Patrick M Moriarty1, Paul D Thompson2, Christopher P Cannon3, John R Guyton4, Jean Bergeron5, Franklin J Zieve6, Eric Bruckert7, Terry A Jacobson8, Stephen L Kopecky9, Marie T Baccara-Dinet10, Yunling Du11, Robert Pordy12, Daniel A Gipe12. 1. Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA. Electronic address: pmoriart@kumc.edu. 2. Hartford Hospital, Hartford, CT, USA. 3. Harvard Clinical Research Institute, Boston, MA, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, MA, USA. 4. Duke University Medical Center, Durham, NC, USA. 5. Lipid Clinic, Centre Hospitalier Universitaire de Québec, Laval University, Québec, Canada. 6. McGuire VA Medical Center, Richmond, VA, USA. 7. Groupe Hospitalier Pitié-Salpêtrière (Assistance Publique-Hôpitaux de Paris), Paris, France. 8. Department of Medicine, Emory University, Atlanta, GA, USA. 9. Mayo Clinic, Department of Cardiovascular Diseases, Rochester, MN, USA. 10. PCSK9 Development and Launch Unit, Sanofi, Montpellier, France. 11. Department of Biostatistics, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA. 12. Department of Clinical Sciences, Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
Abstract
BACKGROUND: Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol (LDL-C) concentrations. Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies. METHODS: ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms. A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance. Patients (n = 361) receivedsingle-blind subcutaneous (SC) and oral placebo for 4 weeks during placebo run-in. Patients reporting muscle-related symptoms during the run-in were to be withdrawn. Continuing patients were randomized (2:2:1) to double-blind alirocumab 75 mg SC every 2 weeks (Q2W; plus oral placebo), ezetimibe 10 mg/d (plus SC placebo Q2W), or atorvastatin 20 mg/d (rechallenge; plus SC placebo Q2W) for 24 weeks. Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values. Primary end point was percent change in LDL-C from baseline to week 24 (intent-to-treat) for alirocumab vs ezetimibe. RESULTS:Baseline mean (standard deviation) LDL-C was 191.3 (69.3) mg/dL (5.0 [1.8] mmol/L). Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38-0.99, P = .042). CONCLUSIONS:Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients, with fewer skeletal-muscle adverse events vs atorvastatin.
RCT Entities:
BACKGROUND: Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol (LDL-C) concentrations. Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies. METHODS: ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms. A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance. Patients (n = 361) received single-blind subcutaneous (SC) and oral placebo for 4 weeks during placebo run-in. Patients reporting muscle-related symptoms during the run-in were to be withdrawn. Continuing patients were randomized (2:2:1) to double-blind alirocumab 75 mg SC every 2 weeks (Q2W; plus oral placebo), ezetimibe 10 mg/d (plus SC placebo Q2W), or atorvastatin 20 mg/d (rechallenge; plus SC placebo Q2W) for 24 weeks. Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values. Primary end point was percent change in LDL-C from baseline to week 24 (intent-to-treat) for alirocumab vs ezetimibe. RESULTS: Baseline mean (standard deviation) LDL-C was 191.3 (69.3) mg/dL (5.0 [1.8] mmol/L). Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38-0.99, P = .042). CONCLUSIONS:Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients, with fewer skeletal-muscle adverse events vs atorvastatin.
Authors: Ann Marie Navar; Eric D Peterson; Shuang Li; Jennifer G Robinson; Veronique L Roger; Anne C Goldberg; Salim Virani; Peter W F Wilson; Michael G Nanna; L Veronica Lee; Joseph Elassal; Tracy Y Wang Journal: Circ Cardiovasc Qual Outcomes Date: 2018-03