Top 10 Medical Stories of 2008: No. 6

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.