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

Discussion

A large cohort of patients who initiated statin or fibrate therapy was followed for the occurrence of new-onset rhabdomyolysis. Crude analyses indicated increased rhabdomyolysis risk on treatment with both statins and fibrates versus no treatment with statins or fibrates and treatment with statins alone. Total follow-up consisted of 2.4 million patient-years. Of the 70 confirmed cases, 52 (74.3%) occurred in patients with no lipid therapy (n = 24) or statin-only therapy (n = 28). The remaining cases were associated with fenofibrate only (n = 5), gemfibrozil (n = 1), statin and fenofibrate (n = 7), or statin and gemfibrozil (n = 5). The small number of cases was associated with broad CIs. The NNH was lower for combination statin-fibrate therapy compared with the NNH for statin therapy alone. Given the variability in the IRs, the NNH reported for the different exposure categories should be interpreted with caution. The NNH reflects the exposure person-time, which is lower for the combination therapy groups versus those exposed to statins alone. Furthermore, the number of confirmed hospitalized rhabdomyolysis events was lower among the combined statin-fibrate exposure groups, thus affecting the precision of the estimates.

Adjusted analyses showed a persistent increased risk of rhabdomyolysis for combination therapy, while statin and fibrate therapy alone showed a similar nonsignificant increase in risk. The finding of increased risk for rhabdomyolysis with combined statin-fibrate use is consistent with results of the study by Graham et al., which reported a 12-fold increase (95% CI, 2.6 to 57.4) when statins other than cerivastatin were used in combination with fibrates compared with use of statins alone.[6]

The IRs for monotherapy with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin were similar (0.00 to 3.34 per 100,000 person-years). An increased risk of rhabdomyolysis was observed with statin-fibrate combination therapy, with an estimated incidence of 123.44 per 100,000 person-years for fluvastatin-fenofibrate therapy and 165.22 per 100,000 person-years for rosuvastatin-gemfibrozil therapy. These IRs were based on only 1 rhabdomyolysis case and should be interpreted with caution. Rhabdomyolysis risk was similar for statins metabolized by CYP3A4 versus no statin therapy.

Cohort members were required to initiate a statin or fibrate but were allowed prior exposure to the other type of drug during the baseline period. One percent of patients initiating statin therapy had a fibrate dispensing, and 23% of those starting a fibrate had a statin dispensing during baseline. This indicates a high proportion of statin use during baseline, before initiation of fibrate therapy, complicating the understanding of the effect of the prior drug exposure. Combination therapy occurred more often in patients with comorbidities such as diabetes and renal disease and also with higher medical costs, suggesting some underlying differences in the health of the different exposure groups, which may not be entirely controlled for in the analyses.

To our knowledge, this is the largest study to examine rhabdomyolysis incidence associated with statin and fibrate therapy. We used a broad case-finding algorithm, previously employed to reduce the number of missed cases, and identified 70 cases of hospitalized rhabdomyolysis through medical record review, using a strict case definition. For several drugs in the monotherapy analysis, the IRs had wide CIs, reflecting the small number of events. However, there was sufficient precision in the estimates to establish the similarities and differences in rhabdomyolysis risk across different exposure categories.

This study has several limitations. To minimize surveillance bias, the outcome definition included cases of rhabdomyolysis associated with inpatient care and excluded less severe forms that may be variably represented in administrative claims data.

The study used information in the claims database that reflects interactions between patients and the health care system for which payment is sought. There is no information about use of over-the-counter medications or alternative medicines. The pharmacy claims used to determine drug exposure status are medication dispensing records and do not reflect whether the patient took the medication. Follow-up duration can be limited if individuals change health insurance plans.

Age is a risk factor for hospitalized rhabdomyolysis.[18] Because the database used in this study underrepresents the over-65 population, IRs for hospitalized rhabdomyolysis may be underestimated.

Medical records could not be obtained for 24% of potential cases of hospitalized rhabdomyolysis; these were subsequently treated as non-cases, which would potentially result in an underestimation of IRs. If the same confirmation rate applied in these cases as applied in the medical records that were obtained, one could expect to find 22 rhabdomyolysis cases among the 290 medical records that were not obtained.

In conclusion, we identified 70 cases of hospitalized rhabdomyolysis with 2.4 million patient-years of observation. Most cases occurred among patients who were untreated or treated with a statin only. Although the incidence of hospitalized rhabdomyolysis is rare, a higher rate of occurrence was observed with statin-fibrate combination therapy than with statin therapy alone or no therapy. The highest rate occurred with statin-gemfibrozil therapy, which is consistent with previous study results.[6] Patient-years of exposure for combination therapy were considerably smaller than for no therapy or statin monotherapy; this is reflected in the wide CIs for these treatment groups. After adjustment for confounding factors in the multivariate Poisson regression model, the incidence of hospitalized rhabdomyolysis for fenofibrate-statin combination therapy was approximately 3 times that of statins alone and approximately 2.5 times that of no therapy. The rate found in this study was consistent with the known profile of the statin-fibrate treatment option for mixed dyslipidemia.

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