PSK9 inhibitor alirocumab reduces nonfatal MI in patients after acute coronary syndrome, but at high cost (ODYSSEY OUTCOMES)

Reference

Schwartz GG, Steg PG, Szarek M, et al, for the ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379(22):2097-2107.

Synopsis

High-intensity statins are recommended after an episode of acute coronary syndrome (ACS). This trial identified adults 40 years or older who had experienced ACS in the previous 12 months who had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg/dL, a non–high-density lipoprotein level of at least 100 mg/dL, or an apolipoprotein B level of 80 mg/dL or higher. Most patients were already taking a statin. A total of 18,924 patients from 1315 sites in 57 countries were randomized to receive the PSK9 inhibitor alirocumab 75 mg subcutaneously every 2 weeks or matching placebo. The alirocumab dose was adjusted in a blinded manner to achieve an LDL level between 25 mg/dL and 50 mg/dL. The relatively small number of patients recruited per site (an average of approximately 5 patients per site per year in the 3-year recruitment period) raises concerns about adherence to trial protocols. The mean age of participants was 58 years, 25% were women, 79% were white, and only 2.5% were black. The bulk of patients came from central or eastern Europe (28.7%) or from western Europe (22%). The index episode of ACS was characterized by ST segment elevation MI (STEMI) in 34.5% of patients, non-STEMI in 48.5%, and unstable angina in 16.8%. Patients were followed up for a median of 2.8 years, with approximately 85% in each group still taking the study drug or placebo at the end of the trial. The primary outcome was an overly broad "apples and oranges" composite that included outcomes ranging from hospitalization to death. The primary outcome was less common in the treatment group (9.5% vs 11.1%, P < .001; number needed to treat [NNT] = 63 over 2.8 years). The outcome was more favorable for those with a baseline LDL level greater than 100 mg/dL (NNT = 16). Although the authors caution against interpreting individual outcomes that they describe as secondary, it is important to understand where the improvement in the primary composite comes from. It was primarily due to a reduction in nonfatal MIs (6.6% vs 7.6%; hazard ratio 0.86; 95% CI 0.77 - 0.96; NNT = 100 over 2.8 years). Death from cardiovascular causes was also reduced, but to a smaller degree (2.5% vs 2.9%), and the difference was not statistically significant. Notably, the authors had a very long list of ties to industry (one full journal page of very fine print).