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
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.
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.
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).
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.
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.
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