Results tagged “Vytorin” from Pathophilia

Another Winter Solstice, another anniversary for the Pathophilia blog. Today marks 2 years of up-and-running blog time, which is 3½ years in Hollywood-marriage time.

And because anniversaries and a closing year prompt reflection, here are Pathophilia's top 10 stories for the year in medicine, pharma, and film noir on DVD. (Ho-ho-ho! So rare that I get to use the blog's strikeout feature as lame joke.)

No. 10: More Dumping on Merck's Vytorin, Zetia

The year began with continued debate (to put it nicely) about how to assess emerging cancer data from clinical trials of the anti-cholesterol combo drug Vytorin (ezetimibe/simvastatin; Merck). (For lots of necessary background, start at last year's No. 6 story.)

In a Smackdown: New England-Style, prominent cardiologist Steven Nissen essentially charged Sir Richard Peto and his colleagues with unethical behavior, when they separately analyzed cancer data from the SEAS trial (which suggested an increased drug-related cancer risk) and data from the ongoing SHARP and IMPROVE-IT studies (which did not). Nissen believed that data from all 3 studies should have been combined for the analysis (which would have affirmed a cancer risk); but Peto, a statistician and epidemiologist, stressed the importance of separating data in a hypothesis-generating study (eg, the SEAS trial) from data in hypothesis-testing studies (eg, SHARP and IMPROVE-IT). His analysis did not indicate an increased cancer risk with the drug.

At the same time, the FDA attempted to quell some of the anti-Vytorin sentiment and downright company-directed schadenfreude caused by the delayed results of 2008's troubled ENHANCE study. (And if you still don't know what the ENHANCE study is, go back to last year's No. 6 story.) The agency emphasized the importance of lowering the LDL cholesterol level (which Vytorin does) to reduce cardiac risks, like MI. The FDA also weighed in on why the ENHANCE study did not show a reduction of another surrogate marker for vascular disease, CIMT, with the addition of ezetimibe to simvastatin. Speculation included the selectiveness of the study population.

Months later, an Abbott-sponsored phase 4 trial (ARBITER 6-HALTS), which pitted the company's Niaspan (extended-release niacin) against Zetia (the ezetimibe half of Vytorin) was terminated early—and not because of safety concerns. The Street speculated that Abbott's drug had outperformed Zetia in the open-label study of high-risk adults. The Street was right.  

At the Scientific Sessions of the American Heart Association in November, results of ARBITER 6-HALTS showed that Niaspan outperformed Zetia in 5 of 7 outcomes, including a composite clinical outcome. Many media reports played up Niaspan's effects on CIMT at the expense of Zetia, while downplaying tolerability issues (eg, flushing) and the fact that the study population was small (N = 208) and selective: enrollees were statin-treated adults who had already attained target LDL levels (<100 mg/dL) and had moderately low HDL levels. Niaspan in such patients would be expected to elevate HDL, and Zetia would be expected to further lower total cholesterol and LDL levels—which is what the investigators found.

Relatively minimal attention was given to another small placebo-controlled study of extended-release niacin, also presented at the AHA sessions, in which changes in carotid-wall plaque (via MRI) were comparable in the 2 treatment groups.

Merck's Zetia/Vytorin-related troubles, vis-a-vis 2-plus years of media coverage, were epitomized in an end-of-year article by Forbes reporter Matthew Herper—who showed his continued disdain for the drugs and their marketing in a less-than-objective synopsis of results from relevant clinical trials.

Herper and others like him have 2 more years to capitalize on the controversies surrounding Zetia and Vytorin. At that time, results of the long-running IMPROVE-IT study, in which Vytorin is compared with simvastatin monotherapy in at-risk adults, will be available. The primary and major secondary endpoints in this study aren't surrogate markers, like LDL and CIMT, but actual clinical events. 

ARBITER 6-HALTS = ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis; CIMT = carotid intima-media thickness; ENHANCE = Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia; HDL = high-density lipoprotein; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis; SHARP = Study of Heart and Renal Protection.

Public-domain image of Hamilton-Burr duel, which admittedly took place in New Jersey (not New England), from Wikipedia.

12/22/09 update: The FDA says it's "unlikely" that Vytorin and Zetia increase the risk of cancer; although the agency can't rule out the possibility, according to today's WSJ. The agency's announcement comes after its own review of cancer data from the SEAS trial.

Never missing an opportunity to engage in a Zetia (aka ezetimibe) pile-on, Forbes reporter Matthew Herper shows his continued disdain for the drug and its marketing in his most lopsided article yet. Herper's less-than-objective synopsis of Merck's Zetia-related troubles follows results of a recent, small head-to-head study, in which Abbott's Niaspan (extended-release niacin) outperformed Zetia in a highly selected population.

The essential problem with Herper's (and others') coverage of Zetia: He fails to stress that the drug significantly lowers LDL cholesterol—a well-recognized risk factor for vascular disease and a primary target of prevention guidelines. Herper is correct in writing, "No trials show that [Zetia] prevents heart attacks"; but he neglects to remind his readers that, at one time, the same could have been said of Pfizer's blockbuster statin Lipitor (atorvastatin).

Lipitor came to market in 1996 because it significantly lowered LDL-C; but Lipitor had not yet been shown to prevent clinical vascular events like other statins. Nevertheless, Lipitor quickly became the number-one statin because 1) it reduced LDL-C by a relatively greater percentage than other statins and 2) clinicians believe that the LDL-C level is directly related to the risk of vascular events. Lipitor wasn't approved to reduce the risk of vascular events until 2004.

Herper claims, "Merck's clever marketers have spun straw into gold"—a metaphor that wrongly equates the lowering of the LDL-C level with worthless "straw." To support his claim, he cites results of the Niaspan study and the infamous ENHANCE study, both of which enrolled highly selective at-risk populations and used another surrogate marker for vascular disease—the ultrasound measurement of carotid intima media thickness (CIMT). Merck (and Schering-Plough) reportedly struggled with the quality of the CIMT measurements in the ENHANCE study, and some investigators have questioned the usefulness of CIMT generally to assess cholesterol-lowering drugs. For instance, in the placebo-controlled CASHMERE trial, Lipitor failed to significantly alter CIMT in postmenopausal women, despite that fact that the statin undeniably reduces the risk of cardiac events and stroke.

Herper adds Zetia-disparaging quotes from prominent cardiologists, like Sanjay Kaul (who described Zetia as "the miracle of marketing, not the miracle of medicine") and renowned Zetia/Vytorin basher Steve Nissen ("We've spent billions on a drug that may turn out to be a placebo.") Herper also implicitly chastises Merck for waiting 3 years after Zetia approval (in 2002) to begin the IMPROVE-IT study, in which Vytorin (the combination of ezetimibe and simvastatin) is being compared with simvastatin alone to reduce the risk of a composite vascular outcome. Vytorin was FDA approved in 2004.

Herper also unfairly casts aspersions at prominent cardiologists Michael H. Davidson and Antonio M. Gotto, Jr, for providing "lecture and consulting" services to Merck after the results of the ENHANCE study became public. Herper implies that these physicians were paid off to promote the drug, despite the fact that the small and troubled ENHANCE study failed to show the benefit of adding Zetia to statin therapy in a highly select group of patients (ie, individuals with familial hypercholesterolemia). Herper's information was evidently supplied by the office of Senator Grassley, ranking minority member of the Senate Finance Committee.

A quick examination of the medical literature reveals that both physicians (like so many others) endorse the vascular benefits of lowering the LDL-C level. For instance, in a recent editorial, Gotto writes, "Lowering elevated [LDL-C] is a surefire way to reduce cardiovascular risk." But he also acknowledges the potential drawbacks of using surrogate markers to assess the protective benefits of drugs by adding, "As monotherapy, [Zetia] at 10 mg reduces LDL-C by approximately 17%, but when added to any dose of statin, it reduces LDL-C by an additional 25%. Given the well-established log-linear relationship between LDL-C and relative risk for [coronary heart disease], these greater degrees of LDL-C reduction can be expected to result in improved clinical outcomes, although this has not yet been proven in the case of ezetimibe."

In another editorial ("Is LDL-C passed its prime?"), Davidson more clearly lays out the shortcomings of applying general guidelines to what is probably a very heterogenous at-risk population. He notes that the rising number of patients with metabolic syndrome and those currently taking statins present more complex portraits of dyslipidemia and its associated vascular risks. He argues that, in these subgroups, other lipid markers—like apoB, LDL-particle number, and non-HDL levels—become relatively more predictive of coronary heart disease. Consequently drugs that specifically affect these levels (for example, niacin) may be more protective in these specific populations.

CASHMERE = Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein.

According to yesterday's WSJ, stock analysts are speculating that Abbott's extended-release niacin (Niaspan) outperformed ezetimibe (Zetia; Merck/Schering-Plough) in a phase 4 head-to-head atherosclerosis study that was terminated early in June. The NIH clinical-trials web site indicates that an independent steering committee stopped the trial on the basis of results from a prespecified, blinded interim analysis and adds that the study was not stopped because of safety concerns.

The principal investigators are otherwise mum, advising that the trial results will be presented in mid-November at the Scientific Sessions of the American Heart Association. But the logical conclusion is that one drug significantly outperformed the other; stock analysts are placing their bets on Niaspan, possibly because the study is cosponsored by Abbott.*

The randomized, open-label, 2-center study, abbreviated ARBITER 6-HALTS, was designed to compare the effects of raising the HDL level (with Niaspan) with those of lowering the LDL level (with Zetia) at 14 months. The primary endpoint, as in the notorious ENHANCE study, was the mean change in the intima-media thickness of the common carotid artery (CIMT). (Presumably all enrollees received statin therapy; so Niaspan and Zetia were add-on medications.)

It's important to note that the NCEP ATP III guidelines stress the lowering of the LDL level as the primary target of cholesterol-altering therapy. Therefore Abbott has a vested interest (and an uphill battle) in showing that raising the HDL level with Niaspan is just as good as, or possibly better than, lowering the LDL level with Zetia. In a previous, placebo-controlled study, ARBITER 2 (N = 167), Niaspan reduced the rate of CIMT progression when added to statin therapy in high-risk patients who did not have insulin resistance; however, the drug did not appear to alter the risk of cardiovascular events at 1 year.

Unlike ARBITER 6-HALTS, ARBITER 2 was placebo controlled, and study drugs were assigned in a double-blind fashion. A drawback of both trials is the fact that the primary endpoint, the mean change in CIMT, is merely a surrogate marker for clinical cardiovascular outcomes.

ARBITER 6-HALTS = ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NCEP ATP III = Third Adult Treatment Panel of the National Cholesterol Education Program.

* The other cosponsor is the Walter Reed Army Medical Center.

At least according to the FDA.

The agency announced yesterday that patients should not stop taking Vytorin (ezetimibe/simvastatin) or any other cholesterol-lowering medication on the sole basis of the ENHANCE trial results. The conclusion follows the FDA's review of the final trial report, in which the combo drug was no better than simvastatin alone for reducing carotid intima-media thickness (CIMT) at 2 years. However, the LDL cholesterol level dropped 56% with Vytorin and 39% with simvastatin alone—a statistically significant difference.

The FDA maintains that an elevated LDL cholesterol level is an important risk factor for cardiovascular disease and that lowering the LDL level reduces that risk. The FDA also speculated as to why a larger reduction of the LDL level with Vytorin was not associated with a significantly reduced CIMT in the ENHANCE trial*:

• Because the ENHANCE population had received prior lipid-altering or statin therapy, subjects demonstrated relatively normal CIMT values at baseline, which made it harder to demonstrate a CIMT difference with Vytorin therapy.
• The duration of the ENHANCE trial, 2 years, was too brief to demonstrate a difference in CIMT with therapy.
• Unknown effects of ezetimibe may negate the beneficial effects of LDL lowering on CIMT.

The FDA advises that the much larger, ongoing IMPROVE-IT study, which pits Vytorin against simvastatin alone and has a primary composite endpoint of cardiovascular events and stroke, should provide more definitive information about the clinical benefits of the drug. The trial, however, won't be completed until 2012.

* The FDA doesn't mention previously reported problems with the CIMT data in the ENHANCE trial, such as missing or biologically implausible data.

ENHANCE = Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein.

So much for looking forward. The new year begins here with leftover business—namely, leftover Vytorin business.

In this year's brand-spanking-new issue of the NEJM, cardiologist and consistent Vytorin critic Steven Nissen officially charges that September's ezetimibe-cancer analysis of Sir Richard Peto et al, in which the authors concluded that the cancer risk with ezetimibe is not increased, "raises disturbing scientific and ethical questions." The Peto analysis was performed in response to a finding in the SEAS trial that ezetimibe, one half of the combo Vytorin pill, may increase the risk of cancer. However, Peto et al found that unblinded adverse-event data from the much larger, ongoing SHARP and IMPROVE-IT studies did not confirm the finding.

Among his criticisms of the Peto analysis, Nissen cites the following in his correspondence:

• The premature unblinding of the ongoing trials, which is "not a reliable approach to the evaluation of drug safety."
• The insufficient exposure to ezetimibe in IMPROVE-IT for assessing drug hazards.
• The failure of Peto et al to report the relative risk of cancer mortality in the 2 studies.
• The limited statistical power of the 2 studies to assess the risk of cancer death with ezetimibe.

Elsewhere Nissen has argued that data from all 3 studies should have been combined to assess cancer risk with the drug.

In their reply, Peto and coauthor Rory Collins stress the importance of separating data in a hypothesis-generating trial—in this case, the SEAS trial—from data in hypothesis-testing studies. They implicitly rationalize the unblinding of cancer data from SHARP and IMPROVE-IT by noting that these are the only large, randomized data sets from which relevant cancer data may be obtained to confirm any increased risk with ezetimibe. They also cite the magnitude of these studies in relation to the SEAS trial; together SHARP and IMPROVE-IT generated 4 times as many cancers as the SEAS trial, but their data did "not suggest any increase in cancer incidence."

Peto and Collins also correct Nissen in his mistaken charge that the authors did not report the relative risk of cancer mortality (and the associated 95% confidence interval) in SHARP and IMPROVE-IT. (The data were right there in the Fig. 4 legend.) Although there were more deaths due to cancer with ezetimibe in the analysis, the difference was not statistically significant (P = .07).

Last, although Nissen did not allege an industry-related conflict of interest by Peto et al (and Nissen's hardly in a position to do so), Peto and Collins, both from the UK, cite their not-so-dispassionate response to the US Congressional Committee on Oversight and Investigations, which raised the issue.

IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis; SHARP = Study of Heart and Renal Protection.

Public-domain image of Hamilton-Burr duel, which admittedly took place in New Jersey (not New England), from Wikipedia.

 ...before looking forward.

Pathophilia's Top 10 Medical Stories of 2008: A Recap

10. Gunvalson v. PTC Therapeutics

9. California v. Roozrokh and Cardiac-Death Organ Donation

8. Hand, Foot, and Mouth Disease in China

7. Continuing Backlash Against Pharma

6. Media Obsession With Delayed Results of ENHANCE Trial

5. Investigational Drugs for Alzheimer's Disease Disappoint

4. Milder Rotavirus Season Coincides With Vaccine Uptake

3. USAMRIID Scientist Identified as Sole Perpetrator of "Anthrax Letter Attacks"

2. Resurgence of Measles

1. Intentional Drug and Food Tampering in China

Other notable stories of 2008 that didn't make Pathophilia's totally arbitrary list:

• More cases of progressive multifocal leukoencephalopathy (PML) with Tysabri (natalizumab) use
• Pig-slaughter neuropathy
• US government compensates Poling family for vaccine-related autism
• Ted Kennedy diagnosed with glioblastoma multiforme

The comarketers of the cholesterol-lowering combo pill Vytorin (ezetimibe/simvastatin) received a protracted and very public comeuppance in 2008—primarily for delaying the negative and controversial results of a relatively small study of the drug in patients with familial hypercholesterolemia.

Unfortunately for Merck and Schering-Plough, most medical reporters and bloggers viewed the delayed publication of the ENHANCE trial results—which failed to show a reduction in carotid plaque with Vytorin use—as highly suspect. Moreover, the negative results were taken as an indicator of the drug's inability to reduce cardiovascular events in a general at-risk population, and prescriptions plummeted.

The companies' explanation for the delay—namely, that missing or implausible carotid ultrasound data* in the ENHANCE trial had to be accommodated—was viewed as unfair to the trial's principal investigator, John Kastelein. With respect to the trial's clinical implications, little was settled in the professional or public arena when the ENHANCE data were simultaneously presented at the annual meeting of the American College of Cardiology and published in the NEJM in the spring.

In April, Senator Chuck Grassley fired off inquiries to the company CEOs, which instigated a kind of journalistic pile-on from the likes of Matthew Herper at Forbes, Ed Silverman at Pharmalot, and the WSJ Health Blog gang. And the schadenfreude ante was upped when, in September, the industry-sponsored SEAS trial failed to show that Vytorin reduced major cardiovascular events in patients with aortic valve or atherosclerotic disease. To add insult to injury, the data suggested an increased risk of cancer with Vytorin treatment. (However, this latter finding was not supported by a meta-analysis of cancer data from 2 other, ongoing Vytorin studies.)

While the primary endpoint in the ENHANCE trial rests entirely on the validity of the ultrasound measurement of carotid intima-media thickness (CIMT), some investigators question the usefulness of CIMT to assess cholesterol-lowering drugs. In the placebo-controlled CASHMERE trial, Pfizer's Lipitor (atorvastatin) failed to significantly alter CIMT in postmenopausal women, despite that fact that Lipitor undeniably reduces the risk of cardiac events and stroke.

These facts may portend a positive outcome in IMPROVE-IT, a comparison of Vytorin with simvastatin alone to reduce the primary composite endpoint of major coronary events, stroke, or cardiovascular death. However, IMPROVE-IT won't be completed until July 2012.

It is with some embarrassment that an inordinate number of Vytorin posts at this blog were dug up for background reading:

• ENHANCE Study: Basically, the Ultrasound Images Were Crap
• ENHANCE Study: More Much Ado About Suboptimal Data
• ENHANCE Study: Frustration With Trial and Coverage of It
• SP Share Price, Insider Trading, and the ENHANCE Timeline: Now in Fancy Graphs
• ENHANCE E-Mail Exchange: Dear John, John, and...Rick
• ENHANCE Study: The Thing That Wouldn't Leave...the Blogosphere
• Pfizer Attempts to Capitalize on Vytorin's Limited Indications: Oh, the Irony
• Another ENHANCE Panel: Still No Discussion of "Missing" or "Implausible" Data
• Independent Reviewer: ENHANCE Data "Not Acceptable"
• Then and Now: Quality Differences in ENHANCE Data
• Media Retain Big Anti-Jones for ENHANCE, Schering-Plough, and Fred Hassan
• Negative Lipitor Data Raise Doubt About CIMT
• Statins and Aortic Stenosis: Retrospective vs Prospective Study
• Vytorin Is Beaten Up Some More
• Need a Negative Vytorin Quote? Call Dr. Nissen
• Pols Piss Off Peto

* Specifically the carotid intima-media thickness (CIMT).

CASHMERE = Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis.

In a public letter dated September 16, Oxford statistician Richard Peto wrote heated responses to questions from US Representatives John Dingell (D-MI) and Bart Stupak (D-MI) about the clinical investigation of Vytorin (ezetimibe/simvastatin; Merck/Schering-Plough). The congressmen's questions, many of which imply professional collusion between Peto and Merck/Schering-Plough, were originally submitted to the drugmakers in letters dated August 21 and September 2.

In his response, Peto seemed to be particularly vexed by the request that the companies "make Dr. Peto available for a staff interview as soon as possible." In reply, Peto advised that "the companies have no control over him." However, Peto did offer his assistance as an epidemiologist and statistician to help the congressmen and their subcommittee (of Oversight and Investigations) understand "statistically appropriate ways of interpreting the hypothesis-generating and hypothesis-testing data sets from trials."

Peto is referring specifically to his and others' recent analysis of cancer data from the ongoing Vytorin studies SHARP and IMPROVE-IT. The analysis was conducted in response to an observed association between the drug and cancer rates in the completed SEAS trial (background here). The conclusion of the analysis of Peto et al, which was recently published in the NEJM, is that there is "no credible evidence" that Vytorin (and in particular, ezetimibe) affects cancer rates.

The debate generated from the NEJM analysis rests on whether data from the 3 studies should have been combined to assess the potential cancer risk with Vytorin, as advocated by US cardiologist Steven Nissen, or whether it is inappropriate to lump data from the hypothesis-generating trial (SEAS) with data from the hypothesis-testing trials (SHARP and IMPROVE-IT), as urged by Peto and "any competent trial statistician."

In response to several questions regarding the NEJM analysis, Peto advised the congressmen, more or less, to read the article. Peto further declared that the analysis was undertaken independently of the drug companies and was coordinated by his Oxford colleague Rory Collins, in agreement with the various chairs of the Data Monitoring and Steering Committees of SHARP and IMPROVE-IT.

Other requests from the congressmen were answered with sharp rebukes, including a request for all correspondence between Peto's department, the Clinical Trial Service Unit (CTSU) at Oxford, and Merck or Schering-Plough. Peto replied that this request seems "to constitute inappropriate harassment," given that CTSU has conducted 4 major independent trials of Merck's cholesterol-modifying drugs for more than 10 years. Peto also denied the existence of a "secret" FDA report of his cancer analysis; nor did he send any advance drafts of the study results to Merck or Schering-Plough.

In a curious postscript, Peto requested that the subcommittee declare its own potential conflicts of interest, suggesting that Dingell, in particular, may hold a personal grudge against Peto and the CTSU. In 1997, Peto and others published an article in Controlled Clinical Trials, in which they described the procedures of the subcommittee in its investigation of the National Surgical Adjuvant Breast and Bowel Project (NSABP) as "inappropriate" and Dingell's statements as prosecutorial.

IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis; SHARP = Study of Heart and Renal Protection.

Photograph of Richard Peto from CTSU website.

Anyone who has followed the Vytorin soap opera, from the troubled ENHANCE study to reports of cancer in the SEAS study, can recognize a pattern. Cardiologist Steven Nissen is certainly available to more than one media outlet for more than one derisive, highly quotable quote about the drug, the drug's studies, or the drug's comarketers (Merck and Schering-Plough).

That's not to say that Dr. Nissen isn't entitled to a scathing opinion...or two, or three, or more. However, the subtext of vitriol in these running opinions, as quoted by the media, suggests that Dr. Nissen's thoughts on anything related to Vytorin are informed by something more than dispassionate assessment—at least in my opinion.

For instance:

On the negative results of the simvastatin-controlled ENHANCE study in patients with heterozygous familial hypercholesterolemia (in which a substantial percentage of the carotid-ultrasound data were allegedly missing or of low quality).

To Alex Berenson of the NYT: "Shocking...This is as bad a result for the drug as anybody could have feared."

To CBS News: "My advice to physicians is not to use this drug Vytorin, nor to use Zetia [ezetimibe], as first-line agents any more. These should be really relegated to drugs of last resort, until we have some evidence that they produce a health-outcomes benefit...Right now, 5 years into this, with nearly 1 million prescriptions per week being written, there is no evidence that the drugs actually produce any benefit for patients."

To the Washington Post/HealthDay: "This wraps it up. That's all there is. There just isn't any evidence that adding ezetimibe to simvastain produces any advantage."

To Forbes: "This drug [Vytorin] doesn't work. Period. It just doesn't work."

On the FDA's approval of Vytorin, which was based on a statistically significant 20% lowering of LDL cholesterol, when compared with simvastatin alone. 

To Alex Berenson (again) of the NYT: "The FDA set the bar too low on the initial approval [of Vytorin]. It would have been a lot better if the agency had said, 'Show us that you do more than lower LDL a little bit; show us evidence of effectiveness.'"

On evidence of an increased cancer risk in the SEAS trial and lack thereof in the ongoing studies of SHARP and IMPROVE-IT (background post here).

To Dow Jones Newswires: "Even though they [SHARP and IMPROVE-IT] are shorter," they nearly reached a statistically significant link to cancer. "They definitely do not rule it out."

To Bloomberg: "There is clearly a signal for excess cancer and cancer mortality in SEAS. I do not believe that unblinding 2 incomplete trials to try to refute that signal is scientifically appropriate. The bottom line is we just don't know if ezetimibe is associated with an increased incidence of cancer or cancer mortality."

To Forbes: "What you're seeing here is the behavior of a company that is under siege by the failure to do the right studies. And they're trying to spin the results using media-relations strategies rather than the proper scientific approach...I think those studies [SHARP and IMPROVE-IT] should never have been unblinded. That's very regrettable."

But Dr. Nissen did provide at least one quotable caveat for patients who may act on medical information (or physicians' quotes) in the lay press.

To CBS News: "People should talk to their doctor. No one should stop taking medication because they hear a news report."

2006 photo of Steven Nissen testifying at the Hearing on Building a 21st Century FDA.

The Vytorin-cancer scare resurfaces with the simultaneous presentation of data from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial at the annual congress of the European Society of Cardiology (ESC) and the online publication of study results in the NEJM. Accompanying the NEJM article are an analysis of cancer data from 3 Vytorin studies (including the SEAS trial) led by biostatistician (Sir) Richard Peto and a cautionary editorial headed by the journal's Jeffrey Drazen.

Peer-reviewed results from the prospective, randomized, double-blind, placebo-controlled SEAS trial (N = 1873) are consistent with those in a Merck/Schering-Plough press release from July (previous post here). Namely Vytorin did not reduce the relative risk of the primary endpoint, major cardiovascular events associated with aortic valve or atherosclerotic disease, at a median follow-up of 52.2 months. Moreover, cancer (but not cancer deaths) occurred significantly more often in Vytorin-treated patients (105 vs 70; P = .01). The latter finding was driven by a significantly higher incidence of (unspecified) skin cancer with Vytorin treatment (18 vs 8; P = .08).

In their analysis of the cancer data, Peto et al compared the rate of cancer in the SEAS trial (mean follow-up, 4.1 years) with unblinded cancer data from 2 larger, ongoing Vytorin studies, SHARP (N = 9264) and IMPROVE-IT (N = 11,353). Data from the SEAS trial revealed an increase in new cancer from several sites with Vytorin treatment in this analysis (105 vs 65), but there was no increase in the risk of cancer overall or at a particular site in SHARP and IMPROVE-IT (313 vs 326). When combining data from these 2 studies, cancer deaths were nonsignificantly increased with Vytorin treatment (97 vs 72; P = .08). But Peto et al argue that any increase in the risk of cancer death should be accompanied by an increased risk of cancer, which was not observed.

In their editorial, Drazen et al advise caution when interpreting the cancer analysis of Peto et al given the relatively short follow-up times of SHARP and IMPROVE-IT (2.7 and 1.0 years, respectively), despite that fact that these studies are much larger than the SEAS trial. The editorial also notes that Peto et al have received research funding from Merck and Schering-Plough (intimating some kind of conflict of interest), although the cancer analysis was performed independently of the companies.

Forbes's Matthew Herper, an avid follower of the Vytorin story, covers the clinical divide created by these recently presented data (a divide that has arguably been fomented by media outlets like Forbes). At the center of the cancer controversy is how Vytorin, and specifically the ezetimibe component, might increase the risk of cancer. Some argue that the drug may block the absorption of anticancer plant sterols, reports Herper, a touchy-feely explanation that MD Anderson's biostatistician Donald Berry* finds "pretty weak."

Another debate is whether it's statistically sound to pool cancer data from all 3 studies, SEAS, SHARP, and IMPROVE-IT, in which case there are significantly more cancer deaths with ezetimibe treatment than placebo or simvastatin (Zocor) treatment. According to Forbes, cardiologist Steven Nissen, who's made a national name for himself by performing inherently problematic meta-analyses, advocates the act; statisticians Peto and Berry advise against it—possibly because of substantial differences in the designs of these studies.

Debate will undoubtedly continue, given the results of the SEAS trial and a fervent interest in anything remotely anti-Vytorin. In the meantime, Merck and Schering-Plough are left with the very difficult task of proving a negative—namely that ezetimibe is not associated with an increased risk of cancer or cancer deaths. Even if clinical doubt could be removed by positive, final data from SHARP or IMPROVE-IT, these data won't be available for at least 2 years.

IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SHARP = Study of Heart and Renal Protection.

* Berry was cited in a previous post on drug-testing stats.