Study protocol for statin web-based investigation of side effects (StatinWISE): a series of randomised controlled N-of-1 trials comparing atorvastatin and placebo in UK primary care

Abstract

IntroductionStatins are effective at preventing cardiovascular disease, widely prescribed and their use is growing. Uncertainty persists about whether they cause symptomatic muscle adverse effects, such as pain and weakness, in the absence of statin myopathy. Discrepancies between data from observational studies, which suggest statins are associated with excess muscle symptoms, and from randomised trials, which suggest no such excess, have caused confusion. N-of-1 trials offer the opportunity to establish whether muscle symptoms during statin use are caused by statins in particular individuals.Methods and analysisThis series of 200 randomised, double-blinded N-of-1 trials in primary care will determine (1) the effect of statins on all muscle symptoms and (2) the effect of statins on muscle pain that is perceived to be statin related. Patients who are considering discontinuing statin use due to muscle symptoms and those who have discontinued in the last 3 years due to such symptoms will be recruited. Participants will be randomised to a sequence of six 2-month treatment periods during which they will receive atorvastatin 20 mg per day or matched placebo. On each of the last 7 days of each treatment period, participants will rate their muscle symptoms on a Visual Analogue Scale (VAS).At the end of their trial, participants will be shown numerical and graphical summaries of their own symptom data during statin and placebo periods. The primary analysis on the aggregate data from all participants will be a linear mixed model for VAS muscle symptom score, comparing scores during treatment with statin and placebo.Ethics and disseminationThis trial received a favourable opinion from South Central-Hampshire A Research Ethics Committee. Results will be published in a peer-reviewed medical journal. Dissemination of results to patients will take place via the media, website (statinwise.lshtm.ac.uk) and patient organisations.Trial registration number ISRCTN30952488.

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

“…Overall, further research is critically needed to identify, validate and integrate novel risk factors for the different SRM phenotypes to improve predictive capability and harmonise understanding of SRM pathogenesis. We propose that the integration of strict clinical phenotyping to identify statin-induced myalgia through the N-of-1 trial paradigm [277], with systems pharmacology omics-based approaches, should be beneficial. Replication of the miR-499-5p and miR-145 signals is needed.…”

Tackling statin intolerance with n-of-1 trials (TaSINI) in primary care: protocol for a feasibility randomised trial to increase statin adherence

“…For each individual’s n-of-1 trial, there was no clinically significant difference in pain symptoms while taking the statin compared with the placebo medication, and most patients resumed statin treatment full time. A larger scale study is currently ongoing which comprises a series of blinded, randomised n-of-1 trials in 200 primary care patients with perceived statin intolerance 15. This study aims to offer the opportunity for participants to determine whether the symptoms they experience are attributable to statins, by alternating between statin and placebo.…”

Demonstrating Heterogeneity of Treatment Effects Among Patients: An Overlooked but Important Step Toward Precision Medicine

“…Examples of similar ongoing efforts include a clinical trial to evaluate the effects of melatonin on sleep in a stimulant‐treated attention deficit hyperactivity disorder population, which plans to enroll 300 participants with three active and three placebo periods . Another published protocol outlines a planned trial with 200 patients to evaluate statin‐induced muscle symptoms with three active and three placebo periods . Analyses of these data similar to the ones performed here may help to determine whether it is worthwhile to invest resources to identify predictors of response to drugs with known efficacy in particular therapeutic areas.…”