Chien-Yi Yang1, Chi-Hua Chen1, Shin-Tarng Deng1, Chi-Shan Huang2, Yu-Jr Lin3, Yi-Ju Chen4, Chun-Ying Wu5, Shuen-Iu Hung6, Wen-Hung Chung7. 1. Division of Clinical Pharmacy, Department of Pharmacy, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 2. National Health Insurance Administration-Northern Division, Ministry of Health and Welfare, Taipei, Taiwan. 3. Statistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan. 4. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan5Department of Dermatology, Taichung Veterans General Hospital, China Medical University, Taichung, Taiwan. 5. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan6Division of Gastroenterology, Taichung Veterans General Hospital, China Medical University, Taichung, Taiwan7Department of Life Sciences, National Chung-Hsing Universit. 6. Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 7. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan10College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Abstract
IMPORTANCE: Allopurinol, a first-line drug used for treating gout, is increasingly prescribed worldwide to patients with asymptomatic hyperuricemia and comorbid renal or cardiovascular diseases. Nevertheless, allopurinol use has been associated with fatal hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The overall risks of allopurinol use remain unclear. OBJECTIVE: To investigate the incidence of, risk factors for, and mortality associated with allopurinol hypersensitivity in new users of allopurinol. DESIGN, SETTING, AND PARTICIPANTS: A retrospective nationwide population study was conducted using data from the Taiwan National Health Insurance Research Database, which includes detailed medical records of more than 23 million insured enrollees. Data were collected from January 1, 2005, through December 31, 2011, using the Anatomical Therapeutic Chemical classification system and International Classification of Diseases, Ninth Revision, Clinical Modification codes. Among 1,613,719 patients receiving allopurinol prescriptions, 495,863 were identified as new users. MAIN OUTCOMES AND MEASURES: Allopurinol hypersensitivity was identified within 3 months since the first prescription. The period for measuring related hospitalizations was 1 month since the episode, and the period for measuring renal complications or mortality was 2 months since the episode. Poisson regression test and multivariable logistic regression analysis were performed, and P < .01 was considered statistically significant. RESULTS: Among the more than 23 million insured enrollees, the annual incidence rates were 4.68 per 1000 new users for allopurinol hypersensitivity, 2.02 per 1000 new users for related hospitalization, and 0.39 per 1000 new users for related mortality. The annual incidence of allopurinol hypersensitivity rose statistically significantly during the study period (P < .001). Risk factors for allopurinol hypersensitivity included female sex, age 60 years or older, initial allopurinol dosage exceeding 100 mg/d, renal or cardiovascular comorbidities, and use for treating asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia and renal or cardiovascular diseases had statistically significantly increased risk of allopurinol hypersensitivity (odds ratio [OR], 1.61; 95% CI, 1.33-1.94; P < .001 for renal diseases and OR, 1.52; 95% CI, 1.19-1.93; P < .001 for cardiovascular diseases). They also had statistically significantly increased risk of mortality (OR, 5.59; 95% CI, 2.61-11.94; P < .001 for renal diseases and OR, 3.57; 95% CI, 2.31-5.51; P < .001 for cardiovascular diseases). CONCLUSIONS AND RELEVANCE: The use of allopurinol in patients with asymptomatic hyperuricemia accompanied by renal or cardiovascular diseases statistically significantly increased the risk of hypersensitivity reactions. Physicians should be cautious when prescribing allopurinol to high-risk populations and should consider the potential risks of fatal adverse reactions.
IMPORTANCE: Allopurinol, a first-line drug used for treating gout, is increasingly prescribed worldwide to patients with asymptomatic hyperuricemia and comorbid renal or cardiovascular diseases. Nevertheless, allopurinol use has been associated with fatal hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The overall risks of allopurinol use remain unclear. OBJECTIVE: To investigate the incidence of, risk factors for, and mortality associated with allopurinolhypersensitivity in new users of allopurinol. DESIGN, SETTING, AND PARTICIPANTS: A retrospective nationwide population study was conducted using data from the Taiwan National Health Insurance Research Database, which includes detailed medical records of more than 23 million insured enrollees. Data were collected from January 1, 2005, through December 31, 2011, using the Anatomical Therapeutic Chemical classification system and International Classification of Diseases, Ninth Revision, Clinical Modification codes. Among 1,613,719 patients receiving allopurinol prescriptions, 495,863 were identified as new users. MAIN OUTCOMES AND MEASURES: Allopurinolhypersensitivity was identified within 3 months since the first prescription. The period for measuring related hospitalizations was 1 month since the episode, and the period for measuring renal complications or mortality was 2 months since the episode. Poisson regression test and multivariable logistic regression analysis were performed, and P < .01 was considered statistically significant. RESULTS: Among the more than 23 million insured enrollees, the annual incidence rates were 4.68 per 1000 new users for allopurinolhypersensitivity, 2.02 per 1000 new users for related hospitalization, and 0.39 per 1000 new users for related mortality. The annual incidence of allopurinolhypersensitivity rose statistically significantly during the study period (P < .001). Risk factors for allopurinol hypersensitivity included female sex, age 60 years or older, initial allopurinol dosage exceeding 100 mg/d, renal or cardiovascular comorbidities, and use for treating asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia and renal or cardiovascular diseases had statistically significantly increased risk of allopurinolhypersensitivity (odds ratio [OR], 1.61; 95% CI, 1.33-1.94; P < .001 for renal diseases and OR, 1.52; 95% CI, 1.19-1.93; P < .001 for cardiovascular diseases). They also had statistically significantly increased risk of mortality (OR, 5.59; 95% CI, 2.61-11.94; P < .001 for renal diseases and OR, 3.57; 95% CI, 2.31-5.51; P < .001 for cardiovascular diseases). CONCLUSIONS AND RELEVANCE: The use of allopurinol in patients with asymptomatic hyperuricemia accompanied by renal or cardiovascular diseases statistically significantly increased the risk of hypersensitivity reactions. Physicians should be cautious when prescribing allopurinol to high-risk populations and should consider the potential risks of fatal adverse reactions.
Authors: Ted R Mikuls; T Craig Cheetham; Gerald D Levy; Nazia Rashid; Artak Kerimian; Kimberly J Low; Brian W Coburn; David T Redden; Kenneth G Saag; P Jeffrey Foster; Lang Chen; Jeffrey R Curtis Journal: Am J Med Date: 2018-11-29 Impact factor: 4.965
Authors: Sarah F Keller; Na Lu; Kimberly G Blumenthal; Sharan K Rai; Chio Yokose; Jee Woong J Choi; Seoyoung C Kim; Yuqing Zhang; Hyon K Choi Journal: Ann Rheum Dis Date: 2018-04-13 Impact factor: 19.103
Authors: Na Lu; Sharan K Rai; Robert Terkeltaub; Seoyoung C Kim; Mariano E Menendez; Hyon K Choi Journal: Semin Arthritis Rheum Date: 2016-03-31 Impact factor: 5.532
Authors: Hamish Farquhar; Ana B Vargas-Santos; Huai Leng Pisaniello; Mark Fisher; Catherine Hill; Angelo L Gaffo; Lisa K Stamp Journal: Rheumatol Adv Pract Date: 2021-01-04