Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy - STABILITY

Sep 02, 2014
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
GlaxoSmithKline
Date Presented:
01/01/2014
Date Published:
01/01/2014
Date Updated:
09/02/2014
Original Posted Date:
09/02/2014
References

Description:

Darapladib is a novel oral lipoprotein phospholipase A2 (Lp-PLA2) inhibitor with favorable effects on atherosclerotic lesions in animal studies. It is considered to be a potent anti-inflammatory agent by interfering with arachidonic acid metabolism. The current trial sought to study the safety and efficacy of darapladib in patients with chronic coronary artery disease (CAD).

Hypothesis:

Darapladib would be superior to placebo in reducing adverse cardiovascular events in patients presenting with chronic CAD on optimal medical therapy.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel
  • Stratified

Patient Populations:

  • Established chronic CAD (prior MI >1 month, prior coronary revascularization, multivessel CAD) with:
    - Age ≥60 years
    - Diabetes requiring pharmacotherapy
    - High-density lipoprotein <40 mg/dl
    - Current smoker or former smoker within 3 months (≥5 cigarettes/day)
    - Significant renal dysfunction (estimated glomerular filtration rate 30-59 ml/min/1.73 m2 or urine ACR ≥3 mg albumin/g creatinine)
    - Polyvascular disease (cerebrovascular disease or peripheral arterial disease)

    Number of enrollees: 15,828
    Duration of follow-up: 3.7 years
    Mean patient age: 65 years
    Percentage female: 19%

Exclusions:

  • Planned coronary revascularization
  • Current liver disease or severe renal impairment
  • Current severe heart failure
  • Poorly controlled hypertension
  • Severe asthma that is poorly controlled
  • History of anaphylaxis, anaphylactoid reactions, or severe allergic responses
  • Concomitant cytochrome P-450 inhibitor use
  • Lp-PLA2 activity ≤20.0 nmol/min/ml

Primary Endpoints:

  • Composite of cardiovascular death, MI, or stroke

Secondary Endpoints:

  • Major coronary events, total coronary events

Drug/Procedures Used:

Patients were randomized in a 1:1 ratio to treatment with darapladib (160 mg/d) or matching placebo.

Concomitant Medications:

At randomization: aspirin (93%), thienopyridine (34%), and beta-blockers (79%)

Principal Findings:

A total of 15,828 patients were randomized, 7,924 to darapladib and 7,904 to placebo. Baseline characteristics were fairly similar between the two arms. Approximately 20% were current smokers, 34% had diabetes, and 15% had polyvascular disease. Qualifying CAD diagnosis was prior myocardial infarction (MI) in 59%, coronary revascularization in 75%, and multivessel disease in 15%. The median baseline low-density lipoprotein was 80 mg/dl (≥100 mg/dl in 26%). Drug discontinuation was reported in nearly 30% of all patients in both arms.

Over a median follow-up of 3.7 years, the primary outcome of cardiovascular mortality, nonfatal MI, or nonfatal stroke was similar between the darapladib and placebo arms (9.7% vs. 10.4%; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.85-1.03; p = 0.20). The composite secondary outcome of major coronary events (cardiovascular mortality, MI, urgent coronary revascularization) was lower in the darapladib arm (9.3% vs. 10.3%; HR, 0.90; 95% CI, 0.82-1.00; p = 0.045), as was the composite of cardiovascular death, MI, any coronary revascularization, and hospitalization for unstable angina (14.6% vs. 16.1%, p = 0.02). Other outcomes including cardiovascular death (4.5% vs. 4.7%), MI (4.6% vs. 5.1%), and mortality (7.3% in both arms) were similar. Rates of adverse events including renal failure were similar.

Patients were stratified based on baseline Lp-PLA2 levels. Higher levels portended worse outcomes. Darapladib reduced Lp-PLA2 levels by 65%. However, there was no differential effect of darapladib on outcomes compared with placebo in the three Lp-PLA2 groups.

Interpretation:

The results of the STABILITY trial indicate that inhibition of Lp-PLA2 and sustained lowering of its levels with darapladib was not associated with an improvement in the primary endpoint of cardiovascular death/MI/stroke at a median of 3.7 years in patients with established CAD, as compared with placebo. However, some of the secondary endpoints that included a need for coronary revascularization were significantly lower. It is possible that this drug might have potential benefit in specific subsets (such as smokers), and will need to be further prospectively explored in future studies.

Recently, the results of the VISTA-16 trial with varespladib were presented. Unlike darapladib, which inhibits Lp-PLA2, varespladib is a nonselective inhibitor of secretory PLA2. In VISTA-16, varespladib was similarly not efficacious for the primary endpoint compared with placebo in patients with recent acute coronary syndrome. Moreover, there was a higher MI risk with varespladib. That signal was not observed in the current trial, and it is unclear if the different targets of action (secretory vs. lipoprotein-associated PLA2) might be responsible for this difference. Other trials with Lp-PLA2 inhibitors (such as SOLID-TIMI 52) are ongoing.

References:

Presented by Dr. Lars Wallentin at the European Society of Cardiology Congress, Barcelona, Spain, September 2, 2014.

The STABILITY Investigators. Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease. N Engl J Med 2014;370:1702-11.

Presented by Dr. Harvey D. White at the American College of Cardiology Annual Scientific Session, Washington, DC, March 30, 2014.

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Follow-Up Studies, Peripheral Arterial Disease, Creatinine, Lipoproteins, LDL, Benzaldehydes, Renal Insufficiency, Oximes, Phospholipases A2, Indoles, Phospholipase A2 Inhibitors, Glomerular Filtration Rate, Confidence Intervals, Diabetes Mellitus, ESC Congress


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