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LOS ANGELES -- The novel drug dalcetrapib substantially boosts HDL levels but with no impact on outcomes and a signal for blood pressure problems, according to results from a phase III trial in patients with recent acute coronary syndromes.

The combined risk of death from heart disease, nonfatal MI, ischemic stroke, hospitalization for unstable angina, and resuscitated cardiac arrest wasn't any lower than with placebo -- a hazard ratio of 1.04 (P=0.52) -- despite the 30% improvement in HDL with the drug, Gregory G. Schwartz, MD, PhD, of the VA Medical Center and University of Colorado in Denver, and colleagues found.

The 0.6 mm Hg higher mean systolic blood pressure seen with dalcetrapib was one possible explanation put forward.

The dal-OUTCOMES trial in patients with a prior acute coronary syndrome was reported here at the American Heart Association meeting and simultaneously online in the New England Journal of Medicine.

These interim results led to early termination of the trial and any further development of dalcetrapib, as drugmaker Roche announced earlier this year.

The drug was the first in the new generation of cholesteryl ester transfer protein (CETP) inhibitors with hard outcome data in phase III, but its dramatic failure doesn't necessarily reflect impending doom for the other candidates, cardiologists here argued.

"There is a concern the tiny blood pressure signal could be a class effect," noted Alan Tall, MD, of Columbia University in New York City, discussant for the trial at the late-breaking clinical trial session and related press briefing.

However, "in pretty big studies already done with anacetrapib and evacetrapib, [there was] no trace of that," he explained.

"It's important to note that the two remaining players in the field are really quite different. They lower LDL quite extensively, they lower VLDL [very low density lipoprotein], and they really raise HDL a lot more than dalcetrapib did."

The Class

CETP helps move cholesterol from HDL to atherogenic LDL, so blocking it is expected to have a positive impact on cardiovascular risk.

All agents in the class to varying degrees boost HDL, which, while still not well understood, appears to move cholesterol out of the blood vessels and back to the liver for excretion.

The class has had to contend with the specter of its predecessor torcetrapib, which failed due to excess mortality blamed on off-target effects on blood pressure and the renin-angiotensin-aldosterone system.

Phase II results with the new CETP inhibitors -- evacetrapib, anacetrapib, and dalcetrapib -- suggested no reason for worry.

Phase III data in the DEFINE trial with anacetrapib were promising as well. Its 40% drop in LDL and 138% increase in HDL compared with placebo came with no price for blood pressure, electrolytes, or aldosterone levels.

That trial was not powered for clinical endpoints but found a reassuring, albeit slight, advantage for anacetrapib in the composite rate of death from cardiovascular causes, MI, hospitalization for unstable angina, and stroke (16 versus 21 events, or 2.0% versus 2.6%).

A phase III outcomes trial, dubbed REVEAL, is under way with anacetrapib but isn't expected to produce data for years.

All of that isn't necessarily a guarantee of a smooth path ahead, Schwartz cautioned, pointing out that phase II trials suggested no blood pressure concerns for dalcetrapib either.

"The findings in the dal-OUTCOMES trial indicate how important it is to do large phase III trials to detect small but perhaps important signals of safety," he told reporters.

"The fact that anacetrapib and evacetrapib in studies of about 1,000 or 1,500 patients have not shown adverse effects on blood pressure does not mean that phase III trials of much larger scale might end up showing something similar."

The findings also raise the question of mechanism.

"Each of these molecules is different," Schwartz noted. "Dalcetrapib had no impact on LDL; evacetrapib and anacetrapib have substantial effects on LDL. So it's conceivable that the HDL effects could be bystander effects and that those drugs will prove to be effective because of their actions on LDL cholesterol."

Failure Analysis

The dal-OUTCOMES trial included 15,871 patients ages 45 or older with recent acute coronary syndromes randomized to double-blind treatment with dalcetrapib at 600 mg or placebo. The trial was terminated at a median 31 months of follow-up.

Participants had to be on treatment for LDL cholesterol, but there were no entry criteria for HDL cholesterol.

The lack of difference in the primary composite endpoint (9.2% versus 9.1% with placebo) was mirrored by nearly identical results between groups for each of the components with P-values of 0.16 to 0.97.

Notably, there was no association between baseline HDL and subsequent risk of events.

"With that knowledge, it's not surprising perhaps that an intervention that raised HDL cholesterol did not influence the cardiovascular risk," Schwartz noted.

Tall pointed out a connection with the AIM-HIGH trial, in which HDL raising by a more modest 15% with niacin failed to have any impact on outcomes in otherwise well-treated patients.

It may have been that patients were just too well-treated already for there to be an impact, Tall proposed.

"A high level of bad cholesterol and its effects on cells may be necessary to see an effect from so-called good cholesterol," he suggested.

Another possibility is that CETP inhibition produces dysfunctional HDL that isn't as effective at reverse cholesterol transport, Tall added, although studies on CETP inhibitor-treated and genetically deficient individuals haven't borne that out.

While the study showed no effect of dalcetrapib on plasma aldosterone, bicarbonate, or potassium, high-sensitivity C-reactive protein levels were slightly but significantly higher with the drug at 3 months (a difference of 0.2 mg/L versus placebo, P<0.001).

CRP elevations were also seen in DEFINE with anacetrapib and could indicate inflammation, Tall noted. But "in my opinion, the clinical significance of such a small change in CRP is questionable," he argued.

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