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Effects of Topical Betaxolol, Timolol, and Placebo on Pulmonary Function in Asthmatic Bronchitis: Reply
Vol. 100, No.3
Correspondence
adverse experiences with either noncardioselective (for example, propranolol) or cardioselective (for example, atenolol) beta-blockers. Therefore, we suggest that topical betablockers of any pharmacologic subclass be used with caution in patients with histories of pulmonary disease. Pulmonary function tests may be useful in determining the benefit-torisk ratio in a given patient in need of topical beta-blocker treatment. Because of the problems associated with this study we believe that it would be wrong to conclude that betaxolol is safer than timolol in patients with bronchospastic airway disease. EUGENE M. SPIRITUS, M.D. RAYMOND CASCIARI, M.D.
Orange, California
_ _ _ _ _ _ _ Reply EDITOR:
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__
We are pleased to respond to the comments of Drs. Spiritus and Casciari. Study design-In previous studies, we determined the adequacy of a 48-hour washout, after a single drop of either ocular betablocker. The 72-hour washout was chosen to insure that no residual effects of previous ocular treatment would influence our study results. Statistical analysis showed that the order of drug administration had no effect on baseline values (P < .545), demonstrating an absence of residual blockade. We concur that a single FEV! may be misleading. Pulmonary function measurements were performed in triplicate, as is our normal procedure. The subject's best effort was used as baseline and for each on-test observation. Also, to minimize intrasubject variability, values for pulmonary function tests after instillation of each drug were collected within 270 minutes. Spiritus and Casciari agree that our study design was appropriate. During a study such as this, intrasubject variability is a common observation. Importantly, however, in this study each person served as his own control for each treatment, a point perhaps not emphasized sufficiently. Subject selection-Our previous study showed that healthy subjects did not have a change in airflow after timolol. Because we wanted to determine the relative safety of ocular beta-blockers in a group at risk, we chose patients with reactive airway disease who had
493
shown detrimental effects from ophthalmic timolol 0.5% and then tested betaxolol at twice the clinical concentration (l %). The criticism that the subjects did not have concomitant glaucoma is somewhat spurious. No evidence exists that reactive airway disease is different in susceptible patients whether or not accompanied by glaucoma; thus, patient selection was appropriate. The long-term use of betaxolol in patients with glaucoma who are unable to tolerate nonselective ocular beta-blockers because of pulmonary complications, as reported by Allen and Boys-Smith;' further supports the subject selection. Most importantly, we believe the number of deaths reported from pulmonary complications of nonselective ocular beta-blockers, presently documented at 16, supports our study objectives." Finally, our design is supported by other studies, including those of Dunn and associates." who reported results parallel to ours, and Cervantes, Frati, and Hernandez," who found timolol and levobunolol, unlike betaxolol, detrimental to asthmatics. Statistical power-The statement about the power to detect a 15% decrease in FEV! appears to refer to a within-treatment difference rather than the between-treatment difference. It fails to consider the increase in power achieved by using each patient as his own control in a Latin-square design. Regardless, the reduction in FEY! with timolol is clear even without the use of statistics (our Figs. 1, 2, and 3). Clinical applications-c-We included the table of individual results to emphasize the importance of individual variability. The three subjects cited by Spiritus and Casciari were particularly sensitive to beta-blockers and did show decreased airflow with betaxolol treatment. For these three patients FEY! values with betaxolol averaged 35% higher than their response's with timolol; even in these patients, the two drugs were hardly equal. Two of these patients required treatment to reverse a timolol-induced pulmonary crisis. When the beta-adrenergic stimulant (isoproterenol) was administered at the end of betax0101 and placebo challenges, these threeasthmatic patients were markedly improved in their ability to breathe, exceeding their baseline values. Conversely, when the betastimulant was administered to the same three patients after the timolol test, their breathing function continued to be impaired. In their conclusion, Spiritus and Casciari in-
494
AMERICAN JOURNAL OF OPHTHALMOLOGY
dicate that betaxolol and timolol have equivalent pulmonary safeties. Most data do not support their conclusion. Four separate centers have now confirmed that the pulmonary safety of betaxolol is superior to that of the nonselective beta-blocker, timolol. 3-5
ROBERT B. SCHOENE, M.D. TAMMY ABUAN, R.N.
Seattle, Washington
RICHARD 1. WARD, B.S., C. HAROLD BEASLEY, M.D.
Fort Worth, Texas
References 1. Allen, R. C.; and Boys-Smith, 1.: Betaxolol in patients with coexistent glaucoma and pulmonary
September, 1985
disease. Invest. Ophthalmo!. Vis. Sci. 25(supp!.): 305, 1984. 2. Fraunfelder, F. T., and Barker, A. E.: Respiratory effects of timolo!. N. Eng!. J. Med. 311:1441, 1984. 3. Dunn, T. L., Gerber, M. J., Sheri, A. S., Fernandez, E., Iseman, M. D., and Cherniack, R. M.: Timolol-induced bronchospasm. Utility of betaxolol as an alternate ocular hypotensive agent in patients with asthma. Clin. Res. 33:20A, 1985. 4. Cervantes. R., Frati, A., and Hernandez y Hernandez, H.: Pulmonary and heart rate changes associated with nonselective beta-blocker glaucoma therapy. Br. J. Ophthalmo!., in press. 5. Vukich, J. A., Leef, D. L., and Allen, R. c.. Betaxolol in patients with co-existent chronic openangle glaucoma and pulmonary disease. Invest. Ophthalmo!. Vis. Sci. 26(supp!.):227, 1985.
Correspondence
adverse experiences with either noncardioselective (for example, propranolol) or cardioselective (for example, atenolol) beta-blockers. Therefore, we suggest that topical betablockers of any pharmacologic subclass be used with caution in patients with histories of pulmonary disease. Pulmonary function tests may be useful in determining the benefit-torisk ratio in a given patient in need of topical beta-blocker treatment. Because of the problems associated with this study we believe that it would be wrong to conclude that betaxolol is safer than timolol in patients with bronchospastic airway disease. EUGENE M. SPIRITUS, M.D. RAYMOND CASCIARI, M.D.
Orange, California
_ _ _ _ _ _ _ Reply EDITOR:
~
__
We are pleased to respond to the comments of Drs. Spiritus and Casciari. Study design-In previous studies, we determined the adequacy of a 48-hour washout, after a single drop of either ocular betablocker. The 72-hour washout was chosen to insure that no residual effects of previous ocular treatment would influence our study results. Statistical analysis showed that the order of drug administration had no effect on baseline values (P < .545), demonstrating an absence of residual blockade. We concur that a single FEV! may be misleading. Pulmonary function measurements were performed in triplicate, as is our normal procedure. The subject's best effort was used as baseline and for each on-test observation. Also, to minimize intrasubject variability, values for pulmonary function tests after instillation of each drug were collected within 270 minutes. Spiritus and Casciari agree that our study design was appropriate. During a study such as this, intrasubject variability is a common observation. Importantly, however, in this study each person served as his own control for each treatment, a point perhaps not emphasized sufficiently. Subject selection-Our previous study showed that healthy subjects did not have a change in airflow after timolol. Because we wanted to determine the relative safety of ocular beta-blockers in a group at risk, we chose patients with reactive airway disease who had
493
shown detrimental effects from ophthalmic timolol 0.5% and then tested betaxolol at twice the clinical concentration (l %). The criticism that the subjects did not have concomitant glaucoma is somewhat spurious. No evidence exists that reactive airway disease is different in susceptible patients whether or not accompanied by glaucoma; thus, patient selection was appropriate. The long-term use of betaxolol in patients with glaucoma who are unable to tolerate nonselective ocular beta-blockers because of pulmonary complications, as reported by Allen and Boys-Smith;' further supports the subject selection. Most importantly, we believe the number of deaths reported from pulmonary complications of nonselective ocular beta-blockers, presently documented at 16, supports our study objectives." Finally, our design is supported by other studies, including those of Dunn and associates." who reported results parallel to ours, and Cervantes, Frati, and Hernandez," who found timolol and levobunolol, unlike betaxolol, detrimental to asthmatics. Statistical power-The statement about the power to detect a 15% decrease in FEV! appears to refer to a within-treatment difference rather than the between-treatment difference. It fails to consider the increase in power achieved by using each patient as his own control in a Latin-square design. Regardless, the reduction in FEY! with timolol is clear even without the use of statistics (our Figs. 1, 2, and 3). Clinical applications-c-We included the table of individual results to emphasize the importance of individual variability. The three subjects cited by Spiritus and Casciari were particularly sensitive to beta-blockers and did show decreased airflow with betaxolol treatment. For these three patients FEY! values with betaxolol averaged 35% higher than their response's with timolol; even in these patients, the two drugs were hardly equal. Two of these patients required treatment to reverse a timolol-induced pulmonary crisis. When the beta-adrenergic stimulant (isoproterenol) was administered at the end of betax0101 and placebo challenges, these threeasthmatic patients were markedly improved in their ability to breathe, exceeding their baseline values. Conversely, when the betastimulant was administered to the same three patients after the timolol test, their breathing function continued to be impaired. In their conclusion, Spiritus and Casciari in-
494
AMERICAN JOURNAL OF OPHTHALMOLOGY
dicate that betaxolol and timolol have equivalent pulmonary safeties. Most data do not support their conclusion. Four separate centers have now confirmed that the pulmonary safety of betaxolol is superior to that of the nonselective beta-blocker, timolol. 3-5
ROBERT B. SCHOENE, M.D. TAMMY ABUAN, R.N.
Seattle, Washington
RICHARD 1. WARD, B.S., C. HAROLD BEASLEY, M.D.
Fort Worth, Texas
References 1. Allen, R. C.; and Boys-Smith, 1.: Betaxolol in patients with coexistent glaucoma and pulmonary
September, 1985
disease. Invest. Ophthalmo!. Vis. Sci. 25(supp!.): 305, 1984. 2. Fraunfelder, F. T., and Barker, A. E.: Respiratory effects of timolo!. N. Eng!. J. Med. 311:1441, 1984. 3. Dunn, T. L., Gerber, M. J., Sheri, A. S., Fernandez, E., Iseman, M. D., and Cherniack, R. M.: Timolol-induced bronchospasm. Utility of betaxolol as an alternate ocular hypotensive agent in patients with asthma. Clin. Res. 33:20A, 1985. 4. Cervantes. R., Frati, A., and Hernandez y Hernandez, H.: Pulmonary and heart rate changes associated with nonselective beta-blocker glaucoma therapy. Br. J. Ophthalmo!., in press. 5. Vukich, J. A., Leef, D. L., and Allen, R. c.. Betaxolol in patients with co-existent chronic openangle glaucoma and pulmonary disease. Invest. Ophthalmo!. Vis. Sci. 26(supp!.):227, 1985.