Statins and Aortic Stenosis: Retrospective vs Prospective Study

By bmartin on July 22, 2008 8:47 AM | Permalink

The fact can never be emphasized sufficiently: The results of retrospective, observational studies do not necessarily predict the outcomes of prospective trials.

Case in point is the missed primary endpoint in the prospective, placebo-controlled SEAS trial, in which the combination of ezetimibe and simvastatin (Vytorin; Schering-Plough/Merck) failed to reduce major cardiovascular events associated with aortic valve or atherosclerotic disease. These results follow those of 2 double-blind, placebo-controlled studies of atorvastatin (Lipitor; Pfizer) in aortic stenosis (AS) (see here and here), which also showed that the cholesterol-lowering drug did not alter AS progression.

The proposal that statins may alter the course of AS isn't a bad one, given the association between hypercholesterolemia, coronary artery disease, and atheroma. And in fact, several retrospective, observational studies showed that statin therapy delayed AS progression, as measured by hemodynamics and valvular calcification. But the idea, clearly, has not been realized to date in prospective evaluations.*

Two other interesting results of the SEAS trial, according to the press release, are 1) a significant reduction of the secondary endpoint of atherosclerotic events (nonfatal MI, CABG, PCI, hospitalization for unstable angina, nonhemorrhagic stroke, and cardiovascular death); and 2) a significant and unexplained increase in the incidence of cancer (9.9% vs 7.0%; P = .02).

The former result may portend a positive outcome in IMPROVE-IT, a comparison of ezetimibe/simvastatin with simvastatin alone to reduce the primary composite endpoint of major coronary events, stroke, or cardiovascular death. As far as a potential cancer risk is concerned, an independent analysis of the data from IMPROVE-IT and another ezetimibe/simvastatin study, SHARP, revealed that the overall risk of cancer is not increased with the drug.

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

* A prospective study of rosuvastatin in AS is ongoing. Results are expected at the end of the year.

Update: Over at the Disease Management Care Blog, Jaan Sidorov considers the blogger-fomented Vytorin-cancer scare and says, more or less, "Drink your juice, Shelby."