SOLID-TIMI 52: Darapladib Fails to Reduce Adverse Events After ACS

BARCELONA, Spain—An oral enzyme inhibitor is ineffective at reducing major coronary events 30 days after an acute coronary syndrome (ACS) event, according to results presented on August 31, 2014, at the European Society of Cardiology Congress and simultaneously published in the Journal of the American Medical Association.

“Overall, as we reflect upon these findings, it reinforces that despite a strong biologic hypothesis, compelling epidemiologic data, as well as imaging studies, ultimately large randomized clinical trials are required to evaluate the clinical efficacy of these novel therapeutics,” said presenter Michelle L. O'Donoghue, MD, MPH, of Brigham and Women's Hospital (Boston, MA).

Darapladib (GlaxoSmithKline; Brentford, England) is an enteric-coated lipoprotein-associated phospholipase A2 inhibitor that reduces enzyme activity in plasma and atherosclerotic plaques. The drug was not associated with an overall reduction of adverse events in patients with stable disease in the STABILITY trial, although it did nominally lowered the occurrence of major and total coronary events. 

Methods
For the SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52) study—conducted at 868 sites in 36 countries from December 7, 2009 to December 6, 2013—Dr. O’Donoghue and colleagues randomized 13,026 patients (median age 64 years; 74.5% male) within 30 days of hospitalization for ACS to either oral darapladib (160 mg daily; n = 6,504) or placebo (n = 6,522). All patients also had at least 1 additional predictor or cardiovascular risk.
Baseline characteristics were well balanced between the study arms. The qualifying event was most commonly STEMI (45.2%), followed by NSTEMI (42.7%) and unstable angina (12.2%). In total, 86.0% of patients underwent cardiac catheterization and 76.6% underwent PCI before randomization; 46.1% had been taking a statin for at least 8 weeks prior to randomization. 


After a median follow-up of 2.5 years (31,167 total patient-years), both the primary endpoint (coronary heart disease death, MI, or urgent coronary revascularization at 3 years) and secondary endpoint (cardiovascular death, MI, or stroke) occurred at similar rates in the study and control arms. There were also no differences in all-cause mortality or any individual components of the primary and secondary endpoints (table 1).

Table 1. Three-Year Outcomes

 

Darapladib

(n = 6,504)

Placebo

(n = 6,522)

HR (95% CI)

P Value

Primary Endpoint

16.3%

15.6%

1.00 (0.91-1.09)

.93

CV Death, MI, or Stroke

15.0%

15.0%

0.99 (0.90-1.09)

.78

All-Cause Mortality

7.3%

7.1%

0.94 (0.82-1.08)

.40

CV Death

4.6%

4.7%

0.91 (0.76-1.08)

.27

Stroke

2.5%

2.7%

1.12 (0.88-1.42)

.35

 

Results for the primary endpoint were maintained in prespecified subgroup analyses by age, region, renal dysfunction, and other comorbid conditions.

The incidence of any reported serious event was 45.5% for darapladib and 46.6% for placebo. Similarly, the rates of discontinuation due to any adverse event were 17% and 12%, respectively. Additionally, darapladib did not reduce the incidence of major coronary events through 12 months (HR 1.04; 95% CI 0.92-1.16) or longer (HR 0.94; 95% CI 0.81-1.09) compared with placebo. 

Compared with control patients, those in the study arm were more likely to report an odor-related concern (predominantly of the feces, urine, and skin; 11.5% vs 2.5%) and diarrhea (10.6% vs 5.6%). Blood pressure changes were similar between treatment groups with a trend observed in the study arm for slightly increased systolic blood pressure vs placebo (P = .01). Darapladib did not affect cholesterol or triglycerides.

No Future for Darapladib

Discussant Robert M. Califf, MD, of Duke University (Durham, NC), said, “I’m afraid that we would probably all agree that this is an example of a definitive result that this pathway with this drug and this dose does not have a future.”

However, he commended the study group on a well-done trial. “Every step was taken to provide modern clinical care for these patients,” he observed. “The background therapy was appropriate and randomization and outcomes were measured, including—almost totally—complete follow-up, a major feat in today’s global environment.” 

The fact that there is no evidence of harm with darapladib is “of little solace when there’s no benefit,” Dr. Califf observed. “And there doesn’t seem to be an off-target effect, so maybe there are other ways to attack other inflammatory pathways [that] could be found there for benefit. It’s also possible that the excellent background therapy made it impossible to see a beneficial effect, but since the background therapies are all generic, one would never propose that a new treatment that would be more expensive should take their place in the absence of demonstrated superior efficacy.”

Additionally, he said, very long-term follow-up cold possibly lead to answers for “something as chronic as coronary disease, but again there are other alternatives that seem more promising.” 

Ultimately, it is imperative to figure out how to reduce the cost of large trials, Dr. Califf said, “because [all] cardiovascular drug development requires evidence of benefit-risk balance.”
  
 


 

Source:
O'Donoghue M, Braunwald E, White HD, et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA. 2014;Epub ahead of print.

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Disclosures
  • SOLID-TIMI 52 was funded by GlaxoSmithKline.
  • Dr. O'Donoghue reports receiving institutional grants from AstraZeneca, Eisai, and GlaxoSmithKline; honoraria from diaDexus; and consulting fees from Aegerion
  • Dr. Califf reports consulting for GlaxoSmithKline and holding research contracts and stock with several pharmaceutical and device manufacturers.

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