Armitage, Jane

Baigent, Colin

Collins, Rory

Smeeth, Liam

Smith, George Davey

LSHTM Research Online

Collins, R; Armitage, J; Baigent, C; Smith, GD; Smeeth, L (2017)Safety and efficacy of statins - Authors’ reply. Lancet, 389 (10074).pp. 1099-1100. ISSN 0140-6736 DOI: 10.1016/S0140-6736(17)30717-1Downloaded from: http://researchonline.lshtm.ac.uk/3682703/DOI: 10.1016/S0140-6736(17)30717-1Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: http://creativecommons.org/licenses/by/2.5/Correspondencewww.thelancet.com   Vol 389   March 18, 2017 1099excess of diabetes with statin therapy4). In a meta-analysis of 26 masked trials (including STOMP, CORONA, OCS, and HPS) with an average treatment duration of 3 years,8 muscle problems were reported by 14 000 patients but there was little difference between the treatment groups: 12·7% of participants assigned statin versus 12·4% of those assigned placebo; an absolute excess of 0·3% (95% CI 0–0·7; p=0·06). Thompson asserts that we concluded that “statin myalgia does not exist”, but we did not. Instead, we concluded that the annual excess of muscle-related problems actually caused by (rather than being attributed to) statin therapy is no more than about 10–20 cases per 10 000 treated individuals, with only about one of those cases associated with substantial elevations in creatine kinase concentrations (ie, myopathy) and requiring statin therapy to be stopped.We are in agreement with Fabrice Bonnet and colleagues that the availability of additional large-scale evidence about the effects of statin therapy from randomised controlled trials in people aged over 75 years would be of value. However, as is discussed in our Review, the inverse associations of cholesterol with mortality in observational studies in older people appear to reflect a failure to take account of reverse causality (which becomes increasingly important with age as more people experience chronic disease). By contrast, Mendelian randomisation studies indicate that the strength of the association of LDL cholesterol with coronary heart disease continues unchanged into older ages.11 Consequently, until additional evidence becomes available, it remains reasonable to extrapolate from the evidence among younger individuals to the use of statin therapy in people older than 75 years.4,12With regard to the comments by Abramson and colleagues, the many misrepresentations of the evidence in their previous paper (including the claim, subsequently withdrawn, that statins cause side-effects in one-fifth of treated patients2,3) are dealt with in to press patients experiencing adverse effects from statins to comply”. We agree; however, it is also important that patients are not encouraged to stop statin therapy if they experience adverse events that are not actually caused by the statin.The STOMP trial5 involved multiple comparisons of several different muscle-related measures: there were no apparent effects of statin therapy on muscle strength or endurance, aerobic performance, or physical activity, and, whether emphasis is put on the on-treatment analysis reported by the investigators5 or on our intention-to-treat analysis based on all randomly assigned patients,4 the observed difference in the muscle pain outcome remains compatible with chance. The assertion by Paul Thompson and Beth Taylor that the “p value exceeds the magical 0·05 of significance, but it is very close to this statistical threshold” represents a misunderstanding of the meaning of p values.6 Moreover, rather than single out one particular result in one particular study, it is more appropriate to base judgments on the totality of the evidence.Thompson and Taylor state that only one randomised trial (CORONA,7 of 5011 elderly patients with heart failure) included in their meta-analysis8 specifically sought information about muscle symptoms. However, this is incorrect: patients were also asked about such symptoms at each follow-up visit in (at least) the Oxford Cholesterol Study (OCS)9 and the Heart Protection Study (HPS),10 which involved more patients (621 and 20 536, respectively) and longer treatment exposure (3·4 and 5·3 years, respectively) than STOMP (468 patients for 6 months5). Consequently, the trial that Thompson and colleagues propose has already been done in large numbers of people with comorbidities.Moreover, as discussed in our Review, randomised masked trials are able to detect differences that exist in the incidence of adverse events even if they are not sought specifically (eg, the small Collins and colleagues should perform a larger STOMP-like RCT to make sure they are right before concluding that statin myalgia does not exist.BT reports grants from Regeneron Pharmaceuticals during the conduct of the study. PDT reports grants and personal fees from Regeneron, grants and personal fees from Sanofi, personal fees from Amgen, grants and personal fees from Amarin, personal fees from Merck, and grants from Genomas, Esperion, and Pfizer, outside the submitted work, and owns stock in the following companies, which are involved in drug manufacture and sales or make medical devices: Abbvie, Abbott Labs, CVS, General Electric, Johnson & Johnson, Medtronic, and Sarepta.*Paul D Thompson, Beth Taylorpaul.thompson@hhchealth.orgHartford Healthcare Cardiovascular Institute, Hartford, CT 06104, USA1  Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388: 2532–61.2  Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation 2013; 127: 96–103.3  Ganga HV, Slim J, Thompson PD. A sytematic review of statin-induced muscle problems in clinical trials. Am Heart J 2014; 168: 6–15.Authors’ replyThe comments by Simon Dimmitt and colleagues have already been addressed in a response to a previous letter from them.1 In particular, lowering LDL cholesterol more intensively with higher-dose statin therapy has been shown to produce larger reductions in vascular events than with smaller LDL reductions. With respect to the suggestion that adverse effects contribute to more than half of patients discontinuing statin therapy, results from randomised masked trials have shown that patients are no more likely to discontinue statin therapy than placebo; that is, Dimmitt and colleagues confuse attribution with causation (as did John Abramson and colleagues2,3). Moreover, as is discussed in our Review,4 many of these trials were started before statin therapy was being widely used, so few of the patients would have been previously exposed to a statin and excluded because of having had problems with it. Dimmitt and colleagues state that it is “unreasonable SciencePhotoCorrespondence1100 www.thelancet.com   Vol 389   March 18, 20171 Smith SC Jr, Grundy SM. Reply: statin dose based on limited evidence. J Am Coll Cardiol 2015; 65: 759–602 Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013; 347: f6123.3 Godlee F. Adverse effects of statins. BMJ 2014; 348: g3306.4 Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388: 2532–61.5 Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation 2013; 127: 96–103.6 Wasserstein RL, Lazar NA. The ASA’s statement on p-values: context, process, and purpose. Am Stat 2016; 70: 129–133.7 Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357: 2248–61.8 Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J 2014; 168: 6–15.9 Keech A, Collins R, MacMahon S, et al. Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study. Eur Heart J 1994; 15: 255–69.10 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22.11 Postmus I, Deelen J, Sedaghat S, et al. LDL cholesterol still a problem in old age? A Mendelian randomization study. Int J Epidemiol 2015; 44: 604–12.12 Greenland P, Bonow RO. Interpetation and use of another statin guideline. JAMA 2016; 316: 1977–78.regimens (without good evidence of higher rates of side-effects other than myopathy).Consequently, it is appropriate to base the estimated magnitude of benefit that can be achieved by the use of an effective statin regimen on the LDL reduction that is likely to be achieved (rather than on the risk reduction per mmol/L): that is, lowering LDL cholesterol by 2 mmol/L for 5 years in 10 000 patients would typically prevent one (or more) major vascular event from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Figure 5 provided estimates for the absolute benefits that would be achieved with different LDL reductions.4 However, because statin therapy reduces vascular disease risk during each year that it continues to be taken, the absolute benefits would be even larger with more prolonged therapy. The Clinical Trial Service Unit & Epidemiological Studies Unit (RC, JA, and CB) has received research grants from Abbott, AstraZeneca, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Schering, and Solvay that are governed by University of Oxford contracts that protect its independence, and it has a staff policy of not taking personal payments from industry (with reimbursement sought only for the costs of travel and accommodation to attend scientific meetings). RC is co-inventor of a genetic test for statin-related myopathy risk, but receives no income from it. GDS has twice received travel and accommodation funding and honoraria from Merck. LS has undertaken advisory work unrelated to statins for AstraZeneca and GlaxoSmithKline.*Rory Collins, Jane Armitage, Colin Baigent, George Davey Smith, Liam Smeethrory.collins@ndph.ox.ac.ukClinical Trial Service Unit & Epidemiological Studies Unit and MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK (RC, JA, CB); MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK (GDS); and Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, University of London, London, UK (LS)detail in our Review. We also explained that analyses based on a composite outcome for which the direction and magnitude of the effects of treatment on the separate components are similar (as is the case with statin therapy and major vascular events) can allow reliable evidence to emerge about the effects in different circumstances, because they are based on much larger numbers of events than for any of the separate components. So, for example, combination of the beneficial effect of statin therapy on vascular mortality overall and the definite reduction in major vascular events among lower-risk patients provides support for concluding that statin therapy reduces the risk of death among lower-risk patients (despite the absence of a significant reduction in the relatively small number of deaths among such individuals considered in isolation).As was discussed in our Review, the use of such composite outcomes does not mean that equal weight should necessarily be given to the different components of the composite in deciding whether or not to use the treatment. However, nor should effects on some types of major vascular events be dismissed entirely, as Abramson and colleagues seek to do, when they are associated with subsequent morbidity and mortality.Additionally, it is a mistake not to recognise that intention-to-treat analyses tend to under estimate the effects of actually taking a treatment. Table 3 in our Review4 indicates that actual use of an effective statin regimen (eg, atorvastatin 40 mg daily) would reduce LDL cholesterol by at least 2 mmol/L in individuals who present with concentrations of 4 mmol/L or more (estimated to be about half of the European or North American population in the absence of statin therapy). As shown in figure 3,4 the reductions in the risks of major vascular events were larger in trials in which there were larger reductions in LDL cholesterol, and more intensive statin therapy produced larger reductions in risk than lower dose Lessons from the controversy over statinsJane Armitage and colleagues, led by senior author Rory Collins, (Nov 5, p 2237)1 and Richard Horton (Nov 5, p 2237)2 appear to believe that retraction of an article from The BMJ will end the debate about statins and primary prevention. Even were there grounds for retraction, I fear they would be disappointed. Questions about the evidence base for statins continue to emerge from many quarters: how strong is the evidence, how large is the benefit for individuals at lowest risk of heart disease, how well did the trials record common minor side-effects, how representative were the trials of women and the elderly, For questions about the evidence base for statins see http://blogs.bmj.com/bmj/2016/09/12/richard-lehman-where-next-with-statins/

Safety and efficacy of statins - Authors' reply.

http://researchonline.lshtm.ac.uk/3682703/1/1-s2.0-S0140673617307171-main.pdf

Safety and efficacy of statins - Authors' reply.

Abstract

Similar works

Full text

Available Versions

LSHTM Research Online