ODYSSEY: Alirocumab scores in ACS, cuts CV events
Not only does treatment with the PCSK9* inhibitor alirocumab reduces cardiovascular (CV) events along with plunges in LDL-C levels, it was also associated with a reduced risk of all-cause mortality compared with placebo in patient with a recent acute coronary syndrome (ACS) and persistently high cholesterol despite maximal statin therapy, according to top-line results from the ODYSSEY** Outcomes trial.
After a median 2.8 years follow-up, the alirocumab arm saw a 15 percent reduction (rate, 9.5 percent vs 11.1 percent, hazard ratio [HR], 0.85; p=0.0003) in the primary endpoint of major adverse cardiovascular events (MACE) ─ comprising coronary heart disease (CHD) death, ischaemic stroke, nonfatal myocardial infarction (MI), or unstable angina requiring hospitalization ─ compared with the placebo arm. [ACC.18, abstract 401-08]
“A 15 percent reduction in MACE is in the range of what aspirin achieves. I also would point out that even statins have not shown a mortality benefit in the post-ACS setting,” said study cochair Professor Gabriel Steg of Hôpital Bichat, Paris, France.
The reduction was driven mainly by a reduced risk of nonfatal MI (HR, 0.86; p=0.006), ischaemic stroke (HR, 0.73; p=0.01), and hospitalization for unstable angina (HR, 0.61; p=0.02).
Also, alirocumab treatment was associated with a 15 percent lower risk of all-cause death compared with placebo (3.5 percent vs 4.1 percent, HR, 0.85; nominal p-value based on hierarchical testing=0.026). This is the first report of a mortality benefit with a PCSK9 inhibitor ─ no such association was observed in the FOURIER*** trial.
The mortality benefit is a “bonus finding”, according to Steg. Nonetheless, he remained cautious in his interpretation of the data, saying “the mortality finding has to be qualified because of a technicality in the hierarchical analysis, where all-cause mortality came after CHD mortality and CV mortality which were not significantly reduced; but we think it is a very important observation.”
Post hoc analyses suggest that the greatest benefit was found in patients with a baseline LDL-C of ≥100 mg/dL, who saw relative risk reductions of 24 percent for MACE and 29 percent for all-cause mortality.
“The treatment was remarkably safe over the duration of the trial,” said Steg. The rates of treatment-emergent adverse events (TEAEs) were comparable between the alirocumab and the placebo arms (any TEAEs, 75.8 percent vs 77.1 percent; serious TEAEs, 23.3 percent vs 24.9 percent).
“We found no evidence of serious increase in side effects. The only side effect which was increased was local [injection] site reactions, which were [mostly] rare and mild (3.8 percent vs 2.1 percent), but no increase in neurocognitive events, new-onset diabetes, cataracts, or haemorrhagic [stroke],” he added, with the caveat that longer term follow-up is awaited to establish this.
The ODYSSEY to practice
The phase III, double-blind, global study involved 18,924 patients (mean age 58 years, 25 percent female) with a recent ACS who had inadequate control of lipids (LDL-C ≥70 mg/dL, non-HDL-C ≥100 mg/dL, or apolipoprotein B ≥80 mg/dL) despite high-intensity statin therapy (atorvastatin 40–80 mg/day, rosuvastatin 20–40 mg/day, or the maximum tolerated dose of either drug). The patients were randomized 4–52 weeks post-ACS to subcutaneous alirocumab 75–150 mg Q2W or a matching placebo, with patients in the alirocumab arms being titrated to a target LDL-C levels of 25–50 mg/dL, allowing levels to drop as low as 15 mg/dL. On-treatment analysis showed that LDL-C levels dropped by more than 50 percent with alirocumab vs placebo through to 48 weeks.
“This study is going to change practice. It was a hypothesis that has been fulfilled – alirocumab vs placebo reduces CV morbidity and mortality,” said invited discussant Dr Valentin Fuster from Mount Sinai School of Medicine, New York, US, during a press conference. “The results were not trivial [in terms of the reduction in the primary endpoint and LDL-C levels].”
“The LDL-C levels which we see success in are very low,” he remarked. “The message is maybe what we consider a normal LDL-C level is too high today, and that we have to go lower and lower.”
Compared with FOURIER which also showed CV events reduction with the PCSK9 inhibitor evolocumab in chronic coronary artery disease, the ODYSSEY trial involved higher-risk patients with a recent ACS, a longer follow-up duration (2–5 years), and a different dosing strategy.
When asked on how the two PCSK9 inhibitors should be used, Steg pointed out that current evidence suggests the use of alirocumab in post-ACS setting and evolocumab in stable atherosclerotic patients with CV disease, but further trials are needed to confirm this.
“Now that we have two trials that consistently show benefits from PCSK9 inhibitors ... I think these results may change the equation for these drugs,” said Steg.
“Up until now, the feasibility and the affordability of using this type of drug have been extremely difficult. I hope this particular study is a trigger, is a catalyzer, for making this drug much more available today for people who use it,” Fuster added.