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STABILITY: Darapladib misses primary endpoint in stable CHD population
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WASHINGTON — In the STABILITY trial, darapladib did not significantly reduce the risk for CV death, MI or stroke in patients with stable CHD.
According to results presented at the American College of Cardiology Scientific Sessions, the primary endpoint of time to CV death, MI or stroke occurred in 9.7% of patients assigned once-daily darapladib compared with 10.4% of patients assigned placebo (HR=0.94; 95% CI, 0.85-1.03; P=.2) during a mean follow-up period of 3.7 years. Harvey D. White, MD, also reported no significant difference with darapladib or placebo in rates of individual components of the primary endpoint or all-cause mortality.
“The STABILITY trial is the first large-scale, randomized, global trial to test a novel mechanism of inhibition of inflammation in the atherosclerotic plaque,” White, director of the Coronary Care Unit, Green Lane Cardiovascular Unit, Auckland City Hospital, New Zealand, said at a press conference.
Harvey D. White
Darapladib (GlaxoSmithKline) is a selective, orally active inhibitor of lipoprotein-associated phospholipase A2, or LP-PLA2.
Researchers conducted the international, double blind, event-driven trial in 15,828 patients with stable CHD randomly assigned to once-daily darapladib 160 mg or placebo. The mean age of patients was 64 years, 19% were women, 59% had prior MI and 75% had prior coronary revascularization.
Other data presented suggest possible benefits for secondary coronary artery-related endpoints. Compared with placebo, darapladib reduced the rate of major coronary events (9.3% vs. 10.3%; HR=0.9; 95% CI, 0.82-1) and total coronary events (14.6% vs. 16.1%; HR=0.91; 95% CI, 0.84-0.98). The P values were .045 and .02, respectively.
“We believe there is a signal on coronary events, and we believe this is very important for patient care as we try and develop new treatments,” White said. However, he noted that this finding “needs to be interpreted cautiously in light of the main results not being significant.”
No major safety concerns arose during the trial.
Patients enrolled in STABILITY had a high rate of background care. At baseline, 93% were taking aspirin, 97% statins, 79% beta-blockers, and 79% ACE inhibitors or angiotensin receptor blockers.
“One of the messages from this trial is that you can achieve high rates of evidence-based medicine in clinical practice,” White said.
Further subgroup analyses based on biomarkers and genetics are ongoing to provide further insight on the potential effects of darapladib on coronary events in patients with stable CHD. Another phase 3 study, SOLID-TIMI 52, is evaluating darapladib in adults with ACS. Data from that study are forthcoming, according to the company.
“The STABILITY trial results indicate that darapladib warrants further evaluation in other clinical settings,” White said. – by Katie Kalvaitis
For more information:
White HD. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Sessions; March 29-31, 2014; Washington, D.C.
The STABILITY Investigators. N Engl J Med. 2014;doi:10.1056/NEJMoa1315878.
Disclosure: The trial was funded by GlaxoSmithKline. White reports no relevant financial disclosures.
Perspective
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Seth S. Martin, MD
The STABILITY results are interesting. The trial enrolled patients with a background of optimal medical therapy, with an impressive 96% of patients on statins at the end of the trial. The median LDL cholesterol was 78 mg/dL and mean BP was 132/77 mm Hg. One message I take away from this trial, and other recent trials, is that it is difficult to show a benefit when the patients are already well treated. The investigators were cautious to say there is a nominal improvement in secondary coronary artery-related endpoints; that was not the primary endpoint. Rather, they viewed the trial as hypothesis-generating.
The bottom line is disappointing — darapladib did not work for the primary endpoint — but one silver lining is the demonstration of effective implementation of optimal medical therapy. I’m hopeful that we’ll learn a lot in secondary analyses of the trial. I personally was curious to see the adverse effect results. When I was a resident at Duke, I was one of the site co-investigators during enrollment for this study. Back then, patients were complaining to me about odor. To see 5%, 6% and 9% of patients in the trial complain of abnormal skin, urine and feces odor was confirmatory of my experience.
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