Estudio ODYSSEY OUTCOMES: los expertos opinan. Dra. Badimon

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

Publication in NEJM

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).

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.

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

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.

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)

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

% (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.

• 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).

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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Estudio ODYSSEY OUTCOMES: los expertos opinan. Dra. Badimon