American Journal of Therapeutics 22, 377–381 (2015)
Is Statin Use Associated With Tendon Rupture? A Population-Based Retrospective Cohort Analysis Tahmeed Contractor, MD,1* Abhimanyu Beri, MD,2 Joseph C. Gardiner, PhD,3 Xiaoqin Tang, PhD,4 and Francesca C. Dwamena, MD, MS5
Previous case reports and small studies have suggested that 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (HMG-CoA-Is) may increase the risk of tendon rupture. We conducted a population-based retrospective cohort evaluation to better assess this relationship. From approximately 800,000 enrollees of a private insurance database, those who were aged #64 years with at least 1 year of continuous enrollment were selected. Exposure was defined as initiation of HMG-CoA-I after the beginning of the study period. Each exposed person was matched with 2 controls of similar age and gender. Baseline characteristics, including known risk factors for tendon rupture, were compared between exposed and control cohorts with fidelity to the study’s matched design. After adjusting for differences in follow-up and baseline characteristics, incidence rate ratios for tendon rupture was assessed in HMG-CoA-I users and nonusers. A total of 34,749 exposed patients were matched with 69,498 controls. There was no difference in the occurrence of tendon ruptures in HMG-CoA-I users versus nonusers. The results remained unchanged after adjustment for age and gender. In conclusion, this population-based retrospective cohort evaluation suggests that use of HMG-CoA-Is as a group are not associated with tendon rupture. Keywords: 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, tendon rupture, adverse drug reaction
INTRODUCTION The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (HMG-CoA-Is) or statins have demonstrated a significant improvement in cardiovascular outcomes in 1
Division of Cardiology, Lehigh Valley Health Network, Allentown, PA; 2Department of Clinical Cardiac Electrophysiology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA; 3 Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI; 4Center for Health Research, Geisinger Health System, Danville, PA; and 5Department of Medicine, Michigan State University, East Lansing, MI. Supported by Resident-Led Research Mini-Grant from Graduate Medical Education, Inc, East Lansing, MI (T.C. and A.B.) and Blue Cross Blue Shield of Michigan Foundation Physician Investigation Research Award from the Blue Cross Blue Shield of Michigan Foundation, Detroit, MI (F.C.D., J.G., T.C., and A.B.). *Address for correspondence: Division of Cardiology, Lehigh Valley Health Network, 1250 S. Cedar Crest Boulevard, Suite 300, Allentown, PA 18103. E-mail: [email protected]
the primary and secondary prevention of coronary artery disease.1,2 HMG-CoA-Is have emerged as the mainstay treatment of hyperlipidemia and their use has increased exponentially over the past 2 decades.3 Common reported side effects include myalgias and elevated aminotranferase levels, with hepatotoxicity, myopathy and rhabdomyolysis being extremely rare. Recent anecdotal reports and postmarketing studies have postulated an association between HMG-CoA-I therapy and tendon rupture.4–6 It is biologically plausible that HMG-CoA-Is can weaken the integrity of tendons by reducing the cholesterol content in cell membranes, inhibiting metalloproteinases and promoting cell apoptosis.7–10 Our previously published casecontrol study suggested a possible association between tendon rupture and HMG-CoA-Is in female patients.11 We conducted a population-based retrospective cohort analysis to further explore the potential association between HMG-CoA-Is and tendon rupture and to determine whether gender or age might modify any potential risk.
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378
METHODS Population selection We selected the patient population from enrollees in a private insurance corporation consisting of .800,000 patients and representing approximately 8% of the population of the state of Michigan. All data were deidentified. Patients aged 30–64 years with at least 1 year of continuous enrollment between January 2003 and June 2010 with both medical and pharmacy benefits were screened for inclusion. Members who were initiated on HMG-CoA-I therapy after enrollment comprised the “exposed cohort.” We excluded anyone with a claim for HMG-CoA-I prescription within 6 months of enrollment. Each exposed person was age- (62 years) and sex-matched with 2 controls from the same database who had no claims for HMG-CoA-Is. To reduce the chances of a “healthy user effect”12 and ensure similar opportunities for the diagnosis of tendon rupture in the 2 groups, we selected controls who had been diagnosed with a chronic condition (hypertension) that usually requires routine doctor’s visits, but is not associated with tendon rupture. Data collection The pharmacy claims database was used to extract information on medication use through 3-segment universal product identifiers for human drugs issued by the Federal Drug Administration. The date of the first HMG-CoA-I prescription in the claims database was selected as the HMG-CoA-I initiation date. We collected data about dose, type, and duration of HMGCoA-Is and other medications previously associated with tendon rupture (specifically any fluoroquinolone13 or steroid14). We used the ninth International Classification of Disease (ICD-9) revision codes to identify the presence of tendon rupture and other comorbidities from outpatient and inpatient claims data. The code 727.xx was used to identify the episode and site of the tendon rupture. We also noted the presence or absence of diagnoses that have been associated with tendon rupture (specifically rheumatoid arthritis,15 systemic lupus erythematosus,16 gout,17,18 diabetes mellitus,19 hyperparathyroidism,20 and chronic kidney disease18).
Contractor et al
use or tendon ruptures, follow-up for the unexposed cohort was started 6 months after enrollment. This was performed to eliminate tendon ruptures secondary to HMG-CoA-Is or other medications in the preenrollment period. Follow-up was censored in the following circumstances: occurrence of first tendon rupture, disenrollment from the insurance, completion of study period (June 2010), discontinuation of HMGCoA-I, or reaching age 65. We defined the date of last HMG-CoA-I use as the date on which exposed members would take the last pill from their last prescription, assuming 100% compliance. To minimize the chances of having missing data, we limited our analysis to patients who were aged younger than 65 years as patients aged 65 and older were more likely to have benefits with claims data from a second insurer (Medicare). Statistical analysis We compared baseline characteristics, including clinical and pharmacologic risk factors for tendon rupture, between the exposed and unexposed groups with fidelity to the matched study design. Since the followup period was variable, different statistical models were applied to conduct a matched analysis for the primary outcomes of the study. To estimate the overall incidence rate ratio (IRR) of tendon rupture in HMGCoA-I users versus nonusers, we modeled the probability of a tendon rupture pij in the i-th matched set for the HMG-CoA-I user (j 5 1) and for the matched nonusers (j 5 2, 3) by pij 5 12expð2lij tij Þ where tij is the follow-up time (years) and lij is the incidence rate for tendon rupture per year of follow-up. The effect of exposure and baseline characteristics xij was modeled as logðlij Þ 5 x9ij b. To account for the matched design, the method of generalized estimating equations was used with an exchangeable working correlation. The model provides IRR comparing HMG-CoA-I-users with nonusers. Because an alternative random-effects model produced similar results, they are not reported here. All analyses were performed using SAS software, version 9.2 (SAS Institute Inc, Cary, NC). The study protocol was approved by the institutional review boards at Michigan State University and at Blue Care Network of Michigan.
RESULTS
Follow-up To maximize the probabilities that reported tendon ruptures were related to HMG-CoA-I therapy in the exposed group, we excluded claims of tendon rupture within the first month of HMG-CoA-I initiation. Since the exposed had at least 6 months free of HMG-CoA-I American Journal of Therapeutics (2015) 22(5)
Baseline characteristics A total of 830,833 members were screened from which 34,749 HMG-CoA-I users and 69,498 age and sexmatched nonusers met criteria for inclusion. In 44 exposed patients, the follow-up period was not www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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accurately determined and therefore, we dropped these patients and their matched controls. The mean age was 47.6 years (SD 5 7.9) and 47.7% were women. The average follow-up was 2.4 years (SD 5 1.9). Distribution of risk factors for tendon rupture in the entire patient population is shown in Table 1. The prevalence of inflammatory conditions, including rheumatoid arthritis and gout, as well as diabetes, chronic kidney disease, and associated hyperparathyroidism was higher in HMG-CoA-I users. The most commonly prescribed HMG-CoA-I was simvastatin (57.4%; n 5 19,902) followed by atorvastatin (19.0%; n 5 6596), lovastatin (16.5%; n 5 5736), pravastatin (5.2%; n 5 1794), and the others accounting for less than 2%. The crude incidence rate of tendon rupture was 334 (5.6 per 1000 patient-years) in the HMG-CoA-I group and 870 (4.7 per 1000 patient-years) in the control group. A comorbidity index (CMI) was calculated for each patient and included in the final analysis based on the presence of risk factors for tendon rupture (systemic lupus erythematosis, rheumatoid arthritis, gout, diabetes mellitus, hyperparathyroidism, chronic kidney disease, fluouroquinolone, and corticosteroid use). In general, HMG-CoA-I users had a higher CMI than nonusers (Table 2). Matched analysis of IRR IRRs were estimated from complementary log (2log) models that simultaneously adjusted for CMI, age, and gender. Although age and gender were used in matching exposed patients to controls, there might be variation across matched sets that could affect the outcome. When adjusted for CMI only, there was no difference in the risk of tendon rupture among users and nonusers (IRR 5 1.12; 95% [confidence limits, CL] 0.98– 1.27). The results remain unchanged after adjusting for
age and gender, and restricting analysis to those with .1 month of follow-up (IRR 5 1.13; 95% CL, 0.98– 1.29). When assessing the risk with individual HMGCoA-Is, atorvastatin users had a significant risk of tendon rupture compared with controls (IRR 5 2.4, P , 0.0001). Conversely, simvastatin use was associated with a lower risk of tendon rupture (IRR 5 0.77; P , 0.05). There was no significant association between tendon rupture and the use of the other HMG-CoA-Is.
DISCUSSION In this population-based cohort study, there was no significant risk of tendon rupture with HMG-CoA-Is as a group. There was no effect of age and sex on this relationship. Subgroup analysis suggested a variable risk with different HMG-CoA-Is. To the best of our knowledge, this is the largest study that has explored this relationship. HMG-CoA-Is have increasingly gained favor as the first-line treatment for dysplipidemia and seem to provide benefit beyond lipid lowering. This has led to their widespread use in patients with coronary artery disease and hyperlipidemia. However, these medications have caught significant media attention due to alleged side effects,21 including tendon ruptures. It is important to clarify the significance or lack of these risks given the health benefits of these medications as has been confirmed by large randomized controlled trials.1,2 Proposed mechanisms for HMG-CoA-I induced tendon rupture include reduced synthesis of mevalonate through inhibition of 3-Hydroxy-3-MethylGlutarylCoenzyme A reductase enzyme. Mevalonate is a precursor of isoprenoids required for posttranslational modification of critical cellular proteins.7,8 Alterations
Table 1. Distribution of risk factors for tendon rupture.
Variable SLE RA Gout Diabetes mellitus Hyperparathyroidism Chronic kidney disease Fluoroquinolone Steroid
Exposed (n 5 34,749) N (%) 121 1150 2012 7537 354 1694 10,021 7025
(0.3) (3.3) (5.8) (21.7) (1) (4.9) (28.9) (20.2)
Unexposed (n 5 69,498) N (%) 286 2010 3245 6650 609 2342 15,521 11,459
(0.4) (2.9) (4.7) (9.6) (0.9) (3.4) (22.3) (16.5)
P 0.12 ,0.01 ,0.01 ,0.01 0.02 ,0.01 ,0.01 ,0.01
SLE, systemic lupus erythematosis; RA, rheumatoid arthritis.
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American Journal of Therapeutics (2015) 22(5)
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Table 2. Distribution of the CMI in exposed and control groups. N (%) subjects by group CMI* Group Statin users Controls Total
0
1
2
3
$4
Total
9779 28.2% 28,032 40.4% 37,811
16,841 48.5% 31,878 45.9% 48,719
6444 18.6% 7804 11.2% 14,248
1308 3.8% 1356 2.0% 2664
333 ,1.0% 340 ,0.5% 673
34,705 69,410 104,115
*Including the presence of systemic lupus erythematosis, rheumatoid arthritis, gout, diabetes mellitus, hyperparathyroidism, chronic kidney disease, fluouroquinolone, and corticosteroid use.
in these proteins cause inhibition of matrix metalloproteinases that are required for the repair and remodeling of injured tendons,9,10 which could potentially predispose them to rupture. A few published case reports have described an association between statin use and tendon ruptures.5,6 Subsequently, a large case series by Marie et al4 from a pharmacological adverse drug event reporting database revealed 33 cases with tendon rupture related to HMG-CoA-Is. A case control study from our electronic medical record database also showed an association between HMG-CoA-I use and tendon rupture in women (adjusted odds ratio, 3.76; P 5 0.03) but not in men.11 The large population size in our current study allowed a more definitive assessment of this possible relationship and the lack of overall risk is reassuring. However, there was an increased risk of tendon rupture noted with atorvastatin and a reduced risk with simvastatin. Reasons for these differential effects cannot be explained. Assessing the risk with different statins was not the primary goal of our study, and it is possible that these findings are related to chance and/or unobserved factors. Further studies are required to assess these findings. Our study has all the inherent limitations of a retrospective evaluation. However, prospective studies with such a large study population will be difficult to perform. Historically, cohort designs have been an important tool for exploring disease pathogenesis.22,23 They remain a valuable resource to answer clinical questions in a large population such as in our study. There are significant baseline differences between the exposed and unexposed cohort. In this study, HMGCoA-I users had a significantly higher number of risk factors for tendon rupture compared with nonusers. The higher incidence of diabetes mellitus and related chronic kidney disease in HMG-CoA-I users was likely due to the coexistent metabolic syndrome in these patients. Similarly, rheumatoid arthritis and gout were American Journal of Therapeutics (2015) 22(5)
expectedly more frequent in HMG-CoA-I users given the association between inflammatory conditions and dyslipidemia. To account for these differences, all the different statistical models used a CMI adjustment while calculating the final IRRs.
CONCLUSIONS In a population-based retrospective cohort evaluation, there was no relationship between the use of HMGCoA-Is as a group and tendon rupture. Additionally, there was no effect of age and gender on these findings. Prospective studies with longer follow-up are required to confirm or refute our findings.
ACKNOWLEDGMENTS The authors thank Tom Fraser, project manager at Blue Care Network, for his help in data collection.
REFERENCES 1. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615–1622. 2. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389. 3. Centers for Disease Control and Prevention. Health, United States, 2010. Available at: http://www.cdc.gov/ nchs/data/hus/2010/fig17pdf. Accessed November 12, 2012. 4. Marie I, Delafenetre H, Massy N, et al. Tendinous disorders attributed to statins: a study on ninety-six spontaneous www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Statins and Tendon Rupture
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6.
7.
8.
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10. 11.
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reports in the period 1990-2005 and review of the literature. Arthritis Rheum. 2008;59:367–372. Pullatt RC, Gadarla MR, Karas RH, et al. Tendon rupture associated with simvastatin/ezetimibe therapy. Am J Cardiol. 2007;100:152–153. Chazerain P, Hayem G, Hamza S, et al. Four cases of tendinopathy in patients on statin therapy. Joint Bone Spine. 2001;68:430–433. Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation. 2004;109:II18–II26. Turner NA, O’Regan DJ, Ball SG, et al. Simvastatin inhibits MMP-9 secretion from human saphenous vein smooth muscle cells by inhibiting the RhoA/ROCK pathway and reducing MMP-9 mRNA levels. FASEB J. 2005;19:804–806. Clegg PD, Strassburg S, Smith RK. Cell phenotypic variation in normal and damaged tendons. Int J Exp Pathol. 2007;88:227–235. Riley G. Symposium: tendon and ligament remodelling and regeneration. Int J Exp Pathol. 2007;88:215–216. Beri A, Dwamena FC, Dwamena BA. Association between statin therapy and tendon rupture: a casecontrol study. J Cardiovasc Pharmacol. 2009;53:401–404. Brookhart MA, Patrick AR, Dormuth C, et al. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect. Am J Epidemiol. 2007;166:348–354. Van Der Linden PD, Van Puijenbroek EP, Feenstra J, et al. Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998. Arthritis Rheum. 2001;45:235–239.
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381 14. Haines JF. Bilateral rupture of the Achilles tendon in patients on steroid therapy. Ann Rheum Dis. 1983;42: 652–654. 15. Peiró A, Ferrandis R, Garcia L, et al Rupture of the patellar tendon in rheumatoid arthritis: a case report. Acta Orthop Scand. 1975;46:700–703. 16. Furie RA, Chartash EK. Tendon rupture in systemic lupus erythematosus. Semin Arthritis Rheum. 1988;18: 127–133. 17. Mahoney PG, James PD, Howell CJ, et al. Spontaneous rupture of the Achilles tendon in a patient with gout. Ann Rheum Dis. 1981;40:416–418. 18. Shah MK. Simultaneous bilateral quadriceps tendon rupture in renal patients. Clin Nephrol. 2002;58:118–121. 19. Burner TW, Rosenthal AK. Diabetes and rheumatic diseases. Curr Opin Rheumatol. 2009;21:50–54. 20. Barasch E, Lombardi LJ, Arena L, et al. MRI visualization of bilateral quadriceps tendon rupture in a patient with secondary hyperparathyroidism: implications for diagnosis and therapy. Comput Med Imaging Graph. 1989;13:407–410. 21. Meade TD. FDA correctly identifies risks from statins. [The Morning Call website]. Available at http://articles.mcall. com/2012-03-10/opinion/mc-statin-side-effects-meadeyv–20120310_1_statins-crestor-people-without-heart-disease. Accessed November 12, 2013. 22. Doll R, Peto R, Wheatley K, et al. Mortality in relation to smoking: 40 years’ observations on male British doctors. BMJ. 1994;309:901–911. 23. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J. 1986;111: 383–390.
American Journal of Therapeutics (2015) 22(5)
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Is Statin Use Associated With Tendon Rupture? A Population-Based Retrospective Cohort Analysis Tahmeed Contractor, MD,1* Abhimanyu Beri, MD,2 Joseph C. Gardiner, PhD,3 Xiaoqin Tang, PhD,4 and Francesca C. Dwamena, MD, MS5
Previous case reports and small studies have suggested that 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (HMG-CoA-Is) may increase the risk of tendon rupture. We conducted a population-based retrospective cohort evaluation to better assess this relationship. From approximately 800,000 enrollees of a private insurance database, those who were aged #64 years with at least 1 year of continuous enrollment were selected. Exposure was defined as initiation of HMG-CoA-I after the beginning of the study period. Each exposed person was matched with 2 controls of similar age and gender. Baseline characteristics, including known risk factors for tendon rupture, were compared between exposed and control cohorts with fidelity to the study’s matched design. After adjusting for differences in follow-up and baseline characteristics, incidence rate ratios for tendon rupture was assessed in HMG-CoA-I users and nonusers. A total of 34,749 exposed patients were matched with 69,498 controls. There was no difference in the occurrence of tendon ruptures in HMG-CoA-I users versus nonusers. The results remained unchanged after adjustment for age and gender. In conclusion, this population-based retrospective cohort evaluation suggests that use of HMG-CoA-Is as a group are not associated with tendon rupture. Keywords: 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, tendon rupture, adverse drug reaction
INTRODUCTION The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (HMG-CoA-Is) or statins have demonstrated a significant improvement in cardiovascular outcomes in 1
Division of Cardiology, Lehigh Valley Health Network, Allentown, PA; 2Department of Clinical Cardiac Electrophysiology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA; 3 Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI; 4Center for Health Research, Geisinger Health System, Danville, PA; and 5Department of Medicine, Michigan State University, East Lansing, MI. Supported by Resident-Led Research Mini-Grant from Graduate Medical Education, Inc, East Lansing, MI (T.C. and A.B.) and Blue Cross Blue Shield of Michigan Foundation Physician Investigation Research Award from the Blue Cross Blue Shield of Michigan Foundation, Detroit, MI (F.C.D., J.G., T.C., and A.B.). *Address for correspondence: Division of Cardiology, Lehigh Valley Health Network, 1250 S. Cedar Crest Boulevard, Suite 300, Allentown, PA 18103. E-mail: [email protected]
the primary and secondary prevention of coronary artery disease.1,2 HMG-CoA-Is have emerged as the mainstay treatment of hyperlipidemia and their use has increased exponentially over the past 2 decades.3 Common reported side effects include myalgias and elevated aminotranferase levels, with hepatotoxicity, myopathy and rhabdomyolysis being extremely rare. Recent anecdotal reports and postmarketing studies have postulated an association between HMG-CoA-I therapy and tendon rupture.4–6 It is biologically plausible that HMG-CoA-Is can weaken the integrity of tendons by reducing the cholesterol content in cell membranes, inhibiting metalloproteinases and promoting cell apoptosis.7–10 Our previously published casecontrol study suggested a possible association between tendon rupture and HMG-CoA-Is in female patients.11 We conducted a population-based retrospective cohort analysis to further explore the potential association between HMG-CoA-Is and tendon rupture and to determine whether gender or age might modify any potential risk.
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378
METHODS Population selection We selected the patient population from enrollees in a private insurance corporation consisting of .800,000 patients and representing approximately 8% of the population of the state of Michigan. All data were deidentified. Patients aged 30–64 years with at least 1 year of continuous enrollment between January 2003 and June 2010 with both medical and pharmacy benefits were screened for inclusion. Members who were initiated on HMG-CoA-I therapy after enrollment comprised the “exposed cohort.” We excluded anyone with a claim for HMG-CoA-I prescription within 6 months of enrollment. Each exposed person was age- (62 years) and sex-matched with 2 controls from the same database who had no claims for HMG-CoA-Is. To reduce the chances of a “healthy user effect”12 and ensure similar opportunities for the diagnosis of tendon rupture in the 2 groups, we selected controls who had been diagnosed with a chronic condition (hypertension) that usually requires routine doctor’s visits, but is not associated with tendon rupture. Data collection The pharmacy claims database was used to extract information on medication use through 3-segment universal product identifiers for human drugs issued by the Federal Drug Administration. The date of the first HMG-CoA-I prescription in the claims database was selected as the HMG-CoA-I initiation date. We collected data about dose, type, and duration of HMGCoA-Is and other medications previously associated with tendon rupture (specifically any fluoroquinolone13 or steroid14). We used the ninth International Classification of Disease (ICD-9) revision codes to identify the presence of tendon rupture and other comorbidities from outpatient and inpatient claims data. The code 727.xx was used to identify the episode and site of the tendon rupture. We also noted the presence or absence of diagnoses that have been associated with tendon rupture (specifically rheumatoid arthritis,15 systemic lupus erythematosus,16 gout,17,18 diabetes mellitus,19 hyperparathyroidism,20 and chronic kidney disease18).
Contractor et al
use or tendon ruptures, follow-up for the unexposed cohort was started 6 months after enrollment. This was performed to eliminate tendon ruptures secondary to HMG-CoA-Is or other medications in the preenrollment period. Follow-up was censored in the following circumstances: occurrence of first tendon rupture, disenrollment from the insurance, completion of study period (June 2010), discontinuation of HMGCoA-I, or reaching age 65. We defined the date of last HMG-CoA-I use as the date on which exposed members would take the last pill from their last prescription, assuming 100% compliance. To minimize the chances of having missing data, we limited our analysis to patients who were aged younger than 65 years as patients aged 65 and older were more likely to have benefits with claims data from a second insurer (Medicare). Statistical analysis We compared baseline characteristics, including clinical and pharmacologic risk factors for tendon rupture, between the exposed and unexposed groups with fidelity to the matched study design. Since the followup period was variable, different statistical models were applied to conduct a matched analysis for the primary outcomes of the study. To estimate the overall incidence rate ratio (IRR) of tendon rupture in HMGCoA-I users versus nonusers, we modeled the probability of a tendon rupture pij in the i-th matched set for the HMG-CoA-I user (j 5 1) and for the matched nonusers (j 5 2, 3) by pij 5 12expð2lij tij Þ where tij is the follow-up time (years) and lij is the incidence rate for tendon rupture per year of follow-up. The effect of exposure and baseline characteristics xij was modeled as logðlij Þ 5 x9ij b. To account for the matched design, the method of generalized estimating equations was used with an exchangeable working correlation. The model provides IRR comparing HMG-CoA-I-users with nonusers. Because an alternative random-effects model produced similar results, they are not reported here. All analyses were performed using SAS software, version 9.2 (SAS Institute Inc, Cary, NC). The study protocol was approved by the institutional review boards at Michigan State University and at Blue Care Network of Michigan.
RESULTS
Follow-up To maximize the probabilities that reported tendon ruptures were related to HMG-CoA-I therapy in the exposed group, we excluded claims of tendon rupture within the first month of HMG-CoA-I initiation. Since the exposed had at least 6 months free of HMG-CoA-I American Journal of Therapeutics (2015) 22(5)
Baseline characteristics A total of 830,833 members were screened from which 34,749 HMG-CoA-I users and 69,498 age and sexmatched nonusers met criteria for inclusion. In 44 exposed patients, the follow-up period was not www.americantherapeutics.com
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379
accurately determined and therefore, we dropped these patients and their matched controls. The mean age was 47.6 years (SD 5 7.9) and 47.7% were women. The average follow-up was 2.4 years (SD 5 1.9). Distribution of risk factors for tendon rupture in the entire patient population is shown in Table 1. The prevalence of inflammatory conditions, including rheumatoid arthritis and gout, as well as diabetes, chronic kidney disease, and associated hyperparathyroidism was higher in HMG-CoA-I users. The most commonly prescribed HMG-CoA-I was simvastatin (57.4%; n 5 19,902) followed by atorvastatin (19.0%; n 5 6596), lovastatin (16.5%; n 5 5736), pravastatin (5.2%; n 5 1794), and the others accounting for less than 2%. The crude incidence rate of tendon rupture was 334 (5.6 per 1000 patient-years) in the HMG-CoA-I group and 870 (4.7 per 1000 patient-years) in the control group. A comorbidity index (CMI) was calculated for each patient and included in the final analysis based on the presence of risk factors for tendon rupture (systemic lupus erythematosis, rheumatoid arthritis, gout, diabetes mellitus, hyperparathyroidism, chronic kidney disease, fluouroquinolone, and corticosteroid use). In general, HMG-CoA-I users had a higher CMI than nonusers (Table 2). Matched analysis of IRR IRRs were estimated from complementary log (2log) models that simultaneously adjusted for CMI, age, and gender. Although age and gender were used in matching exposed patients to controls, there might be variation across matched sets that could affect the outcome. When adjusted for CMI only, there was no difference in the risk of tendon rupture among users and nonusers (IRR 5 1.12; 95% [confidence limits, CL] 0.98– 1.27). The results remain unchanged after adjusting for
age and gender, and restricting analysis to those with .1 month of follow-up (IRR 5 1.13; 95% CL, 0.98– 1.29). When assessing the risk with individual HMGCoA-Is, atorvastatin users had a significant risk of tendon rupture compared with controls (IRR 5 2.4, P , 0.0001). Conversely, simvastatin use was associated with a lower risk of tendon rupture (IRR 5 0.77; P , 0.05). There was no significant association between tendon rupture and the use of the other HMG-CoA-Is.
DISCUSSION In this population-based cohort study, there was no significant risk of tendon rupture with HMG-CoA-Is as a group. There was no effect of age and sex on this relationship. Subgroup analysis suggested a variable risk with different HMG-CoA-Is. To the best of our knowledge, this is the largest study that has explored this relationship. HMG-CoA-Is have increasingly gained favor as the first-line treatment for dysplipidemia and seem to provide benefit beyond lipid lowering. This has led to their widespread use in patients with coronary artery disease and hyperlipidemia. However, these medications have caught significant media attention due to alleged side effects,21 including tendon ruptures. It is important to clarify the significance or lack of these risks given the health benefits of these medications as has been confirmed by large randomized controlled trials.1,2 Proposed mechanisms for HMG-CoA-I induced tendon rupture include reduced synthesis of mevalonate through inhibition of 3-Hydroxy-3-MethylGlutarylCoenzyme A reductase enzyme. Mevalonate is a precursor of isoprenoids required for posttranslational modification of critical cellular proteins.7,8 Alterations
Table 1. Distribution of risk factors for tendon rupture.
Variable SLE RA Gout Diabetes mellitus Hyperparathyroidism Chronic kidney disease Fluoroquinolone Steroid
Exposed (n 5 34,749) N (%) 121 1150 2012 7537 354 1694 10,021 7025
(0.3) (3.3) (5.8) (21.7) (1) (4.9) (28.9) (20.2)
Unexposed (n 5 69,498) N (%) 286 2010 3245 6650 609 2342 15,521 11,459
(0.4) (2.9) (4.7) (9.6) (0.9) (3.4) (22.3) (16.5)
P 0.12 ,0.01 ,0.01 ,0.01 0.02 ,0.01 ,0.01 ,0.01
SLE, systemic lupus erythematosis; RA, rheumatoid arthritis.
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Table 2. Distribution of the CMI in exposed and control groups. N (%) subjects by group CMI* Group Statin users Controls Total
0
1
2
3
$4
Total
9779 28.2% 28,032 40.4% 37,811
16,841 48.5% 31,878 45.9% 48,719
6444 18.6% 7804 11.2% 14,248
1308 3.8% 1356 2.0% 2664
333 ,1.0% 340 ,0.5% 673
34,705 69,410 104,115
*Including the presence of systemic lupus erythematosis, rheumatoid arthritis, gout, diabetes mellitus, hyperparathyroidism, chronic kidney disease, fluouroquinolone, and corticosteroid use.
in these proteins cause inhibition of matrix metalloproteinases that are required for the repair and remodeling of injured tendons,9,10 which could potentially predispose them to rupture. A few published case reports have described an association between statin use and tendon ruptures.5,6 Subsequently, a large case series by Marie et al4 from a pharmacological adverse drug event reporting database revealed 33 cases with tendon rupture related to HMG-CoA-Is. A case control study from our electronic medical record database also showed an association between HMG-CoA-I use and tendon rupture in women (adjusted odds ratio, 3.76; P 5 0.03) but not in men.11 The large population size in our current study allowed a more definitive assessment of this possible relationship and the lack of overall risk is reassuring. However, there was an increased risk of tendon rupture noted with atorvastatin and a reduced risk with simvastatin. Reasons for these differential effects cannot be explained. Assessing the risk with different statins was not the primary goal of our study, and it is possible that these findings are related to chance and/or unobserved factors. Further studies are required to assess these findings. Our study has all the inherent limitations of a retrospective evaluation. However, prospective studies with such a large study population will be difficult to perform. Historically, cohort designs have been an important tool for exploring disease pathogenesis.22,23 They remain a valuable resource to answer clinical questions in a large population such as in our study. There are significant baseline differences between the exposed and unexposed cohort. In this study, HMGCoA-I users had a significantly higher number of risk factors for tendon rupture compared with nonusers. The higher incidence of diabetes mellitus and related chronic kidney disease in HMG-CoA-I users was likely due to the coexistent metabolic syndrome in these patients. Similarly, rheumatoid arthritis and gout were American Journal of Therapeutics (2015) 22(5)
expectedly more frequent in HMG-CoA-I users given the association between inflammatory conditions and dyslipidemia. To account for these differences, all the different statistical models used a CMI adjustment while calculating the final IRRs.
CONCLUSIONS In a population-based retrospective cohort evaluation, there was no relationship between the use of HMGCoA-Is as a group and tendon rupture. Additionally, there was no effect of age and gender on these findings. Prospective studies with longer follow-up are required to confirm or refute our findings.
ACKNOWLEDGMENTS The authors thank Tom Fraser, project manager at Blue Care Network, for his help in data collection.
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