Stabilization of Plaque Using Darapladib–Thrombolysis in Myocardial Infarction 52 - SOLID-TIMI 52

Aug 31, 2014
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, 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:
08/31/2014
Original Posted Date:
08/31/2014
References

Description:

The goal of the trial was to evaluate treatment with darapladib compared with placebo among participants within 30 days of an acute coronary syndrome (ACS). Darapladib is a direct lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor that reduces Lp-PLA2 activity in plasma and atherosclerotic plaques.

Hypothesis:

Darapladib will reduce adverse cardiovascular events.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Participants within 30 days of an ACS plus additional marker of cardiovascular risk defined as:
    - Age ≥60 years
    - Documented MI before qualifying ACS event
    - Chronic kidney disease (estimated glomerular filtration rate [eGFR] 30-59 ml/min/1.73 m2)
    - Diabetes requiring pharmacotherapy
    - Polyvascular disease (atherosclerosis in another vascular bed)

    Number of enrollees: 13,026
    Duration of follow-up: median 2.5 years
    Mean patient age: 64 years
    Percentage female: 26%

Exclusions:

  • No obstructive coronary disease
  • Planned coronary artery bypass grafting
  • Severe liver disease
  • Severe renal disease (eGFR <30 ml/min/1.73 m2)
  • Severe heart failure (New York Heart Association III-IV)
  • Life expectancy <2 years
  • Poorly controlled hypertension or asthma
  • History of anaphylaxis or severe allergic reaction

Primary Endpoints:

  • CHD death, MI, or urgent coronary revascularization for myocardial ischemia

Secondary Endpoints:

  • Cardiovascular death, MI, or stroke
  • Total coronary events
  • CHD death or MI
  • Any coronary revascularization
  • All-cause mortality
  • Individual components of the primary endpoint

Drug/Procedures Used:

Participants within 30 days of an ACS were randomized to darapladib 160 mg daily (n = 6,504) versus placebo (n = 6,522).

Concomitant Medications:

  • Aspirin: 96%
  • P2Y12 inhibitor: 88%
  • Statin: 94% (45% on high-potency statin therapy)
  • Beta-blocker: 87%
  • Angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker: 83%

Principal Findings:

Overall, 13,026 patients were randomized. The median age was 64 years, 26% were women, mean body mass index was 28 kg/m2, 19% were current smokers, 31% had a prior myocardial infarction (MI), and 35% had diabetes. The qualifying event was unstable angina in 12%, non-ST-segment elevation MI (NSTEMI) in 43%, and STEMI in 45%. Percutaneous coronary intervention was performed in 77%. The median low-density lipoprotein cholesterol was 75 mg/dl.

At a median of 2.5 years, the primary outcome of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia occurred in 16.3% of the darapladib group versus 15.6% of the placebo group (p = 0.93). There was possible treatment interaction by gender (p = 0.04): Men appeared to favor treatment with darapladib, while women appeared to favor treatment with placebo.

CHD death: 3.8% vs. 4.2% (p = 0.16), respectively
MI: 10.3% vs. 10.2% (p = 0.63), respectively
Urgent coronary revascularization: 4.2% vs. 3.6% (p = 0.36), respectively
Cardiovascular death, MI, or stroke: 15.0% vs. 15.0% (p = 0.78), respectively

Serious adverse events were similar between the groups; however, any odor-related concern was more common in the darapladib group (11.5%) vs. the placebo group (2.5%), and diarrhea was more common in the darapladib group (10.6%) vs. the placebo group (5.6%).

Interpretation:

Among patients with recent ACS, darapladib was not associated with a reduction in adverse cardiovascular events compared with placebo. In the STABILITY trial, among patients with stable CHD, darapladib was also not associated with a reduction in adverse cardiovascular events compared with placebo. Among patients receiving standard medical therapy, Lp-PLA2 does not appear to be a favorable therapeutic target to reduce adverse events.

References:

O’Donoghue ML, Braunwald E, White HD, et al., on behalf of the SOLID-TIMI 52 Investigators. Effect of Darapladib on Major Coronary Events After an Acute Coronary Syndrome: The SOLID-TIMI 52 Randomized Clinical Trial. JAMA 2014;Aug 31:[Epub ahead of print].

Presented by Dr. Michelle O’Donoghue at the European Society of Cardiology Congress, Barcelona, Spain, August 30, 2014.

Keywords: Myocardial Infarction, Stroke, Acute Coronary Syndrome, Odorants, Plaque, Atherosclerotic, Cholesterol, LDL, Diarrhea, Coronary Disease, Percutaneous Coronary Intervention, Benzaldehydes, Lipoproteins, LDL, Oximes, Body Mass Index, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Diabetes Mellitus, ESC Congress


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