NICE guidance on inclisiran should be reconsideredBMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n2462 (Published 12 October 2021) Cite this as: BMJ 2021;375:n2462
- Paula Byrne, research fellow1,
- Maryanne Demasi, investigative reporter2,
- Susan M Smith, professor of primary care medicine1
- 1HRB Centre for Primary Care Research, RCSI University of Medical and Health Sciences, Ireland
- 2Institute for Scientific Freedom, Copenhagen, Denmark
- Correspondence to: P Byrne
The National Institute for Health and Care Excellence (NICE) recently published draft guidance recommending inclisiran, a new cholesterol lowering drug, for selected patient groups.1 The director of the Centre for Health Technology Evaluation at NICE, Meindert Boysen, stated: “Inclisiran represents a potential game-changer in preventing thousands of people from dying prematurely from heart attacks and strokes.”2
The new guidance attracted media attention345 and will be of interest to clinicians, patients, and the wider public. Inclisiran has been found to lower low density lipoprotein (LDL) cholesterol by about 50% in people not responding to other lipid lowering treatments.6 This injectable drug requires biannual administration, which may improve adherence.
The pharmaceutical industry is another interested party. All statins are now off patent, so drug companies could benefit from alternatives that are patented. Lipid regulating drugs account for substantial drug expenditure worldwide; global sales of statins alone were estimated to approach $1tn by 2020.7 Statins were the most frequently prescribed medicine in England in 2018.8
NICE’s appraisal of inclisiran considered both clinical and cost effectiveness.9 Clinical effectiveness was based on data from three placebo controlled trials. Orion-9 included 482 patients with familial hypercholestrolaemia10; Orion-10 and Orion-11 were reported together and included 1561 patients with cardiovascular disease and 1617 people at high risk of cardiovascular disease (type 2 diabetes, familial hypercholestrolaemia, or a 10 year risk of at least 20% as assessed by the Framingham risk score or equivalent).6
These trials ran for 18 months, and the primary outcome was change from baseline in participants’ serum concentrations of LDL cholesterol. LDL cholesterol is a surrogate outcome for cardiovascular disease, and doubts remain over whether improvements in surrogate endpoints are an accurate reflection of patient benefit.11
Secondary outcomes included an exploratory cardiovascular endpoint—a composite of death, cardiac arrest, non-fatal myocardial infarction, and stroke—but the overall number of events was too low to draw conclusions. Inclisiran was well tolerated and no safety signals emerged. Further studies are planned to evaluate the efficacy (LDL cholesterol lowering), safety, and tolerability of inclisiran over four years,1213 and another trial, Orion-4, will report cardiovascular outcomes in 2026.14
NICE’s analysis assumes that because inclisiran lowers LDL cholesterol, it will also reduce cardiovascular events, an assumption based on published meta-analyses by the Cholesterol Treatment Triallists.1516 However, these analyses have been criticised because the underlying data are not available for independent scrutiny,1718 and the clinical importance of reduced LDL cholesterol in relation to cardiovascular risk remains uncertain. The Accelerate trial, for example, reported that while evacetrapib reduced mean LDL cholesterol by 31% in high risk adults, it did not reduce risk of cardiovascular events.19 Similarly, a systematic review of statins, ezetimibe, and PCSK9 inhibitors found a “lack of consistent mortality and cardiovascular benefit” despite participants achieving recommended LDL cholesterol concentrations.20 Furthermore, efficacy outcomes reported by the Cholesterol Treatment Triallists relate to statins only, and these drugs’ anti-inflammatory and anti-thrombotic properties may have contributed to reported reductions in cardiovascular events.
NICE concluded that inclisiran was cost effective above certain thresholds of LDL cholesterol, but the underlying cost data were not made public. The committee strongly recommended that the guidance should be reviewed once more mature cardiovascular outcome data are available as these would show whether LDL cholesterol reduction is an appropriate surrogate outcome for inclisiran.21
In trials, the safety profile of inclisrian seemed comparable with placebo. However, this long acting drug is intended for lifelong use, and data on long term harms is currently inadequate. Despite remaining uncertainties, both NICE and the National Institute for Health Research have described inclisiran as ground breaking.24 The health secretary, Sajid Javid, called it “life changing.”3 This follows earlier public endorsement by the previous health secretary, Matt Hancock, in 2020—well before NICE’s recommendation—at the launch of a clinical trial collaboration between the NHS and inclisiran’s manufacturer, Novartis.2
Serious questions arise from these developments. Firstly, why did NICE recommend inclisiran without any data on clinically meaningful cardiovascular outcomes when clinical outcomes and better safety data will be available within five years? Secondly, although a long-standing practice, is it ethical for NICE, a publicly funded organisation, to keep its cost analysis confidential?22 Thirdly, is the public endorsement of a new but unproved drug by senior politicians and public bodies, appropriate?
We do not know if inclisiran will improve cardiovascular outcomes for patients, we do not know how much it will cost, and we have insufficient data on safety given the relatively small number of patients in trials to date. The drug may prove to be a “game changer,” or it may not. Clinicians and their patients need to be aware of the limitations in the evidence. NICE should reconsider its decision until patient relevant outcomes are available, and these, and all cost data, should be released for independent analysis.
Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare no other interests.
Provenance and peer review: Commissioned; not externally peer reviewed.