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 - Darapladib


The goal of the trial was to evaluate darapladib, a selective lipoprotein-associated phospholipase A2 inhibitor (Lp-PLA2), on biomarkers of cardiovascular risk in patients with stable coronary heart disease.


Darapladib will be more effective in reducing biomarkers of cardiovascular risk.

Study Design

Study Design:

Patients Screened: 1,410
Patients Enrolled: 959
Mean Follow Up: 12 weeks
Mean Patient Age: 63
Female: 29

Patient Populations:

• Age 18-80 years with stable coronary heart disease or risk equivalents
• Risk equivalents were defined as diabetes, carotid stenosis >50% or prior carotid revascularization, peripheral arterial disease, or 10-year Framingham risk score >20%


• Cardiovascular event or vascular procedure within the preceding 6 months
• Contraindication to atorvastatin therapy
• Serum triglycerides >200 mg/dl
• Elevated liver tests
• Hemoglobin A1c >10%
• Chronic inflammatory disease
• Uncontrolled hypertension
• Renal dysfunction (creatinine >2.5 mg/dl)
• Congestive heart failure (New York Heart Association functional class III or IV)
• Prolonged QTc interval (>440 ms for men or >450 ms for women)

Primary Endpoints:

Change in plasma Lp-PLA2 activity

Secondary Endpoints:

Change in lipid profile, inflammatory biomarkers, and platelet-related biomarkers

Drug/Procedures Used:

Patients with stable coronary heart disease or risk equivalents were initially randomized to 4 weeks of atorvastatin 20 mg versus 80 mg after a 2-week run-in period of atorvastatin 20 mg. Patients who tolerated atorvastatin therapy were then randomized to 12 weeks of darapladib (160 mg, n = 238; 80 mg, n = 239; 40 mg, n = 240) or placebo (p = 242).

Concomitant Medications:

At baseline, the use of antiplatelet agents (aspirin, clopidogrel, or ticlopidine) was 83%, atorvastatin was 100%, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was 68%, and beta-blockers was 48%.

Principal Findings:

At baseline, 49% of participants were diabetics, body mass index was 30 kg/m2, low-density lipoprotein (LDL) cholesterol was 67 mg/dl, and hemoglobin A1c was 6.7%.

The mean Lp-PLA2 was 123 nmol/min/ml. Higher Lp-PLA2 activity was associated with older age, men, nondiabetics, LDL cholesterol ≥70 mg/dl, high-density lipoprotein (HDL) cholesterol <40 mg/dl, low-dose atorvastatin, and peripheral vascular disease.

At 12 weeks, Lp-PLA2 activity was 43 nmol/min/ml with the 160 mg darapladib dose, 56 nmol/min/ml with the 80 mg dose, 68 nmol/min/ml with the 40 mg dose, and 124 nmol/min/ml with placebo (p < 0.001 for all doses compared with placebo).

Darapladib did not affect total cholesterol, LDL cholesterol, HDL cholesterol, or triglycerides. There was no treatment modification of darapladib on Lp-PLA2 according to LDL cholesterol (p = 0.12), HDL cholesterol (p = 0.13), or atorvastatin dose (p = 0.60). Darapladib 160 mg decreased interleukin-6 by 12.3% compared with placebo (p = 0.028). Cardiovascular events were 1% in the darapladib 160 mg group, <1% in the 80 and 40 mg groups, and 2% in the placebo group.


Among patients with stable coronary heart disease or risk for coronary heart disease, darapladib is beneficial in reducing Lp-PLA2 activity at 12 weeks. In this dose-finding study, all tested doses of darapladib reduced Lp-PLA2 activity; however, the effect appeared to be strongest in the 160 mg group. LDL cholesterol, HDL cholesterol, and atorvastatin dose did not modify the effect of darapladib. This agent also reduced interleukin-6 compared with placebo. Importantly, there were no serious adverse events noted in this relatively large patient population at 12 weeks of follow-up.

Since elevated Lp-PLA2 activity has been associated with adverse cardiovascular events, darapladib may ultimately prove to have clinical utility. The effect of darapladib on intravascular ultrasound endpoints, IBIS-2, is currently being studied.


Mohler ER III, Ballantyne CM, Davidson MH, et al., on behalf of the Darapladib Investigators. 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.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Statins

Keywords: Follow-Up Studies, Cholesterol, LDL, Interleukin-6, Peripheral Arterial Disease, Risk Factors, Heptanoic Acids, Pyrroles, Benzaldehydes, Oximes, Hemoglobins, Body Mass Index, Biological Markers, Phospholipase A2 Inhibitors, Pyrrolidines, Cholesterol, HDL, Carotid Stenosis, Triglycerides, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Diabetes Mellitus

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