N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects

Wood, Frances A.; Howard, James P.; Finegold, Judith A.; Nowbar, Alexandra N.; Thompson, David M.; Arnold, Ahran; Rajkumar, Christopher; Connolly, Susan; Cegla, Jaimini; Stride, Chris; Sever, Peter; Norton, Christine; Thom, Simon; Shun-Shin, Matthew; Francis, Dárrel P.

doi:10.1056/nejmc2031173

“…Comparison with other literature StatinWISE and the concurrent SAMSON trial 19 are the first large series of n-of-1 trials to investigate the effect of statins on muscle symptoms. Our findings support the limited evidence from one small n-of-1 trial and large systematic reviews and meta-analyses of randomised trials that have not established a clear effect of statins on muscle symptoms in the absence of myopathy.…”

Section: Principal Findingsmentioning

confidence: 99%

Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials

Herrett

¹

,

Williamson

²

,

Brack

³

et al. 2021

BMJ

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Objective To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins. Design Series of randomised, placebo controlled n-of-1 trials. Setting Primary care across 50 sites in the United Kingdom, December 2016 to April 2018. Participants 200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms. Interventions Participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo. Main outcome measures At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods. Results 151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo −0.11, 95% confidence interval −0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins. Conclusions No overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment. Trial registration ISRCTN30952488 , EUDRACT 2016-000141-31, NCT02781064 .

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“…StatinWISE, along with the concurrent SAMSON trial, 35 are the first large-scale N-of-1 trials to investigate the effect of statins on muscle symptoms. Our findings largely support evidence from large systematic reviews and meta-analyses of randomised controlled trials, which have shown no effect of statins on muscle symptoms in the absence of myopathy, 3,4,22 despite being powered to have detected extremely rare and serious side effects of statins (e.g.…”

Section: Comparison With Other Literaturementioning

confidence: 99%

The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs

Herrett

¹

,

Williamson

²

,

Brack

³

et al. 2021

Health Technol Assess

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Background Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis. Objectives To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related. Design A series of 200 double-blinded N-of-1 trials. Setting Participants were recruited from 50 general practices in England and Wales. Participants Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms. Interventions Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo. Main outcome measures The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant’s belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant’s decision about statin treatment following the trial, and whether or not they found their own trial result helpful. Results A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo –0.11, 95% confidence interval –0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods. Conclusions Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial. Future work We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications. Limitations This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations. Trial registration Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 16. See the NIHR Journals Library website for further project information.

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“…James P. Howard, PhD, of Imperial College London, presented the results of the SAMSON (Self-Assessment Method for Statin Side-effects Or Nocebo) trial, which were simultaneously published online as a research letter in The New England Journal of Medicine [ 4 , 5 ]. Investigators in the SAMSON trial used a three-arm, double-blinded, n-of-1 design to investigate whether symptoms were reinduced by statin or placebo tablets.…”

Section: Primary Preventionmentioning

confidence: 99%