New England Journal of Medicine November 29, 2018

Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (ODYSSEY OUTCOMES)

Gregory G. Schwartz, Ph. Gabriel Steg, Michael Szarek et al.

Bottom Line

In patients with a recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy, the PCSK9 inhibitor alirocumab significantly reduced the risk of recurrent ischemic cardiovascular events and was associated with a lower rate of all-cause death.

Key Findings

1. The primary outcome (MACE) occurred in 9.5% (903/9462) of patients in the alirocumab group compared to 11.1% (1052/9462) in the placebo group (Hazard Ratio [HR] 0.85; 95% Confidence Interval [CI], 0.78-0.93; P<0.001).

2. Alirocumab treatment resulted in an absolute risk reduction (ARR) of 1.6% for MACE over a median follow-up of 2.8 years.

3. Death from any cause was nominally lower in the alirocumab arm, occurring in 3.5% of patients versus 4.1% in the placebo arm (HR 0.85; 95% CI, 0.73-0.98).

4. In a prespecified subgroup analysis of patients with a baseline LDL-C ≥100 mg/dL, the benefit was most pronounced, with a 24% relative risk reduction for MACE (ARR 3.4%; HR 0.76; 95% CI 0.65-0.87) and a 29% reduction in all-cause death (ARR 1.7%; HR 0.71; 95% CI 0.56-0.90).

5. Alirocumab was generally well-tolerated, with no significant differences in most adverse events, though local injection-site reactions were slightly more frequent in the alirocumab group (3.8% vs. 2.1%).

Study Design

Design

RCT

Double-Blind

Sample

18,924

Patients

Duration

2.8 yr

Median

Setting

Multicenter, multinational

Population Patients who had an acute coronary syndrome 1 to 12 months earlier, had an LDL-C level ≥70 mg/dL, non-HDL-C ≥100 mg/dL, or apolipoprotein B ≥80 mg/dL, and were already receiving statin therapy at a high-intensity dose or at the maximum tolerated dose.

Intervention Alirocumab (75 mg or 150 mg administered subcutaneously every 2 weeks), with the dose blindly titrated to target an LDL cholesterol level of 25 to 50 mg/dL.

Comparator Placebo administered subcutaneously every 2 weeks.

Outcome Composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization (MACE).

Study Limitations

• Themedianfollow-updurationof2.8yearsisrelativelyshort, whichlimitstheabilitytoevaluatetheverylong-termsafetyanddefinitivelong-termmortalitybenefitsofprofoundLDL-Creduction[1.2].

• The trial utilized a complex dose-titration and blinding scheme (blindly switching patients to placebo if LDL-C fell below 15 mg/dL), which may have attenuated the maximum observed efficacy compared to a fixed-dose continuous strategy.

• The study specifically enrolled patients already tolerating high-intensity or maximally tolerated statins, providing less direct evidence regarding the efficacy and safety profile in strictly statin-intolerant patients.

Clinical Significance

ODYSSEY OUTCOMES solidifies the role of PCSK9 inhibitors as an effective secondary prevention strategy for high-risk post-ACS patients who cannot achieve optimal LDL-C levels on maximum tolerated statins. By demonstrating that patients with a baseline LDL-C ≥100 mg/dL derive the greatest absolute benefit in both MACE and all-cause mortality, the trial provides critical, actionable data to help clinicians target this expensive therapy cost-effectively.

Historical Context

Prior to this trial, the 2017 FOURIER trial demonstrated that the PCSK9 inhibitor evolocumab reduced cardiovascular events in a broad population with stable atherosclerotic cardiovascular disease, but it did not show an all-cause mortality benefit. ODYSSEY OUTCOMES built upon these findings by specifically investigating a higher-risk population with a recent acute coronary syndrome (1-12 months prior), becoming the first trial of a PCSK9 inhibitor to demonstrate a nominal mortality benefit and further validating the 'lower is better' lipid hypothesis.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of alirocumab (a PCSK9 inhibitor) differ biologically from that of statins, and why is this combination synergistic for lowering LDL cholesterol?

Key Response

Statins inhibit HMG-CoA reductase, decreasing intracellular hepatic cholesterol and upregulating LDL receptors. PCSK9 normally binds to and degrades these LDL receptors. Inhibiting PCSK9 prevents this degradation, allowing more receptors to recycle to the hepatocyte surface. Combining both maximizes LDL receptor density and blood clearance of LDL.

Resident

Based on the ODYSSEY OUTCOMES trial, which specific subset of post-ACS patients is most likely to derive the greatest absolute risk reduction from the addition of alirocumab to high-intensity statin therapy?

Key Response

Subgroup analyses of the trial demonstrated that patients with baseline LDL-C levels of 100 mg/dL or higher derived the most pronounced absolute risk reduction for major adverse cardiovascular events and all-cause mortality, guiding clinicians to prioritize this therapy for those with the highest residual lipid risk.

Fellow

ODYSSEY OUTCOMES demonstrated a reduction in all-cause mortality with alirocumab, a finding not observed with evolocumab in the FOURIER trial. What patient population and trial design differences might explain this discrepancy in mortality benefit between the two major PCSK9 inhibitor trials?

Key Response

ODYSSEY enrolled a higher-risk acute population (recent ACS within 1-12 months) followed for a median of 2.8 years, whereas FOURIER enrolled a stable secondary prevention population (remote MI/stroke). The higher baseline risk and longer follow-up relative to the acute event in ODYSSEY likely provided the necessary event rate to unmask an all-cause mortality benefit.

Attending

In ODYSSEY OUTCOMES, the trial utilized a treat-to-target strategy with dose titration and blinded substitution to placebo if LDL-C dropped below 15 mg/dL. How does this protocol inform our clinical comfort and management strategy regarding extremely low LDL-C levels in secondary prevention?

Key Response

The trial's design reflects historical concerns about the safety of profoundly low LDL-C. While subsequent data have largely reassured us about the safety of LDL-C under 20 mg/dL, the ODYSSEY titration protocol provides a framework to discuss personalized dose adjustments versus a 'lower is always better' maximalist approach to avoid theoretical neurocognitive or hemorrhagic risks.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ODYSSEY OUTCOMES trial employed a prespecified hierarchical testing sequence for its secondary endpoints to control the Type I error rate. How does this statistical approach affect the formal interpretation of the all-cause mortality benefit?

Key Response

Hierarchical testing requires that each endpoint be statistically significant to formally test the next. Because coronary heart disease death and cardiovascular death (which preceded all-cause death in the hierarchy) did not reach statistical significance, the nominal p-value for all-cause death could only be considered exploratory, highlighting the tension between rigorous alpha-control and clinical interpretation.

Journal Editor

From an editorial perspective evaluating trial integrity, how does the rate of premature discontinuation of the trial regimen (over 14 percent in the alirocumab group) impact the validity of the intention-to-treat analysis, and what potential biases does this introduce?

Key Response

High discontinuation rates dilute the observable treatment effect in an intention-to-treat analysis, potentially biasing the results toward the null. A reviewer would heavily scrutinize whether discontinuations were informative (e.g., due to adverse events) and demand robust sensitivity analyses to confirm the robustness of the primary MACE outcomes.

Guideline Committee

How do the findings of ODYSSEY OUTCOMES directly support and refine the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol regarding thresholds for initiating non-statin therapies in very high-risk ASCVD?

Key Response

The 2018 guidelines recommend considering PCSK9 inhibitors for very high-risk ASCVD patients whose LDL-C remains at or above 70 mg/dL on maximally tolerated statin and ezetimibe. ODYSSEY provides Level of Evidence A support for this, but also suggests the mortality benefit is most profound in those with LDL above 100 mg/dL, prompting guideline committees to consider staggered risk-stratification thresholds for cost-effectiveness prioritization.

Clinical Landscape

Noteworthy Related Trials

2004

PROVE IT-TIMI 22 Trial

n = 4,162 · NEJM

Tested

Intensive statin therapy (Atorvastatin 80 mg)

Population

Patients with acute coronary syndrome within the preceding 10 days

Comparator

Moderate statin therapy (Pravastatin 40 mg)

Endpoint

Death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization, or stroke

Key result: Intensive lipid-lowering therapy provided greater protection against death or major cardiovascular events than standard therapy.

2015

IMPROVE-IT Trial

n = 18,144 · NEJM

Tested

Ezetimibe added to simvastatin

Population

Patients stabilized after an acute coronary syndrome

Comparator

Simvastatin alone

Endpoint

Composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke

Key result: The addition of ezetimibe to statin therapy resulted in incrementally lower LDL cholesterol levels and improved cardiovascular outcomes.

2017

FOURIER Trial

n = 27,564 · NEJM

Tested

Evolocumab (PCSK9 inhibitor)

Population

Patients with atherosclerotic cardiovascular disease

Comparator

Placebo

Endpoint

Composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization

Key result: Evolocumab significantly reduced the risk of cardiovascular events and lowered LDL-C levels by 59 percent.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis