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Prophylactic Use of Apraclonidine for Intraocular Pressure Increase After Nd:YAG Capsulotomies
Prophylactic Use of Apraclonidine for Intraocular Pressure Increase After Nd:YAG Capsulotomies David E. Silverstone, M.D., S t e p h e n F. Brint, M.D., K e n n e t h W. Olander, M.D., Robert B. Taylor, George R. McCarty, P h . D . , Joseph M. deFaller, and Linda L. Burk, M.D.
We evaluated the prophylactic effect of 1% apraclonidine HC1 in controlling the increase in intraocular pressure after Nd:YAG posteri or capsulotomy in a large, multicenter doublemasked clinical trial. One hundred sixty-four patients were enrolled into the apraclonidinetreated group, and 165 into the vehicle-treated group. The incidence of increase in intraocu lar pressure (greater than 5 mm Hg) in the apraclonidine-treated group (7%, 11 of 163 patients) was significantly less than that in the vehicle-treated group (39%, 64 of 164 pa tients). Similarly, the mean maximal change in intraocular pressure in the apraclonidinetreated group (1.3-mm Hg decrease) was sig nificantly different from the increase in the vehicle-treated group (5.3-mm Hg increase). Few adverse reactions were observed. The risk for significant loss of visual function after Nd:YAG laser posterior capsulotomy, com bined with the efficacy and relative safety of prophylactic apraclonidine, suggest its addi tion to the treatment armamentarium. I OSTERIOR CAPSULOTOMY with the Nd:YAG la ser is one of the most frequently performed anterior segment laser procedures. A complica tion of this otherwise generally successful pro cedure is an increase in intraocular pressure within the first several hours after laser treatAccepted for publication Jan. 22, 1992. From the Department of Ophthalmology a n d Visual Sciences, Yale University School of Medicine, New Ha ven, Connecticut (Dr. Silverstone); Eye Surgery Center of Louisiana, New Orleans, Louisiana (Dr. Brint); Eye Physician Associates, Milwaukee, Wisconsin (Dr. Olander); Department of Clinical Sciences, Alcon Labo ratories, Fort Worth, Texas (Mr. Taylor, Dr. McCarty, and Mr. deFaller); a n d Department of Ophthalmology, Southwestern Medical School, Dallas, Texas (Dr. Burk). Mr. Taylor, Dr. McCarty, and Mr. deFaller are employed by Alcon Laboratories. Reprint requests to David E. Silverstone, M.D., Temple Medical Building, 60 Temple St., New Haven, CT 06510.
ment. The incidence of significant increases in intraocular pressure may be greater than 30%. 1 6 Pilocarpine, timolol, and levobunolol have attenuated the incidence and severity of increases in intraocular pressure after Nd:YAG laser capsulotomies. 3 ' 4 ' 7 ' 8 However, the use of these agents is restricted by limited efficacy or potential for systemic adverse reactions. Recently, the ocular hypotensive efficacy of apraclonidine, an a-adrenoceptor agonist, 910 has been described in normal subjects and patients with increased intraocular pressure.11"13 Apraclonidine may reduce intraocular pressure by reducing anterior segment blood flow1415 that, in turn, decreases aqueous humor produc tion. 1617 Apraclonidine eyedrops elicit little or no reduction of cardiovascular function, 1118 in contrast to topical use of its chemical analogue, clonidine.19"23 The polarity of apraclonidine rel ative to clonidine may be responsible for the infrequency of adverse reactions related to cen tral o 2 -adrenoceptor agonists. This polarity conveys apraclonidine's relatively poor affinity to lipids, limiting its penetration through both the blood-brain barrier and the cornea. Access to the anterior chamber after instillation ap pears to be caused primarily by transconjunctival and transscleral penetration. 23 In placebo-controlled, double-masked stud ies, prophylactic use of apraclonidine has at tenuated the incidence and severity of increases in intraocular pressure after Nd:YAG laser cap sulotomies. These studies involved 6324 and 46 eyes.25 We desired to further these observations in a large population (329 eyes) at many geo graphically diverse sites.
Patients and Methods Patients who were candidates for Nd:YAG posterior capsulotomy at the 19 study centers were considered for entry into the study. Ex-
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eluded from participation were patients with hydrogel or silicone intraocular lenses and pa tients who had vision in one eye only, or active ocular infection or inflammation. Also excluded from the study were patients using systemic clonidine; patients with unstable cardiovascu lar disease; or women who were pregnant, nursing, or of child-bearing potential. The na ture of the study was explained to patients who met these enrollment criteria, and written in formed consent was obtained from those choos ing to participate. Only one eye from each patient was included in the study. At entry, patients underwent a prestudy ex amination, which included measurement of in traocular pressure, heart rate, and blood pres sure. In a double-masked fashion by which patients were randomly assigned to treatment, patients received one drop of either 1.0% apraclonidine HC1 or its vehicle one hour before the laser procedure, and again immediately at the conclusion of the surgical procedure. Intraocu lar pressure, heart rate, and blood pressure were measured one, two, and three hours after the procedure. The capsulotomies were per formed using a Q-switched Nd:YAG laser with the patients topically anesthetized and with the minimal energy settings required to create an adequate central opening in the posterior cap sule. Changes in intraocular pressure, heart rate, blood pressure, and demographic characteris tics after the laser procedure were evaluated with the stratified Cochran-Mantel-Haenszel test with values as ranks.26,27 A P value of .05 or less was considered statistically significant.
Results One hundred sixty-four patients were en rolled into the apraclonidine-treated group, and 165 into the vehicle-treated group. The mean age of the patients in the apraclonidinetreated group was approximately two years greater than that of the vehicle-treated group (Table 1). Although this difference was statisti cally significant, it was judged of little clinical significance. The patient population was pre dominantly female and white. Approximately 20% of the patients had glaucoma, most under going topical ocular hypotensive treatment. Ex cept for age, there were no significant differenc es in demographic or historical measures between the treatment groups.
TABLE 1 DEMOGRAPHIC CHARACTERISTICS OF PATIENTS*
Age Mean ± S.D. Gender Female Male Race White Other/not available Glaucoma Ocular hypotensive medications /3-adrenoceptor antagonists Pilocarpine
APRACLONIDINE-
VEHICLE-
TREATED PATIENTS (N = 164)
TREATED PATIENTS (N = 165)
74.0 ± 8.8
71.7 ± 12.0
111 (68%) 53 (32%)
115(70%) 50 (30%)
151 (93%) 13 (8%) 32 (20%)
145 (88%) 20(12%) 30(18%)
29 (17%)
31 (19%)
27 (16%) 12 (7%)
27(16%) 11 (7%)
There were no significant differences between the groups, except for age, for which the P value was .020. S.D. indicates standard deviation.
The mean number of spots used to produce a capsulotomy was 36, and the mean pulse power used was 1.6 mj, with no notable difference between the treatment groups. The mean intra ocular pressure before administration of study medications or laser treatment was approxi mately 16 mm Hg, with no significant differ ence between treatment groups. During the three-hour observation period after the laser procedure, the intraocular pressure decreased in the apraclonidine-treated group (mean de crease, 2.6 to 2.9 mm Hg). During the same period, the intraocular pressure increased in the vehicle-treated group (mean increase, 3.2 to 3.6 mm Hg). Using the maximal intraocular pressure in each patient at any point during the observation period, there was a mean decrease of 1.3 mm Hg in the apraclonidine-treated group, and a mean increase of 5.3 mm Hg in the vehicle-treated group. This approximately 5- to 7-mm Hg difference between the decrease in the apraclonidine-treated group and the in crease in the vehicle-treated group was statisti cally significant for all evaluations (Table 2). In the vehicle-treated group, 64 of 164 pa tients (39%) experienced an increase in intraoc ular pressure greater than 5 mm Hg (Figure). Forty-one of 164 patients (25%) in the vehicletreated group experienced an increase in in traocular pressure greater than 10 mm Hg. Significantly fewer patients in the apracloni-
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TABLE 2 MEAN CHANGE IN INTRAOCULAR PRESSURE (MM HG)* VEHICLE-
APRACLONIDINETREATED PATIENTS
TREATED PATIENTS
TIME
OF PATIENTS
MEAN
S.D.
NO. OF PATIENTS
MEAN
S.D.
P VALUE
Baseline 1 hour 2 hours 3 hours At any time
164 162 163 161
15.5 -2.6 -2.9 -2.7
3.7 3.4 4.1 4.2
164 164 163 164
15.7 3.2 3.6 3.2
3.2 5.5 6.2 6.2
.332 .001 .001 .001
163
-1.3
4.0
164
5.3
6.5
.001
NO.
*One apraclonidine-treated and one vehicle-treated patient were randomly assigned to treatment and considered in the demographic analysis, but did not receive medication or the laser procedure or both. S.D. indicates standard deviation.
dine-treated group experienced increases in intraocular pressure (P = .001). In the apra clonidine-treated group, increases greater than 5 mm Hg occurred in 11 of 163 patients (7%), and increases greater than 10 mm Hg occurred in three of 163 patients (2%). Three hours after the laser, the mean de crease in systolic blood pressure in the apraclo nidine-treated group, 4.8 mm Hg, was statisti cally different than that in the vehicle-treated group, 1.9 mm Hg (P = .018). There were no other statistically significant differences be tween the treatment groups in mean heart rate or blood pressure at any observation period. Eight treatment-related adverse reactions oc curred. Seven occurred among the apracloni dine-treated group. These consisted of the fol lowing: two cases of mild ocular inflammation, one case of corneal edema, one case of nasal burning, one case of ipsilateral eyelid retrac tion, one case of irregular heart rate, and one case of postoperative blepharospasm. The one reaction that occurred in the placebo-treated group was a dramatic increase in blood pres sure after the laser procedure. All reactions were transient and without sequelae.
Discussion
The incidence of significant increases in our vehicle-treated group, 25% to 39%, demon strated the ability of this procedure to elicit an increase in intraocular pressure, and was simi lar to previous reports. 1 6 Our observations of the efficacy and relative safety of apraclonidine as a prophylactic agent for increases in intraoc ular pressure were also similar to previous reports. 24,26 Impairment of the outflow facility appears to be the principal mechanism that brings about the transient intraocular pressure increase after Nd:YAG posterior capsulotomy. A decrease in the coefficient of outflow has been documented during the postoperative period after Nd:YAG capsulotomy procedures. 5 ' 28,29 Work in primates suggested that this impairment of outflow was caused by the lodging or accumulation of debris
P S ! Spikes
S.1M o
I—i_J No spikes
]E »
Apraclonidine
Vehicle
> 5 mm Hg
We found apraclonidine to be effective in attenuating the incidence of severity of increas es in intraocular pressure after Nd:YAG posteri or capsulotomy. The drug-related adverse reac tions were few and without long-term clinical significance.
Apraclonidine
Vehicle
> 10 mm Hg
Figure (Silverstone and associates). Incidence of increases in intraocular pressure (spikes) at any time point during the three-hour follow-up period. The difference between the apraclonidine- and vehi cle treated groups was statistically significant for increases greater than 5 mm Hg and greater than 10 mm Hg (P = .001).
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a n d to d e v e l o p m e n t of i n f l a m m a t i o n in either the i n t e r n a l t r a b e c u l a r m e s h w o r k , the j u x t a c a n alicular m e s h w o r k , or the p o r e s of t h e i n t e r n a l wall of S c h l e m m ' s canal. Posterior c a p s u l a r r e m n a n t s have b e e n v i s u a l i z e d in the a n t e r i o r c h a m b e r a n d w i t h i n the t r a b e c u l a r m e s h w o r k after Nd:YAG capsulotomy. 3 0 O t h e r factors s u c h as the d i s r u p t i o n of the b l o o d - a q u e o u s b a r r i e r , laser s h o c k - w a v e effects, a n d t h e r e l e a s e of unspecified n e u r o h u m o r a l a g e n t s m a y also im pair outflow facility a n d t h e r e b y c o n t r i b u t e to the p o s t o p e r a t i v e i n c r e a s e in i n t r a o c u l a r p r e s sure. The p r i m a r y effect of a p r a c l o n i d i n e o n a q u e ous h u m o r d y n a m i c s a p p e a r s to b e a r e d u c t i o n in a q u e o u s h u m o r flow. 1617 A l t h o u g h this differs from the a p p a r e n t m e c h a n i s m of the i n c r e a s e of i n t r a o c u l a r p r e s s u r e after Nd:YAG laser c a p s u lotomy, it still a p p e a r s to b e clinically effective. Clinically a p p a r e n t optic n e r v e d a m a g e , p r o gression of visual field loss, a n d loss of vision can result from an a c u t e t r a n s i e n t i n c r e a s e in i n t r a o c u l a r p r e s s u r e after Nd:YAG c a p s u l o t o my. 3 1 3 3 P a t i e n t s w i t h g l a u c o m a r e p r e s e n t a large g r o u p of i n d i v i d u a l s w h o h a v e a n i n c r e a s e d risk of visual loss if i n t r a o c u l a r p r e s s u r e i n c r e a s e s p o s t o p e r a t i v e l y . O n e of t h e b e s t - d o c u m e n t e d o c c u r r e n c e s of visual field loss c a u s e d b y an acute i n c r e a s e in i n t r a o c u l a r p r e s s u r e w a s in a patient with glaucoma w h o had u n d e r g o n e an Nd.YAG laser posterior capsulotomy. 3 3 Tran sient loss of vision a c c o m p a n i e d b y ocular p a i n , nausea, and vomiting has occurred within h o u r s after Nd:YAG c a p s u l o t o m y w i t h a c u t e increase in i n t r a o c u l a r pressure. 3 1 3 2 T h e s e clini cal findings d o c u m e n t the d e t r i m e n t a l effects of acute t r a n s i e n t increase in i n t r a o c u l a r p r e s s u r e after Nd:YAG laser c a p s u l o t o m y o n v i s i o n . The risk for m a r k e d loss of visual function after Nd:YAG laser p o s t e r i o r c a p s u l o t o m y c o m b i n e d w i t h the efficacy a n d relative safety of p r o p h y l a c t i c a p r a c l o n i d i n e suggest its a d d i t i o n to our t r e a t m e n t a r m a m e n t a r i u m .
STUDY CENTERS A N D P R I N C I P A L INVESTIGATORS
Ophthalmic Consultants of Boston (Boston, Massa chusetts); Principal Investigator: A. Robert Bellows, M.D. Eye Surgery Center of Louisiana (New Orleans, Louisiana); Principal Investigator: Stephen F. Brint, M.D. Eye Associates (Dallas, Texas); Principal Investiga tor: Donald P. Brotherman, M.D. Dallas Ophthalmology Center (Dallas, Texas); Principal Investigator: Linda L. Burk, M.D.
Hunkeler Eye Clinic (Kansas City, Missouri); Prin cipal Investigator: John D. Hunkeler, M.D. University of Wisconsin, Center for Health Service (Madison, Wisconsin); Principal Investigator: Paul L. Kaufman, M.D. Kraff Eye Institute, Ltd. (Chicago, Illinois); Princi pal Investigator: Manus C. Kraff, M.D. Scheie Eye Institute (Philadelphia, Pennsylvania); Principal Investigator: Theodore Krupin, M.D. Henry F. Lenartz, M.D., Private Practice (Mountain View, California); Principal Investigator: Henry F. Lenartz, M.D. University of California-Davis, Dept. of Ophthal mology (Sacramento, California); Principal Investi gator: Richard A. Lewis, M.D. Irving Ophthalmology Clinic (Irving, Texas); Prin cipal Investigator: Jay L. Merten, M.D. Eye Physician Associates (Milwaukee, Wisconsin); Principal Investigator: Kenneth W. Olanders, M.D. Jacksonville Eye Center (Jacksonville, Florida); Principal Investigator: Robert J. Schnipper, M.D. Washington Eye Physicians & Surgeons (Chevy Chase, Maryland); Principal Investigator: Arthur L. Schwartz, M.D. Temple Eye Physicians, P.C. (New Haven, Connec ticut); Principal Investigator: David E. Silverstone, M.D. Houston Eye Associates (Houston, Texas); Princi pal Investigator: Robert H. Stewart, M.D. South Texas Cataract and Glaucoma Center (San Antonio, Texas); Principal Investigator: Stuart A. Terry, M.D. Mark J. Weiss, M.D., Inc. (Tulsa, Oklahoma); Prin cipal Investigator: Mark J. Weiss, M.D. University of Texas Health Science Center, Dept. of Ophthalmology (San Antonio, Texas); Principal In vestigator: Roy Witaker, Jr., M.D.
References 1. Channell, M. M., and Beckman, H.: Intraocular pressure changes after neodymium-YAG laser poster ior capsulotomy. Arch. Ophthalmol. 102:1024, 1984. 2. Slomovic, A. R., and Parrish, R. K.: Acute eleva tions of intraocular pressure following Nd:YAG laser posterior capsulotomy. Ophthalmology 92:973, 1985. 3. Richter, C. U., Arzeno, G., Pappas, H. R., Arrigg, C. A., Wasson, P., and Steinert, R. F.: Preven tion of intraocular pressure elevation following neo dymium-YAG laser posterior capsulotomy. Arch. Ophthalmol. 103:912, 1985. 4. Migliori, M. E., Beckman, H., and Channell, M. M.: Intraocular pressure changes after neodymi um-YAG laser capsulotomy in eyes pretreated with timolol. Arch. Ophthalmol. 105:473, 1987. 5. Brown, S. V. L., Thomas, J. V., Belcher, C. D., and Simmons, R. J.: Effect of pilocarpine in treatment of intraocular pressure elevation following neodymi-
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um:YAG laser posterior capsulotomy. Ophthalmolo gy 92:354, 1985. 6. Flohr, M. J., Robin, A. L., and Kelley, J. S.: Early complications following Q-switched neodymium:YAG laser posterior capsulotomy. Ophthalmolo gy 92:360, 1985. 7. Silverstone, D. E., Novack, G. D., Kelley, E. P., and Chen, K. S.: Prophylactic treatment of intraocu lar pressure elevations after neodymium:YAG laser posterior capsulotomies and extracapsular cataract extractions with levobunolol. Ophthalmology 95:713, 1988. 8. Stilma, J. S., and Boen-Tan, T. N.: Timolol and intra-ocular pressure elevation following neodymium:YAG laser surgery. Doc. Ophthalmol. 61:233, 1986. 9. Stump, D. C , and MacFarlane, D. E.: Clonidine and para-aminoclonidine, partial agonists for the alpha2-adrenergic receptor on intact human blood platelets. J. Lab. Clin. Med. 102:779, 1983. 10. Cavero, I., Deportere, H., and LeFevre-Borg, F.: Pharmacological studies on para aminoclonidine. Br. J. Pharmacol. 69:295, 1980. 11. Abrams, D. A., Robin, A. L., Pollack, I. P., deFaller, J. M., and DeSantis, L.: The safety and efficacy of topical 1% ALO 2145 (p-aminoclonidine hydrochloride) in normal volunteers. Arch. Ophthal mol. 105:1205, 1987. 12. Jampel, H. D., Robin, A. L., Quigley, H. A., and Pollack, I. P.: Apraclonidine. A one-week doseresponse study. Arch. Ophthalmol. 106:1069, 1988. 13. Morrison, J. C , and Robin, A. L.: Adjunctive glaucoma therapy. A comparison of apraclonidine to dipivefrin when added to timolol maleate. Ophthal mology 96:3, 1989. 14. Serdahl, C. L., Galustian, J., and Lewis, R. A.: The effects of apraclonidine on conjunctival oxygen tension. Arch. Ophthalmol. 107:1777, 1989. 15. Chandler, M. L., and DeSantis, L.: Studies of p-amino clonidine as a potential antiglaucoma agent. ARVO abstracts. Supplement to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1985, p. 227. 16. Bartels, S. P., and Schlerman, F. J.: Effects of timolol, apraclonidine, or enalaprilat on aqueous humor flow in monkeys. ARVO abstracts. Supple ment to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1990, p. 902. 17. Gharagozloo, N. Z., Relf, S. J., and Brubaker, R. F.: Aqueous flow is reduced by the alpha-adrenergic agonist, apraclonidine hydrochloride (ALO 2145). Ophthalmology 95:1217, 1988. 18. Coleman, A. L., Robin, A. L., Pollack, I. P., Rudikoff, M. T., Enger, C , and Mayer, P. R.: Cardio vascular and intraocular pressure effects and plasma concentrations of apraclonidine hydrochloride. Arch. Ophthalmol. 108:1264, 1990. 19. Heilmann, K.: Augendruck, Blutdruck und Glaukomscheden. Buch Augen. 61:1, 1972.
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20. Harrison, R., and Kaufmann, C. S.: Clonidine. Effects of a topically administered solution on intra ocular pressure and blood pressure in open-angle glaucoma. Arch. Ophthalmol. 95:1368, 1977. 21. Petursson, G., Cole, R., and Hanna, C : Treat ment of glaucoma using minidrops of clonidine. Arch. Ophthalmol. 102:1180, 1984. 22. Hodapp, E., Kolker, A. E., Kass, M. A., Gold berg, I., Becker, B., and Gordon, M.: The effect of topical clonidine on intraocular pressure. Arch. Oph thalmol. 99:1208, 1981. 23. Chien, D., Tang-Liu, D., and Gluchowski, C : Corneal and conjunctival/scleral absorption of a2adrenergic agents in rabbit eyes. ARVO abstracts. Supplement to Invest. Ophthalmol. Vis. Sci. Phila delphia, J. B. Lippincott, 1990, p. 1982. 24. Pollack, I. P., Brown, R. H., Crandall, A. S., Robin, A. L., Stewart, R. H., and White, G. L.: Pre vention of the rise in intraocular pressure following neodymium:YAG posterior capsulotomy using topi cal 1% apraclonidine. Arch. Ophthalmol. 106:754, 1988. 25. Brown, R. H., Stewart, R. H., Lynch, M. G., Crandall, A. S., Mandell, A. I., Wilensky, J. T., Schwartz, A. L., Gaasterland, D. E., DeFaller, J. M., and Higginbotham, E. J.: AL02145 reduces the intra ocular pressure elevation after anterior segment laser surgery. Ophthalmology 95:378, 1988. 26. Blyth, C. R., and Still, H. A.: Binomial confi dence intervals. J. Am. Stat. Assoc. 78:108, 1983. 27. Mantel, N.: Chi-square tests with one degree of freedom. Extensions of the Mantel-Haenszel pro cedure. J. Am. Stat. Assoc. 58:690, 1963. 28. Terry, A. C , Stark, W. J., Quigley, H. A., Radulovic, D., and Maumenee, E.: Decreased aque ous outflow, the mechanisms for elevated intraocular pressure following Nd:YAG capsulotomy. Ophthal mology 91(suppl.):86, 1984. 29. Richter, C. U., Arzeno, G., Pappas, H. R., Steinert, R. F., Puliafito, C , and Epstein, D. L.: Intra ocular pressure following Nd:YAG laser posterior capsulotomy. Ophthalmology 92:636, 1985. 30. Hotchkiss, M. L., Quigley, H. A., Robin, A. L., Pollack, I. P., and Green, W. R.: YAG laser posterior capsulotomy. Primate studies. ARVO abstracts. Sup plement to Invest. Ophthalmol. Vis. Sci. 25:95, 1984. 31. Vine, A. K.: Ocular hypertension following Nd:YAG laser capsulotomy. A potentially blinding complication. Ophthalmic Surg. 15:283, 1984. 32. Blackwell, C , Hirst, L. W„ and Kinnas, S. ].: Neodymium:YAG capsulotomy and potential blind ness. Am. J. Ophthalmol. 98:521, 1984. 33. Kurata, F., Krupin, T., Sinclair, S., and Karp, L.: Progressive glaucomatous visual field loss after neodymium:YAG laser capsulotomy. Am. J. Ophthal mol. 98:632, 1984.
We evaluated the prophylactic effect of 1% apraclonidine HC1 in controlling the increase in intraocular pressure after Nd:YAG posteri or capsulotomy in a large, multicenter doublemasked clinical trial. One hundred sixty-four patients were enrolled into the apraclonidinetreated group, and 165 into the vehicle-treated group. The incidence of increase in intraocu lar pressure (greater than 5 mm Hg) in the apraclonidine-treated group (7%, 11 of 163 patients) was significantly less than that in the vehicle-treated group (39%, 64 of 164 pa tients). Similarly, the mean maximal change in intraocular pressure in the apraclonidinetreated group (1.3-mm Hg decrease) was sig nificantly different from the increase in the vehicle-treated group (5.3-mm Hg increase). Few adverse reactions were observed. The risk for significant loss of visual function after Nd:YAG laser posterior capsulotomy, com bined with the efficacy and relative safety of prophylactic apraclonidine, suggest its addi tion to the treatment armamentarium. I OSTERIOR CAPSULOTOMY with the Nd:YAG la ser is one of the most frequently performed anterior segment laser procedures. A complica tion of this otherwise generally successful pro cedure is an increase in intraocular pressure within the first several hours after laser treatAccepted for publication Jan. 22, 1992. From the Department of Ophthalmology a n d Visual Sciences, Yale University School of Medicine, New Ha ven, Connecticut (Dr. Silverstone); Eye Surgery Center of Louisiana, New Orleans, Louisiana (Dr. Brint); Eye Physician Associates, Milwaukee, Wisconsin (Dr. Olander); Department of Clinical Sciences, Alcon Labo ratories, Fort Worth, Texas (Mr. Taylor, Dr. McCarty, and Mr. deFaller); a n d Department of Ophthalmology, Southwestern Medical School, Dallas, Texas (Dr. Burk). Mr. Taylor, Dr. McCarty, and Mr. deFaller are employed by Alcon Laboratories. Reprint requests to David E. Silverstone, M.D., Temple Medical Building, 60 Temple St., New Haven, CT 06510.
ment. The incidence of significant increases in intraocular pressure may be greater than 30%. 1 6 Pilocarpine, timolol, and levobunolol have attenuated the incidence and severity of increases in intraocular pressure after Nd:YAG laser capsulotomies. 3 ' 4 ' 7 ' 8 However, the use of these agents is restricted by limited efficacy or potential for systemic adverse reactions. Recently, the ocular hypotensive efficacy of apraclonidine, an a-adrenoceptor agonist, 910 has been described in normal subjects and patients with increased intraocular pressure.11"13 Apraclonidine may reduce intraocular pressure by reducing anterior segment blood flow1415 that, in turn, decreases aqueous humor produc tion. 1617 Apraclonidine eyedrops elicit little or no reduction of cardiovascular function, 1118 in contrast to topical use of its chemical analogue, clonidine.19"23 The polarity of apraclonidine rel ative to clonidine may be responsible for the infrequency of adverse reactions related to cen tral o 2 -adrenoceptor agonists. This polarity conveys apraclonidine's relatively poor affinity to lipids, limiting its penetration through both the blood-brain barrier and the cornea. Access to the anterior chamber after instillation ap pears to be caused primarily by transconjunctival and transscleral penetration. 23 In placebo-controlled, double-masked stud ies, prophylactic use of apraclonidine has at tenuated the incidence and severity of increases in intraocular pressure after Nd:YAG laser cap sulotomies. These studies involved 6324 and 46 eyes.25 We desired to further these observations in a large population (329 eyes) at many geo graphically diverse sites.
Patients and Methods Patients who were candidates for Nd:YAG posterior capsulotomy at the 19 study centers were considered for entry into the study. Ex-
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eluded from participation were patients with hydrogel or silicone intraocular lenses and pa tients who had vision in one eye only, or active ocular infection or inflammation. Also excluded from the study were patients using systemic clonidine; patients with unstable cardiovascu lar disease; or women who were pregnant, nursing, or of child-bearing potential. The na ture of the study was explained to patients who met these enrollment criteria, and written in formed consent was obtained from those choos ing to participate. Only one eye from each patient was included in the study. At entry, patients underwent a prestudy ex amination, which included measurement of in traocular pressure, heart rate, and blood pres sure. In a double-masked fashion by which patients were randomly assigned to treatment, patients received one drop of either 1.0% apraclonidine HC1 or its vehicle one hour before the laser procedure, and again immediately at the conclusion of the surgical procedure. Intraocu lar pressure, heart rate, and blood pressure were measured one, two, and three hours after the procedure. The capsulotomies were per formed using a Q-switched Nd:YAG laser with the patients topically anesthetized and with the minimal energy settings required to create an adequate central opening in the posterior cap sule. Changes in intraocular pressure, heart rate, blood pressure, and demographic characteris tics after the laser procedure were evaluated with the stratified Cochran-Mantel-Haenszel test with values as ranks.26,27 A P value of .05 or less was considered statistically significant.
Results One hundred sixty-four patients were en rolled into the apraclonidine-treated group, and 165 into the vehicle-treated group. The mean age of the patients in the apraclonidinetreated group was approximately two years greater than that of the vehicle-treated group (Table 1). Although this difference was statisti cally significant, it was judged of little clinical significance. The patient population was pre dominantly female and white. Approximately 20% of the patients had glaucoma, most under going topical ocular hypotensive treatment. Ex cept for age, there were no significant differenc es in demographic or historical measures between the treatment groups.
TABLE 1 DEMOGRAPHIC CHARACTERISTICS OF PATIENTS*
Age Mean ± S.D. Gender Female Male Race White Other/not available Glaucoma Ocular hypotensive medications /3-adrenoceptor antagonists Pilocarpine
APRACLONIDINE-
VEHICLE-
TREATED PATIENTS (N = 164)
TREATED PATIENTS (N = 165)
74.0 ± 8.8
71.7 ± 12.0
111 (68%) 53 (32%)
115(70%) 50 (30%)
151 (93%) 13 (8%) 32 (20%)
145 (88%) 20(12%) 30(18%)
29 (17%)
31 (19%)
27 (16%) 12 (7%)
27(16%) 11 (7%)
There were no significant differences between the groups, except for age, for which the P value was .020. S.D. indicates standard deviation.
The mean number of spots used to produce a capsulotomy was 36, and the mean pulse power used was 1.6 mj, with no notable difference between the treatment groups. The mean intra ocular pressure before administration of study medications or laser treatment was approxi mately 16 mm Hg, with no significant differ ence between treatment groups. During the three-hour observation period after the laser procedure, the intraocular pressure decreased in the apraclonidine-treated group (mean de crease, 2.6 to 2.9 mm Hg). During the same period, the intraocular pressure increased in the vehicle-treated group (mean increase, 3.2 to 3.6 mm Hg). Using the maximal intraocular pressure in each patient at any point during the observation period, there was a mean decrease of 1.3 mm Hg in the apraclonidine-treated group, and a mean increase of 5.3 mm Hg in the vehicle-treated group. This approximately 5- to 7-mm Hg difference between the decrease in the apraclonidine-treated group and the in crease in the vehicle-treated group was statisti cally significant for all evaluations (Table 2). In the vehicle-treated group, 64 of 164 pa tients (39%) experienced an increase in intraoc ular pressure greater than 5 mm Hg (Figure). Forty-one of 164 patients (25%) in the vehicletreated group experienced an increase in in traocular pressure greater than 10 mm Hg. Significantly fewer patients in the apracloni-
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403
TABLE 2 MEAN CHANGE IN INTRAOCULAR PRESSURE (MM HG)* VEHICLE-
APRACLONIDINETREATED PATIENTS
TREATED PATIENTS
TIME
OF PATIENTS
MEAN
S.D.
NO. OF PATIENTS
MEAN
S.D.
P VALUE
Baseline 1 hour 2 hours 3 hours At any time
164 162 163 161
15.5 -2.6 -2.9 -2.7
3.7 3.4 4.1 4.2
164 164 163 164
15.7 3.2 3.6 3.2
3.2 5.5 6.2 6.2
.332 .001 .001 .001
163
-1.3
4.0
164
5.3
6.5
.001
NO.
*One apraclonidine-treated and one vehicle-treated patient were randomly assigned to treatment and considered in the demographic analysis, but did not receive medication or the laser procedure or both. S.D. indicates standard deviation.
dine-treated group experienced increases in intraocular pressure (P = .001). In the apra clonidine-treated group, increases greater than 5 mm Hg occurred in 11 of 163 patients (7%), and increases greater than 10 mm Hg occurred in three of 163 patients (2%). Three hours after the laser, the mean de crease in systolic blood pressure in the apraclo nidine-treated group, 4.8 mm Hg, was statisti cally different than that in the vehicle-treated group, 1.9 mm Hg (P = .018). There were no other statistically significant differences be tween the treatment groups in mean heart rate or blood pressure at any observation period. Eight treatment-related adverse reactions oc curred. Seven occurred among the apracloni dine-treated group. These consisted of the fol lowing: two cases of mild ocular inflammation, one case of corneal edema, one case of nasal burning, one case of ipsilateral eyelid retrac tion, one case of irregular heart rate, and one case of postoperative blepharospasm. The one reaction that occurred in the placebo-treated group was a dramatic increase in blood pres sure after the laser procedure. All reactions were transient and without sequelae.
Discussion
The incidence of significant increases in our vehicle-treated group, 25% to 39%, demon strated the ability of this procedure to elicit an increase in intraocular pressure, and was simi lar to previous reports. 1 6 Our observations of the efficacy and relative safety of apraclonidine as a prophylactic agent for increases in intraoc ular pressure were also similar to previous reports. 24,26 Impairment of the outflow facility appears to be the principal mechanism that brings about the transient intraocular pressure increase after Nd:YAG posterior capsulotomy. A decrease in the coefficient of outflow has been documented during the postoperative period after Nd:YAG capsulotomy procedures. 5 ' 28,29 Work in primates suggested that this impairment of outflow was caused by the lodging or accumulation of debris
P S ! Spikes
S.1M o
I—i_J No spikes
]E »
Apraclonidine
Vehicle
> 5 mm Hg
We found apraclonidine to be effective in attenuating the incidence of severity of increas es in intraocular pressure after Nd:YAG posteri or capsulotomy. The drug-related adverse reac tions were few and without long-term clinical significance.
Apraclonidine
Vehicle
> 10 mm Hg
Figure (Silverstone and associates). Incidence of increases in intraocular pressure (spikes) at any time point during the three-hour follow-up period. The difference between the apraclonidine- and vehi cle treated groups was statistically significant for increases greater than 5 mm Hg and greater than 10 mm Hg (P = .001).
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AMERICAN JOURNAL OF OPHTHALMOLOGY
a n d to d e v e l o p m e n t of i n f l a m m a t i o n in either the i n t e r n a l t r a b e c u l a r m e s h w o r k , the j u x t a c a n alicular m e s h w o r k , or the p o r e s of t h e i n t e r n a l wall of S c h l e m m ' s canal. Posterior c a p s u l a r r e m n a n t s have b e e n v i s u a l i z e d in the a n t e r i o r c h a m b e r a n d w i t h i n the t r a b e c u l a r m e s h w o r k after Nd:YAG capsulotomy. 3 0 O t h e r factors s u c h as the d i s r u p t i o n of the b l o o d - a q u e o u s b a r r i e r , laser s h o c k - w a v e effects, a n d t h e r e l e a s e of unspecified n e u r o h u m o r a l a g e n t s m a y also im pair outflow facility a n d t h e r e b y c o n t r i b u t e to the p o s t o p e r a t i v e i n c r e a s e in i n t r a o c u l a r p r e s sure. The p r i m a r y effect of a p r a c l o n i d i n e o n a q u e ous h u m o r d y n a m i c s a p p e a r s to b e a r e d u c t i o n in a q u e o u s h u m o r flow. 1617 A l t h o u g h this differs from the a p p a r e n t m e c h a n i s m of the i n c r e a s e of i n t r a o c u l a r p r e s s u r e after Nd:YAG laser c a p s u lotomy, it still a p p e a r s to b e clinically effective. Clinically a p p a r e n t optic n e r v e d a m a g e , p r o gression of visual field loss, a n d loss of vision can result from an a c u t e t r a n s i e n t i n c r e a s e in i n t r a o c u l a r p r e s s u r e after Nd:YAG c a p s u l o t o my. 3 1 3 3 P a t i e n t s w i t h g l a u c o m a r e p r e s e n t a large g r o u p of i n d i v i d u a l s w h o h a v e a n i n c r e a s e d risk of visual loss if i n t r a o c u l a r p r e s s u r e i n c r e a s e s p o s t o p e r a t i v e l y . O n e of t h e b e s t - d o c u m e n t e d o c c u r r e n c e s of visual field loss c a u s e d b y an acute i n c r e a s e in i n t r a o c u l a r p r e s s u r e w a s in a patient with glaucoma w h o had u n d e r g o n e an Nd.YAG laser posterior capsulotomy. 3 3 Tran sient loss of vision a c c o m p a n i e d b y ocular p a i n , nausea, and vomiting has occurred within h o u r s after Nd:YAG c a p s u l o t o m y w i t h a c u t e increase in i n t r a o c u l a r pressure. 3 1 3 2 T h e s e clini cal findings d o c u m e n t the d e t r i m e n t a l effects of acute t r a n s i e n t increase in i n t r a o c u l a r p r e s s u r e after Nd:YAG laser c a p s u l o t o m y o n v i s i o n . The risk for m a r k e d loss of visual function after Nd:YAG laser p o s t e r i o r c a p s u l o t o m y c o m b i n e d w i t h the efficacy a n d relative safety of p r o p h y l a c t i c a p r a c l o n i d i n e suggest its a d d i t i o n to our t r e a t m e n t a r m a m e n t a r i u m .
STUDY CENTERS A N D P R I N C I P A L INVESTIGATORS
Ophthalmic Consultants of Boston (Boston, Massa chusetts); Principal Investigator: A. Robert Bellows, M.D. Eye Surgery Center of Louisiana (New Orleans, Louisiana); Principal Investigator: Stephen F. Brint, M.D. Eye Associates (Dallas, Texas); Principal Investiga tor: Donald P. Brotherman, M.D. Dallas Ophthalmology Center (Dallas, Texas); Principal Investigator: Linda L. Burk, M.D.
Hunkeler Eye Clinic (Kansas City, Missouri); Prin cipal Investigator: John D. Hunkeler, M.D. University of Wisconsin, Center for Health Service (Madison, Wisconsin); Principal Investigator: Paul L. Kaufman, M.D. Kraff Eye Institute, Ltd. (Chicago, Illinois); Princi pal Investigator: Manus C. Kraff, M.D. Scheie Eye Institute (Philadelphia, Pennsylvania); Principal Investigator: Theodore Krupin, M.D. Henry F. Lenartz, M.D., Private Practice (Mountain View, California); Principal Investigator: Henry F. Lenartz, M.D. University of California-Davis, Dept. of Ophthal mology (Sacramento, California); Principal Investi gator: Richard A. Lewis, M.D. Irving Ophthalmology Clinic (Irving, Texas); Prin cipal Investigator: Jay L. Merten, M.D. Eye Physician Associates (Milwaukee, Wisconsin); Principal Investigator: Kenneth W. Olanders, M.D. Jacksonville Eye Center (Jacksonville, Florida); Principal Investigator: Robert J. Schnipper, M.D. Washington Eye Physicians & Surgeons (Chevy Chase, Maryland); Principal Investigator: Arthur L. Schwartz, M.D. Temple Eye Physicians, P.C. (New Haven, Connec ticut); Principal Investigator: David E. Silverstone, M.D. Houston Eye Associates (Houston, Texas); Princi pal Investigator: Robert H. Stewart, M.D. South Texas Cataract and Glaucoma Center (San Antonio, Texas); Principal Investigator: Stuart A. Terry, M.D. Mark J. Weiss, M.D., Inc. (Tulsa, Oklahoma); Prin cipal Investigator: Mark J. Weiss, M.D. University of Texas Health Science Center, Dept. of Ophthalmology (San Antonio, Texas); Principal In vestigator: Roy Witaker, Jr., M.D.
References 1. Channell, M. M., and Beckman, H.: Intraocular pressure changes after neodymium-YAG laser poster ior capsulotomy. Arch. Ophthalmol. 102:1024, 1984. 2. Slomovic, A. R., and Parrish, R. K.: Acute eleva tions of intraocular pressure following Nd:YAG laser posterior capsulotomy. Ophthalmology 92:973, 1985. 3. Richter, C. U., Arzeno, G., Pappas, H. R., Arrigg, C. A., Wasson, P., and Steinert, R. F.: Preven tion of intraocular pressure elevation following neo dymium-YAG laser posterior capsulotomy. Arch. Ophthalmol. 103:912, 1985. 4. Migliori, M. E., Beckman, H., and Channell, M. M.: Intraocular pressure changes after neodymi um-YAG laser capsulotomy in eyes pretreated with timolol. Arch. Ophthalmol. 105:473, 1987. 5. Brown, S. V. L., Thomas, J. V., Belcher, C. D., and Simmons, R. J.: Effect of pilocarpine in treatment of intraocular pressure elevation following neodymi-
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um:YAG laser posterior capsulotomy. Ophthalmolo gy 92:354, 1985. 6. Flohr, M. J., Robin, A. L., and Kelley, J. S.: Early complications following Q-switched neodymium:YAG laser posterior capsulotomy. Ophthalmolo gy 92:360, 1985. 7. Silverstone, D. E., Novack, G. D., Kelley, E. P., and Chen, K. S.: Prophylactic treatment of intraocu lar pressure elevations after neodymium:YAG laser posterior capsulotomies and extracapsular cataract extractions with levobunolol. Ophthalmology 95:713, 1988. 8. Stilma, J. S., and Boen-Tan, T. N.: Timolol and intra-ocular pressure elevation following neodymium:YAG laser surgery. Doc. Ophthalmol. 61:233, 1986. 9. Stump, D. C , and MacFarlane, D. E.: Clonidine and para-aminoclonidine, partial agonists for the alpha2-adrenergic receptor on intact human blood platelets. J. Lab. Clin. Med. 102:779, 1983. 10. Cavero, I., Deportere, H., and LeFevre-Borg, F.: Pharmacological studies on para aminoclonidine. Br. J. Pharmacol. 69:295, 1980. 11. Abrams, D. A., Robin, A. L., Pollack, I. P., deFaller, J. M., and DeSantis, L.: The safety and efficacy of topical 1% ALO 2145 (p-aminoclonidine hydrochloride) in normal volunteers. Arch. Ophthal mol. 105:1205, 1987. 12. Jampel, H. D., Robin, A. L., Quigley, H. A., and Pollack, I. P.: Apraclonidine. A one-week doseresponse study. Arch. Ophthalmol. 106:1069, 1988. 13. Morrison, J. C , and Robin, A. L.: Adjunctive glaucoma therapy. A comparison of apraclonidine to dipivefrin when added to timolol maleate. Ophthal mology 96:3, 1989. 14. Serdahl, C. L., Galustian, J., and Lewis, R. A.: The effects of apraclonidine on conjunctival oxygen tension. Arch. Ophthalmol. 107:1777, 1989. 15. Chandler, M. L., and DeSantis, L.: Studies of p-amino clonidine as a potential antiglaucoma agent. ARVO abstracts. Supplement to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1985, p. 227. 16. Bartels, S. P., and Schlerman, F. J.: Effects of timolol, apraclonidine, or enalaprilat on aqueous humor flow in monkeys. ARVO abstracts. Supple ment to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1990, p. 902. 17. Gharagozloo, N. Z., Relf, S. J., and Brubaker, R. F.: Aqueous flow is reduced by the alpha-adrenergic agonist, apraclonidine hydrochloride (ALO 2145). Ophthalmology 95:1217, 1988. 18. Coleman, A. L., Robin, A. L., Pollack, I. P., Rudikoff, M. T., Enger, C , and Mayer, P. R.: Cardio vascular and intraocular pressure effects and plasma concentrations of apraclonidine hydrochloride. Arch. Ophthalmol. 108:1264, 1990. 19. Heilmann, K.: Augendruck, Blutdruck und Glaukomscheden. Buch Augen. 61:1, 1972.
405
20. Harrison, R., and Kaufmann, C. S.: Clonidine. Effects of a topically administered solution on intra ocular pressure and blood pressure in open-angle glaucoma. Arch. Ophthalmol. 95:1368, 1977. 21. Petursson, G., Cole, R., and Hanna, C : Treat ment of glaucoma using minidrops of clonidine. Arch. Ophthalmol. 102:1180, 1984. 22. Hodapp, E., Kolker, A. E., Kass, M. A., Gold berg, I., Becker, B., and Gordon, M.: The effect of topical clonidine on intraocular pressure. Arch. Oph thalmol. 99:1208, 1981. 23. Chien, D., Tang-Liu, D., and Gluchowski, C : Corneal and conjunctival/scleral absorption of a2adrenergic agents in rabbit eyes. ARVO abstracts. Supplement to Invest. Ophthalmol. Vis. Sci. Phila delphia, J. B. Lippincott, 1990, p. 1982. 24. Pollack, I. P., Brown, R. H., Crandall, A. S., Robin, A. L., Stewart, R. H., and White, G. L.: Pre vention of the rise in intraocular pressure following neodymium:YAG posterior capsulotomy using topi cal 1% apraclonidine. Arch. Ophthalmol. 106:754, 1988. 25. Brown, R. H., Stewart, R. H., Lynch, M. G., Crandall, A. S., Mandell, A. I., Wilensky, J. T., Schwartz, A. L., Gaasterland, D. E., DeFaller, J. M., and Higginbotham, E. J.: AL02145 reduces the intra ocular pressure elevation after anterior segment laser surgery. Ophthalmology 95:378, 1988. 26. Blyth, C. R., and Still, H. A.: Binomial confi dence intervals. J. Am. Stat. Assoc. 78:108, 1983. 27. Mantel, N.: Chi-square tests with one degree of freedom. Extensions of the Mantel-Haenszel pro cedure. J. Am. Stat. Assoc. 58:690, 1963. 28. Terry, A. C , Stark, W. J., Quigley, H. A., Radulovic, D., and Maumenee, E.: Decreased aque ous outflow, the mechanisms for elevated intraocular pressure following Nd:YAG capsulotomy. Ophthal mology 91(suppl.):86, 1984. 29. Richter, C. U., Arzeno, G., Pappas, H. R., Steinert, R. F., Puliafito, C , and Epstein, D. L.: Intra ocular pressure following Nd:YAG laser posterior capsulotomy. Ophthalmology 92:636, 1985. 30. Hotchkiss, M. L., Quigley, H. A., Robin, A. L., Pollack, I. P., and Green, W. R.: YAG laser posterior capsulotomy. Primate studies. ARVO abstracts. Sup plement to Invest. Ophthalmol. Vis. Sci. 25:95, 1984. 31. Vine, A. K.: Ocular hypertension following Nd:YAG laser capsulotomy. A potentially blinding complication. Ophthalmic Surg. 15:283, 1984. 32. Blackwell, C , Hirst, L. W„ and Kinnas, S. ].: Neodymium:YAG capsulotomy and potential blind ness. Am. J. Ophthalmol. 98:521, 1984. 33. Kurata, F., Krupin, T., Sinclair, S., and Karp, L.: Progressive glaucomatous visual field loss after neodymium:YAG laser capsulotomy. Am. J. Ophthal mol. 98:632, 1984.