Statins are foundational for the management of hypercholesterolaemia to prevent atherosclerotic cardiovascular disease (ASCVD), as reaffirmed in the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) lipid guidelines (1). A key deterrent to the efficacious use of statin therapy, however, is statin intolerance, which contributes to treatment non-adherence and/or discontinuation, and adverse cardiovascular outcomes (2). Management of statin intolerance is hampered by the heterogeneity of symptoms reported by patients, and the lack of internationally agreed clinical criteria, validated biomarkers or diagnostic tools.
The predominant adverse effects reported to statin therapy are muscle symptoms. Many may be due to non-specific muscle pain, and therefore estimating the prevalence of true statin muscle-related intolerance is difficult (3). To address these issues, the EAS Consensus Panel developed a definition of statin-associated muscle side effects (SAMS) (4,5). Based on these criteria, the PROSISA study showed that a prevalence of 9.6% in more than 16,000 statin-treated patients in 23 lipid clinics in Italy, although only a third still had symptoms after statin dechallenge/rechallenge (6).
Yet the debate around the veracity of SAMS, and more generally statin intolerance, continues. This has been largely fuelled by discrepancies in reporting rates between randomised comparator trials versus observational or surveillance programmes, leading some to suggest that SAMS is a ‘nocebo effect.’ Supporting this view is a retrospective analysis from the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA) (7), which evaluated the incidence of muscle-related adverse events in the blinded phase of the trial (when atorvastatin 10 mg daily or matching placebo were randomly allocated), and in the non-blinded phase (when all patients were offered open-label atorvastatin 10 mg daily). The reporting rate of muscle adverse events was higher among statin users than non-users in the non-blinded phase but did not differ between atorvastatin and placebo groups in the blinded phase. Despite this, the overall reporting rate was lower in the non-blinded than blinded phases. This appears counter intuitive as if patients knew they were on a statin, reporting rates should have increased in the open phase. This contradiction may be explained by inappropriate quantification of the ‘nocebo effect’; in the context of a randomised controlled trial, the placebo arm should be compared to a no‐treatment group (8). Some have proposed an alternative term – a ‘negative drucebo effect’ – when referring to adverse effects of a drug resulting from patient expectations based on information rather a pharmacological cause (9).
Irrespective of semantics, this debate continues with publication of the SAMSON study, a double-blind, three-group, n-of-1 trial which specifically investigated symptoms on statin or placebo (10). SAMSON incorporated a number of design features in response to patient feedback. The study was of reasonable duration (12 months), with each patient receiving 12 bottles (four months supply each of statin or placebo tablets or empty) according to a random sequence. The one-month allocation for each (or no) treatment was considered adequate for reporting of symptoms, which were not restricted to muscle aches. The primary endpoint was symptom intensity, assessed by the nocebo ratio, i.e., the ratio of symptom intensity induced by taking placebo to the symptom intensity induced by taking a statin. The secondary endpoint was the proportion of patients who successfully restarted statin treatment following discontinuation.
Of 62 patients screened, 60 were randomised and completed at least one month of the trial; over half (60%) had received one or two statins previously. On average, symptom intensity was similar during placebo or statin months (15.4 and 16.3, respectively), and both were significantly higher (p<0.001) than during no-treatment months (8.0). The nocebo proportion was 0.90, i.e., while patients reported side effects while taking statin tablets, 90% of their symptom burden was also elicited while taking placebo tablets. Thus, the authors concluded that side effects on a statin are mainly due to the act of taking the tablets rather than the components of the tablets (10).
The study does, however, have several limitations. The lack of washout between the different treatments suggests the potential for carryover of symptoms between statin and placebo arms. The onset of symptoms was limited to 4 weeks; however, in practice many patients may develop symptoms later. Indeed, while muscle pain/weakness typically occurs within 4-6 weeks after starting statin treatment, the onset may be delayed to months or even years later (11). The analysis was also not restricted to muscle symptoms, the most common presentation of statin adverse effects (12). This is an important point, as appraisal by the EAS Consensus Panel and other groups concluded that there was evidence for causality for only three statin‐related adverse effects: SAMS, new onset diabetes, and transient elevations of liver enzymes (4,5,13). Thus, inclusion of all symptoms may have favoured a nocebo effect.
Six months after the trial, half of the patients had successfully restarted statin treatment (10). These findings underscore the need for clinicians to acknowledge their patients’ symptoms on statin therapy, and using a structured work-up, to ensure that as many as possible continue on a statin and therefore gain cardiovascular benefit. Listening to and managing patient expectations are critical to a favourable outcome in the management of statin intolerance, and more specifically SAMS.
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