To the Editor
Studies of rare adverse drug reactions (ADRs) are difficult because they require large numbers of exposed persons to identify an adequate number of cases. Spontaneous adverse events reports have been used to identify cases of rhabdomyolysis, a rare but serious complication of statin use.1 A complex algorithm based on administrative data has also been used to identify cases of rhabdomyolysis and myopathy among enrollees of several large health plans.2,3 We conducted this population-based epidemiologic study to evaluate use of the new diagnostic code for rhabdomyolysis, introduced in 2006, as a method of estimating the incidence of statin-related rhabdomyolysis and myopathy.
METHODS
Computerized pharmacy data were used to estimate the total person-years of statin use by statin type and dose among all enrollees of Group Health Cooperative (GHC) from January 2006 to December 2010. Trained abstractors reviewed the full electronic medical record (EMR) of all GHC enrollees: 1) who had a statin prescription within 3 months before an outpatient or inpatient encounter with an International Classification of Diseases-9 (ICD-9) code for rhabdomyolysis; 2) who had a statin prescription within 3 months before an ICD-9 code for an adverse reaction from a lipid-lowering drug or a creatine kinase (CK) level 1,000 IU/L or higher in the GHC laboratory database; and 3) who were identified by natural language processing software as having the words “rhabdo” and “statin” appear near each other anywhere in the EMR during 2006–2010. Statin-related rhabdomyolysis and myopathy were defined as muscle symptoms with a peak CK level 10 or more times and 5 to 10 times the upper limit of normal, respectively, in the absence of another etiology.
Incidence rates (IR) were calculated from the number of cases validated by EMR review divided by the person-time of use for various doses of simvastatin and for all other statins combined. Among cases who switched statins, rhabdomyolysis was classified according to the statin being used at the time of onset of symptoms. Incidence rate ratios (IRR) comparing simvastatin with other statins, and comparing high-vs-low doses of simvastatin, were calculated by dividing IRs, both for validated cases and rhabdomyolysis ICD-9 code-identified cases. Confidence intervals were estimated with STATA version 11.0 (StataCorp, College Station, TX). This study was approved and a waiver of consent granted by the GHC Institutional Review Board.
RESULTS
Among 292 statin users with an ICD-9 code for rhabdomyolysis, 22 cases of statin-related rhabdomyolysis were validated (positive predictive value 7.5%; 95% confidence interval [CI], 5.0–11.1%) (Table 1). Seven additional cases were identified by other methods, for a sensitivity of 76% (95% CI, 58–88%). Common etiologies for rhabdomyolysis other than statin use included prolonged immobility, arterial ischemia, recent surgery, and severe infection.
Table 1.
Statin-related rhabdomyolysis and myopathy cases identified using administrative data.
| Case-identification method | Number reviewed | Validated Cases* | |
|---|---|---|---|
| Rhabdomyolysis N (%, 95% CI) | Myopathy N (%, 95% CI) | ||
| Rhabdomyolysis ICD-9 code | |||
| Inpatient | 250 | 18 (7.2%, 4.6–11.1%) | 2 (0.8%, 0.2–2.9%) |
| Outpatient | 42 | 4 (9.5%, 3.8–22.1%) | 0 (0%, 0–8.4%) |
| Rhabdomyolysis ICD-9 code total | 292 | 22 (7.5%, 5.0–11.1%) | 2 (0.7%, 0.2–2.5%) |
| Other criteria | |||
| Adverse event of lipid agent ICD-9 code | 30 | 1 (3.3%, 0.6–16.7%) | 0 (0%, 0–11.4%) |
| Creatine kinase ≥ 1000 IU/L | 39 | 1 (2.6%, 0.5–13.2%) | 10 (25.6%, 14.6–41.1%) |
| Natural language processing | 438 | 5 (1.1%, 0.5–2.6%) | 6 (1.4%, 0.6–3.0%) |
| Other criteria total | 507 | 7 (1.4%, 0.7–2.8%) | 16 (3.2%, 2.0–5.1%) |
| Total, all methods | 799 | 29 | 18 |
Rhabdomyolysis is defined as creatine kinase (CK) 10 or more times the upper limit of normal (ULN) and myopathy as CK 5 to 10 times the ULN. ICD-9 codes: rhabdomyolysis 728.88, adverse event of lipid agent code E942.2.
Positive predictive values and 95% confidence intervals are listed in parentheses.
Of the 29 validated cases of statin-related rhabdomyolysis, 26 (90%) were hospitalized, 8 (29%) had at least a doubling of serum creatinine, and none died. The median peak CK level was 7,450 (range 1,477–150,510). IRs are listed in Table 2. The rhabdomyolysis IRR for simvastatin compared with other statins was 2.61 (95% CI, 1.03–7.84) using validated cases vs 1.03 (95% CI 0.80–1.34) using the rhabdomyolysis ICD-9 code. The IRR for simvastatin 80mg/day or greater compared with 20 to 39 mg/day was 12.2 (95% CI, 3.6–52.3) using validated cases vs. 1.77 (95% CI 1.05–2.88) using the rhabdomyolysis ICD-9 code.
Table 2.
Incidence rates for statin-related rhabdomyolysis and myopathy.
| Statin | Person-years of use | Cases | Incidence rates (95% CI)* | ||
|---|---|---|---|---|---|
| Rhabdomyolysis | Myopathy | Rhabdomyolysis | Myopathy | ||
| Simvastatin | |||||
| <20mg/day | 21,832 | 0 | 0 | 0 (0–16.9) | 0 (0–16.9) |
| 20–39mg/day | 75,082 | 4 | 2 | 5.3 (1.5–13.6) | 2.7 (0.3–9.6) |
| 40–79mg/day | 56,703 | 8 | 4 | 14.1 (6.1–27.8) | 7.1 (1.9–18.1) |
| ≥80mg/day | 16,876 | 11 | 4 | 64.8 (32.3–116.9) | 23.6 (6.4–60.3) |
| All doses | 170,605 | 23 | 10 | 13.5 (8.6–20.2) | 5.9 (2.8–10.8) |
| Other statins** | 116,154 | 6 | 8 | 5.2 (1.9–11.2) | 6.9 (3.0–13.6) |
| All statins | 286,758 | 29 | 18 | 10.1 (7.8–14.5) | 6.3 (3.7–9.9) |
Rhabdomyolysis is defined as creatine kinase (CK) 10 or more times the upper limit of normal (ULN) and myopathy as CK 5 to 10 times the ULN.
Cases per 100,000 person-years
Non-simvastatin use was primarily lovastatin (69%) and atorvastatin (24%)
COMMENT
These results confirm in a community setting findings from a recent clinical trial that prompted the Food and Drug Administration to issue a warning about the use of high-dose simvastatin.4,5 The ICD-9 code for rhabdomyolysis was nonspecific for this ADR, and the resulting misclassification markedly attenuated the estimated relative risk for high-vs-low dose simvastatin. We did not adjust for potential confounding factors and may have failed to identify all cases of statin-related rhabdomyolysis, although these limitations are unlikely to account for the large relative risks observed. The use of administrative data alone in studies of other ADRs with multiple causes, such as drug-induced liver injury, may fail to detect actionable and clinically important harms.6
Acknowledgments
James Floyd had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis.
FUNDING
This research was supported in part by grants HL078888 and HL085251 from the National Heart, Lung, and Blood Institute. Dr. Floyd was supported by National Heart, Lung and Blood Institute training grant T32 HL007902. The National Heart, Lung, and Blood Institute played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Footnotes
POTENTIAL FINANCIAL CONFLICTS OF INTEREST
No authors reported potential financial conflicts of interest.
References
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