Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs

Graham DJ, Staffa JA, Shatin D, et al. J Am Med Assoc 2004; 292:2585-90

Reviewer: K. W. Tim Park, MD
Beth Israel Deaconess Medical Center
Boston, MA

Background: Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are prescribed to lower serum cholesterol. They have been demonstrated not only to lower cholesterol levels, but also to have beneficial effects in primary and secondary prevention of coronary artery disease (CAD),1-4 retard aortic valve calcification and degeneration,5-7 and to reduce the incidence of new-onset atrial fibrillation.8 Moreover, statin use in the perioperative period has been associated with a reduced mortality after vascular surgery.9 Accordingly, statins are widely prescribed. In the study cohort of this study, there were around 1,500 prescriptions for a statin per 10,000 patients per month in 2003.

The voluntary withdrawal of cerivastatin by its manufacturer 10 highlighted the possible association of statins with rhabdomyolysis. In addition, fibric acid derivatives (fibrates) have also been associated with muscle injury. 11, 12 Despite the wide use of statins, however, there had not been a large-scale epidemiological study describing statin- and fibrate-associated myopathy. The current study addresses this need.

The following SCA newsletter review articles on statins are archived on the SCA website:http://www.scahq.org/sca3/newsletters/2004feb/lit1.shtml (February 2004), http://www.scahq.org/sca3/newsletters/2003dec/lit1.shtml (December 2003), and http://www.scahq.org/sca3/newsletters/february2002/drug_2.shtml (February 2002).

Methods: Inception cohorts of statin and fibrate users were obtained from patients enrolled in 11 US health plans dispersed geographically, from January 1998 to June 2001. Potential cases of rhabdomyolysis were identified by flagging for discharge diagnoses of myoglobinuria, myositis, myopathy, other muscle-related disorders, adverse effect from antihyperlipidemic agents, and acute renal failure with elevated serum creatinine kinase or with any muscle-related disorder. A patient was classified as having rhabdomyolysis if there was a diagnosis of rhabdomyolysis or if the serum creatinine kinase (CK) was more than 10 times the upper limits of normal in the presence of severe muscle injury at the time of hospital admission. Incidence rates of rhabdomyolysis per 10,000 person-years of treatment with 95% confidence interval (CI) and the number needed to treat to observe a case (NNT) were calculated. Relative risk (RR) estimates of rhabdomyolysis were adjusted for age, gender, and diabetes mellitus using Poisson regression.

Results: There were a total of 225,640 person-years of monotherapy with either a statin or a fibrate and 7,300 person-years of combined therapy with both a statin and a fibrate. Of 194 potential cases, 31 met the criteria for incident rhabdomyolysis. Of these, seven were excluded because the patients were not actually on a lipid-lowering regimen at the time of the diagnosis. Of the remaining 24, 16 cases occurred with monotherapy and eight with a combined therapy. Eighteen of the 24 patients had severe rhabdomyolysis with CK more than 50 times the upper limits of normal. Two patients required hemodialysis and one died. Cases occurred after a mean length of therapy of 348 days for monotherapy with atorvastatin or simvastatin, 56 days for cerivastatin, 77 days for gemfibrozil, and 32 days after combined statin-fibrate therapy. The incidence rates of rhabdomyolysis with monotherapy with atorvastatin, pravastatin, and simvastatin were statistically indistinguishable, with a summary estimate of 0.44 per 10,000 person-years of use (95% CI, 0.20-0.84), which was barely greater than the incidence rate without exposure of 0 (95% CI, 0-0.48). On the other hand, the summary incidence rates of rhabdomyolysis per 10,000 person-years were 5.34 (95% CI, 1.46-13.68) with monotherapy with cerivastatin and 2.82 (95% CI, 0.58-8.24) with monotherapy with a fibrate. The incidence rates of rhabdomyolysis did not change with duration of therapy up to two years. The incidence rates with combined therapy were 1,035 (95% CI, 389-2,117) per 10,000 person-years when the statin was cerivastatin and 5.98 (95% CI, 0.72-216) when the statin was not cerivastatin. The risk of rhabdomyolysis with statin monotherapy was increased in those older than 65 (RR of 5.4; 95% CI, 1.3-21.6) and in those with diabetes mellitus (RR of 2.9; 95% CI, 0.7-11.8). The risk of hospitalization with rhabdomyolysis was increased 48-fold if the patient was older than 65 with diabetes and was on a combined statin-fibrate therapy, translating to a NNT of 484. With combined cerivastatin and gemfibrozil, the NNT ranged from 9.7 to 12.7 patients. With monotherapy with other statins, the NNT was 22,727 patients per year of therapy.

Comments: This is the first large-scale epidemiological study of rhabdomyolysis incidence associated with statin and fibrate therapy, focusing on rhabdomyolysis severe enough to require hospitalization. Although the number of cases was quite small, there was adequate statistical power, because of a large exposure cohort, encompassing 225,640 person-years of monotherapy with either a statin or a fibrate and 7,300 person-years of combined therapy. The study demonstrates that, except for cerivastatin which has been withdrawn from the market, 13 the commonly prescribed statins (atorvastatin, simvastatin, and pravastatin) are associated with a very low incidence of rhabdomyolysis. Potential benefits of using the drugs would far outweigh the potential risk of rhabdomyolysis.

The risk is increased by about 5.5-fold with fibrate use and by an additional two-fold with a combined therapy. This increased risk of the combined therapy may in part be due to a two - 5.5-fold increase in serum concentrations of the statin when used in combination with gemfibrozil.14-16 Since all statins except pravastatin are metabolized by the liver cytochrome P450 system (cytochrome P450 isoenzyme 3A4 for atorvastatin, cerivastatin, simvastatin, and lovastatin), competitive inhibitors of cytochrome P450 3A4 such as ketoconazole, erythromycin, and cyclosporine may also increase serum concentrations of a concomitantly administered statin and increase the risk of rhabdomyolysis. 17-19 In addition, it may be surmised that patients with hepatic dysfunction may be at increased risk for rhabdomyolysis from statin use. Lastly, this study identifies another group at an increase risk for rhabdomyolysis from statin use - namely, the elderly, especially if those with diabetes mellitus, who may often have hypertriglyceridemia and require a fibrate. The possibility of rhabdomyolysis with statin use should be kept in mind for the high-risk groups and appropriate evaluation and treatment undertaken, if suggestive symptoms develop.

References

  1. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9
  2. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333:1301-7
  3. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335:1001-9
  4. Downs JR, Clearfield M, Weiss S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/Tex CAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. J Am Med Assoc 1998; 279:1615-22
  5. Pohle K, Maffert R, Ropers D, et al. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation 2001; 104:1927-32
  6. Shavelle DM, Takasu J, Budoff MJ, et al. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 2002; 359:1125-6
  7. Antonini-Canterin F, Zuppiroli A, Popescu BA, et al. Effect of statins on the progression of bioprosthetic aortic valve degeneration. Am J Cardiol 2003; 92:1479-82
  8. Young-Xu Y, Jabbour S, Goldberg R, et al. Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. Am J Cardiol 2003; 92:1379-83 (Reviewed in the February 2004 issue of the SCA Newsletter: http://www.scahq.org/sca3/newsletters/2004feb/lit1.shtml)
  9. Poldermans D, Bax JJ, Kertai MD, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003; 107:1848-51 (Reviewed in the December 2003 issue of the SCA Newsletter: http://www.scahq.org/sca3/newsletters/2003dec/lit1.shtml)
  10. Reviewed in the February 2002 issue of the SCA Newsletter: http://www.scahq.org/sca3/newsletters/2004feb/lit1.shtml
  11. Barket BJ, Goodenough RR, Falko JM. Fenofibrate monotherapy induced rhabdomyolysis [letter]. Diabetes Care 2003; 26:2482-3
  12. Gorriz JL, Sancho A, Lopez-Martin JM, et al. Rhabdomyolysis and acute renal failure associated with gemfibrozil monotherapy. Nephron 1996; 74:437-8
  13. Psaty BM, Furberg CD, Ray WA, Weiss NS. Potential for conflict of interest in the evaluation of suspected adverse drug reactions. Use of cerivastatin and risk of rhabdomyolysis. J Am Med Assoc 2004; 292:2622-31
  14. Backman JT, Kyrklund C, Kivisto KT, et al. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther 2000; 68:122-9
  15. Kyrklund C, Backman JT, Kivisto KT, et al. Plasma concentrations of active lovastatin are markedly increased by gemfibrozil but not by bezafirate. Clin Pharmacol Ther 2001; 69:340-5
  16. Prueeksaritanont T, Tang C, Qui Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 2002; 30:1280-7
  17. Rosenson RS. Current overview of statin-induced myopathy. Am J Med 2004; 116:408-16
  18. Baker SK, Tarnopolsky MA. Statin myopathies: pathophysiological and clinical perspectives. Clin Invest Med 2001; 24:258-72
  19. Evans M, Rees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf 2002; 25:649-63
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