Incidence of Hospitalized Rhabdomyolysis With Statin and Fibrate Use in an Insured US Population

Kandace L Amend PhD; Joan Landon MPH; Veena Thyagarajan MPH; Steve Niemcryk PhD; Andrew McAfee MD MSc

Disclosures

The Annals of Pharmacotherapy. 2011;45(10):1230-1239. 

In This Article

Results

We identified 1,116,805 statin and/or fibrate initiators who met eligibility criteria from January 1, 1998, through December 31, 2007. Of these, 86.6% were statin initiators, 12.9% were fibrate initiators, and 0.5% initiated both a statin and fibrate on the same day. Table 1 shows the baseline characteristics of the cohort by initiation drug class.

We identified 2309 claims-based hospitalized rhabdomyolysis events from 2171 unique patients, using all cohort follow-up time. Claims-profiles were reviewed for each potential rhabdomyolysis event, and among those, 1232 potential events were selected for medical record review. We obtained medical records for 942 cases (76%) and confirmed 70 rhabdomyolysis events. Medical records could not be obtained for 24% of potential cases of hospitalized rhabdomyolysis because the charts were unavailable, the provider refused to release the chart, the provider requested patient authorization, or the patient was not seen by the provider contacted and no other provider information was available.

Table 2 shows the number of cases and IRs based on current drug exposure category. The statin-only category contained the largest amount of person-time. While IRs during periods of statin monotherapy were comparable to those during periods of no lipid-lowering drug use (2.46 vs 2.24), fenofibrate monotherapy was associated with a higher IR (6.20 per 100,000 person years, 95% CI 2.01 to 14.47), albeit not statistically significantly different from statin monotherapy, as indicated by overlapping confidence intervals. Combination use of fibrates and statins was associated with statistically significantly higher rates of hospitalized rhabdomyolysis compared with no use or statin monotherapy (statin and fenofibrate therapy IR 12.37, 95% CI 4.97 to 25.48; statin and gemfibrozil therapy IR 38.57, 95% CI 12.52 to 90.01).

The NNH to observe 1 case of rhabdomyolysis was 454,545 patients receiving statin therapy; 25,253 patients receiving fenofibrate therapy; 112,360 patients receiving gemfibrozil therapy; 9872 patients receiving statin-fenofibrate therapy; and 2753 patients receiving statin-gemfibrozil therapy.

The crude IRR of rhabdomyolysis was 5.51 (95% CI 2.37 to 12.79) for statin-fenofibrate therapy versus no statin or fibrate therapy (Table 3). The adjusted IRR was 2.46 (95% CI 0.92 to 6.60) for statin-fenofibrate therapy versus no statin or fibrate therapy.

Adjusted IRRs are displayed in Table 4. Adjustment had a minor effect on the estimate for fibrate monotherapy. The crude IRR was 2.52 (95% CI 0.97 to 6.52) for fenofibrate therapy versus statin therapy alone, while the adjusted IRR was 2.25 (95% CI 0.85 to 5.95). However, IRRs estimated for combination use were attenuated with adjustment. After adjustment, combination therapy was associated with an increased risk for hospitalized rhabdomyolysis compared with no statin therapy. The crude IRR was 5.03 (95% CI 2.20 to 11.51) for statin-fenofibrate therapy versus statin therapy, while the adjusted IRR was 3.26 (95% CI 1.21 to 8.80). The adjusted IRR was 11.93 (95% CI 3.96 to 35.93) for statin-gemfibrozil therapy versus statin therapy.

Table 5 shows the number of person-years in each monotherapy statin, monotherapy fibrate, and individual statin and fibrate exposure categories. The no exposure to statins or fibrates category had the most person-time. Eleven cases occurred during exposure to atorvastatin alone (IR 1.97 per 100,000 person-years, 95% CI 0.99 to 3.53). Eleven cases also occurred during exposure to simvastatin alone (IR 3.34, 95% CI 1.67 to 5.97). Five cases occurred during exposure to fenofibrate alone (IR 6.2, 95% CI 2.01 to 14.47). Four cases occurred during exposure to both atorvastatin and fenofibrate (IR 16.09, 95% CI 4.39 to 41.21). One case occurred during exposure to fluvastatin-fenofibrate therapy (IR 123.44, 95% CI 3.13 to 687.77). All other combinations had zero cases of rhabdomyolysis.

The crude IRR was 7.17 for atorvastatin and fenofibrate versus no statin or fibrate therapy (95% CI 2.49 to 20.67). The crude IRR was 55.00 (95% CI 7.44 to 406.55) for fluvastatin-fenofibrate therapy versus no statin or fibrate therapy (Table 5). Due to modeling constraints, the final regression model included only the drug exposure variable without any other covariates.

The adjusted IRR for statins metabolized by CYP3A4 versus no statin therapy was 1.17 (95% CI 0.71 to 1.93) and 1.22 (95% CI 0.53 to 2.79) for statins not metabolized by CYP3A4 versus no statin therapy.

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