HPS-4/TIMI 65/ORION-4: A double-blind randomized placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease: Trial design, recruitment, and baseline characteristics

@article{mafham2026hps4timi,
  title = {{HPS-4/TIMI 65/ORION-4: A double-blind randomized placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease: Trial design, recruitment, and baseline characteristics}},
  author = {Marion Mafham and Mohammed Zayed and Rory Collins and Marc Steven Sabatine and Jane Armitage and D Brittain and Bruno R. da Costa and F Chen and Michelle Abhayawardena Goonasekera and Michael Hill and Jemma C. Hopewell and Martin J. Landray and Michael Lay and Anastasia Lesogor and Aldo Pietro Maggioni and David A. Morrow and Michelle Nunn and Michelle L. O’Donoghue and Kausik Kumar Ray and Adel R. Rizkala and Gregory G. Schwartz and William Stevens and Karl Wallendszus and R. Scott Wright and Rohan Sajeev Wijesurendra and E Wincott and David Preiss and Louise J. Bowman},
  journal = {American Heart Journal},
  year = {2026},
  month = aug,
  doi = {10.1016/j.ahj.2026.107546},
  url = {https://doi.org/10.1016/j.ahj.2026.107546},
  note = {CC BY},
}

TY  - JOUR
TI  - HPS-4/TIMI 65/ORION-4: A double-blind randomized placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease: Trial design, recruitment, and baseline characteristics
AU  - Marion Mafham
AU  - Mohammed Zayed
AU  - Rory Collins
AU  - Marc Steven Sabatine
AU  - Jane Armitage
AU  - D Brittain
AU  - Bruno R. da Costa
AU  - F Chen
AU  - Michelle Abhayawardena Goonasekera
AU  - Michael Hill
AU  - Jemma C. Hopewell
AU  - Martin J. Landray
AU  - Michael Lay
AU  - Anastasia Lesogor
AU  - Aldo Pietro Maggioni
AU  - David A. Morrow
AU  - Michelle Nunn
AU  - Michelle L. O’Donoghue
AU  - Kausik Kumar Ray
AU  - Adel R. Rizkala
AU  - Gregory G. Schwartz
AU  - William Stevens
AU  - Karl Wallendszus
AU  - R. Scott Wright
AU  - Rohan Sajeev Wijesurendra
AU  - E Wincott
AU  - David Preiss
AU  - Louise J. Bowman
PY  - 2026
DA  - 2026/08/07
JO  - American Heart Journal
DO  - 10.1016/j.ahj.2026.107546
UR  - https://doi.org/10.1016/j.ahj.2026.107546
AB  - BACKGROUND: Despite widespread statin use, atherosclerotic cardiovascular disease remains a leading cause of morbidity and mortality worldwide. Monoclonal antibodies targeting circulating proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular events. However, the requirement for self-administration every 2 to 4 weeks may limit adherence to treatment. Inclisiran, a first-in-class small interfering ribonucleic acid (siRNA) therapy targeting hepatic PCSK9 production, has several potential advantages over the anti-PCSK9 monoclonal antibodies, principally longer duration of action. To date, however, the efficacy and safety of inclisiran have not been proven in a cardiovascular outcomes trial. METHODS: The ORION-4 study is the first large-scale clinical outcomes trial of an siRNA therapy, aiming to assess the efficacy and safety of inclisiran among participants with pre-existing atherosclerotic cardiovascular disease. The primary assessment is an intention-to-treat comparison of the effect of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran), given by subcutaneous injection at randomization, at approximately 3 months and then approximately every 6 months thereafter, on major adverse cardiovascular events (MACE), defined as the composite of coronary death, myocardial infarction, fatal or nonfatal ischemic stroke, or urgent coronary revascularization. Participants will be followed until the median time since randomization is at least 5 years and at least 1,700 participants have a recorded adjudicated MACE. With a planned sample size of ∼15,000 participants, ORION-4 was designed to have >99% power to detect a relative reduction in the primary outcome of about 1 quarter, while also providing an opportunity to assess efficacy in different subgroups as well as on secondary outcomes of interest. RESULTS: Between 2019 and 2023 a total of 16,124 participants were randomized in the UK and the US. The mean (SD) age was 70 (8) years and 30% were female. At baseline, 78% had a history of coronary heart disease, 22% of ischemic stroke, 15% of revascularization for peripheral arterial disease, and 23% had diabetes mellitus. 85% were on statin therapy (53% high intensity statin, 29% moderate and 3% low intensity statins). Overall, baseline mean (SD) LDL-C was 96 (32) mg/dL, and was similar among participants on high- and moderate/low-intensity statin regimens (87 [27] mg/dL and 93 [26] mg/dL respectively), with higher levels in those receiving no statin therapy (133 [33] mg/dL). Follow-up will complete during 2026 and results will be available in early 2027. INTERPRETATION: Inclisiran potentially offers a scalable lipid-lowering treatment, either alone or in combination with other agents. ORION-4 will evaluate the clinical efficacy of inclisiran, and provide a robust assessment of the safety of prolonged use of an siRNA therapeutic. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT03705234) and the EU Clinical Trials Register (EudraCT Number: 2017-005066-22).
SN  - 0002-8703
SN  - 1097-6744
ER  -