Recently in Cardiology Category

A case of cardioversion by Taser is published in the Annals of Emergency Medicine. The WSJ Health Blog reports.

Just when you thought it was safe to go back to reading mainstream pharma coverage, Forbes now questions the propriety of CEO Fred Hassan's $13-million bonus from Schering-Plough. Writers Matthew Herper and Michael Maiello imply today that the delay of the negative results of the ENHANCE study* directly benefited SP's leader by maintaining the company's stock price for as long as possible. The story was snapped up this morning by Sarah Rubenstein at the WSJ Health Blog and Ed Silverman at Pharmalot.

The results of the ENHANCE study were made public by SP in January of this year and presented in full by principal investigator John Kastelein at the annual meeting of the American College of Cardiology in March, after longstanding concerns of data quality. However, Kastelein believes that the study results could have been presented as early as March 2007 (but not November 2006), according to media reports, and Forbes argues that an earlier release would have cost Hassan at least $4 million in bonus money, given SP's sales requirements for generating bonuses.

SP's share price began dropping in October 2007 and took a preciptious plunge after the release of the ENHANCE results in January 2008, when highly critical reports of the study's data handling flooded pharma-related press outlets. For its part, the WSJ Health Blog doesn't blame itself or other media sources for fomenting the drop in SP stock—long before lower Vytorin sales could ever be reflected in the company's earnings.

*Which, if you've just come out of an extended coma (and congratulations, BTW), showed that the combination of ezetimibe and simvastatin (Vytorin) was no more effective for reducing carotid intima-media thickness than simvastatin alone. Data-quality issues in ENHANCE have been discussed previously at the Pathophilia blog (see here, here, here, here, here, here, here, here, and here, for instance).

What's harder to get than a drug prescription from your doctor? Answer: an implanted stent from your doctor.

Nevertheless, there's much ado about a DTC television ad for the Cypher stent from Cordis (a JNJ subsidiary), which aired nationally last fall but can now only be viewed in the Baltimore area, according to the WSJ Health Blog. Today both the NYT and the WSJ report on an NEJM editorial against the ad, which was published online yesterday.

In the NEJM perspective, cardiologists William Boden, MD, and George Diamond, MD, question the propriety of airing a medical-device ad to "millions of people who are ill-equipped to make judgments about the many clinically relevant but subtle and complex therapeutic issues that even specialists continue to debate." Despite acknowledged benefits of DTC advertising to both the public and industry, the authors write that they are troubled by the limits of TV ads generally to disclose risks and find the Cypher ad, in particular, overpromising with respect to depicted functional outcomes.*

The curious aspect of the editorial, however, is Boden's and Diamond's objection to promoting a medical device that "can be selected and implanted only by someone with a very sophisticated medical understanding." They write, "It seems almost unimaginable that a patient would challenge an interventional cardiologist's judgment about the use of a particular stent or that a cardiologist would accede to a patient's request for a particular stent on the basis of the information gleaned from a television ad."

So at this point, I'm not sure what their objection is to the Cypher ad: Is the Cypher ad objectionable because it is misleading and therefore potentially harmful, or is the ad objectionable because it is useless, even absurd?

*Last year, Boden et al published "Optimal medical therapy with or without PCI for stable coronary disease," in which the rates of a number of vascular outcomes were no different between patients who underwent percutaneous coronary intervention and those who received optimal medical therapy alone. For what it's worth, Boden reports consulting fees from CV Therapeutics and PDL BioPharma; lecture fees from CV Therapeutics, sanofi-aventis, BMS, and Abbott; and grant support from Abbott.

Photo of Cypher (sirolimus-eluting coronary stent) from http://www.cypherusa.com/cypher-j2ee/cypherjsp/main_splash/stent.jsp.

Peter Libby, MD, now refuses pharma fees for his consulting services not because of impropriety, but because of the growing perception of impropriety. The chief cardiologist at Brigham and Women's Hospital in Boston told NPR's Madeline Brand last week that his decision was motivated by negative comments in the blogosphere after he appeared in a public-service documentary on PBS.

The documentary, "The Hidden Epidemic: Heart Disease in America," was a 4-year, unpaid labor for the doctor, according to a recent mini-profile in the NYT. However, shortly after the show's airing in October, Roy Poses, MD, at the Health Care Renewal blog raised conflict-of-interest (COI) issues, given that the show was funded by pacemaker-producer Medtronic and statin-maker AstraZeneca and that Libby, in particular, had an undisclosed relationship with AstraZeneca (although that relationship was not specified by Poses, other than in the form of grant support, consulting services, or participation on a speakers' bureau—which are important to distinguish [see below]).

Poses also discovered that another program participant, Douglas Zipes, MD, of Indiana University, had an undisclosed relationship with Medtronic. However, Poses did not identify particular instances in the documentary in which undue influence appeared to be exerted by the funding companies or by the participating experts themselves—other than to cite the unbranded claim that some cardiac arrhythmias are treated with implantable pacemakers (ho hum).

Yet despite the lack of specific examples suggesting commercial influence on the documentary's content, Pharmalot's Ed Silverman posted the story, arguably fomenting the unfounded perception that the program or its physician participants were biased, solely on the basis of their undefined relationships with the 2 supporting companies. Silverman (and Poses) also neglected to call out other documentary participants, including outspoken pharma critic Steven Nissen, MD, of the Cleveland Clinic.

In a moment of needed clarity, one Pharmalot commenter ("Reality") wrote:

Oh dear, another case of the COI vapors! Overall, I'd say this ranks around an 8 out of 10 on the conflict-of-interest overreaction scale...[F]rom what I've read, this was a simple, layman's educational series. No specific products were mentioned and what they reported in terms of treatments was straigh[t]forward and followed expert guidelines...

Should the advisors' ties to AZ and Medtronics...been noted? Probably. But I think the level of criticism here goes far beyond the seriousness of the infraction, or lack thereof. Look, there are some very real and very troubling COI issues out there, but to me, this is not one of them. This is a case of someone looking for a problem.

When Libby was asked by NPR last week if he could have been unconsciously* biased given his relationships with pharma, he denied influence. Because he has worked with "virtually every company that has produced, manufactured, sold, or even thought about producing, manufacturing, or selling" any cardiovascular product, he could claim no particular commercial allegiance.

Libby believes that academic investigators should be involved with pharma to ensure the integrity of clinical trials and, ultimately, the public good. Unfortunately Libby's decision to now refuse pharma money may confirm to a suspect crowd that his previous choice to do so was, somehow, improper.

N.B. In the 5-minute segment featuring Libby, NPR made a disingenuous, if not inaccurate, segue from the discussion of Robert Jarvik^† appearing in Lipitor's DTC ads to physicians consulting for or receiving grant support from commercial interests. In doing so, NPR failed to make important distinctions among 1) the appearance of physicians in advertisements, 2) their participation in speakers' bureaus, 3) their participation in advisory boards, and 4) the receipt of grant support.

*Of course, consciously assessing unconscious influence is really difficult, given that the influence, by definition, hasn't bubbled up to consciousness. So it's a very difficult question to answer, other than to ensure that there are conditions (such as consulting for everybody) that make unconscious bias toward one company unlikely.

†NPR also falsely stated that Jarvik is not a medical doctor. Jarvik evidently earned his MD from the University of Utah; however, to my knowledge, he does not hold an active license to practice medicine.

Executives at managed care companies anticipate fewer prescriptions for Vytorin (ezetimibe/simvastatin) and Zetia (ezetimibe) but no immediate changes in coverage for these medications. These conclusions are based on data generated by Cognet-X, a healthcare market research firm, after negative results from Merck's and Schering-Plough's overly scrutinized ENHANCE study were presented at the annual meeting of the American College of Cardiology in March.

According to a Cognet-X press release, more than 75% of pharmacy and medical executives surveyed earlier this month expect prescriptions to shift from Vytorin to generic simvastatin and, to a lesser extent, AstraZeneca's Crestor (rosuvastatin) and Pfizer's Lipitor (atorvastatin). But approximately two thirds expect few changes in coverage for Vytorin or Zetia because of formulary rules already in place, like tier placement and step therapy.

This afternoon's WSJ Health Blog provides access to drafts of after-the-fact "minutes" from the November 2007 meeting of independent reviewers of the ENHANCE study data. The draft documents, which include inserted comments from imaging expert James H. Stein, MD, were originally obtained by a Congressional subcommittee, according to the WSJ blog. Many of Stein's comments relate to the integrity and quality of ENHANCE's image database, which he concluded was "not acceptable." The image database resided at Amsterdam's Core Echo Laboratories (CEL), which is directed by ENHANCE's primary investigator John Kastelein, MD, PhD.

A few excerpted comments from Stein:

The imaging and reading protocols in ENHANCE were suboptimal even relative to methodologies employed at the time the study commenced and relative to procedures in clinical and epidemiological studies conducted in the 1990s.

We did not state the data and analysis "are reportable."

When we looked at images and considered the CIMT [carotid intima-media thickness] values of individual subjects over time, almost all the examples we saw showed measurement errors, biologically implausible measurements, biologically implausible changes in CIMT measurements, and/or failure to adhere to the protocol.

Great concern was expressed that the aggregate values may look reasonable, but that they may not reflect reality.

The concerns about unreported and later updated file segments were serious. I recall that I and other panel member[s] specifically stated that we could not determine if the database was "clean and credible" based on the information presented.

It is my recollection that there also were concerns about data management, such as the existence of data files with measurements that either were not entered into the official measurement database or that reflected more "recent" measurements than those in the measurement database. A statement should be inserted here that reflects concerns about the integrity of the data [which] was part of the reason for convening the expert panel. 

It is also revealed in the documents that data for 485 of 640 (~76%) subjects in ENHANCE were missing, and that data for 75 (~12%) subjects were biologically implausible (defined as >0.1-mm CIMT change between baseline and endpoint).* Because the missing data for the common carotid artery were considerably less, either 3% or 8% (depending on which source you take), it was suggested that the primary endpoint might be changed to the CCA measurement.

*The Pathophilia blog has repeatedly expressed its frustration that the volume of missing or implausible data, which would certainly undermine the integrity of and conclusions from the ENHANCE study, had not been revealed. 

MedPage Today provides an online video recording of another panel discussion of the ENHANCE study that was held at the recent ACC meeting. The panel was convened "just hours" after the report of the Vytorin-trial results by primary investigator John Kastelein, MD, PhD, on March 30 and the alleged monopoly of a follow-up panel discussion by Yale cardiologist Harlan Krumholz.

In the video recording, Kastelein maligned the day's previous panel discussion, during which a "single individual" conferred a "verdict" on the drug, and no questions were taken from the audience. The day's second, counterpoint panel included not only Kastelein, but also Schering-Plough officers Bob Spiegel, MD, Enrico Veltri, MD, and Tom Musliner, MD, as well as University of Chicago cardiologist Michael Davidson, and the panel was opened for questions from the on-site audience and by phone.

Most of the questions were posed by the media (eg, DocGuide, MedPage Today, ABC News, CBS News) and were disappointingly fixated on previously covered issues, such as the validity of cholesterol lowering as a surrogate marker for atherosclerosis reduction.* Only one questioner, from CBS News, requested more information regarding the delayed release of the trial results (and therefore, alluded to the missing or implausible data). Kastelein fielded the question and gave a passing reference to "data cleaning" during his explanation; however, no other direct explanation of the reasons for or manner of data handling were discussed. 

*The panel consensus is that, according to the overwhelming bulk of the data, the lowering of total and LDL cholesterol levels are associated with the significant reduction of atherosclerosis and atherosclerosis-related events.

More concerning than the delayed results of Merck's and Schering-Plough's ENHANCE study are allegations in a recent FDA letter to GlaxoSmithKline that the company failed to report multiple Avandia (rosiglitazone) postmarketing studies. Lapses in annual, required NDA reporting of this information by GSK date as far back as 2001, according to the letter, and include more than 20 studies. At least 2 of the studies, which were requested by European regulatory agencies, were intended to identify cardiac-related or -aggravating adverse events. (The FDA did acknowledge that information from 10 studies had been reported to the agency by other means.)

The lapses in the reporting of the studies were discovered during an extended FDA inspection last year of GSK's corporate headquarters, in the wake of widespread concerns about the cardiac safety of the oral antidiabetic agent. The FDA letter also charged that GSK "lacked appropriate knowledge of the studies associated with Avandia, resulting in the reporting deficiencies noted" and concluded, "Absent a clear explanation of the extent and cause of these deficiences and an adequate plan to correct them, we are concerned that similar deficiencies in the postmarket reporting for your firm's other FDA-approved drugs may exist." GSK markets more than 60 prescription pharmaceuticals, including Flonase (fluticasone), Paxil (paroxetine), and Valtrex (valacyclovir), in the United States.

In a press release today, GSK acknowledged the warning letter and described last year's on-site FDA inspection as "routine." The company also stated that the "observations from the inspection primarily relate to omissions from periodic reports to the FDA regarding Avandia...such as the start and progress of clinical trials, and summaries of final data from some clinical trials [emphasis added]." GSK stressed that the FDA inspection did not result in any citations, despite the fact that the FDA letter threatened "seizure and/or injunction" and the holdup of any pending NDAs or export certificates if the reporting deficiences weren't corrected in a timely manner.

Hat tip to Pharmalot.

Mike Huckman at Pharma's Market recently highlighted Pfizer's new, sober-looking DTC print campaign for Lipitor (atorvastatin), which may be taking advantage of Schering-Plough's recent woes with Vytorin (ezetimibe/simvastatin) and the exhaustively covered* ENHANCE study.

The print ad reads, "Unlike Vytorin and Zetia, Lipitor is FDA approved to reduce the risk of heart attack, stroke, and certain kinds of heart surgery in patients with several common risk factors for heart disease."

The head-slapping irony here is that Lipitor, when first FDA approved in 1996, was indicated to reduce LDL cholesterol but had not been shown to prevent clinical vascular events like its 4 existing competitors at the time. Nevertheless, Lipitor quickly became the number-one statin (and an uber-blockbuster) because 1) it reduced LDL cholesterol by a relatively greater percentage than the other statins and 2) clinicians believe (or at least believed) that the LDL cholesterol level is directly related to the risk of vascular events. Lipitor wasn't approved to reduce the risk of vascular events until 2004.

*But not entirely accurately covered.

In response to criticism (mainly in the WSJ) that Harlan Krumholz, MD, unfairly monopolized Sunday's ACC panel discussion of the ENHANCE study, which recommended that Vytorin be relegated to last-resort cholesterol management, the Yale cardiologist fired back yesterday in a blog post to Pharmalot.

"We [the 4-physician panel] were asked to comment on the ENHANCE study and discovered over the course of several weeks of discussion that we had a clear consensus about the recommendations for practice. My comments reflected that consensus," reads an excerpt.

Others on the ACC panel, who have not yet chimed in publicly one way or the other, were Joseph Messer, MD, Rick Nishimura, MD, and Patrick O’Gara, MD, whose selection for discussion of the ENHANCE study at the ACC was questioned by Schering-Plough CEO Fred Hassan. However, criticism of the panel generally and that of Krumholz specifically are not limited to SP insiders like Hassan or chief medical officer Robert Spiegel. A Sanford Bernstein analyst reported to the WSJ that the panel discussion "was essentially not a panel discussion at all, but rather a monologue by Dr. Harlan Krumholz, who was very negative on Vytorin."

Another legitimate criticism from Hassan, a criticism which has nevertheless been cast in a negative light by Pharmalot's Ed Silverman, is the lack of allowed participation by the ACC audience to specifically question the ENHANCE results and the panel. Such an open forum would have (or, at least, should have) raised the issue of the missing or implausible data in the ENHANCE study and their effect on the trial's validity.

Image: The SNL Archives.