SAMS: Statin-Associated Muscle Symptoms
In 2015, the European Atherosclerosis Society (EAS) Consensus Panel published a key statement focused on statin-associated muscle symptoms (SAMS).1 This paper provided important information to assist clinicians in the assessment and management of SAMS in their routine practice, and, uniquely, appraised what is known to date regarding the pathophysiology of SAMS. Readers are referred to the publication for full details.
Nocebo or not?
More than 2 years later, SAMS continues to attract much interest. A key issue has been whether SAMS is a real or nocebo effect, i.e. related to negative expectancies about the effects of treatment, including adverse effects, arising from information about possible side effects provided by clinicians and/or the media.2,3 Indeed, a report from the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA) claimed that SAMS was due to a nocebo effect. This study evaluated the incidence of muscle-related adverse events in both the blinded phase of the trial, when patients were randomly assigned to atorvastatin 10 mg daily or matching placebo, and in the non-blinded phase, when all patients were offered open-label atorvastatin 10 mg daily.4 The ASCOT-LLA group reported that when patients knew they were taking statins (in the open phase), there was an excess of muscle adverse events among statin users compared with non-users (annual event rate 1.26% versus 1.0%). In contrast, there was no significant difference in the reporting rate between atorvastatin and placebo groups in the blinded phase. On this basis, the authors concluded that their findings provided evidence that the nocebo effect was the main contributor to reporting rates for SAMS.
But, to counter this, inspection of the paper shows that the overall reporting rate for muscle-related symptoms decreased from the blinded to open phases of the trial (from 2.03% to 1.26%). If SAMS was a nocebo effect, surely an increase in overall reporting of muscle symptoms would be expected when patients knew they were on a statin?
New genetic insights
Added to this, there are clear genetic signals for statin-induced myalgia. Studies have previously identified variants of genes encoding drug transporters in both the liver and skeletal muscle, most notably SLCO1B1, encoding organic anion-transporting polypeptide 1B1 (OATP1B1).5,6 In a very recent report, a variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B), linked with lower creatine phosphokinase (CK) and lactate dehydrogenase levels, markers of injury to muscle tissue, was also implicated in statin myalgia.7 Using electronic medical record data from the Genetics of Diabetes and Audit Research Tayside Study (GoDARTS) cohort, investigators showed that this variant was associated with statin intolerance. In this study, statin intolerance was defined clinically as raised CK and non-adherence with statin therapy, or inability to tolerate the lowest approved dose of a statin before being switched to two or more other statins (independent of CK elevation). Individuals with at least one copy of this variant had more than 30% increased risk for developing statin intolerance. These findings also suggest an immunogenetic contribution to statin intolerance.
SAMS: a cardiovascular risk factor
The critical point why SAMS is important is its detrimental impact on cardiovascular risk. While guidelines recommend high intensity statin therapy in very high-risk patients with clinical atherosclerotic cardiovascular disease, surveys such as EUROASPIRE IV show that only minority of such patients maintain high dose treatment in the longer-term, and thus remain at risk of recurrent events.8,9
Statin intolerance contributes to lack of adherence and thus an increase in risk for cardiovascular events. This has been highlighted in a recent US analysis of more than 100,000 patients who were initiated on moderate- or high-intensity statin after hospital admission for myocardial infarction (MI).10 Patients were defined as statin intolerant if they underwent down-titration of statin doses and initiation of ezetimibe; switched from statin to ezetimibe monotherapy; developed rhabdomyolysis or an antihyperlipidaemic adverse event, followed by statin down-titration or discontinuation; or switched between three or more statins within one year after initiation. Overall, 1,741 patients (1.65%) had statin intolerance; these individuals had a 36% higher rate of recurrent MI, and a 43% higher rate of all coronary heart disease events during the follow-up period of about 2 years.
It is imperative that, wherever possible, patients at high risk of (recurrent) cardiovascular events remain on statin therapy. Allocating time is the critical factor in the management of these patients; sufficient time should be allowed to explain why patients need a statin, to reassure the patient, and for assessment of statin dechallenge/rechallenge, which is essential to differentiate true SAMS. The EAS Consensus Panel statement provided a clinical algorithm to aid in assessment. There is also interest in the development of a rating scale to assist identification of SAMS in routine practice. The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI) is one proposal for differentiating SAMS from nonspecific muscle symptoms.11 This index assesses SAMS as “probable” (score 9 to 11), “possible” (score 7 to 8), or “unlikely” (score 2 to 6) based on 4 scales relating to the location, pattern, timing of onset, and timing of improvement of symptoms after statin withdrawal. An initial investigation of the utility of this tool in a randomized study of statin myopathy showed promise, as patients with confirmed SAMS on a statin had higher scores than those with muscle symptoms on placebo, muscle symptoms on statin or placebo, or no muscle symptoms on either treatment.12 However, validation in large prospective studies is needed before this tool (or an adaptation) is available for routine use.
Forgotten patient groups
It is well recognized that older patients have specific issues with medication adherence. Despite this, adherence and persistence patterns among older statin users have been less well researched. Insights from a meta-analysis including data from more than three million statin users aged >65 years in 82 studies conducted in over 40 countries, showed that about 60% of patients in either primary or secondary prevention settings were adherent (medication taken on at least 80% of days) one year after starting a statin. Yet, when the data were analyzed by age group, adherence was worse in those aged over 75 years.13 Given an ageing society,14 with older individuals increasingly accounting for a larger proportion of the cardiovascular disease burden, improving statin adherence in this patient group is essential to reduce both the individual and societal cost of cardiovascular-related disability. A systematic review and meta-analysis aims to address the lack of information about the risk of SAMS, as well as nonadherence due to SAMS, among older patients receiving statins for primary prevention of cardiovascular events, based on data from randomized placebo-controlled trials with at least one year of follow-up.15
The EAS Consensus Panel statement on SAMS has undoubtedly driven new research into the aetiology, and assessment of SAMS, with the ultimate aim of improving management, and thus overcoming the detrimental impact of SAMS on clinical outcome.
- Stroes ES, Thompson PD, Corsini A et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015;36:1012-22.
- Colloca L. Nocebo effects can make you feel pain. Science 2017;358:44.
- Matthews A, Herrett E, Gasparrini A et al. Impact of statin related media coverage on use of statins: interrupted time series analysis with UK primary care data. BMJ 2016;353:i3283.
- Gupta A, Thompson D, Whitehouse A et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet 2017;389:2473-81.
- SEARCH Collaborative Group, Link E, Parish S, Armitage J et al. SLCO1B1 variants and statin-induced myopathy–a genome wide study. N Engl J Med 2008;359:789-99.
- Bakar NS, Neely D, Avery P et al. Genetic and clinical factors are associated with statin-related myotoxicity of moderate severity: A case-control study. Clin Pharmacol Ther 2017 Sep 22. doi: 10.1002/cpt.887. [Epub ahead of print].
- Siddiqui M, Maroteau C, Veluchamy A et al. A common missense variant of LILRB5 is associated with statin intolerance and myalgia. Eur Heart J 2017. doi: 10.1093/eurheartj/ehx467. [Epub ahead of print]
- Reiner Ž, De Backer G, Fras Z et al. Lipid lowering drug therapy in patients with coronary heart disease from 24 European countries–Findings from the EUROASPIRE IV survey. Atherosclerosis 2016;246:243-50.
- Colantonio LD, Huang L, Monda KL et al. Adherence to high-intensity statins following a myocardial infarction hospitalization among medicare beneficiaries. JAMA Cardiol 2017;2:890-5.
- Serban MC, Colantonio LD, Manthripragada AD et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol 2017;69:1386-95.
- Rosenson RS, Miller K, Bayliss M et al. The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): revision for clinical use, content validation, and inter-rater reliability. Cardiovasc Drugs Ther 2017;31:179-86.
- Taylor BA, Sanchez RJ, Jacobson TA et al. Application of the Statin-Associated Muscle Symptoms-Clinical Index to a randomized trial on statin myopathy. J Am Coll Cardiol 2017;70:1680-1.
- Ofori-Asenso R, Jakhu A, Zomer E et al. Adherence and Persistence among statin users aged 65 years and over: a systematic review and meta-analysis. J Gerontol A Biol Sci Med Sci 2017 Sep 2. doi: 10.1093/gerona/glx169. [Epub ahead of print]
- World population ageing 2015. United Nations 2015 http://www.un. org/ en/ development/ desa/ population/ publications/ pdf/ ageing/WPA2015_ Report. Pdf
- Zhou Z, Albarqouni L, Breslin M et al. Statin-associated muscle symptoms (SAMS) in primary prevention for cardiovascular disease in older adults: a protocol for a systematic review and meta-analysis of randomized controlled trials. BMJ Open 2017;7:e017587.