- Email: [email protected]
The additive effect of latanoprost to maximum-tolerated medications with low-dose, high-dose, or no pilocarpine therapy
The Additive Effect of Latanoprost to Maximum-tolerated Medications with Lowdose, High-dose, or No Pilocarpine Therapy Dong H. Shin, MD, PhD,1 Michael S. McCracken, MD,1 Rick E. Bendel, MD,1 Robert Pearlman, MD,1 Mark S. Juzych, MD,1 Bret A. Hughes, MD,1 Laura L. Schulz, CNA,1 Chaesik Kim, BSEE,1 Nam H. Baek, MD2 Objective: To assess the efficacy of latanoprost additive therapy in patients with intraocular pressure (IOP) out of control while taking maximum-tolerated medications and to determine whether pilocarpine therapy has a dose-dependent adverse effect on the efficacy of latanoprost therapy. Design: Noncomparative case series. Participants: Sixty-one eyes of 61 patients with chronic glaucoma with IOP out of control while receiving maximum-tolerated medications were treated with latanoprost additive therapy on a compassionate basis. Main Outcome Measures: Follow-up was up to 22 months with a mean of 13.9 ⫾ 5.7 months. Kaplan–Meier survival analysis with Mantel–Cox log–rank test was performed to determine the overall success of latanoprost additive therapy and to compare the success rates of high-dose pilocarpine, low-dose pilocarpine, and no pilocarpine therapies. The criterion for success was avoiding glaucoma surgery with IOP decrease of 20% or greater and final IOP less than 22 mmHg. The IOP change and its significance for patients satisfying and failing the criterion for success also were determined to assess the latanoprost additive therapy. In addition, a number of pretreatment variables, including pilocarpine therapy, were analyzed for a significant effect on the efficacy of latanoprost additive therapy using Cox proportional hazards regression analysis. Results: Latanoprost additive therapy significantly lowered mean IOP by 3.9 ⫾ 5.5 mmHg at 3 months and by 3.5 ⫾ 5.8 mmHg at 12 months. The cumulative success rate of the latanoprost additive therapy was 70% at 1 month, 42% at 3 months, 40% at 6 months, and 30% at 12 months. Of the variables studied, only increased number of previous incisional glaucoma surgeries and IOP greater than 24 mmHg before latanoprost additive therapy were significant prognostic factors for failure of latanoprost additive therapy. Pilocarpine therapy in any dose had no significant effect. Conclusion: This study supports a trial of latanoprost additive therapy before glaucoma surgery in patients with IOP out of control while receiving maximum-tolerated medications irrespective of pilocarpine therapy and the pilocarpine dosage, especially when the number of previous incisional glaucoma surgery is less than three and the IOP is less than 25 mmHg. Ophthalmology 1999;106:386 –390 Latanoprost is a prostaglandin analog known to increase the uveoscleral outflow of aqueous humor.1– 8 Clinical trials have found latanoprost monotherapy effective in lowering intraocular pressure (IOP).9 –14 Because latanoprost lowers
Originally received: March 13, 1998. Revision accepted: July 13, 1998. Manuscript no. 98139. 1 Kresge Eye Institute, Wayne State University School of Medicine, Detroit, Michigan. 2 Catholic University, Seoul, Korea. Presented in part at the American Academy of Ophthalmology annual meeting, Chicago, Illinois, 1996, and the Association for Research in Vision and Ophthalmology annual meeting, Fort Lauderdale, Florida, 1997. Supported in part by a grant from Research to Prevent Blindness, Inc., New York, New York. Reprint requests to Dong H. Shin, MD, PhD, Kresge Eye Institute and Wayne State University School of Medicine, 4717 St. Antoine Blvd., Detroit, MI 48201-1423.
386
IOP by a mechanism different from that of any other traditional glaucoma medication, it should be an effective medication to add in patients already receiving maximum-tolerated medical therapy. Indeed, latanoprost has shown efficacy as an additive to other glaucoma medications.4,15,16 However, there is a controversy as to whether concurrent miotic therapy lessens the efficacy of latanoprost (Kruger E, et al. Invest Ophthalmol Vis Sci 1997;38[Suppl]:279; Camras CB, et al. Invest Ophthalmol Vis Sci 1990;31[Suppl]: 150).2– 4,6,17–19 We investigated the additive efficacy of latanoprost in patients with chronic glaucoma in need of surgical therapy with IOP out of control while receiving maximum-tolerated medications with low-dose, high-dose, and no pilocarpine therapy.
Patients and Methods In a prospective study begun before latanoprost was available commercially, we treated 61 patients with chronic glaucoma with
Shin et al 䡠 Additive Effect of Latanoprost and Pilocarpine Therapy Table 1. Patient Demographics Total No. Age (yrs) ⫾ SD Range Race Black White Sex Female Male Diabetes Hypertension C:D ratio Pretreatment IOP (mmHg) No. of medications Treatment with pilocarpine Low dose High dose FU period (mos)
Pilocarpine
Control
P
61 64.7 ⫾ 15.7 22–87
36 67.1 ⫾ 14.2 22–87
25 61.2 ⫾ 17.4 26–87
38(61%) 23(39%)
22 14
16 9
0.82†
38(62%) 23(38%) 18(30%) 29(48%) 0.85 ⫾ 0.14 23.5 ⫾ 6.3 3.6 ⫾ 1.1 36(59%) 7(19%) 29(81%) 13.9 ⫾ 5.7
22 14 10 15 0.85 ⫾ 0.11 22.1 ⫾ 5.2 4.0 ⫾ 0.9
16 9 8 14 0.85 ⫾ 0.17 25.4 ⫾ 7.2 3.0 ⫾ 1.1
0.82† 0.72† 0.27 0.96* 0.038* ⬍0.0003‡
13.3 ⫾ 5.8
14.9 ⫾ 5.4
0.28*
0.15*
SD ⫽ standard deviation; C:D ⫽ cup-to-disc; IOP ⫽ intraocular pressure; FU ⫽ follow-up. * Unpaired t test. † Chi-square test. ‡ Mann-Whitney U test.
latanoprost on a compassionate basis. There were 61 eyes of 61 patients with chronic glaucoma (mean age, 64.7 ⫾ 15.7; 38.6% white vs. 61.4% black; 37.7% males) with IOP out of control (23.5 ⫾ 6.3 mmHg) while receiving maximum-tolerated medications (mean ⫾ standard deviation number of 3.6 ⫾ 1.1) (Table 1) and therefore in need of surgical intervention. These patients had already undergone on average 2.0 ⫾ 2.1 various incisional ocular surgeries, including 1.6 ⫾ 1.9 prior incisional glaucoma surgeries or a cyclodestructive procedure as listed in Table 2. In addition, 40 eyes (66%) or two thirds of the 61 eyes had had argon laser trabeculoplasty. Of the total 61 eyes, 36 eyes (59%) were receiving varying strengths of pilocarpine included in their regimens: pilocarpine 1/2% four times a day (2 eyes), pilocarpine 2% four times a day (2 eyes), pilocarpine 3% four times a day (1 eye), pilocarpine 4% gel at bedtime (2 eyes), pilocarpine 4% four times a day (14 eyes), and pilocarpine 6% four times a day (15 eyes). Thus, 7 (19%) of the 36 eyes were receiving pilocarpine less than 4% four times a day (low-dose pilocarpine) and 29 eyes (81%) on 4% or 6% four times a day (high-dose pilocarpine). The 7 eyes on low-dose pilocarpine could not tolerate high-dose pilocarpine, and 25 eyes receiving no pilocarpine could not tolerate even low-dose pilocarpine, because of visual or ciliary symptoms. Before treatment, all patients signed an informed consent form to participate in this compassionate study. Pretreatment IOP was measured by experienced technicians using Goldmann applanation tonometry. The patients were treated with 0.005% latanoprost, one drop in the evening, in addition to their previous medical regimen. There was no washout period before the addition of latanoprost to the patients’ glaucoma medical regimens. During serial follow-up visits, IOP was measured in the same manner as during the pretreatment visit. In addition, any changes in the patients’ glaucoma medical regimens were monitored. Furthermore, patients’ subjective complaints of side effects were recorded. The study did not track iris color. Follow-up was up to 22 months with a mean of 13.9 ⫾ 5.7 months for all patients. Follow-up ended at the last patient visit, the occurrence of an additional glaucoma procedure, or the discontinuation of latanoprost.
The criteria for success of latanoprost additive therapy were arbitrarily defined as final IOP less than 22 mmHg and IOP decrease of 20% or greater. The mean IOP change and percentage IOP change for patients satisfying and failing the criterion were calculated, and the statistical significances were determined. Success probabilities of latanoprost additive therapy were analyzed by Kaplan–Meier survival analysis, and statistical significances were determined by Mantel–Cox log–rank test. In addition, Cox proportional hazards regression model was used to identify possible prognostic factors for failure. Each variable was modeled individually, then all variables (age, race, gender, diabetes mellitus, hypertension, C:D ratio, pretreatment IOP, number of pretreatment glaucoma medications, prior argon laser trabeculoplasty, prior cataract surgery, number of prior glaucoma incisional surgery, and pilocarpine use) were entered into a model, and insignificant variables were eliminated by backward stepwise selection (the probability values for entry and removal of a variable were set at 0.05 and 0.05, respectively).
Table 2. Numbers of Previous Ocular Surgery Previous Ocular Surgery
Total
Pilocarpine
Control
P*
Trabeculectomy Cataract surgery Combined trabeculectomy and cataract surgery Penetrating keratoplasty Molteno or other drainage implant surgery Cyclocryo or cyclophotocoagulation Vitreoretinal surgery
58 13
38 8
20 5
0.50 0.84
18 8
11 1
7 7
0.83 0.02
18
7
11
0.13
1 8
0 4
1 4
— 0.69
* Chi-square test.
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Ophthalmology Volume 106, Number 2, February 1999 Table 3. Intraocular Pressures (mmHg) on Latanoprost Additive Therapy Months
n (%*)
Pre-Tx
Post-Tx
IOP Decrease
% IOP Decrease
P†
1
61 (100) 43 (70) 18 (30) 61 (100) 28 (42) 33 (58) 61 (100) 27 (40) 34 (60) 61 (100) 25 (30) 36 (70)
23.5 ⫾ 6.3 24.0 ⫾ 5.8 22.1 ⫾ 7.2 23.5 ⫾ 6.3 23.5 ⫾ 5.1 23.4 ⫾ 7.2 23.5 ⫾ 6.3 23.6 ⫾ 5.2 23.4 ⫾ 7.1 23.5 ⫾ 6.3 23.8 ⫾ 5.3 23.2 ⫾ 7.0
18.7 ⫾ 7.1 17.5 ⫾ 5.8 21.8 ⫾ 9.0 19.4 ⫾ 6.7 16.2 ⫾ 3.9 22.2 ⫾ 7.5 20.1 ⫾ 7.0 15.9 ⫾ 6.5 22.1 ⫾ 7.4 19.6 ⫾ 7.3 15.2 ⫾ 3.0 21.6 ⫾ 7.5
4.5 ⫾ 7.0 6.5 ⫾ 6.6 0.5 ⫾ 5.5 3.9 ⫾ 5.5 7.4 ⫾ 4.3 0.9 ⫾ 4.5 2.8 ⫾ 5.4 6.7 ⫾ 5.3 1.0 ⫾ 4.5 3.5 ⫾ 5.8 8.6 ⫾ 4.2 1.4 ⫾ 4.8
17.2 25.4 3.9 15.3 30.4 2.2 10.6 28.1 2.4 13.5 35.3 4.2
⬍0.0001 ⬍0.0001 0.72 ⬍0.0001 ⬍0.0001 0.26 0.0009 0.0002 0.23 0.0002 ⬍0.0001 0.11
Total Success Failure 3 Total Success Failure 6 Total Success Failure 12 Total Success Failure
Tx ⫽ therapy; IOP ⫽ intraocular pressure. * Cumulative success rate. † Paired t test.
Results The study patients’ demographics are presented in Table 1. The pilocarpine and control groups were similar to each other in demographics and clinical profile except that the pilocarpine group had a greater number of medications than did the control group. There also was no significant difference in previous ocular surgeries between the pilocarpine and control groups (Table 2). In addition, there was no significant difference in the percentage of patients with previous argon laser trabeculoplasty between the two groups (72% in the pilocarpine group vs. 56% in the control group, P ⫽ 0.19). Mean IOP of all patients decreased from 23.5 ⫾ 6.3 mmHg before the latanoprost therapy to 19.4 ⫾ 6.7 mmHg at 3 months (by 3.9 ⫾ 5.5 mmHg, P ⬍ 0.0001) and to 19.6 ⫾ 7.3 mmHg at 12 months (by 3.9 ⫾ 5.8 mmHg, P ⬍ 0.0002) of latanoprost additive therapy (Table 3). Mean reductions in IOP at 12 months was 8.6 ⫾ 4.2 mmHg (from 23.8 ⫾ 5.3 to 15.2 ⫾ 3.0 mmHg, P ⬍ 0.0001) for patients who satisfied the success criterion (Table 3). For the patients failing the criterion, the change in IOP was not significant (⫺1.4 ⫾ 4.8 mmHg from 23.2 ⫾ 7.0 to 21.6 ⫾ 7.5 mmHg, P ⫽ 0.11) (Table 3). The probability of success was 70% at 1 month, 42% at 3 months, 40% at 6 months, and 30% at both 9 and 12 months (Fig 1).
A Cox proportional hazards regression analysis showed that prelatanoprost IOP greater than 24 mmHg and number of prior glaucoma incisional surgeries greater than two were significant covariates predicting for a treatment failure of latanoprost additive therapy (Tables 3, 4). Other pretreatment variables were not significant predictors of failure of latanoprost additive therapy (P ⬎ 0.05 for each). Specifically, pilocarpine therapy was not a significant predictor of failure of latanoprost therapy (P ⫽ 0.44) (Cox proportional hazards regression). Furthermore, the Kaplan–Meier survival analysis also failed to show a significant difference between patients with and without pilocarpine therapy (P ⫽ 0.82) (Fig 2) or among the curves for patients receiving high-dose pilocarpine, low-dose pilocarpine, and no pilocarpine therapy (P ⫽ 0.39) (Fig 3). Among all patients, ocular irritation was observed in 13.1% and conjunctival hyperemia was observed in 8.2%. In addition, one patient with pseudophakia experienced hypotony (IOP ⫽ 1 mmHg) and decrease of visual acuity at 5 months because of the development of iritis; latanoprost was discontinued; and the iritis, hypotony, and decrease of visual acuity resolved.
Discussion Latanoprost additive therapy showed statistically significant reductions in IOP of 3.9 ⫾ 5.5 mmHg at 3 months and 3.5 ⫾ 5.8 mmHg at 12 months in patients with chronic Table 4. Prognostic Factors for Failure of Latanoprost Use by Cox Proportional Hazards Regression Model
P
Risk Ratio*
95% Confidence Intervals on Risk Ratios
1.30 ⫾ 0.43
0.002
3.62
1.56–8.37
1.06 ⫾ 0.45
0.016
2.92
1.21–7.02
Coefficient ⴞ Prognostic Factor Standard Error Pre-Tx IOP ⬎ 24 mmHg No. of glaucoma surgery ⬎ 2
Figure 1. Success probability of latanoprost additive therapy by Kaplan– Meier survival analysis.
388
Tx ⫽ latanoprost additive therapy; IOP ⫽ intraocular pressure. * Indicator contrast is used for categorical covariates.
Shin et al 䡠 Additive Effect of Latanoprost and Pilocarpine Therapy glaucoma who were surgical candidates with IOP out of control while receiving maximum-tolerated medications. Furthermore, over the period of 12 months, these patients had a 30% probability of satisfying our criterion for success. Patients surviving the criterion for success showed a significant IOP reduction of 8.6 ⫾ 4.2 mmHg at 12 months. In addition, our study identified two prognostic factors for failure of latanoprost additive therapy. Pretreatment IOP greater than 24 mmHg and a number of prior incisional glaucoma surgeries greater than two were predictive of failure. Thus, our study supports a trial of latanoprost additive therapy before glaucoma surgery in patients receiving maximum-tolerated medical therapy, especially in the absence of the prognostic factors for its failure. Also noteworthy is the fact that the Kaplan–Meier survival analysis did not show any significant effect of pilocarpine therapy in any dose on success of latanoprost additive therapy. The primary mechanism of action of latanoprost is believed to be increased uveoscleral outflow.1– 8 Because miotic treatment causes contraction of the ciliary muscle2,4 – 6,20 and decreases the uveoscleral outflow, it is often believed that miotic therapy would decrease the efficacy of latanoprost. Indeed, several studies have shown this effect in monkey eyes (Camras CB, et al. Invest Ophthalmol Vis Sci 1990;31[Suppl]:150).2,21 Some authors also have shown a mild impairment of latanoprost efficacy by miotics in human eyes (Villumsen J, et al. Invest Ophthalmol Vis Sci 1992;33[Suppl]:1248).4,17 However, the longterm effect of latanoprost may be the result of remodeling of the extracellular matrix of the ciliary muscle, a phenomenon that may not be hampered by miotics.1,3,6,21–23 It also may be that the ciliary body of patients with glaucoma is weaker than that of monkeys.24 These examples may explain why our study found no significant effect of miotic therapy on the efficacy of latanoprost additive therapy. Conversely, we have not compared the efficacy of latanoprost additive therapy between miotics of short, direct action such as pilocarpine and long, indirect action such as phospholine iodide or demecarium bromide. The percentage of patients reporting side effects in our trial was relatively low, although the most salient side effect, increased iridial pigmentation, was not monitored. Ocular
Figure 3. Success probabilities of latanoprost additive therapy for patients on high-dose (filled circles), low-dose (open squares), and no pilocarpine therapy (open circles) (P ⫽ 0.39, log–rank test).
irritation and conjunctival hyperemia were the two most common side effects in our study. One patient did experience development of iritis, hypotony, and visual acuity reduction, which may have been caused by latanoprost therapy.25 This minimal side effect profile, along with the convenience of once-daily dosing, makes latanoprost an attractive alternative to glaucoma surgery in appropriate patients. Our study concludes that latanoprost additive therapy is effective in some patients with IOP out of control while receiving maximum-tolerated medications regardless of pilocarpine therapy, in agreement with two recent reports,18,19 and irrespective of the dosage of the pilocarpine therapy. Our study has also shown two prognostic factors for failure of latanoprost additive therapy: prelatanoprost therapy IOP greater than 24 mmHg and number of prior incisional glaucoma surgeries greater than two. Although clinical trials have showed a long-term stability in the efficacy of latanoprost monotherapy, further follow-up is warranted to evaluate the long-term efficacy of additive latanoprost therapy in patients with IOP out of control while receiving maximum-tolerated medications with and without inclusion of miotics. Furthermore, more studies are warranted to determine the mechanism of action of latanoprost in humans.
References
Figure 2. Success probabilities of latanoprost additive therapy in patients receiving no pilocarpine (open circles) vs. patients receiving pilocarpine therapy (filled circles) by Kaplan–Meier survival analysis (P ⫽ 0.82, log–rank test).
1. Bito LZ. Prostaglandins: a new approach to glaucoma management with a new, intriguing side effect. Surv Ophthalmol 1997;41(Suppl 2):S1–S14. 2. Crawford K, Kaufman PL. Pilocarpine antagonizes prostaglandin F2␣-induced ocular hypotension in monkeys. Evidence for enhancement of uveoscleral outflow by prostaglandin F2␣ Arch Ophthalmol 1987;105:1112– 6. 3. Gabelt BT, Kaufman PL. Prostaglandin F2␣ increases uveoscleral outflow in the cynomolgus monkey. Exp Eye Res 1989;49:389 – 402. 4. Hoyng PFJ, Rulo A, Greve E, et al. The additive intraocular pressure-lowering effect of latanoprost in combined therapy with other-ocular hypotensive agents. Surv Ophthalmol 1997; 41(Suppl 2):S93– 8. 5. Mishima HK, Shoge K, Takamatsu M, et al. Ultrasound biomicroscopic study of ciliary body thickness after topical
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application of pharmacologic agents. Am J Ophthalmol 1996; 121:319 –21. Nilsson SFE, Samuelsson M, Bill A, Stjernschantz J. Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2␣—1-isopropylester in the cynomolgus monkey. Exp Eye Res 1989;48:707–16. Watson P, Stjernschantz J. A six-month, randomized, doublemasked study comparing latanoprost with timolol in openangle glaucoma and ocular hypertension. The Latanoprost Study Group. Ophthalmology 1996;103:126 –37. Ziai N, Dolan JW, Kacere RD, Brubaker RF. The effects on aqueous dynamics of PhXA41, a new prostaglandin F2␣ analogue, after topical application in normal and ocular hypertensive human eyes. Arch Ophthalmol 1993;111:1351– 8. Alm A, Stjernschantz J. Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group. Ophthalmology 1995;102:1743–52. Alm A, Camras CB, Watson PG. Phase III latanoprost studies in Scandinavia, the United Kingdom and the United States. Surv Ophthalmol 1997;41(Suppl 2):S105–10. Camras CB, Alm A, Watson P, Stjernschantz J. Latanoprost, a prostaglandin analog, for glaucoma therapy. Efficacy and safety after 1 year of treatment in 198 patients. Latanoprost Study Groups. Ophthalmology 1996;103:1916 –24. Camras CB. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma. A six-month, masked, multicenter trial in the United States. The United States Latanoprost Study Group. Ophthalmology 1996;103:138 – 47. Ra´cz P, Ruzsonyi MR, Nagy ZT, Bito LZ. Maintained intraocular pressure reduction with once-a-day application of a new prostaglandin F2␣ analogue (PhXA41). An in-hospital, placebo-controlled study. Arch Ophthalmol 1993;111:657– 61. Villumsen J, Alm A. PhXA34-a prostaglandin F2␣ analogue. Effect on intraocular pressure in patients with ocular hypertension. Br J Ophthalmol 1992;76:214 –7. Alm A, Widenga¨rd I, Kjellgren D, et al. Latanoprost administered once daily caused a maintained reduction of intraocular
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pressure in glaucoma patients treated concomitantly with timolol. Br J Ophthalmol 1995;79:12– 6. Rulo AH, Greve EL, Hoyng PF. Additive effect of latanoprost, a prostaglandin F2␣ analogue, and timolol in patients with elevated intraocular pressure. Br J Ophthalmol 1994;78:899 –902. Fristro¨m B, Nilsson SEG. Interaction of PhXA41, a new prostaglandin analogue, with pilocarpine. A study on patients with elevated intraocular pressure. Arch Ophthalmol 1993; 111:662–5. Linden C, Alm A. Latanoprost and physostigmine have mostly additive ocular hypotensive effects in human eyes. Arch Ophthalmol 1997;115:857– 61. Patelska B, Greenfield DS, Liebmann JM, et al. Latanoprost for uncontrolled glaucoma in a compassionate case protocol. Am J Ophthalmol 1997;124:279 – 86. Kaufman PL, Ba´ra´ny EH. Loss of acute pilocarpine effect on outflow facility following surgical disinsertion and retrodisplacement of the ciliary muscle from the scleral spur in the cynomolgus monkey. Invest Ophthalmol Vis Sci 1976;15: 793– 807. Lindsey JD, Kashiwagi K, Kashiwagi F, Weinreb RN. Prostaglandin action on ciliary smooth muscle extracellular matrix metabolism: implications for uveoscleral outflow. Surv Ophthalmol 1997;41(Suppl 2):S53–9. Lindsey JD, To HD, Weinreb RN. Induction of c-fos by prostaglandin F2␣ in human ciliary smooth muscle cells. Invest Ophthalmol Vis Sci 1994;35:242–50. Toris CB, Camras CB, Yablonski ME, Brubaker RF. Effects of exogenous prostaglandins on aqueous humor dynamics and blood–aqueous barrier function. Surv Ophthalmol 1997; 41(Suppl 2):S69 –75. Stjernschantz J, Alm A. Latanoprost as a new horizon in the medical management of glaucoma. Curr Opinion Ophthalmol 1996;7:11–7. Warwar RE, Bullock JD, Ballal D. Cystoid macular edema and anterior uveitis associated with latanoprost use. Experience and incidence in a retrospective review of 94 patients. Ophthalmology 1998;105:263– 8.
Originally received: March 13, 1998. Revision accepted: July 13, 1998. Manuscript no. 98139. 1 Kresge Eye Institute, Wayne State University School of Medicine, Detroit, Michigan. 2 Catholic University, Seoul, Korea. Presented in part at the American Academy of Ophthalmology annual meeting, Chicago, Illinois, 1996, and the Association for Research in Vision and Ophthalmology annual meeting, Fort Lauderdale, Florida, 1997. Supported in part by a grant from Research to Prevent Blindness, Inc., New York, New York. Reprint requests to Dong H. Shin, MD, PhD, Kresge Eye Institute and Wayne State University School of Medicine, 4717 St. Antoine Blvd., Detroit, MI 48201-1423.
386
IOP by a mechanism different from that of any other traditional glaucoma medication, it should be an effective medication to add in patients already receiving maximum-tolerated medical therapy. Indeed, latanoprost has shown efficacy as an additive to other glaucoma medications.4,15,16 However, there is a controversy as to whether concurrent miotic therapy lessens the efficacy of latanoprost (Kruger E, et al. Invest Ophthalmol Vis Sci 1997;38[Suppl]:279; Camras CB, et al. Invest Ophthalmol Vis Sci 1990;31[Suppl]: 150).2– 4,6,17–19 We investigated the additive efficacy of latanoprost in patients with chronic glaucoma in need of surgical therapy with IOP out of control while receiving maximum-tolerated medications with low-dose, high-dose, and no pilocarpine therapy.
Patients and Methods In a prospective study begun before latanoprost was available commercially, we treated 61 patients with chronic glaucoma with
Shin et al 䡠 Additive Effect of Latanoprost and Pilocarpine Therapy Table 1. Patient Demographics Total No. Age (yrs) ⫾ SD Range Race Black White Sex Female Male Diabetes Hypertension C:D ratio Pretreatment IOP (mmHg) No. of medications Treatment with pilocarpine Low dose High dose FU period (mos)
Pilocarpine
Control
P
61 64.7 ⫾ 15.7 22–87
36 67.1 ⫾ 14.2 22–87
25 61.2 ⫾ 17.4 26–87
38(61%) 23(39%)
22 14
16 9
0.82†
38(62%) 23(38%) 18(30%) 29(48%) 0.85 ⫾ 0.14 23.5 ⫾ 6.3 3.6 ⫾ 1.1 36(59%) 7(19%) 29(81%) 13.9 ⫾ 5.7
22 14 10 15 0.85 ⫾ 0.11 22.1 ⫾ 5.2 4.0 ⫾ 0.9
16 9 8 14 0.85 ⫾ 0.17 25.4 ⫾ 7.2 3.0 ⫾ 1.1
0.82† 0.72† 0.27 0.96* 0.038* ⬍0.0003‡
13.3 ⫾ 5.8
14.9 ⫾ 5.4
0.28*
0.15*
SD ⫽ standard deviation; C:D ⫽ cup-to-disc; IOP ⫽ intraocular pressure; FU ⫽ follow-up. * Unpaired t test. † Chi-square test. ‡ Mann-Whitney U test.
latanoprost on a compassionate basis. There were 61 eyes of 61 patients with chronic glaucoma (mean age, 64.7 ⫾ 15.7; 38.6% white vs. 61.4% black; 37.7% males) with IOP out of control (23.5 ⫾ 6.3 mmHg) while receiving maximum-tolerated medications (mean ⫾ standard deviation number of 3.6 ⫾ 1.1) (Table 1) and therefore in need of surgical intervention. These patients had already undergone on average 2.0 ⫾ 2.1 various incisional ocular surgeries, including 1.6 ⫾ 1.9 prior incisional glaucoma surgeries or a cyclodestructive procedure as listed in Table 2. In addition, 40 eyes (66%) or two thirds of the 61 eyes had had argon laser trabeculoplasty. Of the total 61 eyes, 36 eyes (59%) were receiving varying strengths of pilocarpine included in their regimens: pilocarpine 1/2% four times a day (2 eyes), pilocarpine 2% four times a day (2 eyes), pilocarpine 3% four times a day (1 eye), pilocarpine 4% gel at bedtime (2 eyes), pilocarpine 4% four times a day (14 eyes), and pilocarpine 6% four times a day (15 eyes). Thus, 7 (19%) of the 36 eyes were receiving pilocarpine less than 4% four times a day (low-dose pilocarpine) and 29 eyes (81%) on 4% or 6% four times a day (high-dose pilocarpine). The 7 eyes on low-dose pilocarpine could not tolerate high-dose pilocarpine, and 25 eyes receiving no pilocarpine could not tolerate even low-dose pilocarpine, because of visual or ciliary symptoms. Before treatment, all patients signed an informed consent form to participate in this compassionate study. Pretreatment IOP was measured by experienced technicians using Goldmann applanation tonometry. The patients were treated with 0.005% latanoprost, one drop in the evening, in addition to their previous medical regimen. There was no washout period before the addition of latanoprost to the patients’ glaucoma medical regimens. During serial follow-up visits, IOP was measured in the same manner as during the pretreatment visit. In addition, any changes in the patients’ glaucoma medical regimens were monitored. Furthermore, patients’ subjective complaints of side effects were recorded. The study did not track iris color. Follow-up was up to 22 months with a mean of 13.9 ⫾ 5.7 months for all patients. Follow-up ended at the last patient visit, the occurrence of an additional glaucoma procedure, or the discontinuation of latanoprost.
The criteria for success of latanoprost additive therapy were arbitrarily defined as final IOP less than 22 mmHg and IOP decrease of 20% or greater. The mean IOP change and percentage IOP change for patients satisfying and failing the criterion were calculated, and the statistical significances were determined. Success probabilities of latanoprost additive therapy were analyzed by Kaplan–Meier survival analysis, and statistical significances were determined by Mantel–Cox log–rank test. In addition, Cox proportional hazards regression model was used to identify possible prognostic factors for failure. Each variable was modeled individually, then all variables (age, race, gender, diabetes mellitus, hypertension, C:D ratio, pretreatment IOP, number of pretreatment glaucoma medications, prior argon laser trabeculoplasty, prior cataract surgery, number of prior glaucoma incisional surgery, and pilocarpine use) were entered into a model, and insignificant variables were eliminated by backward stepwise selection (the probability values for entry and removal of a variable were set at 0.05 and 0.05, respectively).
Table 2. Numbers of Previous Ocular Surgery Previous Ocular Surgery
Total
Pilocarpine
Control
P*
Trabeculectomy Cataract surgery Combined trabeculectomy and cataract surgery Penetrating keratoplasty Molteno or other drainage implant surgery Cyclocryo or cyclophotocoagulation Vitreoretinal surgery
58 13
38 8
20 5
0.50 0.84
18 8
11 1
7 7
0.83 0.02
18
7
11
0.13
1 8
0 4
1 4
— 0.69
* Chi-square test.
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Ophthalmology Volume 106, Number 2, February 1999 Table 3. Intraocular Pressures (mmHg) on Latanoprost Additive Therapy Months
n (%*)
Pre-Tx
Post-Tx
IOP Decrease
% IOP Decrease
P†
1
61 (100) 43 (70) 18 (30) 61 (100) 28 (42) 33 (58) 61 (100) 27 (40) 34 (60) 61 (100) 25 (30) 36 (70)
23.5 ⫾ 6.3 24.0 ⫾ 5.8 22.1 ⫾ 7.2 23.5 ⫾ 6.3 23.5 ⫾ 5.1 23.4 ⫾ 7.2 23.5 ⫾ 6.3 23.6 ⫾ 5.2 23.4 ⫾ 7.1 23.5 ⫾ 6.3 23.8 ⫾ 5.3 23.2 ⫾ 7.0
18.7 ⫾ 7.1 17.5 ⫾ 5.8 21.8 ⫾ 9.0 19.4 ⫾ 6.7 16.2 ⫾ 3.9 22.2 ⫾ 7.5 20.1 ⫾ 7.0 15.9 ⫾ 6.5 22.1 ⫾ 7.4 19.6 ⫾ 7.3 15.2 ⫾ 3.0 21.6 ⫾ 7.5
4.5 ⫾ 7.0 6.5 ⫾ 6.6 0.5 ⫾ 5.5 3.9 ⫾ 5.5 7.4 ⫾ 4.3 0.9 ⫾ 4.5 2.8 ⫾ 5.4 6.7 ⫾ 5.3 1.0 ⫾ 4.5 3.5 ⫾ 5.8 8.6 ⫾ 4.2 1.4 ⫾ 4.8
17.2 25.4 3.9 15.3 30.4 2.2 10.6 28.1 2.4 13.5 35.3 4.2
⬍0.0001 ⬍0.0001 0.72 ⬍0.0001 ⬍0.0001 0.26 0.0009 0.0002 0.23 0.0002 ⬍0.0001 0.11
Total Success Failure 3 Total Success Failure 6 Total Success Failure 12 Total Success Failure
Tx ⫽ therapy; IOP ⫽ intraocular pressure. * Cumulative success rate. † Paired t test.
Results The study patients’ demographics are presented in Table 1. The pilocarpine and control groups were similar to each other in demographics and clinical profile except that the pilocarpine group had a greater number of medications than did the control group. There also was no significant difference in previous ocular surgeries between the pilocarpine and control groups (Table 2). In addition, there was no significant difference in the percentage of patients with previous argon laser trabeculoplasty between the two groups (72% in the pilocarpine group vs. 56% in the control group, P ⫽ 0.19). Mean IOP of all patients decreased from 23.5 ⫾ 6.3 mmHg before the latanoprost therapy to 19.4 ⫾ 6.7 mmHg at 3 months (by 3.9 ⫾ 5.5 mmHg, P ⬍ 0.0001) and to 19.6 ⫾ 7.3 mmHg at 12 months (by 3.9 ⫾ 5.8 mmHg, P ⬍ 0.0002) of latanoprost additive therapy (Table 3). Mean reductions in IOP at 12 months was 8.6 ⫾ 4.2 mmHg (from 23.8 ⫾ 5.3 to 15.2 ⫾ 3.0 mmHg, P ⬍ 0.0001) for patients who satisfied the success criterion (Table 3). For the patients failing the criterion, the change in IOP was not significant (⫺1.4 ⫾ 4.8 mmHg from 23.2 ⫾ 7.0 to 21.6 ⫾ 7.5 mmHg, P ⫽ 0.11) (Table 3). The probability of success was 70% at 1 month, 42% at 3 months, 40% at 6 months, and 30% at both 9 and 12 months (Fig 1).
A Cox proportional hazards regression analysis showed that prelatanoprost IOP greater than 24 mmHg and number of prior glaucoma incisional surgeries greater than two were significant covariates predicting for a treatment failure of latanoprost additive therapy (Tables 3, 4). Other pretreatment variables were not significant predictors of failure of latanoprost additive therapy (P ⬎ 0.05 for each). Specifically, pilocarpine therapy was not a significant predictor of failure of latanoprost therapy (P ⫽ 0.44) (Cox proportional hazards regression). Furthermore, the Kaplan–Meier survival analysis also failed to show a significant difference between patients with and without pilocarpine therapy (P ⫽ 0.82) (Fig 2) or among the curves for patients receiving high-dose pilocarpine, low-dose pilocarpine, and no pilocarpine therapy (P ⫽ 0.39) (Fig 3). Among all patients, ocular irritation was observed in 13.1% and conjunctival hyperemia was observed in 8.2%. In addition, one patient with pseudophakia experienced hypotony (IOP ⫽ 1 mmHg) and decrease of visual acuity at 5 months because of the development of iritis; latanoprost was discontinued; and the iritis, hypotony, and decrease of visual acuity resolved.
Discussion Latanoprost additive therapy showed statistically significant reductions in IOP of 3.9 ⫾ 5.5 mmHg at 3 months and 3.5 ⫾ 5.8 mmHg at 12 months in patients with chronic Table 4. Prognostic Factors for Failure of Latanoprost Use by Cox Proportional Hazards Regression Model
P
Risk Ratio*
95% Confidence Intervals on Risk Ratios
1.30 ⫾ 0.43
0.002
3.62
1.56–8.37
1.06 ⫾ 0.45
0.016
2.92
1.21–7.02
Coefficient ⴞ Prognostic Factor Standard Error Pre-Tx IOP ⬎ 24 mmHg No. of glaucoma surgery ⬎ 2
Figure 1. Success probability of latanoprost additive therapy by Kaplan– Meier survival analysis.
388
Tx ⫽ latanoprost additive therapy; IOP ⫽ intraocular pressure. * Indicator contrast is used for categorical covariates.
Shin et al 䡠 Additive Effect of Latanoprost and Pilocarpine Therapy glaucoma who were surgical candidates with IOP out of control while receiving maximum-tolerated medications. Furthermore, over the period of 12 months, these patients had a 30% probability of satisfying our criterion for success. Patients surviving the criterion for success showed a significant IOP reduction of 8.6 ⫾ 4.2 mmHg at 12 months. In addition, our study identified two prognostic factors for failure of latanoprost additive therapy. Pretreatment IOP greater than 24 mmHg and a number of prior incisional glaucoma surgeries greater than two were predictive of failure. Thus, our study supports a trial of latanoprost additive therapy before glaucoma surgery in patients receiving maximum-tolerated medical therapy, especially in the absence of the prognostic factors for its failure. Also noteworthy is the fact that the Kaplan–Meier survival analysis did not show any significant effect of pilocarpine therapy in any dose on success of latanoprost additive therapy. The primary mechanism of action of latanoprost is believed to be increased uveoscleral outflow.1– 8 Because miotic treatment causes contraction of the ciliary muscle2,4 – 6,20 and decreases the uveoscleral outflow, it is often believed that miotic therapy would decrease the efficacy of latanoprost. Indeed, several studies have shown this effect in monkey eyes (Camras CB, et al. Invest Ophthalmol Vis Sci 1990;31[Suppl]:150).2,21 Some authors also have shown a mild impairment of latanoprost efficacy by miotics in human eyes (Villumsen J, et al. Invest Ophthalmol Vis Sci 1992;33[Suppl]:1248).4,17 However, the longterm effect of latanoprost may be the result of remodeling of the extracellular matrix of the ciliary muscle, a phenomenon that may not be hampered by miotics.1,3,6,21–23 It also may be that the ciliary body of patients with glaucoma is weaker than that of monkeys.24 These examples may explain why our study found no significant effect of miotic therapy on the efficacy of latanoprost additive therapy. Conversely, we have not compared the efficacy of latanoprost additive therapy between miotics of short, direct action such as pilocarpine and long, indirect action such as phospholine iodide or demecarium bromide. The percentage of patients reporting side effects in our trial was relatively low, although the most salient side effect, increased iridial pigmentation, was not monitored. Ocular
Figure 3. Success probabilities of latanoprost additive therapy for patients on high-dose (filled circles), low-dose (open squares), and no pilocarpine therapy (open circles) (P ⫽ 0.39, log–rank test).
irritation and conjunctival hyperemia were the two most common side effects in our study. One patient did experience development of iritis, hypotony, and visual acuity reduction, which may have been caused by latanoprost therapy.25 This minimal side effect profile, along with the convenience of once-daily dosing, makes latanoprost an attractive alternative to glaucoma surgery in appropriate patients. Our study concludes that latanoprost additive therapy is effective in some patients with IOP out of control while receiving maximum-tolerated medications regardless of pilocarpine therapy, in agreement with two recent reports,18,19 and irrespective of the dosage of the pilocarpine therapy. Our study has also shown two prognostic factors for failure of latanoprost additive therapy: prelatanoprost therapy IOP greater than 24 mmHg and number of prior incisional glaucoma surgeries greater than two. Although clinical trials have showed a long-term stability in the efficacy of latanoprost monotherapy, further follow-up is warranted to evaluate the long-term efficacy of additive latanoprost therapy in patients with IOP out of control while receiving maximum-tolerated medications with and without inclusion of miotics. Furthermore, more studies are warranted to determine the mechanism of action of latanoprost in humans.
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Figure 2. Success probabilities of latanoprost additive therapy in patients receiving no pilocarpine (open circles) vs. patients receiving pilocarpine therapy (filled circles) by Kaplan–Meier survival analysis (P ⫽ 0.82, log–rank test).
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