Intensity of statin therapy and muscle symptoms: a network meta-analysis of 153,000 patients

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 (>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