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Letter by Zhou et al Regarding Article, "Statin Toxicity: Mechanistic Insights and Clinical Implications".

Letter by Zhou et al Regarding Article, “Statin Toxicity: Mechanistic Insights and Clinical Implications” To the Editor: We read with interest the review by Ward et al on statin toxicity, with its focus on adverse events (AEs) in routine clinical practice particularly statin-associated muscle symptoms (SAMS). The authors have provided a broad and deep insight into the potential mechanisms of statin toxicity and its clinical importance. However, some statements are problematic. Ward et al stated twice that the relatively low rate of statin intolerance in clinical trials is believed to be attributed to the selective study population because statin-intolerant participants were excluded either before randomization or during statin run-in periods. Peto and Collins have shown that most large, long-term randomized controlled trials of statins used a placebo run-in period to exclude noncompliant participants. They have also suggested that few of the trial participants would have had prior experience of statin use. Therefore, it is not likely that statin-intolerant participants were routinely excluded. Ward et al also pointed out that, although no excess risk of SAMS was observed in randomized controlled trials, the overall frequency of muscle-related symptoms had been underreported as a result of the lack of clear definition of SAMS and systematic query of muscle symptoms during the follow-up. However, one should note that both a broad definition and systematic query of SAMS that capture more statin-unrelated AEs could lower the specificity of diagnosis, thus reducing the study power to demonstrate the between-group difference. Diagnosing symptoms as being attributable to statins in the routine care setting is even more problematic as consequences of misattribution are forgone potential benefits. Ward et al also stated that few trials had assessed the creatine kinase level and other biomarkers which may affect the trialability to identify statin-related adverse effects. It should be noted that most SAMS are simple myalgia (without raised creatine kinase levels) rather than myositis. Ward et al stated that SAMS are by far the most prevalent AEs, accounting for up to 72% of all statin-related AEs. This evidence was derived from a large-scale, web-based clinician survey conducted in 12 countries. However, in the original article, it was reported that among 6% of patients who were statin-intolerant, 64% were confirmed to have SAMS. Although it is correct that SAMS were the most common form of AE, in absolute terms they occurred in only 3.8% of all statin users. This shows that the frequency of SAMS in this survey is as low as that seen in randomized controlled trials (around 1%–5%). Ward et al also stated that age is considered the leading predisposing risk factor for statin-associated AEs. This claim, however, is not supported by the existing trial evidence. PROSPER trial (Prospective Study of Pravastatin in the Elderly at Risk), which is the only major trial exclusively recruiting older individuals (aged 70 to 82 years), have shown that no increased risk of SAMS was seen in the statin group compared with the placebo. In the ASCOT-LLA trial (Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm) in atorvastatin group, participants aged ≥65 years had a lower rate of myalgia than those aged <65 years (2.6% versus 2.9%). We emphasize that evidence from randomized controlled trials should be given more weight when assessing the safety of statins as they are the most rigorous and only way to establish the causal relationship of statins to AEs.