2,135,280 views.

Draw your own conclusions. Here’s just one from me: we need to figure out how we can use social media better than we do now.

FDA Advisory Panel Gives Green Light to Qnexa Diet Pill 2

Breaking a long streak of bad news for diet drugs, an FDA advisory panel on Wednesday voted 20-2 in favor of approval for Qnexa, the combination of  phentermine and topiramate under development by Vivus. Panel members strongly suggested that Vivus be required to perform a cardiovascular outcomes trial, though it was not immediately clear if this would have to be completed prior to approval.

Birth defects associated with Qnexa were another source of concern. The panel expressed strong support for a risk evaluation and mitigation strategy (REMS) to accompany any approval. But the panel ultimately was impressed by data showing a 10% weight loss at two years for people taking the drug.

“Of all the obesity drugs, this one has the highest efficacy in terms of weight loss, so that shifts the balance in terms of requiring a post-approval study rather than a pre- approval study,” panel member Sanjay Kaul told Bloomberg News.

Kaul told CardioBrief that the 20-2 vote appears more enthusiastic than the actual sentiment of the panel. Panel members remain concerned about the uncertainty regarding cardiovascular risk of the drug, including the possible adverse effects on blood pressure and heart rate. Kaul said the panel was impressed by the company’s proposed REMS, but that there is little evidence demonstrating that even a strong REMS can significantly reduce adverse outcomes like birth defects.

Two other diet drugs, Contrave, the combination of naltrexone and bupropion, from Orexigen, and locaserin, from Arena, have been struggling to gain FDA approval in recent years. No new diet drug has been approved for marketing in the United States since 1999.

Guest Post: More Lessons From the Riata ICD Lead Recall 7

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH. This post is longer and far more technical than most of the content published on CardioBrief. Due to the extraordinary nature of the material, however, I believe this post will likely be of considerable interest to many cardiovascular healthcare professionals.

More Lessons From the Riata ICD Lead Recall

by Edward J. Schloss, MD

In an earlier guest post (What are the Lessons of the Riata ICD Lead Recall?) I summarized points from Robert Hauser’s  important perspective in the New England Journal of Medicine regarding the St. Jude Riata ICD lead recall. In this followup, I’d like to discuss St. Jude’s responses to this piece and place the arguments into a broader context.

Last week Mark Carlson MD, Chief Medical Officer of St. Jude Medical, posted a response to Hauser’s perspective, and he made similar points in a letter subsequently published in NEJM. In the original response, Carlson writes “we believe that there were inaccuracies and omissions in the editorial that are important to recognize in order to more fully understand this issue.”

Major points of disagreement in the two pieces include:

  1. Timing of the initiation of a prospective trial looking at Riata externalizations and failures.
  2. Similarities and differences between the currently marketed Durata lead and it’s recalled predecessor Riata ST.
  3. Robustness of the existing St. Jude lead surveillance systems.

Having looked at this issue in some depth, I feel it would be reasonable for me to weigh in on these matters.

Regarding the timing of the recent trial, Dr. Carlson writes:
Click to continue reading…

More Rigorous Family History Improves CV Risk Assessment Reply

Although family history has long been recognized as an important cardiovascular risk factor, usual methods to assess risk have not incorporated the family history in a rigorous manner. A new study published in Annals of Internal Medicine finds that systematically collecting family history in a primary practice setting significantly increases the identification of high risk people.

Nadeem Quereshi and colleagues in the ADDFAM (Added Value of Family History in CVD Risk Assessment) Study Group studied 748 people without known CV disease who were seen in a family practice setting in the UK. In addition to a Framingham-based assessment of risk, half the patients were randomized to a systematic review of their family history.
Click to continue reading…

FDA Approves Medtronic’s Resolute Drug-Eluting Stent for Treatment of CAD, Including Diabetics Reply

The FDA has approved the Medtronic Resolute zotarolimus-eluting stent for the treatment of coronary artery disease. The Resolute DES is approved for use in a wide variety of patients, including diabetics. The new stent uses the same drug-and-polymer combination as the popular Resolute Integrity DES. The Resolute clinical trial program enrolled more than 5,000 patients worldwide, a third of whom had diabetes.

“The Resolute Integrity DES offers several notable benefits, starting with outstanding deliverability, which means it’s exceptionally easy to navigate the stent on the delivery system through the coronary vasculature to the narrowed arterial segment that requires treatment,” said Martin B. Leon, a principal investigator of the RESOLUTE US clinical study, in a Medtronic press release. “Its approval by the FDA is based on the impressive performance of the Resolute DES in a wide variety of patients. With the device’s compelling combination of deliverability, efficacy and safety, not to mention that it is the first DES approved for patients with diabetes, the Resolute Integrity DES promises to gain rapid acceptance in cath labs nationwide.”
Click here to read the Medtronic press release…

Industry Supported Editorial Assistance: The Debate Continues 3

Editor’s Note: Here is the latest installment of a debate over industry-sponsored editorial assistance between Tom Yates, a UK-based physician critical of the role of industry in medical publishing, and Karen Wooley, who owns a medical education company and is a representative of the the Global Alliance of Publication Professionals (GAPP). (The previous installments of the debate can be found here and here.)

Karen Wooley responds to questions raised by Yates in the earlier posts:
Click to continue reading…

Japanese Researcher With Harvard Connections Retracts 3 Articles in AHA Journals 1

Akio Kawakami, a well published lipid researcher at Tokyo Medical and Dental University, has retracted 3 papers from AHA journals, including one article in AHA’s flagship journal Circulation. News of the retractions was first reported on Retraction Watch.

Two of Kawakami’s co-authors are well known researchers affiliated with Harvard University and the Brigham and Women’s Hospital, Peter Libby and Frank Sacks. Prior to his position in Tokyo, Kawakami had been at the Harvard School of Public Health in the Department of Nutrition, where Sacks also works. Sacks is a co-author on all three of the retracted papers, while Peter Libby is a co-author on one of the retracted papers. Kawakami was also the first author of 4 other papers on which Libby and Sacks were co-authors, including two papers published in 2006 in Circulation (here and here).

Donna Arnett, the incoming president of the AHA, told CardioBrief that the retractions were requested by Kawakami himself. She said he initially contacted each of the individual journals, which then informed the AHA’s scientific publishing committee. (Arnett is a former chair of the committee.) “In this case it was the author himself coming forward, so it was fairly straightforward,” said Arnett. The retraction was then coordinated with the three journals.

Here are the 3 retractions:
Click to continue reading…

AHA Scientific Statement Spotlights Peripheral Artery Disease in Women Reply

Although peripheral artery disease (PAD) raises the risk of heart disease and stroke, it often goes undiagnosed and untreated, especially in women, according to a scientific statement issued by the American Heart Association and published in Circulation.

Here are a few highlights of the statement:

  • Although women develop PAD later than men, the total number of women with PAD is greater than the number of men.
  • Like men, most women with PAD do not present with “classic symptoms” of intermittent claudication; rather, many are asymptomatic or have atypical leg symptoms.
  • Women with PAD are more likely than women without PAD to have greater functional impairment and a more rapid functional decline. Women, and black women in particular, have a greater risk for graft failure and limb loss than men.
  • Although women have slightly lower normal ABI levels than men, physicians should use the same diagnostic criteria for PAD in men and women.
  • Although the evidence is limited because of the underrepresentation of women in clinical trials, exercise training is equally effective in men and women.
  • At-risk women should be educated about PAD risk factors, symptoms, and cardiovascular risk by all healthcare providers.

“The rate of deaths and the healthcare costs associated with PAD are at least comparable to those of heart disease and stroke,” said the lead of the author of the AHA statement, Alan Hirsch, in an AHA press release. “Women, in particular, suffer an immense burden from peripheral artery disease, yet current data demonstrate most women still remain unaware of their risk.”

Adapted with permission from Physician’s First Watch.
Click here to read the AHA press release…

Metaanalysis: Air Pollutants Raise Short Term Risk of MI Reply

Air pollution significantly raises the short-term seven-day risk of myocardial infarction (MI), according to a new metaanalysis published in JAMA. Hazrije Mustafic and colleagues analyzed data from 34 studies and found a significant increase in the relative risk (RR) of MI for all the main air pollutants except ozone:

  • carbon monoxide: RR 1.048, CI 1.026-1.070
  • nitrogen dioxide: 1.011, 1.006-1.016
  • sulfur dioxide: 1.010, 1.003- 1.017
  • PM10: 1.006, 1.002-1.009
  • PM2.5: 1.025, 1.015-1.036)
  • ozone: 1.003, 0.997-1.010
The authors acknowledged that the magnitude of increased risk was small, but calculated that because of the broad exposure of the population to air pollution the attributable fraction ranged from 0.6% to 4.5% for the different pollutants.
Click here to read the press release from JAMA…

Guest Post: What Are the Lessons of the Riata ICD Lead Recall? 2

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH.

What Are the Implications of the Riata ICD Recall?

by Edward J. Schloss, MD

This week the New England Journal of Medicine published an important perspective piece from Robert G. Hauser of the Minneapolis Heart Institute regarding the St. Jude Riata ICD lead recall.

For those involved in cardiac arrhythmia care, Dr. Hauser needs no introduction. He has effectively served a watchdog role for the ICD industry over the last several years.

It was Hauser who first brought to attention the failures of the Guidant Corporation Prizm 2 DR ICD in 2005. That action had far reaching actions including a major New York Times article, a large product recall, and Justice Department fines. The Guidant Corporation was later sold to Boston Scientific.

In 2008, Hauser wrote the seminal article on the Medtronic Fidelis Lead. This lead was found to have excess failures in his clinic, a finding now clearly confirmed in many subsequent studies. Hauser has continued to publish follow up studies showing an increasing failure rate over time. The Fidelis lead recall has had an even more far reaching effect on the medical device industry as well as device doctors and patients.

Ironically, it is now the third large US cardiac rhythm company, St. Jude Medical, that has fallen under Hauser’s scrutiny.

In today’s New England Journal of Medicine, Hauser writes a perspective on the Riata and Riata ST ICD Leads. This lead has exhibited a unique form of failure. The leads have been shown to have exteriorization of the inner conductors through the outer silicone jacket of the lead. This was first recognized fluoroscopically in 2008 and has now been shown in multiple centers to occur in up to 15% of these leads. The functional significance of this exteriorization remains uncertain.
Click to continue reading…

A Defense of Professional Medical Writers 2

Updated on February 16 with a response by Tom Yates to Karen Woolley.

Editor’s Note: In response to a recent guest post by Tom Yates on industry sponsored editorial assistance, the following comment was submitted  by Karen Woolley on behalf of the Global Alliance of Publication Professionals. This thoughtful statement deserves attention, but I would point out that Woolley does not actually address the problems raised by Yates about industry sponsorship of articles. Specifically, I would invite Woolley and her group to respond to these questions posed by Yates:

  • What expertise do publications professionals have have in the field about which they are writing?
  • Can Woolley point to industry-sponsored publications that do  not recommend prescribing a drug manufactured by the sponsor?
  • Will the industry sponsor or the communications company make public the details of their contract?

Click to continue reading…

Metaanalysis Raises More Questions About Routine Use of Aspirin for Primary Prevention Reply

Although aspirin can reduce the risk of cardiovascular (CV) events, the associated increase in bleeding suggests that it should not be used routinely in  people without prior CV disease, say the authors of a new meta-analysis published in Archives of Internal Medicine.

Sreenivasa Rao Kondapally Seshasai and colleagues combined data from 9 clinical studies including more than 100,000 participants who were followed for a mean of 6 years. They found a significant reduction in CV events, but not CV mortality, and an increased risk of important bleeding events:
Click to continue reading…

Guest Post: Industry Sponsored Editorial Assistance 4

Editor’s Note: The following guest post by Tom Yates is reprinted with permission from his blog Sick Populations. Yates is a UK-based physician with an interest in epidemiology and population health.

Industry Sponsored Editorial Assistance

by Tom Yates

The September 2011 edition of the Quarterly Journal of Medicine contained two review articles which dealt with the use of new oral anticoagulants in patients withatrial fibrillation.

The first was by Prof Richard Hobbs and Isabelle Leach, who works for a reputable sounding organisation called Chameleon Communications. The funding and conflict of interest statements read as follows.

F.D.R.H. received no funding for this work. Bayer AG and Johnson & Johnson Pharmaceutical Research & Development, LLC, through funding of the professional medical writing services provided by IL. The sponsors were not involved in writing or editing the material. The authors take full responsibility for all content…F.D.R.H. has received occasional speaker fees or sponsorship from a variety of pharmaceutical companies, some with interests in AF including Boehringer Ingelheim, Pfizer, and Bayer. I.L. is an employee of Chameleon Communications International which received funding from the sponsors for her time on this manuscript.

Bayer, who funded the editorial assistance, make Rivaroxaban, one of the drugs discussed in the article. Many of the companies from which Prof Hobbs has received money also make new oral anticoagulants. Chameleon Communications has been involved in preparing several other manuscripts in other journals on new anticoagulants over recent months.

The second, by Prof Joerg Kreuzer, was that edition’s “Editor’s Choice” article. Prof Kreuzer’s funding and conflict of interest statement read as follows.

This work was supported by Boehringer Ingelheim. The author was fully responsible for all content and editorial decisions. The author received no financial support or other compensation related to the development of the paper. Editorial support was funded by Boehringer Ingelheim…Conflict of interest: None declared… The authors would like to thank Rebecca Gardner of PAREXEL, UK, for editorial assistance in the preparation of this article.

Boehringer Ingelheim, make Dabigatran etexilate, a drug promoted in the article’s conclusion.

Concerned about these clear conflicts of interests, I wrote a letter to QJM arguing that the involvement of industry in the funding of review articles generates bias, probably above and beyond the mere choice of topics on which they focus. I requested answers to these four questions:
Click to continue reading…

The Y Chromosome May Explain Why Men Have Earlier Coronary Disease 1

The earlier onset of coronary artery disease in men has long provoked speculation and research. Now a new study in the Lancet suggests that common variations in the Y chromosome (which is transmitted directly from father to son and does not undergo recombination) may play an important role in the increased risk seen in men.

Using genetic information on the Y chromosome, an international team of researchers identified 9 different ancient lineages– haplogroups– in 3,233 British men. Two of the haplogroups accounted for nearly  90% of the subjects and men in one of these haplogroups, haplogroup I, had a 50% increase in the risk of coronary artery disease compared to  men with other haplotypes. This increase in risk was independent of other known risk factors. The investigators noted that haplogroup I appeared to exert a powerful effect on genes relating to inflammation and immunity. They further noted that haplotype I is generally more prevalent in northern than in southern Europe, and that this distribution is paralleled by an increased risk of coronary artery disease in northern Europe.

In an accompanying comment, Virginia Miller writes that the results of the study are “exciting because they identify a genetic haplotype linking response to infection (adaptive immunity) rather than innate immunity with perhaps an exaggerated inflammatory response and cardiovascular disease in men.”

Click here to read the press release from the Lancet…

Prominent Interventionalists Attack Appropriate Use Criteria For PCI 5

A group of leading interventional cardiologists has launched an attack on the growing role of appropriate use criteria (AUC) for PCI in the US. They argue that severe flaws in current guidelines render unreliable current attempts to assess the rate of appropriate procedures.

In a paper published in  JACC: Cardiovascular Interventions, Steven Marso and colleagues (Paul Teirstein, Dean Kereiakes, Jeffrey Moses, John Lasala, and J Aaron Grantham) criticize a study in JAMA published last year from the National Cardiovascular Data Registry (NCDR) that found a large degree of inappropriate or uncertain PCI procedures, as well as a wide range of variability among institutions. Marso et al write that the JAMA paper sensationalized the data by focusing attention on the low rate of appropriate indications for nonacute PCI– 50.4%– while failing to point out that the study found that 84.6% of procedures in the entire study population– acute and nonacute alike– were deemed appropriate. Furthermore, given the imprecision built into the system, they ask: what is the “acceptable threshold” of inappropriate PCI?

The authors write that the AUC panel “purposefully limited involvement of the interventional community during the development process, in order to avoid having a majority of committee members “whose livelihood is tied to the technology under study.” But the under-representation of interventionists may have biased the results, they argue. One particular case as graded by the AUC panel was the most common reason for cases to be categorized as inappropriate: the AUC committee decided that PCI was inappropriate for a patient with 1- to 2-vessel disease, no proximal LAD involvement or prior CABG, class I or II symptoms, low-risk noninvasive findings, and on no or minimal medications. But most clinicians believe this is an uncertain but not inappropriate indication, they say.  The AUC panel may have “got this one wrong,” they write.
Click to continue reading…

Bleeding Problems Continue To Bedevil Merck’s Novel Antiplatelet Agent Vorapaxar 1

In the large TRA-2P  study of more than 26,000 patients with  MI, ischemic stroke, or documented peripheral vascular disease, the novel antiplatelet agent vorapaxar significantly reduced the primary endpoint of CV death, MI, stroke or urgent coronary revascularization. But vorapaxar treatment resulted in a significant increase in bleeding, including intracranial hemorrhage.

The fate of vorapaxar now appears to be uncertain, as the company said it will review data from the drug’s two large clinical trials with the investigators of the trials and external experts to inform the company’s next steps.

The full results of the TRA-2P  (Thrombin Receptor Antagonist in Secondary Prevention of atherothrombotic ischemic events) trial are scheduled to be presented in March at the American College of Cardiology. Merck today released the top-line results in a press release.

TRACER, the large ACS trial with vorapaxar, was terminated early last year due to similar safety concerns. As reported here last year, at the same time TRACER was stopped the TRA-2P trial was modified. TRA-2P investigator Eugene Braunwald said that vorapaxar would be discontinued in patients who experienced a stroke prior to entry or during the trial because of an increase in intracranial hemorrhage in these patients.

On his blog on Forbes Matt Herper provides some additional perspective on this story.
Click here to read the press release from Merck…

Women and ICDs: More Complications and Fewer Benefits Reply

After consulting an electrophysiologist, women are just as likely as men to receive an ICD but they suffer more complications and are less likely to benefit from the device, according to a new study from Canada published in Annals of Internal Medicine.

Derek MacFadden and colleagues analyzed data from 6,021 patients treated at 18 ICD implantation centers in Canada. 21.4% of the patients were women. The rate of ICD implantation was similar in men and women, but women were more likely to have complications and less likely to receive appropriate shocks or antitachycardia pacing:
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CMS Releases Details Of Proposed National Coverage For TAVR 5

(Updated with statement from the ACC and STS)

On Thursday the Centers for Medicare & Medicaid Services (CMS) released a memo containing details of its proposed Medicare coverage for TAVR (transcatheter aortic valve replacement). The memo is a response to a formal request for national coverage determination (NCD) from the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC). The memo will be open for public comment until March 3, after which a final determination will be made.

In the memo CMS proposes coverage for TAVR only if 5 conditions are met, including
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Study Explores Role of Periprocedural Dabigatran in AF Ablation 1

Updated with a comment from John Mandrola– As dabigatran becomes more widely used in atrial fibrillation (AF) patients, electrophysiologists are now trying to figure out how to handle anticoagulation in patients taking dabigatran (Pradaxa) for whom AF ablation is planned. In a new study published in the Journal of the American College of Cardiology, Dhanunjaya Lakkireddy and colleagues report on a multicenter, observational study of 290 patients who underwent an AF ablation procedure. Half the patients were taking periprocedural dabigatran and half were matched controls taking warfarin.

There were significantly more thromboembolic  and bleeding complications in the dabigatran group than in the warfarin group:
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Meta-Analysis Confirms Benefits Of Statins In Women Reply

Although clinical trials have consistently found a beneficial effects for statins, some critics have questioned the strength of the evidence in women, who are often under-represented in clinical trials.  A large new meta-analysis published in the Journal of the American College of Cardiology provides the best evidence yet that the relative reductions in events observed in men also occur in women, but doesn’t provide evidence about the absolute risk benefit in women.

William Kostis and colleagues analyzed data from 18 randomized trials of primary and secondary prevention, including 141,235 men and 40,275 women.  The reduction in risk was similar for both groups:
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