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Estudio ODYSSEY OUTCOMES: los expertos opinan. Dra. Badimon

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Ponencia presentada por la Dra. Lina Badimon Maestro en el directo online ‘Estudio ODYSSEY OUTCOMES: los expertos opinan’, realizado el 20 de noviembre de 2018 en la Casa del Corazón

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Estudio ODYSSEY OUTCOMES: los expertos opinan. Dra. Badimon

  1. 1. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro Alirocumab and Cardiovascular Outcomes After Acute Coronary Syndrome Gregory G. Schwartz,1 P. Gabriel Steg,2 Michael Szarek,3 Deepak L. Bhatt,4 Vera A. Bittner,5 Rafael Diaz,6 Jay M. Edelberg,7 Shaun G. Goodman,8 Corinne Hanotin,9 Robert A. Harrington,10 J. Wouter Jukema,11 Guillaume Lecorps,9 Kenneth W. Mahaffey,10 Angèle Moryusef,7 Robert Pordy,12 Kirby Quintero,13 Matthew T. Roe,13,14 William J. Sasiela,12 Jean-François Tamby,7 Pierluigi Tricoci,13 Harvey D. White,15 Andreas M. Zeiher,16 for the ODYSSEY OUTCOMES Committees and Investigators Schwartz GG, et al. N Engl J Med 2018 (epub ahead of print) 1Division of Cardiology, University of Colorado School of Medicine, Aurora; CO, USA; 2Assistance Publique–Hôpitaux de Paris, Hôpital Bichat, Paris Diderot University, Sorbonne Paris Cité, FACT (French Alliance for Cardiovascular Trials), and INSERM U1148, Paris, France; 3The State University of New York Downstate School of Public Health, Brooklyn; 4Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston, MA, USA; 5The Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA; 6Estudios Cardiológicos Latinoamérica, Instituto Cardiovascular de Rosario, Rosario, Argentina; 7Sanofi, Bridgewater, NJ, USA; 8The Canadian VIGOUR Centre, University of Alberta, Edmonton, and St. Michael’s Hospital, University of Toronto, Toronto, Canada; 9Sanofi, Paris, France; 10Stanford Center for Clinical Research, Department of Medicine, Stanford University, Stanford, CA, USA; 11The Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; 12Regeneron Pharmaceuticals, Tarrytown, NY, USA; 13Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA; 14The Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA; 15Green Lane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand; 16The Department of Medicine III, Goethe University, Frankfurt am Main, Germany ClinicalTrials.gov: NCT01663402
  2. 2. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro Publication in NEJM
  3. 3. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro Treatment Assignment †High-intensity statin defined as atorvastatin 40 or 80 mg daily or rosuvastatin 20 or 40 mg daily. ACS, acute coronary syndromes; Q2W, every two weeks; SC, subcutaneous. ACS patients (hospitalized 1 to 12 months before randomization) Run-in period of 2−16 weeks on high-intensity† or maximum-tolerated dose of atorvastatin or rosuvastatin At least one lipid entry criterion met Placebo SC Q2WAlirocumab SC Q2W Randomization Patient and investigators remained blinded to treatment and lipid levels for the entire duration of the study Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).
  4. 4. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro Primary Endpoint • Composite of: • CHD death, or • Non-fatal MI, or • Fatal or non-fatal ischemic stroke, or • Unstable angina requiring hospitalization • All endpoints were adjudicated by physicians blinded to the study group assignments. †All endpoints were adjudicated by physicians blinded to the study group assignments. CHD, coronary heart disease; MI, myocardial ischemia. Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).
  5. 5. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro Undesirably high baseline range LDL-C (mg/dL) Target range Alirocumab Belowtarget 705025150 Acceptablerange LDL-C Target Range LDL-C, low-density lipoprotein cholesterol; Q2W, every two weeks; SC, subcutaneous. The investigators attempted to maximize the number of patients in the target range and minimize the number below target by blindly: • titrating alirocumab (75 or 150 mg SC Q2W), or • switching to placebo Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).
  6. 6. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro LDL-C Levels Over Time (ITT † and On-Treatment ‡ Analyses) Alirocumab ITT Alirocumab On Treatment Placebo ITT Placebo On Treatment 105 90 60 45 15 0 MeanLDL-C(mg/dL) 0 4 48 Months since randomization 75 30 8 12 16 20 24 28 32 36 40 44 2.5 2.0 1.5 1.0 0.5 0 103 mg/dL 101 mg/dL 66 mg/dL 53 mg/dL 93 mg/dL 96 mg/dL 40 mg/dL 48 mg/dL 38 mg/dL 42 mg/dL MeanLDL-C(mmol/L) The increase in LDL-C over time in the ITT analysis reflects: • Premature discontinuation of treatment • Dose reduction or crossover to placebo under blinded conditions • Attenuation of the intensity of statin treatment (probably also contributed to rise in LDL-C in the placebo group and in the on-treatment analysis in the alirocumab group) †All LDL-C values, including those after premature treatment discontinuation, blinded dose decrease, and blinded switch to placebo. ‡Excludes LDL-C values obtained after premature treatment discontinuation or blinded switch from alirocumab to placebo (but includes LDL-C values obtained after blinded titration of alirocumab between the 75 and 150 mg doses). ITT, intention-to-treat; LDL-C, low-density lipoprotein cholesterol. Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).
  7. 7. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro 100 90 60 40 10 0 Cumulativeincidence(%) 0 4 Years since randomizationNumber at risk Placebo Alirocumab 9462 9462 8805 8846 8201 8345 3471 3574 629 653 70 30 1 2 3 80 50 20 16 12 9 6 3 0 1 2 3 4 HR 0.85 (95% CI, 0.78–0.93) P<0.001 0 Alirocumab Placebo To prevent one primary end point event, 49 patients (95% CI: 28–164) would need to be treated for 4 years *For BL LDL-C ≥ 100 mg/dL, 16 patients (95% CI, 11 to 34) would need to be treated for 4 years Composite Primary Endpoint: CHD death, Non-fatal MI, Fatal or non-fatal ischemic stroke, or Unstable angina requiring hospitalization 0 4 8 12 16 20 0 1 2 3 4 Years since randomization 2815 2814 2568 2602 2371 2431 986 1053 178 207 MACE(%) HR 0.76 (95% CI: 0.65–0.87) The inset shows the same data on an enlarged y-axis. CI, confidence interval; HR, hazard ratio. In a non-prespecified analysis, absolute reduction in the risk of the primary endpoint with alirocumab was greatest in the group of patients with baseline LDL-C ≥100 mg/dL (P<0.0001). All patients Patients with baseline LDL-c > 100mg/dL Schwartz GG et al. N Engl J Med 2018 (epub ahead of print)
  8. 8. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro All Cause Death in general population of the study & in patients with baseline LDL-c > 100mg/dL All patients Patients with baseline LDL-c > 100mg/dL The insets shows the same data on an enlarged y-axis. †P-value not calculated for cardiovascular death or all cause-death. The hierarchical analysis was stopped after the first nonsignificant P value was observed, in accordance with the hierarchical testing plan. CHD, coronary heart disease; CI, confidence interval; HR, hazard ratio. Hence P Schwartz GG et al. N Engl J Med 2018 (epub ahead of print). All-cause death All-cause death Alirocumab Placebo
  9. 9. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro % (n) Alirocumab (N=9451) Placebo (N=9443) Any TEAEs 75.8 (7165) 77.1 (7282) Serious TEAEs 23.3 (2202) 24.9 (2350) TEAEs leading to death 1.9 (181) 2.4 (222) TEAEs leading to study discontinuation 3.6 (343) 3.4 (324) Local injection-site reaction 3.8 (360) 2.1 (203) General allergic reaction 7.9 (748) 7.8 (736) Diabetes worsening or diabetic complication among patients with diabetes at baseline, % (n/N) 18.8 (506/2688) 21.2 (583/2747) New-onset diabetes among patients without diabetes at baseline, % (n/N) 9.6 (648/6763) 10.1 (676/6696) Neurocognitive disorder 1.5 (143) 1.8 (167) Hepatic disorder 5.3 (500) 5.7 (534) Cataracts 1.3 (120) 1.4 (134) Hemorrhagic stroke, adjudicated <0.1 (9) 0.2 (16) Adverse Events (Safety Analysis Population) TEAEs, treatment-emergent adverse events. Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).
  10. 10. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro • Among patients who had a previous ACS and whose levels of atherogenic lipoproteins remained elevated despite intensive statin therapy, the risk of MACE was lower among those who were treated with alirocumab than among those who received placebo (HR 0.85; 95% CI: 0.78–0.93; P<0.001) • A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (HR 0.85; 95% CI: 0.73–0.98) • The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL-C level of ≥100 mg/dL than among patients who had a lower baseline level • The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group) Summary of ODYSSEY OUTCOMES Study Results ACS, acute coronary syndromes; CI, confidence interval; HR, hazard ration; LDL-C, low-density lipoprotein cholesterol; MACE, major cardiovascular events. Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).
  11. 11. Estudio ODYSSEY OUTCOMES: los expertos opinan Dra. Lina Badimon Maestro 2018 JAN FEB MAR APR MAY JUN JUL AUG SEPT OCT NOV DEC ODYSSEY OUTCOMES Topline Results ODYSSEY OUTCOMES Diabetes Sub-study ODYSSEY OUTCOMES Lp(a) Sub-study ODYSSEY OUTCOMES Mortality Sub-study Cost-effectiveness Study Total events Sub-study ODYSSEY OUTCOMES Publication

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