TY - JOUR
T1 - Interpretation of the evidence for the efficacy and safety of statin therapy
AU - Collins, Rory
AU - Reith, Christina
AU - Emberson, Jonathan
AU - Armitage, Jane
AU - Baigent, Colin
AU - Blackwell, Lisa
AU - Blumenthal, Roger
AU - Danesh, John
AU - Smith, George Davey
AU - DeMets, David
AU - Evans, Stephen
AU - Law, Malcolm
AU - MacMahon, Stephen
AU - Martin, Seth
AU - Neal, Bruce
AU - Poulter, Neil
AU - Preiss, David
AU - Ridker, Paul
AU - Roberts, Ian
AU - Rodgers, Anthony
AU - Sandercock, Peter
AU - Schulz, Kenneth
AU - Sever, Peter
AU - Simes, John
AU - Smeeth, Liam
AU - Wald, Nicholas
AU - Yusuf, Salim
AU - Peto, Richard
N1 - Funding Information:
JA, CB, LB, RC, JE, RP, DP, and CR work in the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU) at the University of Oxford. The CTSU 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. DP has participated in advisory meetings for Sanofi related to PCSK9 inhibitor therapy in his previous employment. The CTT Collaboration, which is coordinated by CTSU with colleagues from the University of Sydney, does not receive industry funding. JD has received research grants from, and served as a consultant to, Merck and Pfizer. GDS has twice received travel and accommodation funding and honoraria from Merck; DD receives compensation for serving on data monitoring committees for clinical trials (including of statins) funded by Abbvie, Actelion, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Sanofi, and Teva. NW and ML are inventors of a combination formulation for the prevention of cardiovascular disease that includes a statin, covered by patents licensed to Polypill in which they both hold shares and which owns the website polypill.com . SMac has received research grants for research on statins and polypill development from Bristol-Myers Squibb and BUPA. SMar is co-inventor on a pending patent for a LDL cholesterol estimation method, and has served as an advisor to Sanofi, Regeneron, Quest Diagnostics, Pressed Juicery, and Abbott Nutrition. NP has received research grants and honoraria for participating in advisory meetings and giving lectures from Amgen, Lilly, Menorini, and Merck. PR has received investigator-initiated research grants from Amgen, AstraZeneca, Kowa, Novartis, and Pfizer. PSe has received research grants and honoraria for consultancies from Amgen and Pfizer. LS has undertaken advisory work unrelated to statins for AstraZeneca and GlaxoSmithKline. SY has received a research grant from AstraZeneca through Hamilton Health Sciences. AR declares that George Health Enterprises, the social enterprise arm of The George Institute, has received investment to develop combination products containing statin, aspirin, and blood-pressure-lowering drugs. JS has received grants from the National Health and Medical Research Council, Australia; Bayer Pharmaceuticals; Roche; and Merck Serono. RB, SE, BN, IR, and PSa declare no competing interests.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/11/19
Y1 - 2016/11/19
N2 - This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events 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). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy—ie, adverse effects of the statin—are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50–100 new cases of diabetes, and 5–10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50–100 patients (ie, 0·5–1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.
AB - This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events 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). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy—ie, adverse effects of the statin—are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50–100 new cases of diabetes, and 5–10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50–100 patients (ie, 0·5–1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.
UR - http://www.scopus.com/inward/record.url?scp=84989187956&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84989187956&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(16)31357-5
DO - 10.1016/S0140-6736(16)31357-5
M3 - Review article
C2 - 27616593
AN - SCOPUS:84989187956
VL - 388
SP - 2532
EP - 2561
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10059
ER -