Physicians' Academy for Cardiovascular Education

PCSK9 siRNA effective and safe in high-risk patients with elevated LDL-c irrespective of PVD status

Efficacy and safety of inclisiran in patients with polyvascular disease: pooled, post hoc analysis of the ORION-9, ORION-10, and ORION-11 phase 3 randomized controlled trials

Literature - Koenig W, Conde LG, Landmesser U, et al. - Cardiovasc Drugs Ther. 2022 Dec 23. doi: 10.1007/s10557-022-07413-0.

Introduction and methods

Background

Approximately 15-30% of patients with ASCVD have polyvascular disease (PVD), defined as atherosclerotic plaques in at least 2 major artery beds [1-3]. PVD is an independent risk factor for cardiovascular events [1-3], stronger than diabetes and prior ischemic events [3-5]. Therefore, patients with PVD require intensive lipid-lowering therapy. Previously, a pooled analysis of ORION-9, ORION-10 and ORION-11 showed that twice-yearly subcutaneous injection of inclisiran (after an initial dose at day 1 and 90) – compared with placebo – reduces LDL-c in patients with heterozygous FH, ASCVD and ASCVD risk equivalent [6].

Aim of the study

This pooled post hoc analysis of ORION-9, ORION-10 and ORION-11 examined the efficacy and safety of inclisiran versus placebo in patients with and without PVD.

Methods

The researchers conducted a pooled post hoc analysis of data from 3 double-blind, randomized phase 3 trials in which adult patients with HeFH (ORION-9), ASCVD (ORION-10 and ORION-11) or an ASCVD risk equivalent (ORION-11) were randomized to 284 mg inclisiran or placebo on day 1, day 90 and every 6 months thereafter. Only patients with elevated LDL-c, despite receiving maximal statin therapy with or without other lipid-lowering agents, were eligible to participate. In this pooled post hoc analysis, 3454 patients were divided into a group with (n=470) and a group without (n=2984) PVD, where PVD was defined as the presence of at least 2 of the following conditions: PAD, CAD, or cerebrovascular disease (CeVD).

Outcomes

The pre-specified co-primary outcomes were the percentage change in LDL-c from baseline to day 510 and the time-corrected percentage change in LDL-c from baseline after day 90 up to day 540. Key secondary outcomes were the absolute change in LDL-c from baseline to day 510, the time-corrected absolute change in LDL-c from baseline after day 90 and up to day 540, and the percentage change in PCSK9, total cholesterol, apo-B and non-HDL-c from baseline to day 510. Changes were expressed as least square mean. Safety was assessed in 3449 patients over 540 days, including treatment-emergent (serious) adverse events (TE(S)AEs) and clinically relevant laboratory measurements.

Main results

Efficacy

Safety

Conclusion

This pooled post hoc analysis of ORION-9, ORION-10 and ORION-11 shows that twice-yearly subcutaneous injection (after initial and 90-day doses) of inclisiran results in effective and sustained lipid-lowering in high-risk patients with elevated LDL-c, irrespective of PVD status.

References

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