Updated IMPROVE-IT results show bigger benefits

SAN DIEGO– The sensational initial presentation of the landmark IMPROVE-IT trial at last November’s AHA Scientific Sessions told only half the story of the actual clinical impact of lipid-lowering with the combination of ezetimibe and simvastatin as opposed to simvastatin alone.

That’s because the main analysis included only the first cardiovascular event patients experienced. Many participants with a nonfatal first event went on to have a second, third, or even a fourth event. And while additional events haven’t traditionally been counted in acute coronary syndrome clinical trials, they should be, Sabina A. Murphy said at the annual meeting of the American College of Cardiology.

^{Bruce Jancin/Frontline Medical News}

“All events, not just first events, are important to patients and clinicians. Total events have implications for patient morbidity, clinical management, need for recurrent hospitalization, and total costs,” said Ms. Murphy, head of biostatistics at the TIMI Study Group at Brigham and Women’s Hospital, Boston.

Analyses that include recurrent events are common in some other medical fields, including oncology and rheumatology, she added.

In last November’s initial findings from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), the combination of 10 mg ezetimibe/40 mg simvastatin (Vytorin) daily resulted in a modest yet statistically significant 6.4% relative risk reduction in the primary composite endpoint, compared with 40 mg of simvastatin alone, reported Dr. Christopher P. Cannon, professor of medicine at Harvard Medical School, Boston.

Most observers hailed this result as clinically important, since IMPROVE-IT was the first study to show that lowering cholesterol with a nonstatin reduces cardiovascular events, and it showed that the lower a patient’s LDL cholesterol, the better the outcomes: The mean LDL with combination therapy was 54 mg/dL, compared with 70 mg/dL in controls.

The double-blind study included 18,144 patients randomized within 10 days of an acute coronary syndrome. The primary composite outcome comprised cardiovascular death, nonfatal MI, nonfatal stroke, rehospitalization for unstable angina, and coronary revascularization. The 6.4% relative risk reduction was based solely on first events, of which there were 5,314 during a median 6 years of follow-up. But there were also 4,231 subsequent primary endpoint events, including 2,297 second events, 972 third events, and 456 fourth ones.

While 170 fewer first events occurred with combination therapy than with simvastatin alone, there were also 251 fewer additional or recurrent cardiovascular events in the ezetimibe/simvastatin group which were not incorporated in the initial analysis.

Here’s the key point: While the relative risk reduction for first primary endpoint events was 6.4% with combination therapy, the risk of additional events was reduced by 12%, resulting in a more substantial 9% relative risk reduction for total events.

For the prespecified secondary composite endpoint consisting of death due to coronary heart disease, nonfatal MI, or urgent coronary revascularization, the initial analysis based solely upon first events showed an 8.8% relative risk reduction with ezetimibe/simvastatin. But the fuller view includes a 21% reduction in the risk of additional events, resulting in a 15% relative risk reduction for total events during a median 6 years of follow-up.

In an exploratory analysis examining the harder endpoints of cardiovascular death, nonfatal MI, or cerebrovascular accident, the relative risk reduction for total events was 12% with combination therapy. Ezetimibe/simvastatin was associated with a 13% reduction in all nonfatal MIs occurring during follow-up and a 23% reduction in nonfatal strokes, according to Ms. Murphy. Among every 1,000 IMPROVE-IT participants on ezetimibe/simvastatin rather than simvastatin alone for 1 year there were 11 fewer total primary outcome events, including 5 fewer nonfatal MIs, 2 less nonfatal strokes, and 4 fewer revascularization procedures.

She reported serving as a consultant to Merck and receiving research grants from AstraZeneca, Daiichi Sanko, GlaxoSmithKline, and Merck.

bjancin@frontlinemedcom.com