Prevention & lipidsTrial design
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
- double-blind randomized placebo-controlled trial
- first large-scale clinical outcomes trial of an small interfering ribonucleic acid (siRNA) therapy
- intention-to-treat
- UK and the US
Study context
- Population
- Participants with pre-existing atherosclerotic cardiovascular diseaserandomized between 2019 and 2023 in the UK and the US, planned sample size ∼15,000
- Participants
- 16,124 participants
- Planned comparison
- intention-to-treat comparison of the effect of inclisiran sodium 300 mg on major adverse cardiovascular events (MACE)
- Primary endpoint
- MACE, defined as the composite of coronary death, myocardial infarction, fatal or nonfatal ischemic stroke, or urgent coronary revascularization
- Follow-up
- Until the median time since randomization is at least 5 years and at least 1,700 participants have a recorded adjudicated MACE
No results yet. This paper sets out the design of a trial; its results are to come.
Baseline
Baseline characteristics
- Mean (SD) age
- 70 (8) years
- Female
- 30%
- History of coronary heart disease
- 78%
- History of ischemic stroke
- 22%
- History of revascularization for peripheral arterial disease
- 15%
- Diabetes mellitus
- 23%
- On statin therapy
- 85%
- High intensity statin
- 53%
- Moderate intensity statin
- 29%
- Low intensity statin
- 3%
Baseline mean (SD) low-density lipoprotein cholesterol (LDL-C)
- Overall
- 96 (32) mg/dL
- High-intensity statin
- 87 [27] mg/dL
- Moderate/low-intensity statin
- 93 [26] mg/dL
- No statin therapy
- 133 [33] mg/dL
Original publication
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. Am Heart J. Published 7 August 2026. doi:10.1016/j.ahj.2026.107546
Summarised from the published abstract; every number is checked against it