Rhabdomyolysis With Statin and Fibrate Use
Background: The incidence of hospitalized rhabdomyolysis is not well characterized among patients taking statin-fibrate combination therapies.
OBJECTIVE: To estimate and compare the rates of hospitalized rhabdomyolysis during periods of exposure to different statins and fibrates.
Methods: We retrospectively identified a cohort of patients who initiated a statin or fibrate between January 1, 1998, and December 31, 2007, using a database of a large US health insurer. Patients were followed for the occurrence of hospitalized rhabdomyolysis, determined by clinical review of medical records. Exposure status during the study period was determined by electronic records of statin and fibrate dispensing. Incidence rates (IRs) and incidence rate ratios (IRRs) for various combinations of fibrate and statin exposure were modeled, using Poisson regression.
Results: There were 1,116,805 patients who initiated statin and/or fibrate therapy, with 2.4 million person-years of observation. Seventy cases of hospitalized rhabdomyolysis were confirmed. Adjusted analyses showed a persistent increased risk of rhabdomyolysis with combination therapy, while statin and fibrate therapy alone showed similar, nonsignificant increases in risk. The adjusted IRR for a statin and fenofibrate was 3.26 (95% CI 1.21 to 8.80), while the adjusted IRR for a statin and gemfibrozil was 11.93 (95% CI 3.96 to 35.93) versus statin therapy alone. The individual IRs for statin monotherapy ranged from 0.00 to 3.34 per 100,000 person-years. The number needed to harm was lower for combination statin-gemfibrozil therapy (2753) compared with that for statin therapy alone (454,545).
Conclusions: The incidence of hospitalized rhabdomyolysis is rare, but higher in patients with concomitant statin-fibrate treatment than in patients on statin therapy alone. The rate found in this study is consistent with the known profile of the statin-fibrate treatment option for mixed dyslipidemia.
In patients with mixed dyslipidemia, single-drug therapy often fails to lower triglycerides (TG) and raise high-density lipoprotein cholesterol (HDL-C) to optimal levels set by the National Cholesterol Education Program (NCEP) guidelines. Statin and fibrate combination therapy can be effective in lowering TG and raising HDL-C.
The risk for rhabdomyolysis with combination therapy is reportedly greater than that for statin or fibrate therapy alone, particularly when statins are combined with gemfibrozil. Concern for a potentiation of adverse effects, such as rhabdomyolysis, in the clinical setting of concomitant therapy exists. However, the NCEP Adult Treatment Panel III recognizes use of statin-fibrate combinations in high-risk patients with mixed dyslipidemias.
Given the growing focus on aggressive lipid management in both high-risk patient groups (eg, diabetes) and the general population, clinicians will likely rely increasingly on combination therapy to achieve low-density lipoprotein cholesterol, TG, and HDL-C goals. Until recently, little was known about the safety profiles of combination therapies. Fenofibric acid, the active metabolite of fenofibrate, was the first fibrate approved (December 2008) by the Food and Drug Administration for combination use with a statin to reduce TG and increase HDL-C in patients with mixed dyslipidemia and coronary heart disease (CHD) or CHD risk equivalent. This approval was based largely on the demonstrated efficacy and safety of fenofibric acid in combination with statins in the largest series to date of clinical trials of fibrate-statin combinations for the treatment of mixed dyslipidemia.
The incidence of hospitalized rhabdomyolysis has not been reliably estimated among those treated with statin-fibrate combination therapy. To our knowledge, only 1 epidemiologic study has evaluated the incidence using medical chart review; investigators reported an increased incidence of hospitalized rhabdomyolysis among patients with combined statin-fibrate use.
This retrospective pharmacoepidemiologic study used a claims-based screening definition from a previously published study, in conjunction with medical record review, to estimate and compare the rates of hospitalized rhabdomyolysis during periods of exposure to various statins and fibrates, alone and in combination.
Abstract and Introduction
Abstract
Background: The incidence of hospitalized rhabdomyolysis is not well characterized among patients taking statin-fibrate combination therapies.
OBJECTIVE: To estimate and compare the rates of hospitalized rhabdomyolysis during periods of exposure to different statins and fibrates.
Methods: We retrospectively identified a cohort of patients who initiated a statin or fibrate between January 1, 1998, and December 31, 2007, using a database of a large US health insurer. Patients were followed for the occurrence of hospitalized rhabdomyolysis, determined by clinical review of medical records. Exposure status during the study period was determined by electronic records of statin and fibrate dispensing. Incidence rates (IRs) and incidence rate ratios (IRRs) for various combinations of fibrate and statin exposure were modeled, using Poisson regression.
Results: There were 1,116,805 patients who initiated statin and/or fibrate therapy, with 2.4 million person-years of observation. Seventy cases of hospitalized rhabdomyolysis were confirmed. Adjusted analyses showed a persistent increased risk of rhabdomyolysis with combination therapy, while statin and fibrate therapy alone showed similar, nonsignificant increases in risk. The adjusted IRR for a statin and fenofibrate was 3.26 (95% CI 1.21 to 8.80), while the adjusted IRR for a statin and gemfibrozil was 11.93 (95% CI 3.96 to 35.93) versus statin therapy alone. The individual IRs for statin monotherapy ranged from 0.00 to 3.34 per 100,000 person-years. The number needed to harm was lower for combination statin-gemfibrozil therapy (2753) compared with that for statin therapy alone (454,545).
Conclusions: The incidence of hospitalized rhabdomyolysis is rare, but higher in patients with concomitant statin-fibrate treatment than in patients on statin therapy alone. The rate found in this study is consistent with the known profile of the statin-fibrate treatment option for mixed dyslipidemia.
Introduction
In patients with mixed dyslipidemia, single-drug therapy often fails to lower triglycerides (TG) and raise high-density lipoprotein cholesterol (HDL-C) to optimal levels set by the National Cholesterol Education Program (NCEP) guidelines. Statin and fibrate combination therapy can be effective in lowering TG and raising HDL-C.
The risk for rhabdomyolysis with combination therapy is reportedly greater than that for statin or fibrate therapy alone, particularly when statins are combined with gemfibrozil. Concern for a potentiation of adverse effects, such as rhabdomyolysis, in the clinical setting of concomitant therapy exists. However, the NCEP Adult Treatment Panel III recognizes use of statin-fibrate combinations in high-risk patients with mixed dyslipidemias.
Given the growing focus on aggressive lipid management in both high-risk patient groups (eg, diabetes) and the general population, clinicians will likely rely increasingly on combination therapy to achieve low-density lipoprotein cholesterol, TG, and HDL-C goals. Until recently, little was known about the safety profiles of combination therapies. Fenofibric acid, the active metabolite of fenofibrate, was the first fibrate approved (December 2008) by the Food and Drug Administration for combination use with a statin to reduce TG and increase HDL-C in patients with mixed dyslipidemia and coronary heart disease (CHD) or CHD risk equivalent. This approval was based largely on the demonstrated efficacy and safety of fenofibric acid in combination with statins in the largest series to date of clinical trials of fibrate-statin combinations for the treatment of mixed dyslipidemia.
The incidence of hospitalized rhabdomyolysis has not been reliably estimated among those treated with statin-fibrate combination therapy. To our knowledge, only 1 epidemiologic study has evaluated the incidence using medical chart review; investigators reported an increased incidence of hospitalized rhabdomyolysis among patients with combined statin-fibrate use.
This retrospective pharmacoepidemiologic study used a claims-based screening definition from a previously published study, in conjunction with medical record review, to estimate and compare the rates of hospitalized rhabdomyolysis during periods of exposure to various statins and fibrates, alone and in combination.
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