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
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 . 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 .
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.
- Mean time-averaged LDL-c levels were 1.31 mmol/L (95%CI: 1.27–1.34) (51 mg/dL; 95%CI: 49–52) in patients first treated with alirocumab and subsequently placebo and 2.11 mmol/L (95%CI: 2.08–2.15) (82 mg/dL; 95%CI: 80–83) in propensity score–matched patients from the placebo group (P<0.001).
- In the first subgroup, the mean LDL-c level rose after substitution with placebo for alirocumab, as expected. By the end of the observation period, the mean time-averaged difference in LDL-c levels between these 2 subgroups was 0.81 mmol/L (31 mg/dL) (P>0.05).
- During a median follow-up time of 2.8 and 2.6 years, respectively, MACE occurred in 47/730 (6.4%) alirocumab/placebo-treated patients compared with 122/1460 (8.4%) matched placebo only–treated patients (estimated treatment HR: 0.72; 95%CI: 0.51–0.997; P=0.047). In comparison, the estimated treatment HR for the overall alirocumab group versus overall placebo group was 0.85 (95%CI: 0.78–0.93; P<0.001).
- The estimated treatment HRs comparing the subgroups for each component of the primary endpoint, all-cause mortality, and ischemia-driven coronary revascularization were not statistically significant .
- Of note, propensity score–matched patients from the placebo group had a lower MACE risk than the entire group of placebo only–treated patients (4-year Kaplan-Meier estimates: 10.7% and 14.5%, respectively).
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.
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