BlueCross and BlueShield of Montana Medical Policy/Codes
Genetic Testing for Statin-Induced Myopathy
Chapter: Genetic Testing
Current Effective Date: March 15, 2014
Original Effective Date: March 15, 2014
Publish Date: January 14, 2014
Description

Background

Statin drugs are the primary pharmacologic treatment for hypercholesterolemia throughout the world. In the United States, there are an estimated 38 million individuals taking statins as of 2008. (1) Use of statins is associated with an approximately 30% reduction in cardiovascular events across a wide variety of populations. (2)

Statin-induced myopathy

Statins are associated with a known risk of muscle-related symptoms, and these are the most common side-effects of statin drugs. Myopathy is a general term for muscle toxicity. The following three categories of statin-induced myopathy have been recommended by an ACC/AHA/NHLBI* advisory committee (3):

  • Statin-induced myalgia, defined as any muscle symptoms that occur without an elevation of serum creatinine kinase (CK);
  • Statin-induced myositis, defined as muscle symptoms with an elevation of serum CK; and
  • Statin-induced rhabdomyolysis, defined as markedly severe muscle symptoms with an elevation of CK greater than 10 times normal with an elevation in serum creatinine.

(*American College of Cardiology/American Heart Association/National Heart Lung Blood Institute)

Statin-induced myalgia is the most common manifestation of myopathy and is characterized by muscle pain, cramps, fatigue, and/or weakness. (4) Myalgias without other clinical manifestations are not associated with clinically important adverse events and resolve when the statin is discontinued.

The incidence of myalgia varies widely in the published literature. In clinical trials, these symptoms have been reported in 1.5-3.0% of patients, and in most trials, the rate of myalgias in patients on statin therapy is not increased compared to placebo treatment. (5) In observational studies, higher rates of 10-15% have been reported. (2)

Myositis is much less common that myalgias, with an estimated rate of 5 per 100,000 patient-years, and an estimated per-person incidence of 0.01%. (5) In virtually all cases, myositis resolves with discontinuation of the statin. Rhabdomyolysis is the most severe clinical manifestation of statin-induced myopathy and can be life-threatening. The National Lipid Association Statin Safety Assessment Task Force estimated that rhabdomyolysis occurs at a rate of 1.6 per 100,000 patient years, and the U.S. Food and Drug Administration (FDA) adverse events reporting system has estimated a rate of 0.7 per 100,000 patient-years. (5) A systematic review published in 2006 combined results from 20 clinical trials, and estimated the rate of rhabdomyolysis to be 1.6 cases per 100,000 patient-years. (6) Fatalities from statin-induced rhabdomyolysis can occur, but the mortality rate is not well-defined. The FDA estimated that deaths for rhabdomyolysis occur at a rate of less than 1 death per million prescriptions. (3)

There are a number of clinical factors that are associated with an increased risk of statin myopathy. Statin dose is probably the strongest risk factor, with an estimated 6-fold increase for patients on high-dose statins. (7) Age is also a strong risk factor. One study reported that patients older than 65 years of age required hospitalization for statin-induced myositis at a rate that was 4 times higher than for younger patients.(8) Some statins may be associated with higher risk than others, and concomitant administration of certain drugs such as gemfibrozil and amiodarone is associated with higher rates of statin myopathy in clinical trials. (7) Other factors that may be associated with myopathy include female gender and intense physical exercise. (7)

The perceived risk of statin-induced myopathy may be a contributing reason for suboptimal statin use in patients with indications. Less than 50% of patients in the U.S. who would benefit from statins are currently taking them, and a substantial part of this is the result of non-adherence to prescribed statins. (1)

Genetic factors associated with statin-induced myopathy

There are a variety of genetic factors associated with statin myopathy. The cytochrome p450 system in the liver is the main pathway by which statins are metabolized. Numerous genetic variants in cytochrome p450 proteins affect the pharmacokinetics of statin metabolism and serum statin levels. (2) Other genetic variants that affect statin metabolism, efficacy, and susceptibility to adverse effects involve variations in the apolipoproteins such as apo E, variations in the cholesterol ester transfer proteins (CETP), or variations in the coenzyme Q pathway. (1)

Variations in the SLCO1B1 gene also affect statin metabolism and are among the most well-studied genetic variants. These are also the genetic markers for which there are commercially available tests. This gene codes for a transporter protein that is part of the solute carrier organic ion transporter (SLCO) system, which mediates the influx and metabolism of statins in the liver. (2) Single nucleotide polymorphisms (SNPs) in this gene are associated with variations in the risk of statin-induced myopathy. The T/T allele is the wild-type and associated with the lowest risk of myopathy. The C/C allele is associated with a higher risk of myopathy, and the T/C allele with an intermediate risk. The T allele has a prevalence of approximately 0.87, and the C allele has a prevalence of approximately 0.13. (4)

There are at least two commercial labs that offer genetic testing for SLCO1B1 variants. Boston Heart Diagnostics™ markets a test for the statin-induced myopathy (SLCO1B1) genotype. This test uses real-time polymerase chain reaction (PCR) to identify patients with the T/T, T/C, or C/C genotype. (Available online at: http://www.bostonheartdiagnostics.com).

Berkeley Heart Lab™ offers a similar genetic test for SLCO1B1 variants. Details of how this test is performed are not provided on the company website (http://www.bhlinc.com ).

Regulatory Status

The commercially available tests for SLCO1B1 are laboratory developed tests and not subject to FDA approval. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Genetic testing for the presence of variants in the SLCO1B1 gene for the purpose of identifying patients at risk of statin-induced myopathy is considered not medically necessary.

Policy Guidelines

As of November 2013:

Tier 1 CPT code: none

Tier 2 CPT code:

81400 Molecular pathology, SLCO1B1 (solute carrier organic anion transported family, member 1B1); V174A variant

Rationale

A literature search was performed for the period of January 1, 2000 through May 15, 2013. Published articles were selected that reported on the analytic validity, clinical validity, and clinical utility of genetic testing for statin-induced myopathy.

Analytic Validity

One lab (Boston Heart Diagnostics™) performs the test by real-time polymerase chain reaction (PCR). This technique allows detection and amplification of DNA fragments to be performed simultaneously. While this is an accepted method for genetic analysis and generally has high accuracy, no published information was found on the accuracy of this technique for detecting genetic variants associated with statin-induced myopathy.

Clinical Validity

There are no studies that report the sensitivity or specificity of genetic testing for statin-induced myopathy. Studies were identified that report the degree of risk for myopathy associated with the SLCO1B1 genetic variants. These include genome-wide association studies, case-control studies, cohort analyses, and clinical trials. Representative types of each study are included below.

Genome-wide association (GWA) studies have reported that SLCO1B1 variants are associated with statin-induced myopathy. The SEARCH study group published a GWA study in 2008 based on data from the SEARCH trial. (4) This was a randomized controlled trial (RCT) of 12,064 individuals with a prior myocardial infarction randomized to 80 mg simvastatin or 20 mg simvastatin. Of the 6,031 patients in the 80-mg-statin group, 48 (0.8%) had an elevation of serum CK level more than 10 times normal, and an additional 48 patients (0.8%) had a creatinine kinase (CK) level that was more than 3 times normal and more than 5 times the baseline level. These subjects were matched with 96 control subjects without CK elevations, matched for gender, age, renal function, and ancillary medication use. Adequate DNA was available for 85 patients with myopathy and 90 controls, and these patients formed the study group for derivation of the genome associations.

The SLCO1B1 locus was the single nucleotide polymorphism (SNP) that had a strong association with myopathy, at a corrected p value of 0.001. The estimated odds ratio for myopathy in patients with a single C allele was 4.3 (95% confidence interval [CI]: 2.5-7.2), and the estimated odds ratio for patients homozygous for the C allele was 17.4 (95% CI: 4.8-62.9). Based on these data, the cumulative risk of developing myopathy after 6 years of treatment with 80 mg simvastatin was 0.6% for patients with the T/T allele, 3% for patients with the T/C allele, and 18% for patients with the C/C allele. Other clinical factors that predicted a risk of myopathy were female gender (relative risk [RR]: 1.8, 95% CI: 1.1-2.8), age >65 (RR 2.2, 95% CI 1.4-3.4), impaired renal function (RR 2.2, 95% CI 1.4-3.4), use of amiodarone (RR 6.4, 95% CI: 3.4-12.1), use of calcium antagonists (RR: 1.7, 95% CI: 1.2-2.6), and diabetes mellitus (RR: 1.7, 95% CI: 1.0-2.9).

The SEARCH investigators replicated the association of the SLCO1B1 with myopathy in 16,664 patients from a separate RCT, the Heart Protection Study. In this study, all patients were treated with 40 mg of simvastatin, and 23 (0.1%) were identified with CK levels greater than 10 times normal. SLCO1B1 variants were also strongly associated with myopathy in this replication study, with a corrected p value of 0.004). The estimated odds ratio for the presence of one C allele was 2.6 (95% CI: 1.3-5.0).

The STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study was a randomized trial that examined statin response and safety by dose of statin, type of statin, and by presence of genetic markers. (9) A total of 509 patients were randomized to various doses of pravastatin or simvastatin and followed for the presence of adverse events, including myopathy. The presence of at least one variant on the SLCO1B1 gene was associated with an increased rate of adverse events (37% vs. 25%, p=0.03). There was also evidence for a “dose-response” effect, with the risk of adverse events being 19% with no variant alleles, 27% with one variant allele, and 50% with two variant alleles (p=0.01 for trend).

A case-control study reporting on the risk of myopathy associated with SLCO1B1 variants was reported in 2012. (10) This study identified cases with statin-induced myopathy, defined as muscle symptoms with a CK elevation at least 10 times normal, from two large lipid clinics in the Netherlands. Twenty-five cases of myopathy were identified from 9,000 total patients, for a prevalence of 0.26%. These patients were matched for age, gender, statin type, and statin dose, with 84 patients who did not have myopathy. In the whole cohort of patients taking any statin, there was a non-significant trend toward an increase in myopathy for patients with a SLCO1B1 variant (odds ratio [OR]: 1.5, 95% CI: 0.58-3.69, p=0.21). When restricted to patients on simvastatin, the association was stronger but did not quite reach statistical significance (OR: 3.2, 95% CI: 0.83-11.96, p=0.06).

Clinical Utility

There were no studies identified that reported direct evidence on the clinical utility of genetic testing for statin myopathy. Indirect evidence includes the predicted number of patients who avoid statin myopathy as a result of genetic testing. This number is uncertain because there are a number of actions that can be taken as a result of genetic testing. Statins can be stopped or not started, a lower dose can be used, and other risk factors can be avoided, such as use of amiodarone. Despite the uncertainty in the precise number of events avoided, the number will necessarily be low due to the low underlying rate of serious events.

When statin use is reduced or eliminated, the reduction in statin myopathy needs to be weighed against the increased cardiovascular events that may occur as a result of this change. In patients with a moderate to high risk of cardiovascular events, the probability of myocardial infarction (MI) over a 10-year period may be in the range of 10-20%. This event rate is substantially higher than the probability of serious myositis and rhabdomyolysis. As a result, if statin drugs are avoided because of genetic testing, the number of MIs that will result may exceed the number of myopathy episodes avoided, and net harm may result. Since there are no alternative agents that can reduce the rate of cardiovascular events to the extent as do statins, it may not be possible to ameliorate this net harm by a change to an alternate lipid-lowering strategy.

Summary

Statin muscle symptoms are the most common side effect of statins, and serious myopathy or rhabdomyolysis occurs in a very small number of patients treated with statins. An association between genetic variants of the SLCO1B1 gene and statin myopathy has been reported. This association has been found in genome-wide association studies that indicate a several-fold risk of statin myopathy associated with genetic variants. Evidence from case-control studies and clinical trials also show a possible association, but the quantity of evidence is small and the association has not been demonstrated to be strong. Statins are associated with a definite decreased risk of cardiovascular events such as myocardial infarction (MI), and this benefit of reduced cardiovascular events is likely to far outweigh the risk of myopathy, even in patients with the highest risk of myopathy, i.e., two abnormal SLCO1B1 alleles. Therefore, there is a possibility of harm if the results of genetic testing for statin-induced myopathy are used as part of the decision-making process for prescribing statins. As a result, genetic testing for statin-induced myopathy is considered not medically necessary.

Practice Guidelines and Position Statements

No practice guidelines or position statements were found.

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

359.24, E947.1

ICD-10 Codes

G71.14, T46.6X5

Procedural Codes: 81400
References
  1. Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin Rheumatol 2008; 20(6):648-55.
  2. Maggo SD, Kennedy MA, Clark DW. Clinical implications of pharmacogenetic variation on the effects of statins. Drug Saf 2011; 34(1):1-19.
  3. Pasternak RC, Smith SC, Jr., Bairey-Merz CN et al. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Circulation 2002; 106(8):1024-8.
  4. SEARCH Collaborative Group, Link E, Parish S et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med 2008; 359(8):789-99.
  5. McKenney JM, Davidson MH, Jacobson TA et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006; 97(8A):89C-94C.
  6. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006; 97(8A):52C-60C.
  7. Wilke RA, Ramsey LB, Johnson SG et al. The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther 2012; 92(1):112-7.
  8. Schech S, Graham D, Staffa J et al. Risk factors for statin-associated rhabdomyolysis. Pharmacoepidemiol Drug Saf 2007; 16(3):352-8.
  9. Voora D, Shah SH, Spasojevic I et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol 2009; 54(17):1609-16.
  10. Brunham LR, Lansberg PJ, Zhang L et al. Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin. Pharmacogenomics J 2012; 12(3):233-7.
  11. Genetic Testing for Statin-Induced Myopathy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (June 2013) Medicine 2.04.96.
History
March 2014  New medical document. Genetic testing for the presence of variants in the SLCO1B1 gene for the purpose of identifying patients at risk of statin-induced myopathy is considered not medically necessary. 
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Genetic Testing for Statin-Induced Myopathy