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Study Summary

Alirocumab is a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) that has been associated with significant and sustained reductions in low-density lipoprotein cholesterol (LDL-C). To test whether the addition of alirocumab would reduce cardiovascular morbidity and mortality after acute coronary syndromes in patients with elevated levels of atherogenic lipoproteins despite intensive or maximally tolerated statin therapy, the ODYSSEY OUTCOMES investigators conducted a multicenter, international randomized controlled trial of alirocumab (every two weeks, subcutaneous, targeting LDL-C 25 to 50 mg/dL, and as low as 15 mg/dL) versus matched placebo in 18,924 patients. At 4 years, treatment with alirocumab was associated with a mean 54.7% reduction in LDL-C, a 1.6% absolute risk reduction in the primary efficacy outcome —coronary heart disease death, non-fatal myocardial infarction, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization — (9.5 vs. 11.1%, p = 0.0003) and a reduction in all-cause death (3.5 vs. 4.1%, p = 0.026). Efficacy was most pronounced in patients with baseline LDL-C ≥ 100 mg/dL. Safety measures were similar with alirocumab and placebo.

Commentary

Study Strengths: ODYSSEY OUTCOMES was a large and well-conducted trial that contributes significant support to the importance of LDL-C lowering in cardiovascular risk reduction. Building upon a series of studies showing iterative reduction in LDL-C and events with statins vs. placebo, high-intensity vs. low-intensity statins, and ezetimibe vs. placebo in addition to statin therapy, ODYSSEY OUTCOMES showed that addition of the PCSK9 inhibitor alirocumab to high-intensity or maximally-tolerated statin therapy markedly reduced LDL-C levels and significantly reduced major adverse cardiovascular events and death after ACS.

Study Limitations: From the time of randomization to 48 months, mean LDL-C rose, but the explanation for this observed attenuation of LDL-C reduction over time is unclear. Potential mechanisms include a per-protocol blinded switch from alirocumab to placebo of subjects with two consecutive LDL-C values <15 mg/dL (~8%), protocol-based treatment dose adjustments in patients with single LDL-C values<15 mg/dL, and development of neutralizing antibodies. Regarding the potential impact of per-protocol blinded switch from alirocumab to placebo, there was divergence in LDL-C values at 48 months post randomization between the intention-to-treatment and on-treatment groups (66.4 mg/dL vs. 53.3 mg/dL, respectively and vs. nearly concordant values of 39.8 mg/dL and 37.6 mg/dL, respectively, at 4 months post randomization). Future studies are needed to explain this phenomenon, which may impact long-term efficacy of alirocumab.

Next Steps/Clinical Perspective: The implications of this trial’s key findings for clinical practice (see accompanying Hurst’s Central Illustration) will depend considerably on the evolution of the affordability and availability of the PCKSK9 inhibitors. More broadly, the results of ODYSSEY OUTCOMES stand to challenge the present paradigm of fixed dose high-intensity statin therapy after ACS, sounding once more the call to treat to targets. The safety of alirocumab and, as seen in other trials of PCSK9 inhibitors, extreme lowering of LDL-C observed in ODYSSEY OUTCOMES upends the current goal LDL-C of <70 mg/dL and challenges us to ask, should we set our sights lower?

An Odyssey Back to the Future: Treat to Target?

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