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Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses

BMJ 2021; 374 doi: (Published 15 July 2021) Cite this as: BMJ 2021;374:n1537

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Value of statins in asymptomatic patients

Dear Editor

Cai et al [1] present a comprehensive and useful meta-analysis of adverse events (AEs) and efficacy in the primary prevention of cardiovascular disease in the published statin trials. Some AEs like renal insufficiency, liver dysfunction, diabetes and cerebral haemorrhage can have serious consequences. The suggestion that the benefit-to-harm balance of statins is favourable is not clearly supported by the numbers, for example the absence of any appreciable improvement in overall survival, i.e. total mortality. [2-4]

The number of patients needed to be treated for one patient to benefit (NNTB), i.e. one cardiovascular event to be avoided in Cai’s and previous analyses [1,5] is around 300, when expressed per annum. AEs are necessarily underestimated in clinical trials, as any history of toxicity usually precludes participation. The risk of AEs even in patients who continued on statins in the trials analysed, listed in Table 2, [1] compared to placebo, adds up to 186/10,000, i.e. 1.86%. Assuming that most AEs develop in the first year, the number needed to harm (NNTB), i.e. for one patient to develop an AE, is thereby around 54, more than 5-fold the NNTB. AEs are likely to persist unless the statin is stopped or the dose is reduced.

The challenge of weighing the severity of the risk and the magnitude of the benefit does not apply to the total mortality data, i.e. overall survival. Such provides a very clear benefit-to-harm measure, particularly given that cardiovascular disease remains the leading cause of death in most countries. In contrast to the unequivocal, highly statistically significant, improved survival reported on statins after a coronary event in several of the largest studies, [6-8] the impact on total mortality in asymptomatic patients has repeatedly been shown to be not significant. [2-4] Informed patients may choose to decline statin treatment, especially if they are already on essential antihypertensive, antithrombotic and/or diabetic drugs, which all have substantial coronary benefits.


1 Cai T, Abel L, Langford O, et al. Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses. BMJ 2021;374:n1537. doi:10.1136/bmj.n1537

2 Warren JB, Dimmitt SB, Stampfer HG. Cholesterol trials and mortality. Br J Clin Pharmacol 2016;82:168-77. doi:10.1111/bcp.12945

3 Yourman LC, Cenzer IS, Boscardin WJ, et al. Evaluation of time to benefit of statins for the primary prevention of cardiovascular events in adults aged 50 to 75 years: a meta-analysis. JAMA Intern Med 2021;181:179-85. doi:10.1001/jamainternmed.202.6084

4 Kristensen ML, Christensen PM, Hallas J. The effect of statins on average survival in randomised trials, an analysis of end point postponement. BMJ Open 2015;5:e007118. doi:10.1136/bmjopen-2014-007118

5 Mortensen MB, Nordestgaard BG. Statin use in primary prevention of atherosclerotic cardiovascular disease according to 5 major guidelines for sensitivity, specificity, and number needed to treat. JAMA Cardiol 2019;4:1131-38. doi:10.1001/jamacardio.2019.3665

6 Pedersen RE, Kjekshus J, Berg K, et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.

7 Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22. doi: 10.1016/S0140-6736(02)09327-3

8 Long-term intervention with pravastatin in ischaemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin inpatients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57. doi: 10.1056/NEJM199811053391902.

Competing interests: No competing interests

30 July 2021
Simon B Dimmitt
Clinical Professor of Medicine
Hans G Stampfer, John B Warren, Jennifer H Martin
University of Western Australia, University of Newcastle
35 Stirling Highway, Crawley, Western Australia 6009