When patients were unaware they were taking statins there was no reported increase in muscle-related symptoms. But, when patients knew they were taking a statin, they were more likely to report symptoms, a finding consistent with the nocebo effect.
Muscle-related symptoms are less commonly reported when patients and their doctors are unaware that statin therapy is being used, compared to when they are aware, according to a new study in The Lancet. The study looks at data on 26 side effects from a trial of approximately 10,000 patients and suggests that cases of muscle pain and weakness are unlikely to be directly caused by statins, but may instead be due to the so-called nocebo effect, where the expectation of side effects can make patients more likely to report them.
Statins are cholesterol lowering drugs that are widely prescribed to patients at increased risk of heart attacks or strokes. A large review of evidence concluded that for every 10,000 people deemed high risk, lowering LDL cholesterol by 2 mmol/L with a daily dose of atorvastatin 40mg for 5 years could prevent 1,000 cases of heart attacks, strokes or coronary bypasses. Known side effects include an increase in the risk of diabetes (50-100 new cases per 10,000 people), haemorrhagic strokes (5-10 per 10,000) and myopathy (5 per 10,000)1.
A contested issue is the rate of muscle pain and weakness, with observational studies in general practice finding that up to a fifth of patients report symptoms, with little to no increase identified in randomised trials. The study published today helps explain this difference.
Professor Peter Sever, lead author from the National Heart and Lung Institute, Imperial College London, UK, says: "Just as the placebo effect can be very strong, so too can the nocebo effect. This is not a case of people making up symptoms, or that the symptoms are 'all in their heads'. Patients can experience very real pain as a result of the nocebo effect and the expectation that drugs will cause harm. What our study shows is that it's precisely the expectation of harm that is likely causing the increase in muscle pain and weakness, rather than the drugs themselves causing them."2
He adds: "We know that statins can prevent a significant number of heart attacks and strokes. We know there is a small increase in the risk of diabetes, and at high doses there is a very small increase in myopathy, but overall the benefits greatly outweigh the harms. Widespread claims of high rates of statin intolerance still prevent too many people from taking an affordable, safe and potentially life-saving medication."2
The first phase of the trial was conducted in 1998-2002 and included 10,180 patients aged 40-79 with hypertension and at least three other cardiovascular risk factors from the UK, Ireland and Scandinavia. Patients were randomly assigned to receive atorvastatin 10mg or placebo and were followed for 3 years. This phase was a blinded randomised trial: neither the doctors nor the participants knew whether they were receiving the drug or a placebo.
At the end of the 3 years, the drug was shown to be effective and the same patients were offered the choice of taking a statin or not. This is the non-blinded, non-randomised phase of the trial. 9899 of the original participants were followed for a further 2 years, and two thirds (65%) of them chose to use a statin.
During the blinded phase of the study, the rate of muscle-related symptoms was similar whether patients received a statin or placebo (2.03% per year vs. 2% respectively). However, during the non-blinded phase of the study, muscle-related symptoms were 41% more common among people taking statins compared to those who weren't (1.26% vs 1.00% per year respectively).
In total, the analysis looked at 26 types of side effects including erectile dysfunction, sleep disturbance and cognitive impairment. These four side effects had previously been identified as possible side effects by the Medicines and Healthcare Products Regulatory Agency and Food and Drug Administration, on the basis of observational studies.
The randomised, blinded phase of the trial found no difference between the statin and placebo groups for erectile dysfunction (1.86% vs 2.14% per year). Sleep disturbance was lower in the statins group compared to placebo (1.00% vs 1.46%) and there was an increase in renal and urinary side effects in the statins group compared to placebo (1.87% vs 1.51%), both of which require further investigation. Too few cases of cognitive impairment were reported to provide reliable data, and no other differences in the other adverse events was identified.
The authors highlight that the trial was conducted in 1998-2004, before claims that statin therapy causes high rates of side effects were as widespread as they are today. They note that this may mean the strength of the nocebo effect is likely underestimated in this trial.
Participants were prescribed atorvastatin at a daily dose of 10mg, and only a few people in the non-blinded phase used simvastatin. This dose would now be considered a low dose, but the authors note that randomised trials of higher doses have not found that statins cause an increase in muscle related symptoms, other than the very small increase in myopathy.
In a linked Comment, Dr Juan Pedro-Botet, Hospital del Mar, and Dr Juan Rubiés-Prat, Universitat Autònoma de Barcelona, Barcelona, Spain, write: "Muscle-related adverse event rates are often argued to be low in randomised controlled trials owing to patient selection. Thus, the strengths of Gupta and colleagues' study lie in the fact that these were the same patients, no run-in period existed to exclude patients intolerant to therapy, and few patients had previously taken any statins. Additionally, the atorvastatin dose typically used in the non-blinded phase was the same as in the blinded phase.... Given that statins are among the best evidence-based lipid-lowering tools available and suitable for many patients, prevention of intolerance is paramount. Thus, physicians should alert their patients to possible statin-associated side-effects without raising negative expectations. Furthermore, they should encourage patient understanding of the rationale for statin treatment, which could optimise and facilitate shared decision making on statin therapy."
The trial was funded by Pfizer, Servier Research Group and Leo Laboratories. ASCOT was conceived, designed, and coordinated by an investigator-led independent Steering Committee with two non-voting members from the principal funding source (Pfizer). Data collection, analysis, and interpretation and preparation of all reports were done independently of the funding sources. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Article: Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase, Ajay Gupta, MRCP, David Thompson, MRCPI, Andrew Whitehouse, MBBS, Tim Collier, MSc, Bjorn Dahlof, MD, Prof Neil Poulter, FMedSci, Prof Rory Collins, FRS, Prof Peter Sever, FRCP on behalf of the ASCOT Investigators, The Lancet, doi: 10.1016/S0140-6736(17)31075-9, published 2 May 2017.