Top 10 for '09: No. 10

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.