Doctors, patients and the public now have more help to make informed decisions about statin therapy, thanks to a major review of the available evidence on the safety and efficacy of the drug published in The Lancet. The authors, including researchers from the London School of Hygiene & Tropical Medicine, warn that the benefits of statin therapy have been underestimated, and the harms exaggerated, because of a failure to acknowledge properly both the wealth of evidence from randomised trials and the limitations of other types of studies.

Research on statins has been ongoing for over 30 years, generating a large amount of data from a wide variety of patients. The review explains how the available evidence on the efficacy and safety of statin therapy should be interpreted.

It concludes that lowering cholesterol by 2 mmol/L with an effective low-cost statin therapy (atorvastatin 40 mg daily, which costs about £2 per month in the UK) for five years in 10,000 patients would: prevent major cardiovascular events (heart attacks, ischaemic strokes and coronary artery bypasses) in 1,000 people with pre-existing vascular disease (‘secondary prevention’), and in 500 people who are at increased risk (due to their age or having hypertension or diabetes) but have not yet had a vascular event (‘primary prevention’); cause five cases of myopathy, involving muscle pain, tenderness, or weakness accompanied by significant increases in blood creatine kinase concentrations, one of which might progress to the more severe condition of rhabdomyolysis if the statin is not stopped. It would also cause 5-10 haemorrhagic strokes, 50-100 new cases of diabetes and up to 50-100 cases of symptomatic adverse events such as muscle pain.

Professor Liam Smeeth, co-author from the London School of Hygiene & Tropical Medicine, said: “The best available scientific evidence tells us that statins are effective, safe drugs that have a crucial role in helping prevent cardiovascular disease: the leading cause of morbidity and mortality worldwide.”

The authors note that although further research may identify small additional beneficial or adverse effects, this is unlikely to materially alter the balance of benefits and harms for patients because of the evidence generated so far.

Professor Rory Collins, review author from the Clinical Trial Service Unit, University of Oxford, said: “Our review shows that the numbers of people who avoid heart attacks and strokes by taking statin therapy are very much larger than the numbers who have side-effects with it. In addition, whereas most of the side-effects can be reversed with no residual effects by stopping the statin, the effects of a heart attack or stroke not being prevented are irreversible and can be devastating.

“Consequently there is a serious cost to public health from making misleading claims about high side-effect rates that inappropriately dissuade people from taking statin therapy despite the proven benefits.”

The review discusses the strengths and limitations of different types of studies. Randomised controlled trials are a robust and well recognised way of determining the effect of treatments. Whereas observational studies based on databases can generate hypotheses about associations between the use of drugs and health outcomes, randomised trials can determine cause and effect.

Summary

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.

Authors
Rory Collins, Christina Reith, Jonathan Emberson, Jane Armitage, Colin Baigent, Lisa Blackwell, Roger Blumenthal, John Danesh, George Davey Smith, David DeMets, Stephen Evans, Malcolm Law, Stephen MacMahon, Seth Martin, Bruce Neal, Neil Poulter, David Preiss, Paul Ridker, Ian Roberts, Anthony Rodgers,
Peter Sandercock, Kenneth Schulz, Peter Sever, John Simes, Liam Smeeth, Nicholas Wald, Salim Yusuf, Richard Peto

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