Physicians' Academy for Cardiovascular Education

PCSK9 siRNA reduces LDL-c in patients with and without polyvascular disease

News - Sep. 6, 2021

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 randomised controlled trials

Presented at the ESC congress 2021 by: Prof. Wolfgang Koenig, MD - Munich, Germany

Introduction and methods

Approximately 1 in 4 patients with ASCVD have polyvascular disease (PVD), which is usually defined as ≥2 affected arterial beds. Inclisiran is a siRNA which prevents PCSK9 protein production resulting in reduced LDL-c levels. The phase 3 randomised controlled trials ORION-9, -10, and -11 previously showed that inclisiran provided sustained LDL-c lowering. The aim of the current pooled, post-hoc analysis of ORION-9, -10, and -11 was to assess the efficacy and safety of inclisiran versus placebo in patients with and without PVD.

ORION-9, -10, and -11 enrolled patients with heterozygous familial hypercholesterolemia (HeFH), established ASCVD or with ASCVD risk equivalent with elevated LDL-c despite maximally tolerated statin therapy (≥2.6 mmol/L for HeFH and ASCVD risk equivalent; ≥1.8 mmol/L for ASCVD). Patients were stratified based on PVD status. PVD was defined as ≥2 of the following diseases: Peripheral artery disease (PAD), coronary heart disease (CHD), or cerebrovascular disease (CeVD). Patients were randomized in a 1:1 ratio to receive 300 mg inclisiran sodium or placebo at day 1, 90, 270 and 450. Patients were followed until day 540 (~18 months). The patient population of this analysis consisted of 470 patients with PVD (228 received inclisiran and 242 placebo), and 2984 patients without PVD (1506 received inclisiran an 1478 placebo).

Efficacy endpoints included percentage and absolute changes in LDL-c from baseline to day 510, percentage and absolute changes in LDL-c between baseline and the average between day 90 and day 540 (time-adjusted change), and the percentage changes in other atherogenic lipids from baseline to day 510. Safety endpoints included reported TEAEs and TESAEs, frequent TEAEs (≥5% in any group), and clinically relevant laboratory measurements.

Main results


This pooled, post-hoc analysis of ORION-9, -10, and -11 showed that inclisiran significantly reduced LDL-c compared placebo in patients with and without PVD. TEAEs were similar between treatment arms, except for an excess of mild or moderate clinically relevant TEAEs at the injection site in the inclisiran arm compared to the placebo arm.

-Our reporting is based on the information provided at the ESC Congress -

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