In contrast to pair-wise MA that directly estimates causal effects, an NMA can indirectly estimate risk between placebo and moderate, moderate and high, and between placebo and high intensity treatment, even though placebo, moderate and high intensity treatment levels were not compared within a single trial. 12 13 This study used a network meta-analysis (NMA) to combine evidence across trials to estimate the risk of SAMS by treatment intensity. Although this is assumed to be true, especially with the evidence against simvastatin 80 mg, 10 11 few RCTs have examined high intensity therapy. SAMS also may be more likely with higher intensity therapy. 7 One review 9 suggested that clinical observations of increased muscle problems with statin therapy may be due to patient expectations. 3 Observational studies suggest that these mild SAMS may occur as often as 7%–29% of patients. 3 These milder symptoms are the major public health concern, as statin non-adherence can lead to significant increases in risk of major adverse cardiovascular events. However, it did not report on the more mundane myalgias that often cause statin attrition. 3 For example, a 2016 MA found a non-significant increase in myopathy. 7 Most RCTs have shown small, insignificant increases in risk for SAMS, although patients taking statins may complain of muscle problems and may discontinue therapy due to muscle problems. 3–8 Statin-associated muscle symptoms (SAMS), however, may lead to non-adherence or discontinuation with therapy and ultimately to poorer cardiovascular outcomes. 1 2 Statin therapy is now prominent in cholesterol management guidelines. The Cholesterol Treatment Trialists’ Collaboration meta-analysis (MA) on patient-level data from large randomised controlled trials (RCTs) demonstrated that statin therapy is efficacious in reducing major vascular events.

There were no significant differences in risk between moderate intensity therapy and placebo for all outcomes.

Due to inconsistency of results across sensitivity analyses, estimates were inconclusive for rhabdomyolysis and CK. NMA results indicated risk was significantly greater for high compared with moderate intensity statin therapy for any muscle problem (RR=1.04, 95% CI 1.00 to 1.07 I 2=0%), myalgia (RR=1.04, 95% CI 1.00 to 1.08 I 2=0%, number needed to harm (NNH)=173), attrition due to muscle problems (RR=1.37, 95% CI 1.09 to 1.73, I 2=0%, NNH=218) and elevated CK (RR=4.69, 95% CI 2.50 to 8.80 I 2=7%, NNH=527). Results Of 2919 RCTs, 24 (n=152 461) met inclusion criteria.

Moderate intensity statin