Editor's Note: Commentary based on STABILITY Investigators, White HD, Held C, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med 2014;370:1702-11.

Background

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂), also known as platelet-activating factor acetylhydrolase, is an enzyme produced by inflammatory cells. Lp-PLA₂ predominantly travels with low-density lipoprotein (LDL) in the serum but can also be produced within atherosclerotic plaque and hydrolyzes oxidized phospholipids on LDL, generating pro-inflammatory and pro-apoptotic mediators. A large meta-analysis from 32 prospective studies involving over 79,036 individuals  demonstrated a positive correlation between Lp-PLA₂ levels and the risk of coronary heart disease and stroke.¹ Darapladib is an oral reversible inhibitor of Lp-PLA₂ that was shown in preclinical studies on swine to reduce Lp-PLA₂ levels, decrease inflammatory effects of macrophages and T lymphocytes, and resulted in stabilizing characteristics in atherosclerotic plaque.² In early randomized placebo-controlled trials, darapladib demonstrated a significant reduction in Lp-PLA₂ levels by 60-66% at a 160 mg daily dose.^3,4 However, the therapy only resulted in a modest reduction in interleukin-6 levels by 12.3% (p=0.03) and a non-significant 13% reduction in high-sensitivty C-reactive protein.3 In a trial assessing the impact of darapladib on atheroma progression in patients with documented coronary artery disease (CAD), darapladib again had no impact on high-sensitivity C-reactive protein and the development of atheroma volume measured by intravascular ultrasound, but did significantly halt necrotic core formation compared with placebo.⁴ This study suggested that while darapladib did not attenuate the progression of atheroma, it may lead to stabilization of atherosclerosis by halting necrotic core formation. Given these findings, a large double-blind placebo-controlled multicenter randomized controlled trial (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy [STABILITY]) was initiated in patients with stable CAD to assess whether darapladib, when added to optimal medical therapy, can significantly reduce major adverse cardiovascular and cerebrovascular events (MACCE).

Methods

Patients were randomly assigned to once-daily placebo or darapladib 160 mg, which was estimated to lower LPA₂ levels by 60%. Patients were eligible for inclusion if they had coronary heart disease (prior myocardial infarction [MI], prior percutaneous coronary intervention [PCI], prior coronary artery bypass graft [CABG], or multivessel CAD) and at least one of the following: 1) Age >60 years, 2) Diabetes mellitus on pharmacotherapy, 3) HDL <40 mg/dL, 4) recent or current smoker, 5) moderate chronic kidney disease, or 6) peripheral arterial disease. Patients were excluded if they had an upcoming  planned revascularization or major surgery, liver disease, severe kidney disease, prior nephrectomy or kidney transplant, NYHA class III or IV, or severe asthma. Patients were followed in clinic and with telephone follow-up. Providers were encouraged to prescribe optimal medical therapy. The primary endpoint of the study was cardiovascular death, MI, or stroke. The secondary endpoints were major cardiovascular events including death from coronary disease, MI, and urgent revascularization for ischemia. Additional secondary endpoints were total coronary events including death from coronary heart disease, MI, hospitalization for unstable angina, and coronary revascularization procedures

Results

A total of 15,828 patients were randomly assigned to placebo or darapladib 160 mg daily between December 2008 to April 2010 and completed a median follow-up of 3.7 years. Baseline patient characteristics were similar between groups and typical of patients with stable coronary heart disease. The primary endpoint occurred in 9.7% of patients in the darapladib group and 10.4% of patients in the control group (hazard ratio 0.94, 95% confidence interval 0.85-1.03, p =0.20).  There was not a reduction in cardiovascular death (HR 0.96[0.83-1.11], p = 0.59), stroke (1.01 [0.81-1.27], p = 0.92), or MI (HR 0.89 [0.77-1.03], p = 0.11).  The combined endpoints of major coronary events (HR 0.90 [0.82-1.00], p=0.045) and total coronary events (HR 0.91 [0.84-0.98], p = 0.02) were significantly reduced in patients taking darapladib, which was largely driven my non-fatal MI. Patients taking darapladib were more likely to discontinue the study drug than those taking placebo due to diarrhea, unpleasant odor, and a small but significant increase in renal failure.

Conclusion

The STABILITY trial demonstrated that darapladib failed to significantly reduce the primary endpoint of MACCE or its individual components of cardiovascular death, myocardial infarction, or stroke. There was a very modest reduction in the secondary endpoints of major coronary events and total coronary events.

Commentary/Perspective

This study highlights the importance of prospective randomized controlled trials to assess novel therapeutics with positive translational data. The concept of suppressing inflammation to reduce cardiovascular events is an area of active research and holds great potential. However, the modest benefit seen with darapladib in early studies should have raised concern that the drug may not result in a significant reduction in MACE.^3,4 The Stabilization of Plaque Using Darapladib–Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) study was another large placebo-controlled, double-blind randomized controlled trial that randomized 13,026 patients with non–ST-elevation MI (NSTEMI) and ST-elevation MI (STEMI) to darapladib 160 mg daily or placebo control on the background of optimal medical therapy following ACS.⁵ The study demonstrated no significant reduction in MACE nor a reduction in all-cause mortality or other secondary endpoints. Given the results of STABILITY and SOLID-TIMI 52, the author of this review does not believe there is a place for darapladib amongst the already large number of medications prescribed for patients with CAD. However, the author of this review still believes in the promise of anti-inflammatory therapy for CAD and eagerly await the results of upcoming trials on anti-inflammatory therapies.

References:

1. Thompson A, Gao P, Orfei L, et al. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet 2010;375:1536-44.
2. Wilensky RL, Shi Y, Mohler ER, 3rd, et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 2008;14:1059-66.
3. Mohler ER, 3rd, Ballantyne CM, Davidson MH, et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A₂ activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2008;51:1632-41.
4. Serruys PW, Garcia-Garcia HM, Buszman P, et al. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008;118:1172-82.
5. O'Donoghue ML, 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;312:1006-15.

Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase, Angina, Unstable, Asthma, Benzaldehydes, Coronary Artery Bypass, Coronary Artery Disease, C-Reactive Protein, Diabetes Mellitus, Diarrhea, Hospitalization, Inflammation, Interleukin-6, Lipoproteins, LDL, Myocardial Infarction, Oximes, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Phospholipase A2 Inhibitors, Plaque, Atherosclerotic, Renal Insufficiency, Chronic, Stroke, Telephone

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