Prevention of Coronary Artery Disease with Lipoprotein-Associated Phospholipase A2 Inhibitor
Measurement of Lp-PLA2, an inflammatory enzyme expressed in atherosclerotic plaques that independently predicts future vascular events, improves global classification of risk. Previous studies have shown that Lp-PLA2 inhibitor reduces Lp-PLA2 activity and cardiovascular biomarkers and decreases the plaque expansion among patients with stable coronary artery disease. To date, however, no prospective outcome trial has directly addressed the question of whether lowering Lp-PLA2 activity with Lp-PLA2 inhibitor in persons with elevated Lp-PLA2 activity reduces the incidence of coronary artery disease.
The primary objective of our study is to investigate whether treatment with Lp-LA2 inhibitor, as compared with placebo, decreases the rate of first major cardiovascular events.
A randomized, double-blind, placebo-controlled, multi-center trial.
Selection of Participants (criteria, recruitment, number)
Coronary screening clinics will be established in primary medical care facilities throughout the United States and Canada. Men 50 years of age or older and women 60 years of age or older will be invited to attend the clinics to assess their coronary risk factors. Persons who have at least one of the following coronary risk factors: hypertension, hypercholesterolemia, diabetes, smoking, peripheral vascular disease and family history of premature coronary artery disease, are eligible for the trial if they do not have a history of cardiovascular disease and if, at the initial and second screening visit, they have a mean Lp-PLA2 level of 200 ng/ml or more. Exclusion criteria are evidence of hepatic or renal dysfunction, severe congestive heart failure, current life-threatening condition and a recent history of alcohol or drug abuse or another medical condition that might compromise safety or the successful completion of the study. All potentially eligible subjects undergo a 4-week run-in phase during which they receive placebo to identify a group of willing and eligible participants who demonstrate good compliance (defined as the taking of more than 80% of all study tablets) during that interval. Only subjects who successfully complete the run-in phase will be enrolled.
Eligible subjects will be randomly assigned in a 1:1 ratio to receive either Lp-LA1 inhibitor, SB-677116, 160 mg daily, or matching placebo. Follow-up visits will be scheduled to occur at 12 weeks and then 6, 12, 24, 30, 36, 42, 28, 54, and 60 months after randomization. A closeout visit will occur after study termination. Follow-up assessments includes laboratory evaluations, pill counts, structured interviews by physicians blinded to the allocation assessing outcomes and potential adverse events. Measurements of Lp-PLA2 levels, lipid levels, hepatic and renal function, blood glucose levels, and hemoglobin A1c values will be performed. Personnel at each sited also contact their participants midmay between scheduled visits to evaluate their well-being and to maintain study participation.
Outcome (definition, information to be obtained)
The primary outcome is the occurrence of a first major cardiovascular events, defined as nonfatal myocardial infarction, hospitalization for unstable angina, or confirmed death from acute coronary syndrome. Secondary end points include the components of the primary end point considered individually - myocardial infarction, hospitalization for unstable angina, or death from acute coronary syndrome –as well as Lp-PLA2 activity, stroke, a coronary revascularization procedure, and death from any cause. All reported primary end points that occur through August 31, 2015, will be adjudicated on the basis of standardized criteria by an independent end-point committee unaware of the randomized treatment assignments. The progress and conduct of the study will be monitored regularly by the independent Data and Safety Monitoring Committee.
The target sample size required is approximately 6,000 men and women with at least one coronary risk factor to provide a statistical power of 90% to detect a 25% reduction in the rate of the primary end pint, with a two-sided significance level of 0.05. An additional 15 % is added to compensate for possible loss to follow-up. Pretrial estimates of the duration of follow-up and number of participants are based on event rate in earlier prevention trials.
All primary analyses will be performed on an intention-to-treat basis. The results of the two Lp-PLA2 values during visits 1 and 2 will be averaged to produce base-line values. The Lp-PLA2 results will be analyzed according to both the treatment actually received and ant the intention-to-treat principle. Study participation will be considered to be complete for any individual participant at the time he or she has an occurrence of the primary end pint, is unable to be followed, or is followed through at least August 31, 2015. The exposure time is calculated as the time between randomization and the first major cardiovascular event, the date of death, the date of the last study visit, the date of withdrawal or loss to follow-up, or August 31,2010, whichever comes first. For each end-point category, the exposure time to a first event will be compared with use of the log-rank test, ant the relation reduction in risk resulting from the treatment, with 95% confidence intervals, will be calculated with the Cox proportional-hazards model. In addition, Kaplan-Meier curves will be used to estimate the absolute risk of each event at five years for each treatment group. For the primary end point, an analysis will be performed for predefined subgroups characterized at base line according to sex, age, race, smoking status, hypertension, diabetes, hypercholesterolemia, peripheral vascular disease and baseline mean LpPLA2 activity.
1. Thompson, A., P. Gao, L. Orfei, et al., Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet, 2010. 375(9725): p. 1536-44.
2. Mohler, E.R., 3rd, C.M. Ballantyne, M.H. Davidson, 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(17): p. 1632-41.
3. Serruys, P.W., H.M. Garcia-Garcia, P. Buszman, et al., Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation, 2008. 118(11): p. 1172-82.
4. Shepherd, J., S.M. Cobbe, I. Ford, et al., Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med, 1995. 333(20): p. 1301-7.