The ODYSSEY OUTCOMES trial: Alirocumab associated with reduced ischemic events after acute coronary syndrome

1. Among patients that suffered a recent acute coronary syndrome (ACS) and had elevated levels of atherogenic lipoproteins despite intensive or maximum-intensive statin therapy, alirocumab reduced the number of recurrent cardiovascular ischemic events. This response was more robust with higher levels of low-density lipoprotein (LDL) cholesterol.

2. The safety profile of alirocumab was similar to placebo, with the exception of an increased number of local injection-site reactions that were mostly mild and self-limited.

Evidence Rating Level: 1 (Excellent)      

Study Rundown: Patients who have suffered a recent acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. This risk is in part due to elevated levels of LDL-C and other atherogenic lipoproteins, and persists despite high intensity statin therapy. While previous randomized trials have established the ability of proprotein convertase subtilisin–kexin type 9 (PCSK-9) inhibitors to substantially reduce LDL cholesterol, it is uncertain if this treatment can reduce cardiovascular risk post-ACS. This study aimed to compare the safety and efficacy of alirocumab, a monoclonal antibody to PCSK-9, with placebo among patients with recent ACS already on intensive or maximum-tolerated statin therapy. The primary outcome – a composite of death from coronary heart disease (CHD), nonfatal myocardial infarction (MI), ischemic stroke, and unstable angina – was significantly reduced in the alirocumab group compared to placebo and the response was more robust with higher levels of LDL cholesterol. Among key secondary outcomes, alirocumab also reduced any CHD event, major CHD events, any cardiovascular event, and a composite of death from any cause, nonfatal MI, or nonfatal stroke. The incidence of adverse events was similar between alirocumab and placebo, with the exception that local injection-site reactions were more common with alirocumab. Though the high cost of PCSK-9 inhibitors should be considered, the results of this trial suggest their use be justified in certain post-ACS patients.

This was a randomized, double-blinded trial that featured a large sample size and was of longer duration than previous trials of PCSK-9 inhibitors; however, additional trials are still needed to confirm long-term safety. The trial was also the first to titrate drug levels to a target LDL cholesterol. Similar to previous trials, the study was limited by the infrequent use of ezetimibe and did not take into account the high cost of PCSK-9 inhibitors, a critical factor in determining whether these drugs will gain widespread use.

Click to read the study in NEJM

Relevant Reading: Evolocumab and clinical outcomes in patients with cardiovascular disease

In-Depth [randomized controlled trial]: Patients (n=18,924) who suffered from an ACS in the prior 1-12 months, were on high-intensity statin therapy (or documented intolerance), and had inadequate lipid control (LDL ³ 70 mg/dl, non-high density lipoprotein ³ 100 mg/dl, or apolipoprotein B ³ 80 mg/dl) were randomized to subcutaneous alirocumab every two weeks (n=9,462) or placebo (n=9,462). Alirocumab was titrated between 75 and 150 mg for a goal LDL cholesterol between 25 and 50 mg/dl. Median follow-up time was 2.8 years. The primary outcome was a composite of: death from CHD, nonfatal MI, fatal or nonfatal ischemic stroke, and unstable angina requiring hospitalization. Baseline LDL cholesterol level was 92±31 mg for all enrolled patients. In the alirocumab group at 4 months, 12 months, and 48 months, the mean LDL cholesterol level was 40 mg/dl, 48 mg/dl, and 66 mg/dl, respectively; in the placebo group, mean LDL levels were 93 mg/dl, 96 mg/dl, and 103 mg/dl, respectively. The composite primary outcome occurred in 903 patients (9.5%) in the alirocumab group compared to 1052 patients (11.1%) in the placebo group (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). Patients with LDL cholesterol levels ³ 100 mg/dl demonstrated the greatest reduction in risk of the primary outcome. Among key secondary outcomes, patients in the alirocumab group had a significantly lower risk of: any CHD event, major CHD event, any cardiovascular event, and a composite of death from any cause, nonfatal MI, or nonfatal ischemic stroke. The incidence of adverse events was similar in both groups, with the exception of local injection-site reactions (3.8 with alirocumab vs. 2.1% with placebo), which were mostly mild and self-limited.

Image: PD

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