Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial
Open accessAbstract
Background Findings of large randomised trials have shown that lowering LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, but limited evidence exists about the long-term efficacy and safety of statin treatment. The aim of the extended follow-up of the Heart Protection Study (HPS) is to assess long-term efficacy and safety of lowering LDL cholesterol with statins, and here we report cause-specific mortality and major morbidity in the in-trial and post-trial periods.Methods 20,536 patients at high risk of vascular and non-vascular outcomes were allocated either 40 mg simvastatin daily or placebo, using minimised randomisation. Mean in-trial follow-up was 5·3 years (SD 1·2), and post-trial follow-up of surviving patients yielded a mean total duration of 11·0 years (SD 0·6). The primary outcome of the long-term follow-up of HPS was first post-randomisation major vascular event, and analysis was by intention to treat. This trial is registered with ISRCTN, number 48489393.Findings During the in-trial period, allocation to simvastatin yielded an average reduction in LDL cholesterol of 1·0 mmol/L and a proportional decrease in major vascular events of 23% (95% CI 19-28; p<0·0001), with significant divergence each year after the first. During the post-trial period (when statin use and lipid concentrations were similar in both groups), no further significant reductions were noted in either major vascular events (risk ratio [RR] 0·95 [0·89-1·02]) or vascular mortality (0·98 [0·90-1·07]). During the combined in-trial and post-trial periods, no significant differences were recorded in cancer incidence at all sites (0·98 [0·92-1·05]) or any particular site, or in mortality attributed to cancer (1·01 [0·92-1·11]) or to non-vascular causes (0·96 [0·89-1·03]).Interpretation More prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards. These findings provide further support for the prompt initiation and long-term continuation of statin treatment.Funding UK Medical Research Council, British Heart Foundation, Merck & Co, Roche Vitamins.
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A clinical benefit of lipid-lowering therapy would not be expected to emerge within a timeframe of less than 6 months.
“a timeframe during which a clinical benefit of lipid-lowering therapy would not be expected to emerge 10”
From Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis (2016) · cites this paper as [10]
The Results report no statistically significant reduction in major vascular events during the first year of simvastatin treatment, with significant reductions in subsequent years. The Discussion nevertheless notes fewer events in the first year. Neither passage establishes that clinical benefit would not be expected within six months, so the specific timeframe is unsupported. (LLM, conf=0.79)
Experimental — accuracy not yet measuredStatins provide consistent cardiovascular benefits and all-cause mortality reduction.
“The Heart Protection Study and Cholesterol Treatment Trialists’ Collaborators meta-analyses have demonstrated that statins provide consistent cardiovascular benefits and all-cause mortality reduction for patients [6, 7].”
Beneficial effects of statin therapy are retained over long-term follow-up.
“Beneficial effects are retained over longterm follow-up.427”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [427]
In managing dyslipidemia expressed by hypertriglyceridemia, the non-HDL-C level is more useful than the LDL-C level.
“However, in managing dyslipidemia expressed by hypertriglyceridemia, the non-HDL-C level is more useful than the LDL-C level. This has been reported in a number of studies177–179, 623, 624, 626, 627, 647).”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [627]
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- Authors
- Heart Protection Study Collaborative Group
- Corresponding author
- Heart Protection Study Collaborative Group
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 378
- Issue
- 9808
- Pages
- 2013-2020
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC3242163
- OpenAlex
- W2133184701
- Cited by
- 373
- References
- 17
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 15 · 2023: 17 · 2022: 14 · 2021: 13 · 2020: 14 · 2019: 20 · 2018: 25 · 2017: 17 · 2016: 28 · 2015: 29 · 2014: 27 · 2013: 41 · 2012: 38
- FWCI
- 38.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The Lancet (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- British Heart Foundation
- Medical Research Council (MC_EX_G0801669)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- statin therapy, simvastatin, LDL cholesterol lowering, long-term efficacy, vascular death, major vascular events, cancer incidence, post-trial follow-up, Heart Protection Study, high-risk patients, statin safety, lipid-lowering therapy, secondary prevention of cardiovascular disease, long-term follow-up, cardiovascular risk reduction
- MeSH terms
- Adult, Aged, Aged, 80 and over, Cholesterol, Female, Follow-Up Studies, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Middle Aged, Myocardial Infarction, Myocardial Revascularization, Neoplasms, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Stroke
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