Physicians' Academy for Cardiovascular Education

Short period of very low LDL-c with PCSK9i plus statin associated with prolonged MACE risk reduction

Transiently achieved very low LDL-cholesterol levels by statin and alirocumab after acute coronary syndrome are associated with cardiovascular risk reduction: the ODYSSEY OUTCOMES trial

Literature - Schwartz GG, Szarek M, Bhatt DL, et al. - Eur Heart J. 2023 Mar 5;ehad144. doi: 10.1093/eurheartj/ehad144

Introduction and methods


In most trials investigating cholesterol-lowering therapies, a smaller reduction in the risk of CV events is seen during the first treatment year, but this clinical benefit does increase in subsequent years [1]. This is referred to as the “legacy effect.” However, it is uncertain whether short-term high-intensity cholesterol-lowering therapy also yields a legacy effect.

Previously, the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial showed a reduced risk of CV events and mortality with the PCSK9i alirocumab versus placebo in patients with recent ACS who were on high-intensity or maximum-tolerated statin treatment, over a median follow-up period of 2.8 years [2-4]. No safety issues were observed in patients who achieved very low LDL-c levels (<0.39 mmol/L or <15 mg/dL) with alirocumab [5].

Aim of the study

In a new post-hoc analysis of the ODYSSEY OUTCOMES trial, the authors compared the CV outcomes in post-ACS patients with very low LDL-c levels during short-term treatment with alirocumab, in addition to high-intensity or maximum-tolerated statin therapy, with those in propensity score–matched patients from the placebo group.


The ODYSSEY OUTCOMES trial was an international, double-blind, placebo-controlled, phase 3 RCT in which 18,924 patients with recent ACS (1–12 months prior) and elevated levels of atherogenic lipoproteins despite high-intensity or maximum-tolerated statin therapy were randomized to alirocumab (75 mg subcutaneously every 2 weeks) or placebo. Plasma lipid levels were measured at baseline, at 1, 2, 4, 8, 12, 16, 20, and 24 months after randomization, and at 6-month intervals thereafter.

At the time the trial was designed, the safety of sustained very low LDL-c levels was unknown. Therefore, in patients who had been assigned to alirocumab and had 2 consecutive LDL-c measurements <0.39 mmol/L (n=730), the study drug was blindly substituted with placebo for the remainder of the trial, at a median time after randomization of 8.3 months. Using propensity score matching in a 1:2 ratio, these patients, who thus achieved very low LDL-c levels for a short period (median time: 6.0 months) on alirocumab before being switched to placebo, were matched with patients from the placebo group who had similar baseline characteristics and study medication adherence (n=1460).


The primary endpoint of the trial was a composite MACE outcome comprising death from coronary heart disease, nonfatal MI, hospitalization for unstable angina, or ischemic stroke. In this post-hoc analysis, the risks of the primary endpoint, all-cause mortality, and ischemia-driven coronary revascularization were calculated.

Main results


In this post-hoc analysis of the ODYSSEY OUTCOMES trial, post-ACS patients who achieved LDL-c <0.39 mmol/L (<15 mg/dL) for a median time of 6.0 months with alirocumab plus high-intensity or maximum-tolerated statin therapy, followed by statin monotherapy, had a lower risk of MACE during a median follow-up time of 2.8 years than propensity score–matched patients who only received statin monotherapy.

“[T]he current findings raise the possibility that a short period of very high–intensity cholesterol lowering with a PCSK9 inhibitor and statin resulting in very low LDL-c levels, followed by long-term statin monotherapy (i.e., an induction and maintenance regimen), may provide clinical efficacy with lower cost and complexity of care than indefinite dual-agent therapy,” according to the authors. They do note they used post-randomization data to define the subgroup that achieved very low LDL-c levels and that this post-hoc analysis should therefore be considered to be exploratory.


Show references

Find this article online at Eur Heart J.

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