Literature Review and Meta-Analysis of Topical Carbonic Anhydrase Inhibitors and Ocular Blood Flow

Home , Alon Harris, Betaxolol, Glaucoma medication, Ophthalmology, Timolol

SURVEY OF OPHTHALMOLOGY VOLUME 54 NUMBER 1 JANUARY–FEBRUARY 2009

MAJOR REVIEW

Literature Review and Meta-Analysis of Topical Carbonic Anhydrase Inhibitors and Ocular Blood Flow Brent Siesky, PhD,1 Alon Harris, MS, PhD,1 Edward Brizendine, MS,2 Clarice Marques, MD,1 Jennifer Loh, MD,1 Joseph Mackey, MD,1 Jennifer Overton, MD,1 and Peter Netland, MD3

1Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana; 2Division of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana; and 3Department of Ophthalmology, University of Tennessee, Memphis, Tennessee, USA

Abstract. The purpose of this literature review and meta-analysis was to determine what, if any, effects topical carbonic anhydrase inhibitors have on ocular hemodynamics in humans. A literature review and meta-analysis was conducted to investigate the effects of topical carbonic anhydrase inhibitors on ocular blood flow. Thirty-five articles were evaluated according to the inclusion criteria with 13 manuscripts meeting requirements for statistical analysis. Each study’s effect size, defined as the change in blood flow measures after treatment with topical carbonic anhydrase inhibitors, was estimated using the weighted mean difference. Based on this meta-analysis, we conclude that topical carbonic anhydrase inhibitors increase ocular blood flow velocities in the retinal circulation, central retinal and short posterior ciliary arteries, but not in the ophthalmic artery. (Surv Ophthalmol 54:33-- 46, 2009. Ó 2009 Elsevier Inc. All rights reserved.)

Key words. carbonic anhydrase inhibitor color Doppler imaging glaucoma ocular blood ﬂow scanning laser ophthalmoscopy

I. Introduction bar12,27,38,63 circulations, and ischemia has been shown to correspond with areas of glaucomatous A. PRIMARY OPEN-ANGLE GLAUCOMA RISK 10 FACTORS visual field loss. Furthermore, POAG has been found to be associated with abnormal blood pres- Primary open-angle glaucoma (POAG) is a multi- sure,50 ocular perfusion pressure,9,77 nocturnal hy- factorial optic neuropathy characterized by progres- potension,40 optic disk hemorrhage,20 migraine,20 sive retinal ganglion cell death and associated visual and aging of the vasculature.34 Chronic optic nerve field loss. Elevated intraocular pressure (IOP) is the ischemia has been shown to induce retinal ganglion major risk factor and the only one that is currently cell loss independent of IOP.15 Reduced ocular approved for treatment in glaucoma management. perfusion may therefore be secondary to IOP For many years, vascular abnormalities have also been elevation or represent a primary insult to the optic reported as contributing factors to glaucomatous nerve in glaucoma. Chronic ocular ischemia may be optic neuropathy.23 Prospective clinical trials have due to faulty vascular autoregulation and the inability demonstrated blood flow deficiencies of POAG of the vasculature to overcome elevated IOP to patients in the retinal,14 choroidal,80 and retrobul- maintain adequate perfusion.

B. TOPICAL POAG THERAPIES AND OCULAR namics in baboons while Chiou and Chen reported BLOOD FLOW increased blood flow in the retina and choroid.13,79 However, some contradictory evidence indicates that Much controversy exists regarding POAG thera- 8,30 pies and their potential influence on ocular blood acetazolamide may have no influence or even 46 flow. The physiological mechanisms of POAG a negative effect on ocular hemodynamics. The therapies differ, as do their potential to influence heterogeneity of methods used to assess ocular vascular smooth muscle.16 To significantly impact hemodynamic effects of acetazolamide preclude ocular blood flow, topical POAG medications must statistical meta-analysis, but the vast majority of these penetrate the anterior surface of the eye, reach articles favor increased hemodynamic parameters. critical concentrations, and exert a physiological Although no studies have directly compared the effect on the vascular tissue. Alternatively, topical ocular hemodynamic effects of systemic and topical medications may be absorbed into the systemic CAI, many small prospective clinical trials suggest circulation, where they may have an effect on the topical CAI therapies also increase ocular perfusion 74 ocular vasculature. Direct vascular effects of thera- parameters. Studies by Sugrue et al and Schmitz et 68 pies in combination with IOP reduction (increasing al indicate significant absorption of topical CAI ocular perfusion pressure) may produce a net effect occurs throughout the various ocular tissues pro- on ocular hemodynamics and POAG pathology. viding a possible pathway for interaction with the vasculature. However, few, if any, conclusive state- ments can be derived from the heterogeneous blood C. CARBONIC ANHYDRASE INHIBITORS AND flow study designs and methodologies spread BLOOD FLOW throughout the literature to date. The purpose of Carbonic anhydrase inhibitors (CAI) are widely this literature review and meta-analysis is to de- utilized to reduce IOP in POAG patients and termine what, if any, effects topical CAI have on suspects. Aqueous humor secretion depends on ocular hemodynamics in humans. - the production of bicarbonate (HCO3) from carbonic anhydrase II,51 an isoenzyme found in the non-pigmented ciliary epithelium. Chemically, car- II. Methods bonic anhydrase catalyzes carbon dioxide (CO2) hydration and interconversion to carbonic acid A. LITERATURE SEARCH AND ELIGIBILITY CRITERIA (H2CO3), which freely dissociates into HCO3 and protons. Blockade of carbonic anhydrase in local A literature search using the OVID Medline tissues may therefore increase tissue CO2 concen- search engine and all available library databases trations and/or lower tissue pH, resulting in was employed with reference cross-matching to vascular dilation and increased blood flow.61,73,75 obtain all relevant peer reviewed articles published Acetazolamide, a systemic CAI, is commonly used on CAI and ocular hemodynamics (Fig. 1). The in provocative tests to study cerebrovascular vasomo- article search included all available published tor reactivity. The cerebral vasodilatory effects of studies from 1966 to January 2006. A total of 39 systemic CAI are therefore well established and often separate searches by two independent researchers utilized to test for vasodilative reserve poten- (J.O and J.M.) were performed until all relevant tial.28,49,73 Acetazolamide has also been reported to articles were identified. The completeness of these increase choroidal and retinal blood flow, possibly searches was then validated by independent increasing oxygenation59 of ocular tissues.13,18,39, searches performed by the Department of Ophthal- 61,62,79 Specifically, Reber et al found acetazolamide mology librarian at the Indiana University School of is capable of relaxing pericytes which may provide Medicine and the primary author (B.S.) using a pathway for possibly improving retinal blood flow.62 all available library databases. All articles using In prospective trials, Dallinger et al found acetazol- systemic CAI were eliminated, leaving articles that amide increased fundus pulsation amplitude in prospectively investigated topical dorzolamide, a dose-dependent manner while decreasing the re- brinzolamide, and a fixed dorzolamide/timolol sistive index of the ophthalmic artery.18 Harris et al combination (Cosopt). At the end of this process, found acetazolamide during hypercapnia caused a total of 36 relevant articles2--4,6,7,11,21,22,24--26, a reduction in the calculated vascular resistive index 29,31--33,36,37,42--45,47,48,52--53,56--58,60,62,64--67,76,81 were of the internal carotid and central retinal arteries.39 obtained for subsequent analysis. For articles not Rassam et al found acetazolamide increased retinal meeting statistical requirements or published after blood flow as measured by laser Doppler velocimetry the meta-analysis literature search closure and vessel diameter assessments.61 Finally, Wilson et al date,17,54,55,70,71,72,78,82 a detailed summary analysis found acetazolamide increased choroidal hemody- is presented. TOPICAL CARBONIC ANHYDRASE INHIBITORS 35

Fig. 1. Medline search ﬂow chart. CAI 5 carbonic anhydrase inhibitors; IOP 5 intraocular pressure.

B. ARTICLE SELECTION AND DATA EXTRACTION disease, thus weighted averages of all data points and standard deviations (SD) were calculated. For clinical applicability only data from human 6 subjects were included, thus eliminating arti- Another article presented the retrobulbar blood cles4,21,44,58,62,76 that used animal models. All articles flow velocity values as a median (range); data were 41 were required to report prospectively quantitative converted to means with SD. ocular hemodynamic parameters directly, eliminating one article.24 Another article65 was excluded because it C. OUTCOME DEFINITION is identical to a second article66 published in a separate As in any meta-analysis, certain assumptions must journal in a different language. Two articles56,57 were be made to provide enough similar data for statistical eliminated because they artificially increased IOP via comparisons. For our investigation, all human sub- suction cup technique during CAI treatment (Fig. 1). jects were considered as participants regardless of Three articles31,36,37 presented data in graph form POAG or healthy patient status and all topical CAI only; the data were converted to numerical values therapies were considered globally as a topical CAI using a rolling ruler (‘‘A’’ style) by one examiner intervention. Thus, the type of ocular blood flow (J.L.) in conjunction with the Department of imaging technologies and their respective units of Biostatistics at the Indiana University School of measure serve as the final differentiation of the Medicine. One article53 subdivided data into cate- results. To perform a statistical meta-analysis, three or gories based upon the extent of the patients’ more qualified prospective trial articles must be 36 Surv Ophthalmol 54 (1) January--February 2009 SIESKY ET AL available for a technology’s specific quantitative methodology and reproducibility of SLO is available hemodynamic outcome parameter. Thirteen arti- elsewhere.35 cles2,3,6,26,31--33,36,37,45,47,53,81 met all of the stringent statistical requirements for the meta-analysis portion E. STATISTICS of this review. For those articles not meeting meta- Each study’s effect size, defined as the change in analysis statistical requirements, a detailed summary blood flow measures after treatment with topical CAI, analysis is presented. was estimated using the weighted mean difference. The overall mean change across studies was estimated D. IMAGING TECHNOLOGIES INCLUDED IN THE using the ‘meta’ package (Guido Schwarzer: Meta- META-ANALYSIS Analysis R package version 0.5, 2005) in the R statistical software (R Development Core Team: R: A Color Doppler imaging (CDI) is an ultrasound language and environment for statistical computing. technology that uses Doppler-shifted frequencies and R Foundation for Statistical Computing, Vienna, pulse-Doppler measurements with B-scan gray scale Austria. ISBN 3-900051-07-0, available at www.R- images to evaluate blood flow velocities in the project.org, 2005). A DerSimonian and Laird random retrobulbar circulation. During CDI examination of effects model19 was assumed using the inverse the eye, the operator identifies the desired vessel and variance as a study’s weight. The overall effect of places a sampling window for pulsed-Doppler mea- topical CAI on blood flow measures was estimated surements on the vessel obtaining flow velocity which along with a 95% confidence interval (CI). For is graphed over time. The CDI is non-invasive, outcomes showing a significant overall effect (p ! allowing hemodynamic data to be obtained in eyes 0.05), a forest plot was produced to assess an individual with poor optical media and regardless of pupil size. paper’s contribution to the overall estimate. CDI can be used to measure the end diastolic velocity (EDV) and peak systolic velocity (PSV) and a calculated ([PSV -- EDV] / PSV) resistivity index. The peak III. Results and trough of the wave are identified by the operator, A. SUMMARY ANALYSIS OF ARTICLES NOT and the computer calculates the PSV and EDV, INCLUDED IN STATISTICAL META-ANALYSIS respectively. Measurements are typically performed in the ophthalmic artery, central retinal artery, and Table 1 summarizes the CAI therapy, imaging short posterior ciliary arteries, often as temporal and technology, number of patients, blood flow effect nasal groupings. Literature exploring the reproduc- and p values for all articles in human subjects which ibility of CDI is available in detail elsewhere.5,35,69 did not meet statistical requirements for inclusion in The scanning laser ophthalmoscope (SLO) uti- the meta-analysis and for articles which appeared in lizes the principals of angiography to make hemo- the literature after the closure date for the statistical dynamic measurements in the ocular circulation. meta-analysis. Of these 25 studies, 17 articles (68%) Fluorescein angiography (FA) and indocyanine report an increase in ocular hemodynamic outcome green (ICG) angiography performed with SLO can parameters as measured by at least one imaging be used to provide quantitative hemodynamic technology. One article reported a decrease in parameters in the retinal (FA) and choroidal a hemodynamic parameter, and seven (28%) reported (ICG) circulations. An SLO employs a laser beam no significant effects during topical CAI treatment. that scans across the retina and collects reflected light through a confocal aperture. Rodenstock SLO B. TOPICAL CARBONIC ANHYDRASE INHIBITORS provides data concerning the passage of blood Tables 2--4 show the published peer-reviewed through the retinal or choroidal vasculature by articles to date investigating ocular hemodynamics recording an injected dye at a speed of 30 frames and topical CAI treatment (includes articles used in per second. The confocal aperture blocks scattered the meta analysis and animal models). Table 2 shows light and light reflected and scattered from sources all published peer-reviewed articles involving pro- outside of the focal plane, thus reducing the effects spective trials of brinzolamide and ocular hemody- of lens and corneal opacities. The detector measures namics. Of the seven prospective trials, four (57%) the intensity of the reflected light in real time, indicated increased ocular hemodynamic parame- creating a video signal. Quantitative outcomes ters, one reported a possible decrease in blood flow include arteriovenous passage (AVP) time which parameters, and two (29%) found no significant represents the shortest passage time through effects. Table 3 shows all published peer-reviewed a vascular segment from the first influx of blood articles involving dorzolamide hydrochloride-timolol in the retinal artery to the return in the correspond- maleate ophthalmic solution (combined solution or ing retinal vein.1 A detailed discussion of the dorzolamide/timolol separately dosed combination) TOPICAL CARBONIC ANHYDRASE INHIBITORS 37

TABLE 1 Summary of articles that did not meet statistical analysis requirements for meta-analysis or were published after the close date for the meta-analysis Author Ref Subjects Technology Drug Blood Flow p-value lester 42 15 HRF Brinzolamide increase !0.001 Sampaolesi 64 24 HRF Brinzolamide decrease not reported Fuchsjager-Mayrl 25 42 HRF Dorzolamide increase !0.001 Brogliatti 11 9 HRF Cosopt increase O0.05 Pillunat 60 15 HRF/LDF Dorzolamide no effect not reported kothy 48 6 RVA Brinzolamide no effect 50.996 Nagel 56 12 RVA Dorzolamide increase !0.02 Nagel 57 11 RVA Dorzolamide increase 50.03 Bernd 7 25 POBF Dorzolamide increase !0.05 Manni 52 12 POBF Cosopt increase 50.007 Januleviciene 43 30 POBF Cosopt increase 50.03 Schmidt 67 14 OPA Cosopt increase !0.0001 Schmidt 66 28 OPA Dorzolamide increase !0.05 Faingold 22 17 Canon Dorzolamide no effect 50.85 Klemm 47 8 LOBF (portion) Brinzolamide no effect not reported Gruwald 29 20 BDLDV Dorzolamide no effect 0.83 ------Siesky 71 16 HRF/CDI/SLO Cosopt increase-CDI only !0.05 Uva 78 16 CDI Cosopt increase !0.01 Martinez 55 22 CDI Cosopt increase !0.002 Zeitz 82 15 CDI Dorzolamide no effect O0.05 Simsek 72 44 CDI Dorzolamide no effect O0.05 Costagliola 17 40 HRF Dorzolamide increase O0.03 Martinez 54 32 CDI Cosopt increase O0.008 Siesky 70 15 CDI/HRF Dorzolamide/Brinzolamide increase-HRF only O0.05 Martinez 55a 40 CDI Cosopt increase !0.05 Heidelberg retina flowmeter (HRF), laser Doppler flowmeter (LDF), retinal vessel analyzer (RVA), pulsatile ocular blood flow meter (POBF and LOBF),ocular pulse amplitude (OPA), Canon laser blood flowmeter (Canon) , color Doppler imaging (CDI), bidirectional laser Doppler velocemetry (BDLDV) and scaning laser ophthalmoscope (SLO). Note: only the entries that have HRF, LDF, Canon, or BDLDV in the ‘‘Technology’’ column measure flow. Other imaging technologies measure parameters which indicate possible flow changes (with assumptions).

(Cosopt; Merck and Co, Inc., Whitehouse Station, NJ) Table 4 shows all published peer-reviewed articles and ocular hemodynamics. Of the ten prospective involving dorzolamide and ocular hemodynamics. Of trials, all ten (100%) indicated increased parameters the 25 prospective trials, 18 (72%) indicated the of ocular hemodynamics during CAI therapy. Two possibility of increased ocular circulation, 7 (28%) studies reported no effect within selective tissues; found no signiﬁcant effects, and no study reported however, all studies found increased ocular hemody- a decrease in hemodynamic parameters during namic paramters in at least one measurement site. treatment.

TABLE 2 Summary of the effects of brinzolamide reported in peer-reviewed published prospective trials Author Ref n Subject Type Duration Technology Blood Flow p - value Iester 42 15 POAG 1 month HRF increase !0.001 Sampaolesi 64 24 PAOG various HRF decrease not reported Kothy 48 6 Normals / PAOG 14 days RVA no effect 50.996 Klemm 47 8 NTG 3-5 weeks CDI/LOBF no effects no reported Barnes 4 -- Rabbits 7 days LDF increase 0.05 Kaup 45 30 Normals 2 weeks CDI/SLO increase SLO only !0.05 Siesky 70 15 POAG 3 months CDI/HRF increase HRF only !0.05 Heidelberg retina flowmeter (HRF), laser Doppler flowmeter (LDF), color Doppler imaging (CDI), retinal vessel analyzer (RVA), pulsatile ocular blood flow meter (LOBF) and scanning laser ophthalmoscope (SLO). Note: only the entries that have HRF, LDF, Canon, or BDLDV in the ‘‘Technology’’ column measure flow. Other imaging technologies measure parameters that indicate possible flow changes (with assumptions). Subject type is defined as primary open- angle glaucoma (POAG), nor mal-tention glaucoma (NTG), healthy subjects (normals) and animals, i.e., (rabbit). Other abbreviations include reference number (Ref) and number of subjects (n). 38 Surv Ophthalmol 54 (1) January--February 2009 SIESKY ET AL

TABLE 3 Summary of the effects of dorzolamide hydrochloride-timolol maleate ophthalmic solution reported in peer-reviewed published prospective Author Ref n Subjects Duration Technology Blood Flow p - value Manni 52 12 POAG -- POBF increase 50.007 Januleviciene 43 30 POAG 4 weeks POBF increase 50.03 Schmidt 67 14 POAG 4 weeks OPA increase !0.0001 Brogliatti 11 9 POAG 4 weeks HRF increase !0.05 Harris 36 15 POAG 4 weeks CDI / SLO increase—SLO only !0.05 Uva 78 16 POAG 4 weeks CDI increase !0.01 Martinez 55 22 POAG 4 weeks CDI increase !0.0003 Siesky 71 16 POAG 4 weeks HRF / CDI / SLO increase—HRF only !0.05 Martinez 54 32 POAG 4 weeks CDI increase !0.008 Martinez 55a 40 POAG 48 months CDI increase !0.05 Heidelberg retina flowmeter (HRF), laser Doppler flowmeter (LDF), color Doppler imaging (CDI), retinal vessel analyzer (RVA), pulsatile ocular blood flow meter (POBF), ocular pulse amplitude (OPA) and scanning laser ophthalmoscope (SLO). Note: only the entries that have HRF, LDF, Conon, or BDLDV in the ‘‘Technology’’ column measure flow. Other imaging technologies measure parameters that indicate possible flow changes (with assumptions). Subject type is defined as primary open-angle glaucoma (POAG), normal-tention glaucoma (NTG), healthy subjects (normals) and animals, i.e., (rabbit). Other abbreviations include reference number (Ref) and number of subjects (n).

C. RETROBULBAR BLOOD FLOW VELOCITIES: current literature require careful dissection. Many META-ANALYSIS ocular hemodynamic imaging technologies measure Table 5 reports the meta-analysis effects seen in a hemodynamic parameter that may indicate in- the retrobulbar blood supply for subjects analyzed creased circulation, but only with certain assump- with CDI. Peak systolic and end diastolic blood flow tions built into the assessment. For instance, CDI velocities are increased in the central retinal artery measures blood flow velocities, not actual flow, and in the nasal and temporal posterior ciliary hence representing a limitation of this method. arteries while calculated vascular resistance is re- Hemodynamic parameters should therefore only be duced in the central retinal and temporal posterior interpreted with caution, each having specific ciliary arteries during topical CAI therapy. No assumptions and limitations. In this capacity, each statistically significant effects are seen in the ocular hemodynamic imaging technology has vari- ophthalmic artery. Figs. 2 and 3 show the CDI ous pros, cons, and limitations which are covered 35 weighted mean differences for all articles meeting elsewhere in greater detail. meta-analysis requirements. Although controversial, topical CAI therapy has been reported to enhance circulation in the central D. RETINAL BLOOD FLOW VELOCITIES: META- nervous system and other vascular beds. In this ANALYSIS meta-analysis we reviewed the heterogeneous literature containing varying techniques and analytic Table 5 reports the meta-analysis effects for approaches in order to assess the effects of CAI on subjects analyzed with scanning laser ophthalmos- the ocular circulation. Treatment with topical CAI copy during fluorescein dye injections. Topical CAI was associated with increased blood flow velocities therapy accelerated blood flow velocities in both the in the central retinal and short posterior ciliary superior and inferior primary retinal artery and vein arteries. In addition, we found that CAI consistently pairs. Fig. 4 shows the weighted mean differences increased circulation velocities within the primary for all articles meeting meta-analysis requirements retinal artery branches. using SLO. Summarizing all of the topical CAI hemodynamic articles examined (both included in the statistical IV. Discussion meta-analysis and those excluded) 32 of 42 articles (76%) report possible increases in ocular hemody- A. TOPICAL CARBONIC ANHYDRASE INHIBITION namic parameters during topical CAI treatment. POSSIBLY INCREASES OCULAR BLOOD FLOW Nine of 42 (21%) report no change in ocular The overall goal of this literature review and meta- circulation parameters and one (~2%) reported analysis was to clarify what effects, if any, topical CAI a decrease. Although many of these articles were have on ocular blood flow. To accomplish this, the excluded from the statistical meta-analysis, the heterogeneous study methodologies, imaging hard- overwhelming majority of all peer-reviewed ware, software, and patient populations of the published articles on this topic indicate increased TOPICAL CARBONIC ANHYDRASE INHIBITORS 39

TABLE 4 Summary of the effects of dorzolamide reported in peer-reviewed published prospective Author Ref n Subjects Duration Technology Blood Flow p - value Fuchsjager-Mayrl 25 42 POAG/OHT 2 weeks HRF increase !0.001 Pillunat 60 15 Normals 3 days HRF/LDF no effect not reported Nagel 56 12 POAG 4 weeks RVA increase !0.02 Nagel 57 11 POAG 4 weeks RVA increase 50.03 Bernd 7 25 -- -- POBF increase !0.05 Schmidt 66 28 POAG 2 days OPA increase !0.05 Faingold 22 17 Normals acute Canon no effect 50.85 Grunwald 29 20 Normals acute BDLDV no effect 50.83 Reber 62 -- Rat acute Cap Diameter increase not reported Harris 31 11 Normals 8 days CDI/AVP increase—AVP only !0.05 Harris 33 18 NTG 4 weeks CDI/AVP increase—AVP only !0.05 Harris 32 9 NTG 4 weeks CDI/AVP increase—AVP only !0.05 Harris 37 20 NTG 4 weeks CDI/AVP increase—AVP only !0.05 Zeitz 81 42 NTG 4 weeks CDI increase !0.05 Arend 2 14 POAG 4 weeks AVP increase 50.009 Galassi 26 20 POAG 4 weeks CDI increase 50.011 Avundk 3 22 POAG 4 weeks CDI increase 50.012 Bergstand 6 47 POAG 6 weeks CDI no effect -- Martinez 53 26 POAG acute CDI increase !0.05 Simsek 72 44 POAG 3 months CDI no effect -- Barnes 4 -- Rabbits 7 days LDF increase !0.05 Tamaki 76 -- Rabbits 20 days L.Speckle no effect !0.05 Zeitz 82 15 POAG acute CDI no effect !0.05 Costagliola 17 40 Juvenile POAG acute HRF increase !0.03 Siesky 70 15 POAG 3 months CDI/HRF increase—HRF only !0.05 Heidelberg retina flowmeter (HRF), laser Doppler flowmeter (LDF), color Doppler imaging (CDI), retinal vessel analyzer (RVA), pulsatile ocular blood flow meter (POBF), ocular pulse amplitude (OPA), retinal vessel analyzer (RVA), scanning laser ophthalmoscope (SLO) measuring arterio-venous passage time(AVP), cappillary diameter (Cap Diameter), laser speckle technique (L.speckle), Canon laser blood flowmeter (Canon), and bidirectional laser Doppler velocimetry (BDLDV). Note: only the entries that have HRF, LDF, Canon, or BDLDV in the ‘‘Technology’’ column measure flow. Other imaging technologies measure parameters that indicate possible flow changes (with assumptions). Subject type is defined as primary open-angle glaucoma (POAG), normal-tention glaucoma (NTG), ocular hypertensive (OHT), healthy subjects (normals) and animals, i.e., (rabbit). ocular hemodynamic parameters with topical CAI indicating significant ocular absorption of the drug treatment. Additionally, a recent study available only occurs after topical dosing. It is unknown, however, online a head of print63a also indicates a positive what concentration of CAI would be required in the effect of dorzolamide/timolol combination. Only human eye to be vasoactive. a single investigation reported decreased ocular As mentioned previously, carbonic anhydrase blood flow parameters during topical CAI therapy. catalyzes CO2 hydration and interconversion to - H2CO3, which freely dissociates into HCO3 and B. CARBONIC ANHYDRASE INHIBITORS AND protons. Blockade of carbonic anhydrase in local OCULAR BLOOD FLOW: POSSIBLE MECHANISMS tissues therefore may increase local tissue CO2 To impact ocular blood flow significantly, topical concentrations and/or lower tissue pH resulting in 61,73,75 POAG medications must penetrate the anterior vascular dilation and increased blood flow. surface of the eye, reach critical concentrations, and Although it is impossible in our analysis to exert a physiological effect on the vascular tissue. separate IOP reduction from the observed hemo- Supporting this requirement, evidence suggests that dynamic effects, it is clear that certain ocular significant absorption of topical CAI occurs through- circulation parameters increase during topical CAI out the ocular tissues. Surgue et al found the treatment. This may be due to direct metabolic concentration of topical dorzolamide in the rabbit effects on the blood vessels, increased ocular eye to be 24.0 mg/g in the cornea, 27.0 mg/g in the perfusion pressures (via IOP reduction) or a com- ciliary body and iris, 7.8 mg/g in the aqueous humor, bination of IOP reduction and direct vascular 4.26 mg/g in the retina after one hour, and 4.16 mg/g interactions. in the retina after 2 hours.74 Studies by Schmitz et al68 Although requiring prospective validation, it is show similar ocular penetration in the human eye, possible to infer (with many assumptions) that 40 Surv Ophthalmol 54 (1) January--February 2009 SIESKY ET AL

TABLE 5 Meta-analysis outcomes for color Doppler imaging of the retrobulbar vasculature: ophthalmic artery (OA), central retinal artery (CRA), nasal and temporal posterior ciliary arteries (N/T PCA) Color Doppler Imaging Articles n Mean change 95% CI p-value OA-PSV 12 186 À0.08 À2.28, 2.11 0.94 OA-EDV 12 186 0.02 À0.74, 0.77 0.97 OA-RI 12 186 0.0 À0.02, 0.02 0.99 CRA-PSV 11 178 0.60 0.21, 0.98 0.003 CRA-EDV 11 178 0.32 0.13, 0.51 0.001 CRA-RI 11 178 À0.02 0.03, 0.0 0.03 TPCA-PSV 6 91 0.24 À0.22, 0.71 0.30 TPCA-EDV 6 91 0.10 0.03, 0.16 0.005 TPCA-RI 6 91 À0.01 À0.02, 0.0 0.04 NPCA-PSV 6 91 0.24 À0.25, 0.73 0.34 NPCA-EDV 6 91 0.10 0.04, 0.16 0.001 NPCA-RI 6 91 À0.01 À0.02, 0.0 0.18 Scanning Laser Opthalmoscope AVP 5 74 À0.37 À0.54, À0.19 !0.001 AVP temporal supperior 3 32 À0.40 À0.52, À0.27 !0.001 In each vessel, peak systolic (PSV) and end diostolic blood floe velocity (EDV) and calculated vascular resistive index (RI) are presented. Scanning laser opthalmoscope parameters include: arterial venous passage time (AVP) in both the general use of the term and specific use to the superior temporal quadrant. Listed are the estimated mean changes and 95% confidence intervals in blood flow parameters after treatment with topical CAI. The mean change is the average change in the blood flow measures after treatemant with topical CAI adjusted (weighted) for each study‘s varience and sample size by using the inverse of the variance as a weight. The maen change is expressed as centimeters per second (cm/s) for PSV and EDV, RI is a calculated ratio with no units, and AVP time is measured in seconds. direct vascular stimulation may occur by looking at effects on ocular blood flow, however, remain the studies where similar IOP reductions were unproven and require validation. found with CAI and a different treatment, but only CAI caused an increase in ocular blood flow C. CARBONIC ANHYDRASE INHIBITORS parameters. Although many issues exist with such INCREASE RETROBULBAR BLOOD FLOW a comparison, such data has been found in four VELOCITIES AS MEASURED BY COLOR DOPPLER of the articles examined in this investiga- IMAGING tion.32,43,55,71 Siesky et al found the fixed combi- The meta-analysis of CDI studies reveals increased nation of dorzolamide/timolol and latanoprost blood flow velocities in the central retinal artery and plus timolol produced statistically similar IOP in the nasal and temporal posterior ciliary arteries. reductions while only dorzolamide/timolol in- Calculated vascular resistance is also reduced in the 71 creased retrobulbar blood flow velocities. Janu- central retinal and temporal posterior ciliary arteries leviciene et al also found statistically similar IOP following topical CAI therapy. No CAI vascular reductions during treatment with the fixed com- effects were detected in the ophthalmic artery. As bination of dorzolamide/timolol and latanoprost mentioned previously, it is important to note that while only the fixed combination of dorzolamide/ resistance is only truly reduced if vascular dilation timolol increased pulse volume.43 Harris et al occurs within a specified blood vessel. A decrease in found dorzolamide and betaxolol had similar IOP the CDI calculated vascular resistance arises from reduction with only dorzolamide increasing retinal a decrease in the pulsatility of the blood flow velocity waveforms. Therefore this decrease in arteriovenous passage time (blood flow velocity) as calculated vascular resistance may indicate changes measured by the SLO.32 Finally, Martinez and either proximal or distal to the measurement site. Sanchez investigated dorzolamide/timolol fixed Acknowledging the CDI technology limitations, combination and latanoprost 0.005% finding no these strict statistical results provide evidence that statistically significant differences in the IOP- topically applied CAI may increase retinal and lowering effect of either treatment while only the retrobulbar blood flow. The posterior ciliary arteries fixed combination dorzolamide/timolol increased that experienced increases in blood flow velocities retrobulbar blood flow velocities.55 All current supply the laminar and pre-laminar regions of the theories regarding mechanisms of direct CAI optic nerve head. TOPICAL CARBONIC ANHYDRASE INHIBITORS 41

CRA-PSV

Kaup (45) Harris (31) Harris (33) Harris (32) Harris (37) Zeitz (81) Galassi (26) Avunduk (3) Bergstrand (6) Martinez (53) Harris (36) Overall

-4 -2 0 2 4 Weighted mean difference

CRA-EDV

Kaup (45) Harris (31) Harris (33) Harris (32) Harris (37) Zeitz (81) Galassi (26) Avunduk (3) Bergstrand (6) Martinez (53) Harris (36) Overall

-2 -1 0 132 Weighted mean difference

CRA-RI

Kaup (45) Harris (31) Harris (33) Harris (32) Harris (37) Zeitz (81) Galassi (26) Avunduk (3) Bergstrand (6) Martinez (53) Harris (36) Overall -0.3 -0.2 -0.1 0.0 0.1 Weighted mean difference

Fig. 2. A forest plot of the individual study effects and overall effect of the change in central retinal artery (CRA) peak systolic velocity (PSV), end diastolic velocity (EDV), and resistive index (RI) after topical CAI treatment. Boxes show the relative weight of each study and the error bars show a 95% conﬁdence interval. The diamond shows the estimate of the overall mean change with its width showing a 95% CI. The weighted mean difference is the average change in the blood ﬂow measures after treatment with topical CAI adjusted (weighted) for each study’s variance and sample size by using the inverse of the variance as a weight. The weighted mean difference is expressed as centimeters per second (cm/sec) for PSV and EDV, RI is a calculated ratio with no units.

D. CARBONIC ANHYDRASE INHIBITORS studies in conjunction with the increased central INCREASE RETINAL BLOOD FLOW VELOCITIES AS retinal artery blood flow velocities via CDI assess- MEASURED BY COLOR DOPPLER IMAGING AND ment suggest that topical CAI may increase blood SCANNING LASER OPHTHALMOSCOPY flow to retinal tissue and ganglion cells. Our meta-analysis of studies utilizing SLO suggests that topical CAI also decreases AVP time in the E. POTENTIAL EFFECTS OF CARBONIC primary retinal arteries. Reductions in AVP time ANHYDRASE INHIBITORS ON THE CHOROID AND occur in both the combined assessment of the OPTIC NERVE HEAD primary retinal arteries and specifically in the In this study, increased central retinal artery superior temporal quadrant of the retina. A re- blood flow velocities were found to occur with use duction in AVP time suggests that circulation within of topical CAI. Increased blood flow velocities in the the retina may be enhanced allowing for increased posterior ciliary arteries may improve blood flow retinal perfusion. in the optic nerve head and possibly even the If we assume constant or increased blood vessel high-flow, low-resistance choroidal circulation. We diameters were maintained during topical CAI were not able to directly evaluate the choroidal treatment, the results obtained from the SLO circulation due to lack of uniform data available for 42 Surv Ophthalmol 54 (1) January--February 2009 SIESKY ET AL

TPCA-EDV Kaup (45) Harris (31) Harris (33) Harris (37) Bergstrand (6) Harris (36) Overall

-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 Weighted mean difference

TPCA-RI

Kaup (45) Harris (31) Harris (33) Harris (37) Bergstrand (6) Harris (36) Overall

-0.10 -0.05 0.00 0.05 0.10 Weighted mean difference

NPCA-EDV

Kaup (45) Harris (31) Harris (33) Harris (37) Bergstrand (6) Harris (36) Overall

-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 Weighted mean difference

Fig. 3. A forest plot of the individual study effects and overall effect of the change in temporal and nasal short posterior ciliary arteries (TPCA, NPCA) end diastolic velocities (EDV) and resistive index (RI) after treatment with topical CAI. Boxes show the relative weight of each study and the error bars show a 95% confidence interval. The diamond shows the estimate of the overall mean change with its width showing a 95% CI. The weighted mean difference is the average change in the blood flow measures after treatment with topical CAI adjusted (weighted) for each study’s variance and sample size by using the inverse of the variance as a weight. The weighted mean difference is expressed as centimeters per second (cm/sec) for PSV and EDV, RI is a calculated ratio with no units. a statistical meta-analysis. This, in turn, may be due 100% (10/10) of dorzolamide hydrochloride-timo- to limited availability of techniques to study choroi- lol maleate investigations have found increases in dal and optic nerve head circulations. On the other ocular circulation parameters. Although not entirely hand, the meta-analysis approach provides im- surprising, considering most studies investigating proved statistical power and overcomes many of dorzolamide (72%) have found increased parame- the statistical limitations inherent in any single ters, dorzolamide hydrochloride-timolol maleate study. appears to retain dorzolamide’s vasoactive profile when combined with timolol. It is possible that the additional IOP reduction of this concomitant F. SUMMARY ANALYSES OF BRINZOLAMIDE, therapy has a dual action of a direct blood flow DORZOLAMIDE, AND DORZOLAMIDE effect and indirect perfusion pressure increases HYDROCHLORIDE-TIMOLOL MALEATE resulting from the IOP reduction. More research is In comparison with monotherapy using dorzola- required with both of these topical CAI therapies mide, the amount of available literature on brinzo- before definitive conclusion can be made. lamide and dorzolamide hydrochloride-timolol maleate combination ocular blood flow effects is limited. Because only four studies have investigated G. LIMITATIONS, CONCLUSIONS, AND brinzolamide in POAG patients more research is SUGGESTED FUTURE WORK required for definitive conclusions to be made The lack of a gold standard for measuring ocular regarding its hemodynamic effects. Also of interest, blood flow in the eye’s various vascular beds is TOPICAL CARBONIC ANHYDRASE INHIBITORS 43

AVP is highly evident. As no current gold standard exists for measuring total ocular blood ﬂow, we strongly Kaup (45) suggest future research should utilize a comprehen- sive circulation assessment using multiple imaging Harris (31) technolgies investigating multiple vascular beds. Topical CAI, and other possible methods of in- Harris (33) creasing ocular circulation, should be further investigated in large, long-term prospective trials to

Arend (2) evaluate any effects on visual function over time. Preliminary data from one recent study suggest that dorzolamide added to timolol may be effective in Bergstrand (6) preventing progression of visual field damage in addition to increasing ocular blood flow and reducing IOP.55a Overall In conclusion, this meta-analysis implies increased blood flow velocities and reduced vascular resistance in the central retinal and short posterior ciliary -1.5 -1.0 -0.5 0.0 0.5 arteries but not in the ophthalmic artery during Weighted mean difference carbonic anhydrase inhibition. Topical CAI also Fig. 4. A forest plot of the individual study effects and increases blood flow velocities within the primary overall effect of the change in arterio-venous passage time retinal artery branches. Other vascular tissues may (AVP) after treatment with topical CAI. Boxes show the experience increased circulation during topical CAI relative weight of each study and the error bars show therapy, but this remains unproven. a 95% confidence interval. The diamond shows the estimate of the overall mean change with its width showing a 95% CI. The weighted mean difference is the References average change in the blood flow measures after treatment with topical CAI adjusted (weighted) for each 1. Arend O, Harris A, Martin BJ, et al. Scanning laser study’s variance and sample size by using the inverse of the ophthalmoscopy-based evaluation of epipapillary velocities: variance as a weight. The weighted mean difference is method and physiologic variability. Surv Ophthalmol. 1999; expressed as time in seconds (sec). 44(Suppl 1):S3--9 2. Arend O, Harris A, Wolter P, et al. Evaluation of retinal haemodynamics and retinal function after application of a shortcoming the scientific community needs to dorzolamide, timolol and latanoprost in newly diagnosed resolve. Current ocular hemodynamic imaging open-angle glaucoma patients. Acta Ophthalmol Scand. technologies measure hemodynamic parameters 2003;81:474--9 3. Avunduk AM, Sari A, Akyol N, et al. The one-month effects which may indicate increased circulation, but only of topical betaxolol, dorzolamide and apraclonidine on with certain assumptions built into the assessment. ocular blood flow velocities in patients with newly diagnosed Further, no current technology is capable of assess- primary open-angle glaucoma. Ophthalmologica. 2001;215: 361--5 ing total ocular circulation. This leaves open the 4. Barnes GE, Li B, Dean T, et al. Increased optic nerve head possibility that one ocular vascular bed experiences blood flow after 1 week of twice daily topical brinzolamide an increase in blood flow while another tissue may treatment in Dutch-belted rabbits. Surv Ophthalmol. 2000; 44(Suppl 2):S131--40 experience a simultaneous reduction in flow. Every 5. Baxter GM, Williamson TH. Color Doppler imaging of the study reviewed in this investigation (both meta- eye: normal ranges, reproducibility, and observer variation. analysis and in review format) presents hemody- J Ultrasound Med. 1995;14:91--6 6. Bergstrand IC, Heijl A, Harris A. Dorzolamide and ocular namic parameters, each with their own limitations, blood flow in previously untreated glaucoma patients: pros and cons of use and tissue specificity. Imaging a controlled double-masked study. Acta Ophthalmol Scand. technologies and their various limitations are 2002;80:176--82 35 7. Bernd AS, Pillunat LE, Bo¨hm AG, et al. [Ocular hemody- covered elsewhere in great detail. namics and visual field in glaucoma treated with dorzola- It is also important to note that this review and mide]. Ophthalmologe. 2001;98:451--5 meta-analysis did not investigate how ocular blood 8. Bill A. Effects of acetazolamide and carotid occlusion on the ocular blood flow in unanesthetized rabbits. Invest Oph- flow and visual function are related. Only large, long- thalmol. 1974;13:954--8 term prospective clinical trials can show if increasing 9. Bonomi L, Marchini G, Marraffa M, et al. Vascular risk the ocular circulation is of benefit to glaucoma or factors for primary open angle glaucoma: the Egna- Neumarkt Study. Ophthalmology. 2000;107:1287--93 other patients. Currently, data is only suggestive 10. Breil P, Krummenauer F, Schmitz S, et al. [The relationship that ocular pathologies, such as glaucoma, may between retrobulbar blood flow velocity and glaucoma involve ocular ischemia. The need for a prospective, damage. An intraindividual comparison]. Ophthalmologe. 2002;99:613--6 longitudinal, and statistically justified study evaluat- 11. Brogliatti B, Rolle T, Vizzeri GM, et al. Comparison of the ing ocular blood flow and glaucomatous progression efficacy on intraocular pressure and retinal blood flow of 44 Surv Ophthalmol 54 (1) January--February 2009 SIESKY ET AL

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Outline C. Carbonic anhydrase inhibitors and blood flow II. Methods I. Introduction A. Literature search and eligibility criteria A. Primary open-angle glaucoma risk factors B. Article selection and data extraction B. Topical POAG therapies and ocular blood flow C. Outcome definition 46 Surv Ophthalmol 54 (1) January--February 2009 SIESKY ET AL

D. Imaging technologies included in the meta- C. Carbonic anhydrase inhibitors increase retro- analysis bulbar blood flow velocities as measured by E. Statistics color Doppler imaging D. Carbonic anhydrase inhibitors increase reti- III. Results nal blood flow velocities as measured by color A. Summary analysis of articles not included in Doppler imaging and scanning laser statistical meta-analysis ophthalmoscopy B. Topical carbonic anhydrase inhibitors E. Potential effects of carbonic anhydrase in- C. Retrobulbar blood flow velocities: meta-analysis hibitors on the choroid and optic nerve head D. Retinal blood flow velocities: meta-analysis F. Summary analyses of brinzolamide, dorzolamide, and dorzolamide hydrochloride-timolol IV. Discussion maleate A. Topical carbonic anhydrase inhibition possi- G. Limitations, conclusions, and suggested bly increases ocular blood flow future work B. Carbonic anhydrase inhibitors and ocular V. Method of Literature Search blood flow: possible mechanisms