Statin-associated muscle-related adverse effects: a case series of 354 patients

Abstract

Study objective: To characterize the properties and natural history of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-associated muscle-related adverse effects (MAEs).

Design: Patient-targeted postmarketing adverse-effect surveillance approach coupling survey design with an open-ended narrative.

Setting: University-affiliated health care system.

Subjects: Three hundred fifty-four patients (age range 34-86 yrs) who self-reported muscle-related problems associated with statin therapy.

Measurements and main results: Patients with perceived statin-associated MAEs completed a survey assessing statin drugs and dosages; characteristics of the MAEs; time course of onset, resolution, or recurrence; and impact on quality of life (QOL). Cases were assessed for putative drug adverse-effect causality by using the Naranjo adverse drug reaction probability scale criteria and were evaluated for inclusion in groups for which mortality benefit with statins has been shown. Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p<0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p<0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and QOL domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy.

Conclusion: This study complements available information on the properties and natural history of statin-associated MAEs, affirming dose dependence and strong QOL impact. The data indicating a dose-dependent relationship between MAE risk and recurrence suggest lower potency statins or discontinuation may bear consideration for ameliorating symptoms.

Figure 1

Expectation of overall mortality benefit from statins among patients with muscle-related adverse effects in the probable or definite causality subgroup as a function of age and sex (data were available for 290 of the 300 patients). ^a“Expected benefit” uses outcomes that balance net risks and benefits from the use of cholesterol-lowering drugs (overall mortality, all-cause serious morbidity). ^bExpected benefit of statin therapy in middle-aged men is expected to be overstated in this figure. Middle-aged men without high risk for cardiovascular disease (Air Force/Texas Coronary Atherosclerosis Prevention Study [AFCAPS]) have shown no trend toward overall mortality or morbidity or serious adverse events benefit. ^cWomen (Scandinavian Simvastatin Survival Study [4S] and Long-term Intervention with Pravastatin in Ischaemic Disease [LIPID]) and those older than 70 years (Prospective Study of Pravastatin in the Elderly at Risk [PROSPER]), even those at high risk for cardiovascular disease, have shown no trend to overall mortality benefit.

Figure 2

Negative impact of statin-associated muscle-related adverse effects on six everyday activities (A) and eight general quality-of-life (QOL) domains (B). Data indicate mean ratings of patients with probable or definite muscle-related adverse effects based on Naranjo criteria. Error bars indicate standard error, 2-sided p<0.000000001 for all domains. Some patients indicated positive values for both everyday muscle-related activity (26 patients) and general QOL domains (18 patients). Some patients responded with positive values to all QOL domains (everyday muscle-related activity [4 patients], general QOL [8 patients]) indicating possible misinterpretation of the visual analog scales. All other patients indicating positive values (everyday muscle-related activity [22 patients], general QOL [10 patients]) reported at least one or more other domains with negative impact on QOL.