Call it the Vytorin Scandal, Part Two. Last month, we learned that University of Oxford researchers, who were running a trial of the Vytorin cholesterol pill in 9,438 people with chronic kidney disease, attempted to change the composite endpoint, which would make it easier to show positive results. Merck (MRK), however, resisted, having absorbed the lessons three years ago when controversy erupted after an attempt to move the primary endpoint prompted lawsuits and investigations (see this).
Over the weekend, the next shoe fell. The Oxford researchers and Merck released results of the latest trial, called Sharp, which ran more than four years and was designed to test whether Vytorin could help prevent cardiovascular disease in people with chronic kidney disease. The trial found that 15 percent of Vytorin patients and 18 percent of patients on a placebo had a heart attack, stroke, stent procedure, or cardiovascular death. This amounts to a 16 percent reduction in risk, which Merck prominently noted in its (press release).
The Oxford press release, though, told a different and very skewed story. In their own statement, the researchers trumpted that “around a quarter of all heart attacks, strokes, and operations to open blocked arteries could be avoided in people with chronic kidney disease by using the combination of ezetimibe (Zetia) and simvastatin (Zocor) to lower blood cholesterol levels.” Where did this figure come from? They offered a scenario based on a pie-in-the-sky outcome that would presumably result if each patient had taken Vytorin for the entire trial (see the last line of the last slide).
At the same time, they never mention the primary endpoint. Moreover, the Oxford researchers maintain that Vytorin is more beneficial than Zocor, or Simvastatin, alone. “The Sharp results,” they write, “are also relevant to people who don’t have chronic kidney disease.” But that turns out to be a fallacy. Why? The Sharp trial fails to offer such a conclusion, because the trial primarily compared Vytorin with a placebo.
As Harlan Krumholz, a Yale University School of Medicine professor, writes us: The study
leaves open the two questions that needed answering: whether statins or lipid lowering by other means is effective in patients undergoing dialysis - and whether (Zetia) adds to the risk reduction of a statin. The trial cannot answer these questions since there was too small a dialysis group to determine whether this strategy was effective in that group alone - and there was no comparison with a statin. So it is impossible to know if the combination of simvastatin and (Zetia) provided any additional benefit to a statin by itself…Overall, it is a study that will leave many confused about its implications for practice.
Ironically, it was Merck (and Schering-Plough (SGP), its former Vytorin partner that is now owned by Merck) that was hammered for distortions when the scandal first erupted. Now, the Oxford researchers stand accused of questionable conduct. “The ‘breathless’ Oxford press release sent to media in advance of the presentation was highly misleading and resulted in many news stories that distorted the benefits of this therapy and minimized its risks,” Steve Nissen of the Cleveland Clinic Foundation writes us, adding that, among Vytorin patients, there was higher all cause mortality (24.6 percent versus 24.1 percent), more hemorrhagic strokes (45 vs. 37), and more cancer deaths (150 vs. 128). As CardioBrief puts it:
It’s a model of a press release that tries to manipulate the reader to adopt its view of the trial and ruthlessly suppresses all information and perspective that doesn’t support its view.
Wall Street wags, meanwhile, view the results as a pleasant surprise, at least for Merck…
They “were about as good as they could have been,” writes Sanford Bernstein analyst Tim Anderson in a note. And Leerink Swann analyst Seamus Fernandez wrote in his own note that regulators will probably approve Vytorin for the additional indication. Nonetheless, the upside is likely to be modest, given that Vytorin was damaged by the scandal and faces a big challenge next year when generic Lipitor debuts. Even the results of Merck’s Improve-It trial, which directly compares Vytorin to simvastatin in patients with acute coronary syndrome, may not make much difference because the outcomes won’t be known until 2013, writes Deutsche Bank’s Barbara Ryan.