A drug designed to increase high-density lipoprotein (HDL) cholesterol levels failed to reduce the risk of recurrent cardiovascular events in patients with an acute coronary syndrome (ACS). The findings were presented Nov. 5 as a late-breaking clinical trial at the American Heart Association (AHA) scientific sessions in Los Angeles and simultaneously published online in the New England Journal of Medicine.

Gregory G. Schwartz, MD, PhD, chief of cardiology at Denver Veterans Affairs Medical Center in Colorado, and colleagues conducted the Phase 3 dal OUTCOMES (The Effects of the Cholesteryl Ester Transfer Protein Inhibitor Dalcetrapib in Patients with Recent Acute Coronary Syndrome) trial to evaluate the effects of the drug dalcetrapib (Roche) on cardiovascular risk in patients who had a recent ACS. Dalcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor, a class of drug that blocks the transfer of cholesterol from HDL to low-density lipoprotein (LDL), and has been associated with higher levels of HDL.

Phase 2 studies of dalcetrapib demonstrated that the drug raised HDL levels by approximately 30 percent. But Schwartz and colleagues noted that it remained uncertain if raising HDL levels by targeting CETP led to decreased cardiovascular risk in these patients.

For the study, they enrolled 15,871 patients from 935 sites in 27 countries between 2008 and 2010 who had a recent ACS. Patients were randomized to receive ether 600 mg daily dose of dalcetrapib or a placebo. All patients also received the best available evidence-based care. The primary efficacy endpoint was a composite of death from coronary heart disease, a major nonfatal coronary event or ischemic stroke.

The mean baseline LDL cholesterol level was 76 mg per deciliter, with 86 percent of the patients with a level of 100 mg per deciliter or lower. The mean HDL cholesterol level was 42 mg per deciliter;  the mean apolipoprotein A1 level was 137 mg per deciliter; and the mean apolipoprotein B level was 81 mg per deciliter.

The study was terminated for futility in May at the recommendation of an independent data and safety monitoring board. Patients were followed for a median of 31 months.

Schwartz and colleagues found that HDL cholesterol levels increased from baseline by 4 to 11 percent in the placebo group compared with 31 to 40 percent in the dalcetrapib group. The drug had a minimal effect on LDL cholesterol levels, though. Dalcetrapib did not alter the risk of the primary endpoint compared with placebo (8.3 percent vs. 8 percent) and had no significant effect on any component of the primary endpoint or on total mortality.

The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib compared with placebo.

“Despite the finding that dalcetrapib, as compared with placebo, produced a substantial increase in HDL cholesterol levels, it had no significant effect on major cardiovascular outcomes, including the rate of death from coronary heart disease and the rates of myocardial infarction, ischemic stroke, unstable angina, cardiac arrest with resuscitation and unanticipated coronary revascularization,” they wrote.

In a release, Schwartz summarized the possible explanations for their findings. “It’s possible that when patients are treated with all these risk-reducing drugs, HDL cholesterol level is no longer a risk factor,” he said. “It’s also possible that HDL is protective in healthy persons, but is altered in patients with heart disease so that it no longer serves the same protective function. Or, it may be that the specific way that dalcetrapib raises HDL is not advantageous.”

The researchers noted that other CETP inhibitors have been associated with modest increases in C-reactive protein levels and blood pressure, but because those drugs and dalcetrapib have dissimilar structures, “the composite findings may indicate adverse effects of CETP inhibition, rather than specific off-target effects of individual agents,” they wrote.

“It remains possible that agents that inhibit CETP and raise HDL cholesterol levels to a greater degree than did dalcetrapib and that also lower LDL cholesterol levels will prove to have clinical effects different from those of dalcetrapib,” they concluded.

The trial was supported by F. Hoffmann-LaRoche.