But these were prespecified secondary outcome measures. Succinobucol failed to achieve a significant impact on the primary end point, a composite of “hard” atherosclerotic outcomes and the “soft” end points of coronary revascularization and hospitalization for unstable angina, said Dr. Tardif, professor of medicine at the University of Montreal and director of research at the Montreal Heart Institute.

 “I'm pretty bullish,” added Dr. Marc A. Pfeffer, ARISE co-principal investigator. “We're all looking for the next step [in cardiovascular risk reduction], and I think this is as promising as anything I've seen in terms of developments.”

“We didn't hit our primary end point, but we're the ones who established that primary. We made it more inclusive. We wish we hadn't, we wish we'd made it the firmer one, but there it is. The firm end points are there, and the diabetes effect was pretty profound. If we can come back here with another study aiming specifically at those end points and we can show positive results, then that would be the highest compliment for a clinical trial—it would change the practice of medicine. That's our aim,” said Dr. Pfeffer, professor of medicine at Harvard Medical School, Boston.

The 6,144 ARISE participants were randomized to 300 mg/day of succinobucol or placebo for a mean of 2 years starting shortly after hospitalization for an acute MI or unstable angina. All were deemed at high risk for further atherosclerotic events. Rates of utilization of secondary preventive therapies were high: 90% of patients were on a statin at baseline, 80% on a β-blocker, 92% on aspirin, and 74% on an ACE inhibitor or angiotensin receptor blocker.

At baseline, 37% of subjects had diabetes, with a mean HbA1c of 7.2%. Among the other nearly 4,000 participants, the incidence of new-onset diabetes was 4.2% with placebo and 1.6% with succinobucol, a 64% relative risk reduction. In patients with diabetes at entry, succinobucol resulted in a mean 0.5% lower HbA1c than placebo did at 12 months, and an improvement in fasting blood glucose. The combined “hard” secondary atherosclerotic end point of cardiovascular death, cardiac arrest, MI, or stroke occurred in 8.2% of the placebo group and 6.7% with succinobucol, for a significant 19% relative risk reduction.

The chief side effect of succinobucol was diarrhea, reported by 23% of patients, although only one in seven of those affected discontinued the study. The incidence of liver function abnormalities was similar to that with placebo.

Discussant Dr. Robert A. Harrington, director of cardiovascular clinical trials at the Duke Clinical Research Institute, Durham, N.C., said ARISE sends mixed signals, including unwelcome trends toward more heart failure hospitalizations, lower HDL, and higher LDL. Succinobucol, a potent lipophilic antioxidant, is the monosuccinic acid ester of probucol. The drug's appeal, he said, is that it operates by mechanisms not changed by conventional risk factors such as blood pressure and lipids.

Presented by Dr. Jean-Claude Tardif at the American College of Cardiology Annual Scientific Session, New Orleans, LA, March 2007.

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