The benefits of statin therapy have been repeatedly underestimated and the harms exaggerated, due to misinterpretation of the evidence, according to researchers.
A major review of the available evidence on the safety and efficacy of statin therapy, published in The Lancet, said there had previously been a failure to acknowledge properly both the wealth of evidence from randomised trials and the limitations of other types of studies.
“The best available scientific evidence tells us that statins are effective, safe drugs that have a crucial role”
The authors said they hoped their review would help both clinicians and patients to make informed decisions about the use of the drugs.
They highlighted that research on statins has been ongoing for over 30 years, generating a large amount of data from a wide variety of patients.
Based on the available evidence, the reviewers looked at the balance of lowering cholesterol by 2mmol/L with low-cost statin therapy – atorvastatin 40mg daily – for five years in 10,000 patients.
They concluded it would prevent major cardiovascular events in 1,000 people with pre-existing vascular disease – secondary prevention – and in 500 people who are at increased risk but have not yet had a vascular event – primary prevention.
However, in contrast, it would also cause five cases of myopathy, five to 10 haemorrhagic strokes, 50-100 new cases of diabetes and up to 50-100 cases of symptomatic adverse events, such as muscle pain.
The authors noted that, although further research may identify small additional beneficial or adverse effects, it was unlikely to materially alter the balance of benefits and harms for patients because of the quantity of evidence generated so far.
Review author Professor Rory Collins, from the clinical trial service unit at Oxford University, 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,” he said.
“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,” he added.
Professor Liam Smeeth, review co-author from the London School of Hygiene and Tropical Medicine, London, added: “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.”
Charities and clinical organisations were almost unanimous in their support for the review’s findings and called for them to be enshrined in guidelines.
Professor Jeremy Pearson, associate medical director at the British Heart Foundation, said: “This comprehensive review reiterates the life saving benefits of statins, which vastly outweigh the rare side effects associated with the medicine.
“Medicine should be guided by evidence and this review will help clinicians to consider the available evidence and judge its strengths and weaknesses,” he said.
Dr Maureen Baker, chair of the Royal College of GPs, said: “This study cuts through a lot of the controversy surrounding statins – it recognises the benefits that these drugs have for many patients, but also the potential side-effects that any prescribing healthcare professional should be aware of.
“A decision to prescribe statins will never be taken lightly and should always be the result of a discussion,” she said. “It remains essential that patients who are prescribed statins undertake regular medication reviews.
“As with any new research, it is now important that this study is taken on board as guidelines for healthcare professionals are updated in the best interests of our patients,” she added.
Heart UK chief executive Jules Payne said: “This review is a significant step forward and dispels any myths about statins. There is an awful lot of nonsense claimed about the side effects of statins and these controversies put lives at risk and harm the health of thousands of people.
“Heart disease can be avoided and statins play a significant part in reducing the numbers of heart attacks and strokes in those at risk,” she said. ”We are delighted at last to see such a significant review clearly detailing the facts.”
Dr Alessandro Ble, senior research fellow at the University of Exeter’s medical school, described the review as a “great contribution to clinical practice”, but also called for more studies into the impact of statins in those over 80, noting that few very old patients were included in the statin clinical trials.
“As large numbers of the oldest patients are prescribed statins, I would welcome more evidence for very elderly patients. The oldest patients often have several diseases and can be more susceptible to adverse effects,” he said.
The review in detail and what it found
Randomised trials vs observational studies
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.
In a randomised trial, patients are randomly divided into two or more groups – eg, one group is given a drug and the other group is given a dummy treatment (ie, a “placebo”). Researchers then compare the rates of health outcomes between these groups. Randomly allocating patients means that any difference in these rates can generally be attributed to the treatment itself (see panel 1). Additionally, by “blinding” the patients and their doctors as to whether they are taking the drug being studied or a placebo, bias in the assessment of health outcomes between the different treatment groups can be avoided.
Meta-analyses bring together evidence from randomised trials that have tested the same treatment and, by including data from a larger and more diverse set of patients, can increase the reliability and generalisability of the results.
By contrast, observational studies compare the health outcomes of people who have been given a particular treatment by their doctors as part of routine care, and people who have not been given the treatment. Doctors give treatments to selected patients for good reasons, so the health of the patients given a treatment may be very different to the health of people who are not given it. These differences in the underlying risks of the different groups of patients are hard to predict, and it is not possible to know that they have been allowed for completely in the analyses.
In addition, patients prescribed a drug in routine care know that they are getting it, and their doctors may have warned them that the drug may cause problems. Consequently, the patients may be more likely to attribute health outcomes (particularly symptoms that are subjective, eg muscle aching) to the drug, whereas people who are not taking the drug would not do so.
As a result, although observational studies may be able to detect large increases in health outcomes that would usually be rare, they are not able to produce reliable evidence about the effects of drug treatments when the health outcomes are common or the effects are not large.
Benefits of statin therapy
Evidence from large population studies, combined with studies in animals, genetic research and randomised controlled trials have confirmed a causal link between higher levels of LDL cholesterol in the blood and higher risks of vascular disease.
Meta-analyses of large randomised controlled trials of statin therapy indicate that each 1mmol/L reduction in LDL cholesterol with statin therapy reduces the risk of coronary deaths and heart attacks, ischaemic strokes (strokes due to blood clots) and coronary revascularisation procedures by about 25% during each year (after the first) that treatment continues to be taken (figure 3 & 5).
The meta-analyses also indicate that larger reductions in LDL cholesterol with statin therapy produce larger reductions in the risks of these major vascular events. For example, using an effective statin regimen (such as generic atorvastatin 40mg daily, which costs about £2 per month in the UK) to reduce LDL cholesterol by 2mmol/L would almost halve a person’s risk of a major vascular event.
It has been claimed, based on observational studies, that statin therapy might also reduce the risks of cancer and various other conditions (including respiratory diseases and infections, deep vein thrombosis, and post-operative atrial fibrillation). However, the evidence from randomised trials shows that these associations in observational studies do not reflect a causal effect of statin therapy.
Harms of statin therapy
Myopathy is a rare condition involving muscle pain, tenderness, or weakness accompanied by significant increases in blood creatine kinase concentrations. Evidence from observational studies and randomised trials points to a causal effect of statin therapy on myopathy. However, the risk of myopathy is low: about 1 extra case per 10,000 patients taking an effective statin regimen (such as atorvastatin 40mg daily) during each year of treatment.
In addition, evidence from randomised trials has identified an increased risk of diabetes due to statin therapy: about 10-20 extra cases of diabetes developing per 10,000 treated patients per year. This excess of diabetes occurs mainly in people who are already at increased risk of developing diabetes, and its clinical significance is uncertain. In particular, although diabetes is associated with increased risk of vascular disease, statin therapy produces substantial reductions in vascular disease.
Some observational studies have suggested statin therapy may be associated with an increased risk of haemorrhagic stroke. And randomised trials indicate that statin therapy may increase the risk of haemorrhagic stroke by about one-fifth. Typically, in Western populations, this would correspond to an increase of about 5-10 extra cases per 10,000 treated patients per year. In most circumstances, the reductions in ischaemic strokes produced by statin therapy are much bigger than the increases in haemorrhagic strokes, so the risk of stroke of any kind is reduced substantially.
Reports of increased rates of muscle pain and weakness in observational studies have led to claims that as many as 20% of patients have “statin intolerance”, mainly due to muscle pain and weakness. The randomised trial evidence demonstrate that these claims represent misattribution of symptoms to the statin therapy. Instead, at most, statin therapy causes an increase in symptomatic adverse events (such as muscle pain and weakness) in about 10-20 of 10,000 treated patients per year.
It has been claimed, based on observational studies, that statin therapy might increase the risks of various other conditions (including memory loss, cataracts, kidney injury, liver disease, sleep disturbance, aggression, suicidal behavioural, erectile disjunction and neuropathy). However, the evidence from the randomised trials shows that these associations in observational studies do not reflect a causal effect of statin therapy.