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SOLID-TIMI 52: Darapladib after ACS did not lower risk for subsequent events
BARCELONA, Spain — After ACS, direct inhibition of lipoprotein-associated phospholipase A2 with darapladib failed to reduce the risk for coronary events when compared with placebo.
The SOLID-TIMI 52 trial included 13,026 patients (mean age, 64 years; 74.5% men) within 30 days of hospitalization with an ACS who were randomly assigned once-daily darapladib 160 mg (n=6,504) or matching placebo (n=6,522) along with guideline-recommended therapy. The phase 3, double blind, placebo-controlled study was conducted at 868 sites in 36 countries. Patients were followed for a median of 2.5 years.
According to data presented at ESC Congress by Michelle O’Donoghue, MD, MPH, during follow-up, the primary endpoint of major coronary events, defined as a composite of CHD death, MI or urgent coronary revascularization for myocardial ischemia, occurred in 16.3% of the darapladib (GlaxoSmithKline) group vs. 15.6% of the placebo group (HR=1; 95% CI, 0.91-1.09; P=.93). The researchers found no significant differences between the treatment groups in the incidence and number of events for the individual components of the primary endpoint.
Michelle O'Donoghue
“Similarly, there was a neutral effect on risk for the secondary endpoint, [a composite of] CV death, MI or stroke,” O’Donoghue, from the TIMI Study Group and cardiovascular division at Brigham and Women’s Hospital, said during a press conference. CV death, MI or stroke occurred in 15% of patients in the darapladib group vs. 15% of the placebo group at 3 years (HR=0.99; 95% CI, 0.9-1.09; P=.78).
At 3 years, there was also no difference in the rate of all-cause mortality: 7.3% in the darapladib group vs. 7.1% in the placebo group (HR=0.94; 95% CI, 0.82-1.08; P=.4).
Serious adverse events occurred at a similar rate in both groups, but the rate of therapy discontinuation was 17% in the darapladib group vs. 12% in the placebo group. Patients assigned darapladib were more likely than those assigned placebo to report an odor-related complaint (11.5% vs. 2.5%) and diarrhea (10.6% vs. 5.6%), which is consistent with previous studies and contributed to the higher rate of discontinuation, according to O’Donoghue. The incidence of cancers was also similar between the two groups.
“These findings do not support a role for lipoprotein-associated phospholipase A2 inhibition in patients after ACS,” she said.
This is the second large trial of darapladib that did not show benefit for this compound. Previously announced results of the STABILITY trial, which evaluated darapladib in patients with stable CHD, demonstrated that the drug also did not achieve the primary endpoint of CV death, MI or stroke, but was associated with reduction of major and total coronary events.
“Evidence continues to support a central role for inflammation in atherosclerosis. However, reliable surrogate endpoints are lacking to gain insight into drug efficacy prior to phase 3 testing,” O’Donoghue said. – by Katie Kalvaitis
For more information:
O’Donoghue ML. Hot Line II. Coronary Artery Disease and Lipids. Presented at: the European Society of Cardiology Congress; Aug. 30-Sept. 3, 2014; Barcelona, Spain.
O’Donoghue ML. JAMA. 2014;doi:10.1001/jama.2014.11061.
Disclosure: The trial was funded by GlaxoSmithKline. O’Donoghue reports receiving institutional grants from AstraZeneca, Eisai and GlaxoSmithKline; honoraria from diaDexus; and consulting fees from Aegerion.
Perspective
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I am afraid that we probably all agree that this is an example of a definitive result that shows that this pathway does not have a future. SOLID-TIMI 52 and STABILITY are the first trials looking at this novel inflammatory pathway, and there will be many other trials trying to tackle the issue of inflammation. SOLID-TIMI 52 and STABILITY are different populations and different pathophysiologies. Luckily, the results are quite consistent.
There doesn’t seem to be any evidence of harm, which is of little solace when there is no benefit. There doesn’t seem to be an off-target effect, so maybe other ways to attack other inflammatory pathways can be found as hope for benefit. It is actually possible that the excellent background therapies made it impossible to see a beneficial effect. Lp-PLA2 appears to be a risk marker, but maybe not an atherogenic risk factor. There is a remote possibility that very long-term follow-up could be required to deal with something as chronic as coronary disease, but there are other alternatives that seem more promising.
After all this, we can say that this drug does not reduce major events. We are left without a critical understanding of whether the pathway could possibly be a valid target, but certainly after this effort it is about as good as you can do in today’s environment. CV drug development requires evidence of minimal risk of outcomes; we have to figure out how to do large trials at the lowest possible cost because every new therapy will have to go through a test like this. This is a gamble where you must take many shots on goal to score a point. I congratulate the investigators on taking the risk. We didn’t win this one, but there will be other shots on goal that will score.