DOI: 10.5061/dryad.kprr4xh2q
title: Intensity of statin therapy and muscle symptoms: a network meta-analysis of 153,000 patients

description: Objective: To estimate relative risk of statin-associated musculoskeletal
 symptoms (SAMS) by statin therapy intensity. Setting: Network
 meta-analysis assessing multi-center RCTs across several countries.
 Participants: Pubmed, Web of Science, Cochrane database, and
 clinicaltrials.gov were searched through January 2021 for doubled-blinded
 RCTs testing the effect of statin therapy on lipids with at least 1000
 participants and two years of intended treatment. Two coders assessed
 articles for final inclusion, quality, and outcomes. Treatment intensity
 was categorized according to American Heart Association definitions.
 Outcomes: Pairwise and network meta-analysis (NMA) estimated relative risk
 (RR) and risk difference (RD) with random effects modeling. Heterogeneity
 was evaluated with the I2 statistic. Outcomes included muscle symptoms
 (any, myalgia, and attrition due to muscle symptoms), rhabdomyolysis, and
 elevated creatine kinase (&gt;10x upper limit of normal). Results: Of
 2801 RCTs, 24 (N=152,461) met inclusion criteria. NMA results indicated
 risk was significantly greater for high compared to moderate intensity
 statin therapy for any muscle problem (RR=1.04, 95% CI: 1.00,1.07; I2=0%
 ), myalgia (RR=1.04, 95% CI: 1.00,1.08; I2=0%, NNH=173), attrition due to
 muscle problems (RR=1.37, 95% CI: 1.09,1.73, I2=0%, NNH=218), and elevated
 CK (RR=4.69, CI: 2.50, 8.80; I2=7%, NNH=527). Risk also was significantly
 higher for high intensity compared to placebo for any muscle problem
 (RR=1.05, 95% CI: 1.01,1.09, I2=0% ), myalgia (RR=1.13, 95% CI: 1.05,1.23;
 I2=0%, NNH=182), attrition due to muscle problems (RR=1.55, 95% CI:
 1.15,2.08, I2=0%, NNH=187), and elevated CK (RR=5.37, CI: 2.48, 11.61;
 I2=7%, NNH=589). Due to inconsistency of results across sensitivity
 analyses, estimates were inconclusive for rhabdomyolysis and CK. There
 were no significant differences in risk between moderate-intensity therapy
 and placebo for all outcomes. Conclusions: For approximately 200
 patients on high-intensity statins, one additional patient may experience
 myalgia or discontinue therapy due to muscle problems compared to
 moderate-intensity therapy. Trial Registration: Prospero #CRD42019112758
description: <b>From the manuscript: </b>
 <b>The Trials</b>.  PubMed, Cochrane Database, Web of
 Science, and clinicaltrials.gov were searched (Prospero #CRD42019112758
 for search terms and strategy) from January 1, 2010 to October 1, 2018 to
 identify eligible trials. Double-blinded RCTs to improve lipid levels that
 comparing statin therapy to placebo or higher-lower dose statin therapy
 were selected. In order to detect most adverse events, RCTs were selected
 that had at least 1,000 participants with two years of intended follow-up,
 where statin treatment was not given with other prescription drug
 therapies, and results contained reports on muscle-related adverse events.
 All included trials were coded for quality with Oxford Center for
 Evidence-based Medicine ratings<sup>14</sup> and a five-point
 Jadad quality score. <b>Exposure
 Variable.</b>  Studies were classified by intensity of statin
 treatment (“high” or “moderate”)  according to American Heart Association
 definitions for potency in reduction of lipid
 levels.<sup>15</sup> High intensity signifies an expected 50%
 or greater reduction in LDL-C levels when taking that statin (i.e., 80 mg
 atorvastatin) and moderate signifies 30-50% reduction in
 LDL-C.<sup>15</sup>
 <b>Outcome Variables</b>. Adverse muscle-related
 events were coded into five main outcomes.  The first outcome was for any
 patient-reported muscle complaint coded from reports of “muscle aches”,
 “pains”, “cramps”, “stiffness,” “musculoskeletal disorders,” etc.  The
 second focused on only myalgia or muscle pain. The third focused on
 attrition due to musculoskeletal complaints. A fourth captured explicit
 reporting of rhabdomyolysis, with or without a trial definition. The fifth
 was elevated creatine kinase, greater than ten times the upper limit of
 normal (CK &gt;10x ULN). This threshold was used to distinguish this
 outcome from less meaningful CK increases and also because
 CK&gt;10xULN is commonly reported in RCTs. All outcomes were coded as
 reported by original investigators in published and online reports, and
 were independently coded by two people (JD, SW). Trial investigators were
 contacted for clarification, where needed.