Michelle L O'Donoghue1, Eugene Braunwald1, Harvey D White2, Dylan P Steen1, Mary Ann Lukas3, Elizabeth Tarka4, P Gabriel Steg5, Judith S Hochman6, Christoph Bode7, Aldo P Maggioni8, KyungAh Im1, Jennifer B Shannon9, Richard Y Davies4, Sabina A Murphy1, Sharon E Crugnale1, Stephen D Wiviott1, Marc P Bonaca1, David F Watson9, W Douglas Weaver10, Patrick W Serruys11, Christopher P Cannon1, Dylan L Steen. 1. TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. 2. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland University, Auckland, New Zealand. 3. Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Philadelphia, Pennsylvania. 4. Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania. 5. Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, and Université Paris-Diderot, Paris, France6NHLI Imperial College, ICMS Royal Brompton Hospital, United Kingdom. 6. Department of Medicine, NYU Langone Medical Center, New York. 7. Heart Center, Department for Cardiology and Angiology I, University of Freiburg, Freiburg, Germany. 8. ANMCO Research Center, Florence, Italy. 9. Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina. 10. Henry Ford Heart and Vascular Institute, Detroit, Michigan. 11. Erasmus University, Thoraxcentrum, Rotterdam, the Netherlands13International Center for Circulatory Health, Imperial College, London, United Kingdom.
Abstract
IMPORTANCE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE: To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event. DESIGN, SETTING, AND PARTICIPANTS: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries. INTERVENTIONS: Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. MAIN OUTCOMES AND MEASURES: The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years. RESULTS: During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%). CONCLUSIONS AND RELEVANCE: In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000727.
RCT Entities:
IMPORTANCE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE: To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event. DESIGN, SETTING, AND PARTICIPANTS: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries. INTERVENTIONS:Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. MAIN OUTCOMES AND MEASURES: The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years. RESULTS: During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%). CONCLUSIONS AND RELEVANCE: In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000727.
Authors: Philip Joseph; Amorina Ishai; Venkatesh Mani; David Kallend; James H F Rudd; Zahi A Fayad; Ahmed Tawakol Journal: Eur J Nucl Med Mol Imaging Date: 2016-10-13 Impact factor: 9.236
Authors: Tracey G Simon; Kathleen E Corey; Christopher P Cannon; Michael Blazing; Jeong-Gun Park; Michelle L O'Donoghue; Raymond T Chung; Robert P Giugliano Journal: Int J Cardiol Date: 2018-05-26 Impact factor: 4.164