ODYSSEY OUTCOMES - Alirocumab added to max-tolerated statins after ACS

Bottom line: In patients with ACS in the past 12 months & LDL-C >1.8 mmol/L on max-tolerated statin therapy, alirocumab reduced the risk of major adverse cardiovascular events (composite of death/MI/stroke) by 1.6% (NNT 63), versus placebo over 2.8 years. Alirocumab increased local injection-site reactions compared to placebo (NNH 59).

1315 sites in 57 countries (15% from Canada/US), enrolling from Nov 2012 to Nov 2015
Included
- 40+ y/o
- Hospitalized for ACS 1-2 months ago
- LDL-C 1.8+ mmol/L, non-HDL-C 2.6+ mmol/L, or ApoB 0.80+ g/L after 2+ weeks on stable high-intensity statin (atorvastatin 40-80 mg/d, rosuvastatin 20-40 mg/d), or max-tolerated statin (including no statin if documented intolerance)
Excluded
- Uncontrolled HTN (>180/110 mm Hg)
- HF with NYHA functional class 3-4
- Hx hemorrhagic stroke
- Fasting triglycerides >4.5 mmol/L
- ALT/AST >3x ULN
Baseline characteristics
- Age 59 y, female (25%), white (79%)
- Randomized median 2.6 months (IQR 1.7-4.3) after ACS
- Index ACS: STEMI (35%), NSTEMI (48%), UA (17%)
- Prior MI (19%), PCI (17%), stroke (3%), HF (15%)
- Smoker (24%), HTN (65%), DM (29%), FHx premature CAD (36%)
- Labs: LDL-C 2.4 mmol/L, HDL-C 1.2, non-HDL-C 3.2, apoB 0.8 g/L, Lp(a) 40 mg/dL
- Meds: Statin (97.5%; high-intensity 89%), ezetimibe (3%)
  - Antiplatelet (99%), ACEI/ARB (78%), beta-blocker (85%)

I: Alirocumab 75 mg subcut every 2 weeks
- Uptitrated to 150 mg every 2 weeks to target an LDL-C 0.65-1.3 mmol/L, or switch to placebo if <0.4 mmol/L
C: Matching placebo

Efficacy

1o outcome (CHD death, non-fatal MI, fatal or non-fatal ischemic stroke, UA hospitalization): Alirocumab 9.5% vs placebo 11.1% (NNT=63, or NNT=~175/year)
- Hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.78-0.93
- No significant difference in efficacy between pre-defined subgroups
- Non-fatal MI: 6.6% vs 7.6% (HR 0.86, 95% CI 0.77-0.96)
- Non-fatal ischemic stroke: 1.2% vs 1.6% (HR 0.73, 0.57-0.93)
- UA hospitalization: 0.4% vs 0.6% (HR 0.61, 0.41-0.92)
Composite of all-cause death, MI, stroke: 10.3% vs 11.9% (HR 0.86, 95% CI 0.79-0.93)
All-cause death: 3.5% vs 4.1% (HR 0.85, 95% CI 0.73-0.98)
- Note: To minimize type 1 error in the secondary outcomes, the investigators performed hierarchical testing, which means they tested for statistical significance of several outcomes in a pre-defined sequence, and stopped testing once they reach an outcome that was not statistically significantly different. The difference between groups for CHD death was not different, & the hierarchical testing therefore stopped before all-cause death.
- Regardless, the mortality findings are not statistically robust with a fragility index of only 6, & do not correspond with a reduction in CV death. For comparison to statin data, the fragility index for mortality was 33 in the 4S trial, 81 in the HPS trial.
HF hospitalization: 1.9% in both groups

Safety

Premature discontinuation: Alirocumab 14.2% vs placebo 15.8%
Adverse events
- Serious (SAEs): 23.3% vs 24.9%
- Local injection-site reaction: 3.8% vs 2.1% (NNH 59)
- No difference in neurocognitive adverse effects, new-onset diabetes, diabetes worsening, or myopathy
Neutralizing antidrug antibodies: 0.5% vs <0.1%

Effect on LDL-C (ITT analysis that includes patients who D/Ced alirocumab/switched to placebo)

Low risk of allocation, performance, detection & attrition bias:
- Computer-generated randomized sequence with centralized allocation of study drug/placebo kits;
- Patients & clinicians blind to study intervention & lipid panel;
- Central, blinded outcome adjudication;
- Loss-to-follow-up 0.2% for death & 0.9% for primary outcome;
- Analyses based on intention-to-treat principle.
Pre-randomization run-in with placebo injection x2-16 weeks to ensure patients could use autoinjector & tolerate stable statin regimen.