Statin-associated Muscle Symptoms: Impact on Statin Therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management

Erik S. Stroes; Paul D. Thompson; Alberto Corsini; Georgirene D. Vladutiu; Frederick J. Raal; Kausik K. Ray; Michael Roden; Evan Stein; Lale Tokgözoğlu; Børge G. Nordestgaard; Eric Bruckert; Guy De Backer; Ronald M. Krauss; Ulrich Laufs; Raul D. Santos; Robert A. Hegele; G. Kees Hovingh; Lawrence A. Leiter; Francois Mach; Winfried März; Connie B. Newman; Olov Wiklund; Terry A. Jacobson; Alberico L. Catapano; M. John Chapman; Henry N. Ginsberg

Disclosures

Eur Heart J. 2015;36(17):1012-1022. 

In This Article

Assessment and Diagnosis of Statin-associated Muscle Symptoms

While consensus groups including the American Heart Association/American College of Cardiology[28] and the National Lipid Association[19] have presented definitions of SAMS based on symptoms and the magnitude of CK elevation, less attention has been paid to clinical diagnostic criteria. Indeed, a definitive diagnosis of SAMS is difficult because symptoms are subjective and there is no 'gold standard' diagnostic test. Importantly, there is also no validated muscle symptom questionnaire, although the National Lipid Association has proposed a symptom scoring system based on the STOMP trial and the PRIMO survey (see Supplementary material online, Table S2 http://eurheartj.oxfordjournals.org/content/suppl/2015/02/18/ehv043.DC1).[19] Consequently, we suggest that assessment of the probability of SAMS being due to a statin take account of the nature of the muscle symptoms, the elevation in CK levels and their temporal association with statin initiation, discontinuation, and re-challenge. Note that this is a clinical definition, which may not be appropriate for regulatory purposes.

In the absence of a standardized classification of SAMS, we propose to integrate all muscle-related complaints (e.g. pain, weakness, or cramps) as 'muscle symptoms', subdivided by the presence or absence of CK elevation (Table 1). Pain and weakness in typical SAMS are usually symmetrical and proximal, and generally affect large muscle groups including the thighs, buttocks, calves, and back muscles. Discomfort and weakness typically occur early (within 4–6 weeks after starting statin therapy[22]), but may still occur after many years of treatment. Onset of new symptoms may occur with an increase in statin dose or initiation of an interacting drug. The symptoms appear to be more frequent in physically active individuals.[11] Statin-associated muscle symptoms often appear more promptly when patients are re-exposed to the same statin.

In the vast majority of cases, SAMS are not accompanied by marked CK elevation.[24,29] For SAMS with CK elevations >10× ULN, usually referred to as myopathy, the incidence is approximately 1 per 10 000 per year with a standard statin dose (e.g. simvastatin 40 mg daily). The risk varies, however, among different statins, and increases not only with the dose of statin, but also with factors associated with increased statin blood concentrations (e.g. genetic factors, ethnicity, interacting drugs, and patient characteristics) (see Box 1).[30] Rhabdomyolysis is a severe form of muscle damage associated with very high CK levels with myoglobinaemia and/or myoglobinuria with a concomitantly increased risk of renal failure. The incidence of rhabdomyolysis in association with statin therapy is ~1 in 100 000 per year.[7] In view of the rarity of CK elevations during statin therapy, it is not recommended to routinely monitor CK. Even if an asymptomatic elevation of CK is detected, the clinical significance is unclear.

Statin-associated muscle symptoms are more likely to be caused by statins when elevated CK levels decrease after cessation of either the statin or the interacting drug, or when symptoms regress markedly within a few weeks of cessation of the statin and/or reappear within a month of drug re-challenge. Time to reappearance of symptoms is also influenced by the dose of statin and the duration of the re-challenge. Individual patient drug–placebo clinical trials have been suggested as an approach to confirming diagnosis of SAMS,[31] but are not feasible in the routine outpatient setting.

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