Jean Claude Tardif1,2,3, Marc A Pfeffer4, Simon Kouz5, Wolfgang Koenig6,7,8, Aldo P Maggioni9, John J V McMurray10, Vincent Mooser11, David D Waters12, Jean C Grégoire1, Philippe L L'Allier1, J Wouter Jukema13,14,15, Harvey D White16, Therese Heinonen17,18, Donald M Black17,18, Fouzia Laghrissi-Thode17,18, Sylvie Levesque3, Marie Claude Guertin3, Marie Pierre Dubé1,2. 1. Department of Medicine, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, PQ, H1T1C8Canada. 2. Beaulieu-Saucier Pharmacogenomics Centre, Université de Montréal, Montreal, Canada. 3. The Montreal Health Innovations Coordinating Center (MHICC), Montreal, Canada. 4. Department of Medicine, The Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 5. Department of Medicine, Centre Hospitalier Régional de Lanaudière, Joliette, Canada. 6. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany. 7. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. 8. Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany. 9. ANMCO Research Center, Florence, Italy. 10. Department of Medicine, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. 11. Department of Medicine, McGill University, Montreal, Canada. 12. Division of Cardiology, San Francisco General Hospital. 13. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. 14. Netherlands Heart Institute, Utrecht, The Netherlands. 15. Department of Medicine, Durrer Center for Cardiovascular Research, Amsterdam, The Netherlands. 16. Green Lane Cardiovascular Unit, Auckland City Hospital, University of Auckland, New Zealand. 17. DalCor Pharmaceuticals, Montreal, Canada. 18. DalCor Pharmaceuticals, Sarasota, FL, USA.
Abstract
AIMS: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. METHODS AND RESULTS: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). CONCLUSION: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. CLINICAL TRIAL REGISTRATION: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.
AIMS: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. METHODS AND RESULTS: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). CONCLUSION: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. CLINICAL TRIAL REGISTRATION: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.
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