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Allopurinol And Cataracts
A L L O P U R I N O L A N D CATARACTS HERSHEL Waltham,
JicK, M.D. Massachusetts
AND D A V I D E. B R A N D T , M.D. Seattle, Washington
We conducted a two-part study to determine whether any positive association between the use of allopurinol and the development of cataracts could be demonstrated. Study 1 included 251 Boston-area patients hospitalized for cataract and 753 matched controls. Two cataract patients were regular allopuri nol users as compared with six control patients. The relative risk for cataract comparing allopurinol users with nonusers was 1.0 (95% exact confidence interval 0.14, 4.7). Study 2 included 389 patients from the Puget Sound, Washington, area who were hospitalized for cataract surgery during a five-year period (551,543 person-years). The rate of hospitalization for cataract in patients 30 to 49 years old was 0/992 person-years for allopurinol users and 78/366,960 (2.1 per 104) person-years for nonusers. The rate of hospitalization for cataract in patients 50 to 64 years old was 3/2,270 (13.2 per 104) person-years for allopurinol users and 308/184,583 (16.7 per 104) person-years for nonusers. Fraunfelder and associates 1 based their suggestion that long-term ingestion of allopurinol may cause cataracts on 30 cases of suspected allopurionol-induced lens changes reported to the National Registry of Drug-Induced Ocular Side Effects. Fraunfelder and associates 1 and Lerman, Megaw, and Gardner 2 used phosphorescence emission peaks to dem onstrate the "probable" presence of alloAccepted for publication June 18, 1984. From the Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Wal tham, Massachusetts (Dr. Jick), and the Group Health Cooperative of Puget Sound, Seattle, Wash ington (Dr. Brandt). This study was supported by the Food and Drug Administration (Cooperative Agree ment 5 U01 FD01223) and the Burroughs Wellcome Co. Reprint requests to Hershel Jick, M.D., Boston Collaborative Drug Surveillance Program, 400-1, Totten Pond Rd., Waltham, MA 02154.
purinol in the cataracts of three patients who had been taking the drug. Lerman, Megaw, and Gardner 2 suggested that younger people might be at particularly high risk. March, Goren, and Shoch 3 de scribed a young woman who developed bilateral equatorial and posterior subcapsular lens opacities after taking allopuri nol for 18 months. To determine whether allopurinol use is associated with the development of cataracts, we reviewed the information in two large data resources available to the Boston Collaborative Drug Surveillance Program. SUBJECTS AND METHODS
Study 1—In 1972 we conducted a large survey study of patients admitted to 24 Boston-area hospitals. 4 In this study, nurse monitors interviewed consecutive
©AMERICAN JOURNAL O F OPHTHALMOLOGY 98:355-358, 1984
355
356
AMERICAN JOURNAL OF OPHTHALMOLOGY
patients admitted to general medical and surgical wards between January and No vember 1972. Patients who had been hospitalized during the previous three months were excluded from the study, as were patients too ill to be interviewed or who were not interviewed because they were hospitalized for less than 72 hours. Shortly after admission, the patients were asked about smoking habits, con sumption of alcohol, coffee, and tea, and any medications used during the previous three months for any of 26 reasons (for example, insomnia, high blood pressure, replacement of hormones, or menopausal symptoms). If they had used drugs, the drug and its frequency and duration of use were recorded. We defined regular use as at least once per week for at least one month. Of the 111 regular allopurinol users in the entire surveyed population, 18 (16%) had used the drug for three to five years, 18 (16%) for five to ten years, and two (2%) for more than ten years. For this study, we identified all the patients with a first-discharge diagnosis of cataract. For each case, three sex- and age-matched (by decade) controls were selected at random from patients with first-discharge diagnoses of benign neo plasm, varicose veins, hemorrhoids, her nia, appendicitis, acute gastroenteritis, gallbladder disease, cystocele, rectocele, dental disease, benign prostatic hyper trophy, or acute respiratory disease. Study 2—We derived these data from the automated files of the Group Health Cooperative of Puget Sound, a consumerowned medical cooperative founded in Seattle in 1947. As of Jan. 1, 1980, there were about 280,000 members. 5 The plan provides virtual prepaid medical cover age for outpatient care, for most drugs, and for hospital services. With few excep tions, members are hospitalized at Seattle-area hospitals maintained by the Cooperative.
SEPTEMBER, 1984
Information on all discharges from Group Health Cooperative hospitals has been recorded and put on computer files by the Commission on Professional and Hospital Activities-Professional Activity Study in Ann Arbor, Michigan, since 1972. This information includes discharge diagnoses and surgical procedures per formed, together with routine demo graphic data. Information on prescrip tions filled at Group Health Cooperative pharmacies has been maintained on com puter files since July 1976. For this study we identified all patients aged 30 to 64 years who were hospitalized for surgical extraction of cataracts be tween Jan. 1, 1977, and Dec. 31, 1981. We also identified all the patients in this age group who had filled prescriptions for allopurinol during the five-year period 1977-1981. We considered any patient who filled one or more prescriptions for allopurinol in a given year to be a user for that year. Fifty-eight percent of patients used the drug on a long-term basis (de fined as use for more than six months) during the five-year period for which pharmacy information was available. We calculated the rates of admission for cata ract extraction for those who used allopu rinol before admission and for those who did not for each year and combined the data. Because the rates of admission for cataract were similar for males and fe males, no adjustment for sex was neces sary in the analysis. However, both allo purinol use and admission for cataract were correlated with age and age was, therefore, controlled in the analysis. RESULTS
Study 1—Of the 251 patients admitted for cataract, two (0.8%) were regular allo purinol users before admission. Of the 753 matched controls, six (0.8%) were regular allopurinol users (Table). The rel ative risk estimate for cataract, compar-
VOL. 98, NO. 3
ALLOPURINOL AND CATARACTS
357
TABLE MATCHED QUADRUPLETS
Case Exposed to allopurinol Not exposed to allopurinol
0 2 243
ing users with nonusers, was 1.0 (95% exact confidence interval 0.14, 4.7). 6,7 Both allopurinol users with cataracts were more than 60 years of age and both had used allopurinol for one to three years. Of the 753 controls, 52 also had secondary diagnoses of cataract but none had used allopurinol regularly. Study 2—The number of person-years of observation for the entire population aged 30 to 64 years was 551,543. A total of 389 patients in this age group were hospi talized for cataract surgery during the five-year study period. The rate of hospi talization for cataract surgery in this age group was thus 389 per 554,805 personyears (7.0 per 104). Among persons 30 to 49 years old, there were no allopurinol users hospital ized for cataract surgery. The rate of hospitalization for cataract was 0/992 person-years for allopurinol users and 78/ 366,960 (2.1 per 104) person-years for nonusers. Among persons 50 to 64 years old, the rate of hospitalization for cataract surgery was 3/2,270 (13.2 per 104) person-years for allopurinol users and 308/184,583 (16.7 p e r 104) person-years for nonusers. The age-adjusted relative risk estimate, comparing users with nonusers, was 0.8 (95% confidence interval 0.2, 2.3).8-10 No patient was admitted more than once for cataract surgery during the study. Twelve patients admitted for other reasons also had secondary diagnoses of cataract, but none were allopurinol users. Also, no
Controls Exposed to Allopurinol 1 2 0 6
0 0
3 0 0
patient was hospitalized for cataract sur gery after discontinuing allopurinol use. DISCUSSION
These results provided evidence against a substantial positive association between allopurinol use and cataracts re quiring surgery. The relative risk esti mates for the two studies were 1.0 and 0.8, respectively. Although the 95% upper confidence limit for the first study was relatively high (4.7), the upper limit for the second study was 2.3. The data also provided some evidence against a positive association between allopurinol use and cataracts not requiring surgery. In both series, 64 patients admitted for other reasons had secondary diagnoses of cataract but none of them used allopuri nol. The results apply primarily to use for less than ten years. REFERENCES 1. Fraunfelder, F. T., Hanna, C , Dreis, M. W., and Cosgrove, K. W. : Cataracts associated with allo purinol therapy. Am. J. Ophthalmol. 94:137, 1982. 2. Lerman, S., Megaw, J., and Gardner, K.: Allopurinol therapy and cataractogenesis in humäns. Am. J. Ophthalmol. 94:141, 1982. 3. March, W. F., Goren, S., and Shoch, D.: Action of allopurinol on the lens. In Leopold, I. H. (ed.): Symposium on Ocular Therapy. St. Louis, C. V. Mosby, 1974, pp. 83-05. 4. Boston Collaborative Drug Surveillance Pro gram: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder dis ease, and breast tumors. Lancet 1:1399, 1973. 5. Jick, H., Watkins, R. N., Hunter, J. R., Dinan, B. J., Madsen, S., Rothman, K. J., and Walker,
358
AMERICAN JOURNAL O F OPHTHALMOLOGY
A. M.: Replacement estrogens and endometrial can cer. N. Engl. J. Med. 300:218, 1979. 6. Miettinen, O. S.: Estimation of relative disk from individually matched series. Biometrics 26:75, 1970. 7. : Comment. JASA 69:380, 1974. 8. : Standardization of risk ratios. Am. J. Epidemiol. 96:383, 1972.
SEPTEMBER, 1984
9. ■: Confounding and effect-modification. Am. J. Epidemiol. 100:350, 1974. 10. Rothman, K. J., and Boice, J. D., Jr.: Epide miologie analysis with a programmable calculator. United States Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health Publication No. 79-1649. Government Print ing Office, 1979.
JicK, M.D. Massachusetts
AND D A V I D E. B R A N D T , M.D. Seattle, Washington
We conducted a two-part study to determine whether any positive association between the use of allopurinol and the development of cataracts could be demonstrated. Study 1 included 251 Boston-area patients hospitalized for cataract and 753 matched controls. Two cataract patients were regular allopuri nol users as compared with six control patients. The relative risk for cataract comparing allopurinol users with nonusers was 1.0 (95% exact confidence interval 0.14, 4.7). Study 2 included 389 patients from the Puget Sound, Washington, area who were hospitalized for cataract surgery during a five-year period (551,543 person-years). The rate of hospitalization for cataract in patients 30 to 49 years old was 0/992 person-years for allopurinol users and 78/366,960 (2.1 per 104) person-years for nonusers. The rate of hospitalization for cataract in patients 50 to 64 years old was 3/2,270 (13.2 per 104) person-years for allopurinol users and 308/184,583 (16.7 per 104) person-years for nonusers. Fraunfelder and associates 1 based their suggestion that long-term ingestion of allopurinol may cause cataracts on 30 cases of suspected allopurionol-induced lens changes reported to the National Registry of Drug-Induced Ocular Side Effects. Fraunfelder and associates 1 and Lerman, Megaw, and Gardner 2 used phosphorescence emission peaks to dem onstrate the "probable" presence of alloAccepted for publication June 18, 1984. From the Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Wal tham, Massachusetts (Dr. Jick), and the Group Health Cooperative of Puget Sound, Seattle, Wash ington (Dr. Brandt). This study was supported by the Food and Drug Administration (Cooperative Agree ment 5 U01 FD01223) and the Burroughs Wellcome Co. Reprint requests to Hershel Jick, M.D., Boston Collaborative Drug Surveillance Program, 400-1, Totten Pond Rd., Waltham, MA 02154.
purinol in the cataracts of three patients who had been taking the drug. Lerman, Megaw, and Gardner 2 suggested that younger people might be at particularly high risk. March, Goren, and Shoch 3 de scribed a young woman who developed bilateral equatorial and posterior subcapsular lens opacities after taking allopuri nol for 18 months. To determine whether allopurinol use is associated with the development of cataracts, we reviewed the information in two large data resources available to the Boston Collaborative Drug Surveillance Program. SUBJECTS AND METHODS
Study 1—In 1972 we conducted a large survey study of patients admitted to 24 Boston-area hospitals. 4 In this study, nurse monitors interviewed consecutive
©AMERICAN JOURNAL O F OPHTHALMOLOGY 98:355-358, 1984
355
356
AMERICAN JOURNAL OF OPHTHALMOLOGY
patients admitted to general medical and surgical wards between January and No vember 1972. Patients who had been hospitalized during the previous three months were excluded from the study, as were patients too ill to be interviewed or who were not interviewed because they were hospitalized for less than 72 hours. Shortly after admission, the patients were asked about smoking habits, con sumption of alcohol, coffee, and tea, and any medications used during the previous three months for any of 26 reasons (for example, insomnia, high blood pressure, replacement of hormones, or menopausal symptoms). If they had used drugs, the drug and its frequency and duration of use were recorded. We defined regular use as at least once per week for at least one month. Of the 111 regular allopurinol users in the entire surveyed population, 18 (16%) had used the drug for three to five years, 18 (16%) for five to ten years, and two (2%) for more than ten years. For this study, we identified all the patients with a first-discharge diagnosis of cataract. For each case, three sex- and age-matched (by decade) controls were selected at random from patients with first-discharge diagnoses of benign neo plasm, varicose veins, hemorrhoids, her nia, appendicitis, acute gastroenteritis, gallbladder disease, cystocele, rectocele, dental disease, benign prostatic hyper trophy, or acute respiratory disease. Study 2—We derived these data from the automated files of the Group Health Cooperative of Puget Sound, a consumerowned medical cooperative founded in Seattle in 1947. As of Jan. 1, 1980, there were about 280,000 members. 5 The plan provides virtual prepaid medical cover age for outpatient care, for most drugs, and for hospital services. With few excep tions, members are hospitalized at Seattle-area hospitals maintained by the Cooperative.
SEPTEMBER, 1984
Information on all discharges from Group Health Cooperative hospitals has been recorded and put on computer files by the Commission on Professional and Hospital Activities-Professional Activity Study in Ann Arbor, Michigan, since 1972. This information includes discharge diagnoses and surgical procedures per formed, together with routine demo graphic data. Information on prescrip tions filled at Group Health Cooperative pharmacies has been maintained on com puter files since July 1976. For this study we identified all patients aged 30 to 64 years who were hospitalized for surgical extraction of cataracts be tween Jan. 1, 1977, and Dec. 31, 1981. We also identified all the patients in this age group who had filled prescriptions for allopurinol during the five-year period 1977-1981. We considered any patient who filled one or more prescriptions for allopurinol in a given year to be a user for that year. Fifty-eight percent of patients used the drug on a long-term basis (de fined as use for more than six months) during the five-year period for which pharmacy information was available. We calculated the rates of admission for cata ract extraction for those who used allopu rinol before admission and for those who did not for each year and combined the data. Because the rates of admission for cataract were similar for males and fe males, no adjustment for sex was neces sary in the analysis. However, both allo purinol use and admission for cataract were correlated with age and age was, therefore, controlled in the analysis. RESULTS
Study 1—Of the 251 patients admitted for cataract, two (0.8%) were regular allo purinol users before admission. Of the 753 matched controls, six (0.8%) were regular allopurinol users (Table). The rel ative risk estimate for cataract, compar-
VOL. 98, NO. 3
ALLOPURINOL AND CATARACTS
357
TABLE MATCHED QUADRUPLETS
Case Exposed to allopurinol Not exposed to allopurinol
0 2 243
ing users with nonusers, was 1.0 (95% exact confidence interval 0.14, 4.7). 6,7 Both allopurinol users with cataracts were more than 60 years of age and both had used allopurinol for one to three years. Of the 753 controls, 52 also had secondary diagnoses of cataract but none had used allopurinol regularly. Study 2—The number of person-years of observation for the entire population aged 30 to 64 years was 551,543. A total of 389 patients in this age group were hospi talized for cataract surgery during the five-year study period. The rate of hospi talization for cataract surgery in this age group was thus 389 per 554,805 personyears (7.0 per 104). Among persons 30 to 49 years old, there were no allopurinol users hospital ized for cataract surgery. The rate of hospitalization for cataract was 0/992 person-years for allopurinol users and 78/ 366,960 (2.1 per 104) person-years for nonusers. Among persons 50 to 64 years old, the rate of hospitalization for cataract surgery was 3/2,270 (13.2 per 104) person-years for allopurinol users and 308/184,583 (16.7 p e r 104) person-years for nonusers. The age-adjusted relative risk estimate, comparing users with nonusers, was 0.8 (95% confidence interval 0.2, 2.3).8-10 No patient was admitted more than once for cataract surgery during the study. Twelve patients admitted for other reasons also had secondary diagnoses of cataract, but none were allopurinol users. Also, no
Controls Exposed to Allopurinol 1 2 0 6
0 0
3 0 0
patient was hospitalized for cataract sur gery after discontinuing allopurinol use. DISCUSSION
These results provided evidence against a substantial positive association between allopurinol use and cataracts re quiring surgery. The relative risk esti mates for the two studies were 1.0 and 0.8, respectively. Although the 95% upper confidence limit for the first study was relatively high (4.7), the upper limit for the second study was 2.3. The data also provided some evidence against a positive association between allopurinol use and cataracts not requiring surgery. In both series, 64 patients admitted for other reasons had secondary diagnoses of cataract but none of them used allopuri nol. The results apply primarily to use for less than ten years. REFERENCES 1. Fraunfelder, F. T., Hanna, C , Dreis, M. W., and Cosgrove, K. W. : Cataracts associated with allo purinol therapy. Am. J. Ophthalmol. 94:137, 1982. 2. Lerman, S., Megaw, J., and Gardner, K.: Allopurinol therapy and cataractogenesis in humäns. Am. J. Ophthalmol. 94:141, 1982. 3. March, W. F., Goren, S., and Shoch, D.: Action of allopurinol on the lens. In Leopold, I. H. (ed.): Symposium on Ocular Therapy. St. Louis, C. V. Mosby, 1974, pp. 83-05. 4. Boston Collaborative Drug Surveillance Pro gram: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder dis ease, and breast tumors. Lancet 1:1399, 1973. 5. Jick, H., Watkins, R. N., Hunter, J. R., Dinan, B. J., Madsen, S., Rothman, K. J., and Walker,
358
AMERICAN JOURNAL O F OPHTHALMOLOGY
A. M.: Replacement estrogens and endometrial can cer. N. Engl. J. Med. 300:218, 1979. 6. Miettinen, O. S.: Estimation of relative disk from individually matched series. Biometrics 26:75, 1970. 7. : Comment. JASA 69:380, 1974. 8. : Standardization of risk ratios. Am. J. Epidemiol. 96:383, 1972.
SEPTEMBER, 1984
9. ■: Confounding and effect-modification. Am. J. Epidemiol. 100:350, 1974. 10. Rothman, K. J., and Boice, J. D., Jr.: Epide miologie analysis with a programmable calculator. United States Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health Publication No. 79-1649. Government Print ing Office, 1979.