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A Double-Masked Randomized Crossover Study Comparing the Efect o !atanoprost"#imolol and $rimonidine"#imolol %i&ed Combination on 'ntraocular(ressure and )cular $lood %lo* in (atients *ith (rimary )pen-Angle +laucoma or)cular ,ypertension

Abstract

(urpose )cular blood .o* dysregulation has been implicated in thepathogenesis o glaucoma/ 0hereas the efect o single antiglaucomasubstances on ocular blood .o* has been addressed in various e&periments1evidence or 2&ed combinations is sparse/ 'n the present study1 *e set out tocompare the efects o latanoprost 3/3345"timolol 3/45 6!#7 2&ed combinationand brimonidine 3/85"timolol 3/45 6$#7 2&ed combination on intraocularpressure 6')(7 and ocular blood .o*/

Methods 'n the present study1 *hich ollo*ed a randomized1 double-masked 8-*ay crossover design1 9: patients *ith primary open-angle glaucoma and 8patients *ith ocular hypertension *ere included/ #he patients under*ent a :-

*eek treatment *ith !# and a :-*eek treatment *ith $# ater a *ashout orprevious antiglaucoma medication/ )ptic nerve head blood .o* 6);,$%7 *asmeasured using laser Doppler .o*metry< retrobulbar .o* velocities *eremeasured using color Doppler imaging in the ophthalmic artery1 the centralretinal artery1 and the posterior ciliary arteries/ ')( *as measured at = AM1 98(M1 and > (M/

Results #he mean baseline ')( *as 84/? @ 8/=mm,g/ $oth drugs *ere euallyefective in reducing ')( 6!# - ?4/35 @ 93/35< $# - ??/:5 @ =/=51 ( B 3/>:?bet*een groups7/ 'n addition1 no diference in ocular perusion pressure *asobserved bet*een the 8 treatment groups 6( B 3/91 bet*een groups7/ ;either !#nor $# altered );,$% 6( B 3/>1 baseline vs/ treatment7 and no efect on .o*velocities in the retrobulbar vessels *as seen *ith either o the 8 treatments/

Conclusions 'n the present study1 a :-*eek treatment *ith !# or $# *as euallyefective in reducing ')(/ 'n addition1 none o the administered drugs induced asigni2cant efect on ocular blood .o* parameters/

'ntroduction

'n glaucoma1 loss o retinal ganglion cells leading to subseuent visual 2elddeterioration is the 2nal end point in the pathogenesis/9 'ncreased intraocularpressure 6')(7 is the most important risk actor or the development andprogression o the disease/8 ,o*ever1 ')( is not necessarily an adeuate

measure o clinical severity some eyes *ith high ')( do not develop glaucoma1*hile some patients sufering rom glaucoma have normal ')(/?1> ,ence1 actorsother than ')( are likely involved in the pathogenesis o glaucoma/

A variety o results indicate that vascular actors are involved in thepathogenesis o glaucomain particular1 ischemia o the optic nerve head/4Along this line o thought1 several investigators have ocused on the vasculardeects in glaucoma pathology/ sing color Doppler imaging 6CD'71 evidence hasbeen provided that retrobulbar blood .o* is reduced in patients *ith glaucomaand may be predictive or the progression o the disease/:@= 'n addition1 studiesusing laser Doppler .o*metry 6!D%7 have sho*n that optic nerve head blood .o*6);,$%7 is reduced in patients *ith primary open-angle glaucoma 6()A+7/Moreover1 systemic hypotension and reduced ocular perusion pressure 6)((7have been identi2ed as risk actors or the disease/93@98 As such1 there is

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considerable interest in the potential vasomotor efects o topical antiglaucomadrugs/

Although several studies have evaluated the efect o single antiglaucomasubstances on ocular blood .o*19? data o 2&ed combination drugs are stillsparse/ #his is o importance because target ')( levels are not al*ays achieved*ith the use o one agent and many patients reuire combination therapy/ %ore&ample1 in the )cular ,ypertension #reatment Study1 >35 o treated subFectsreuired more than one medication to achieve the target pressure/

Current combination therapies combine a b-blocking agent *ith either a carbonicanhydrase inhibitor1 a prostaglandin analogue1 or a selective a-agonist/94 Amongthose1 the concomitant administration o latanoprost and timolol is *idely used1producing an additive ')( reducing efect compared to the individualcomponents alone/9:19G #his has been e&plained by diferent sites o action o the substances1 given that latanoprost lo*ers ')( levels by increasinguveoscleral out.o* *ith little or no efect on aueous humor ormation19=*hereas b-blockers reduce aueous humor production/9

As an alternative1 a 2&ed combination o timolol and brimonidine has beenintroduced also e&erting better ')( lo*ering efects than either o the 8 drugsalone/83 As a selective a8 agonist1 brimonidine e&erts its ')( lo*ering efect byreducing aueous humor production and increasing uveoscleral out.o*/8

 #here is some evidence that brimonidine and clonidine are vasoconstrictors1*hich may also be e&pected rom the pharmacological pro2le o the drugs/8818?Although no efect o topical brimonidine tartrate 3/85 on retinal capillary blood.o* *as reported using conocal scanning !D%8> or on retrobulbar blood .o*84ater a 8-*eek treatment1 it has1 ho*ever1 been sho*n that a singleadministration o brimonidine reduces ocular blood .o* parameters and canalter blood .o* autoregulation during isometric e&ercise in healthy humans/ 8:'n this previous study1 a higher dosage reuency than usually used in clinicalpractice *as applied/ #he reason or the con.icting results bet*een short- andlong-time treatment is unclear and deserves urther investigation/

 #he main purpose o this study *as to evaluate *hether brimonidine"timolol maysigni2cantly reduce blood .o* at the posterior pole o the eye *hen usedclinically/ A study against dorzolamide"timolol may *ell have given a statisticalsigni2cance bet*een the treatment arms/ ,o*ever1 *hat *ould *e have learnedrom this in terms o the efects o brimonidine"timololH 0e thereore decided touse latanoprost" timolol as a comparator1 *hich1 based on the e&isting literature1

has only minor efects on ocular blood .o*/ Conseuently1 the current study *asdesigned to identiy *hether the 2&ed combination latanoprost 3/3345"timolol3/45 6!#7 or the 2&ed combination brimonidine 3/85" timolol 3/45 6$#7 alterocular blood .o* parameters/ %or this purpose1 ocular hemodynamics and ')(*ere measured in a 8-*ay crossover design in a group o patients *ith ()A+ andsubFects *ith ocular hypertension 6),#7/

Methods

SubFects

 #he study protocol *as approved by the Ethics Committee o the Medicalniversity o Iienna and ollo*ed the guidelines o +ood Clinical (ractice and theDeclaration o ,elsinki/ Si&teen patients *ith ()A+ and 8 subFects *ith ),# *ereincluded/ All subFects signed a *ritten inormed consent and passed an

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ophthalmologic e&amination/ SubFects *ith ocular disease other than glaucomaand ),# *ere e&cluded rom the study/ 'n addition1 patients *ith severesystemic diseases such as uncontrolled systemic hypertension1 diabetes mellitus1or other systemic vascular disease *ere not included in the study/

'nclusion and e&clusion criteria

(atients *ith ()A+/ 'nclusion criteria *ere ()A+ de2ned as pathological opticdisc appearance and characteristic visual 2eld loss1 ametropia o less than ?diopters1 and anisometropia o less than 9 diopter/ An abnormal visual 2eld *asde2ned as a glaucoma hemi2eld test outside normal limits and"or a correctedpattern standard deviation 6SD7 *ith ( J 45/8G Any o the ollo*ing e&cluded aglaucoma patient rom participation in the trial e&oliation glaucoma1pigmentary glaucoma1 history o acute angle closure1 mean deviation o visual2eld testing 6,umphrey ?3-8 program7 o - 93 d$ or *orse1 intraocular surgery*ithin the last : months1 ocular in.ammation or inection *ithin the last ?months/

(atients *ith ),#/ ),# *as de2ned as an untreated ')( o 89mm,g or more onleast at ? measurements *ithout any glaucomatous changes in the visual 2eld orthe optic nerve head/

Design and drugs

!# 2&ed combination 6KalacomL< (2zer A+7 9 drop per day or $# 2&edcombination 6CombiganL< Allergan7 9 drop t*ice a day *as administered or :*eeks in a balanced1 double-masked1 8-*ay crossover design/ #o maintain thedouble-masked nature o the study *ith the diferent dose regimen or !# and $#1subFects received 8 sets o bottles labeled morning and evening/ %or patientsassigned to $# both1 the morning and the evening bottles contained this

treatment combination/ %or patients assigned to !#1 only the morning bottlecontained the drug combination1 *hereas the evening bottle *as 2lled *ithphysiologic saline solution/

E&perimental paradigm

%or eligible patients1 current ocular hypotensive treatment *as suspended beorethe baseline visit/ #he *ashout periods lasted > *eeks or b-adrenergic receptorantagonists and prostaglandins1 8 *eeks or adrenergic agonists1 and 4 days orcholinergic agonists and carbonic anhydrase inhibitors/ #hree study visits *erescheduled to assess ocular perusion parameters and ')( At the baseline visit1ocular hemodynamic parameters *ere assessed by measurement o optic disc

blood .o* *ith a laser Doppler .o*meter and by a measurement o retrobulbar.o* velocities using CD' in both groups/ 'n addition1 ')( *as measured intriplicate in each eye at =33 AM 6beore scheduled dosing71 9833 noon1 and>33 (M/ ')( *as calculated as the mean o these ? measurements/

 #he second visit *as scheduled ater : *eeks and the 2nal 6third7 visit at *eek98/ All ? visits *ere perormed as described or the baseline visit/ )cularhemodynamic parameters *ere assessed as described or the baseline visit/Ater the second visit 6*eek :71 all patients crossed over to the alternativetreatment/ A timetable is given in %ig/ 9/

!aser Doppler .o*metry

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);,$% *as measured by !D% 6Model >333< )culi&7/ #he !D% techniue has beendescribed in detail else*here/8= #he vascularized tissue is illuminated bycoherent laser light1 *hile the laser beam is directed a*ay rom visible vessels/Scattering by moving red blood cells 6R$Cs7 leads to a reuency shit in thescattered light/ 'n contrast1 static scatterers in tissue do not change light

reuency1 but lead to randomization o light directions impinging on R$Cs1ofering a reerence signal/ #his light difusion in vascularized tissue leads to abroadening o the spectrum o scattered light/ %rom this spectrum1 the mean R$Cvelocity and the R$C volume *ithin the scattering volume o the illuminatedtissue can be calculated in relative units/ #he product o velocity and volume isthe .o* and is proportional to R$C .u&/8 'n the present study1 !D% *asperormed in the temporal neuroretinal rim bet*een the superior and ineriorbranches o the retinal vessels1 avoiding visible vessels to assess );,$%

Color Doppler imaging

Retrobulbar blood .o* *as measured using a highresolution ultrasound system6+E Iingmed Iivid G scanner< +E Medical Systems7/ #his noninvasive method isbased on the backscattering o ultrasound by the ormed elements in the bloodvessels/ Measurement o the reuency shits due to the Doppler efect yieldsinormation about blood velocity/ (eak systolic .o* velocity 6(SI7 and enddiastolic .o* velocity 6EDI7 o the arteries *ere assessed using a G/4-M,z probe*ith a pulsed Doppler device in the ophthalmic artery 6)A71 the central retinalartery 6CRA71 and the posterior ciliary arteries 6(CA7/?3 'n addition1 the resistanceinde& 6R'7 *as calculated as 6(SI - EDI7"(SI/

$lood pressure measurement

Systolic1 diastolic1 and mean blood pressures 6MA(7 *ere measured on the upperarm by an automated oscillometric device 6,(-CMS patient monitor< ,e*lett(ackard7/ #he pulse rate *as automatically recorded rom a 2ngerpulseo&ymetric device/

'ntraocular pressure

A slit-lamp mounted +oldmann applanation tonometer *as used to measure ')(/$eore each measurement1 9 drop o 3/>5 beno&inate hydrochloride combined*ith 3/845 sodium .uorescein *as used or local anesthesia o the cornea/ All')( measurements *ere perormed by the same person/

Calculation o )((

)(( in the sitting position *as calculated as 8"? MA(@ ')(/

Statistics

Data are presented as mean @ SD/ #reatment efects as *ell as group interactions*ere tested using a repeated measures A;)IA model/ A post hoc analysis *asdone using planned comparisons/ A ( J 3/34 *as considered as the level o signi2cance/ %or all statistical analyses1 absolute data *ere used/ Calculations*ere perormed using the StatisticaL sot*are package 6Statsot7/

Reproducibility data o the methods used in the current study have beenpublished previously/?91?8 #he sample size calculation or the current study is

based on the least reproducible o the ocular blood .o* techniues1 namely !D%/

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'n this crossover design1 a minimum diference o 945 is detectable in 9=subFects using an a error o 45 and a po*er o =35/

Results

Systemic hemodynamics and ')(

Eighteen patients *ere randomized to the 8 diferent treatment groups1 resultingin a total number o patients per group/ $aseline characteristics o both groupsare presented in #able 9/ ;o diference *as observed bet*een the baselineparameter o the 8 groups/ #he mean baseline ')( *as 84/? @ 8/=mm,g/ Ase&pected1 both $# and !# induced a pronounced decrease in ')( 6( J 3/391A;)IA baseline vs/ treatment7/ $oth drugs *ere eually efective in reducing ')(6!# - ?4/35 @ 93/35< $# - ??/:5 @ =/=51 ( B 3/>:? A;)IA bet*een groups1 %ig/87/ 'n both groups1 )(( signi2cantly increased ater treatment 6!# 84/5 @83/:51 $# 8:/>5 @ 84/851 ( J 3/391 A;)IA baseline vs/ treatment71 but nodiference in )(( *as observed bet*een the 8 treatment groups 6( B 3/91 A;)IAbet*een groups7/

)cular hemodynamics

As sho*n in %ig/ 81 );,$% sho*ed no change ater drug administration 6( B 3/>1A;)IA baseline vs/ treatment7/ Similarly1 no efect o the treatment *asobserved in (SI)A 6( B 3/8871 the EDI)A 6( B 3/G9>71 or in the R')A 6( B 3/=?81A;)IA baseline vs/ treatment1 #able 87/ 'n addition1 treatment had no in.uenceon (CA hemodynamics 6(SI(CA ( B 3/9G=1 EDI(CA ( B 3/:?1 R'(CA ( B 3/?4>all ( values A;)IA baseline vs/ treatment7/ Also no treatment efect *asobserved on CRA hemodynamic values 6(SICRA ( B 3/1 EDICRA ( B 3/G9>1R'CRA ( B 3/G9 all ( values A;)IA baseline vs/ treatment7/

Discussion

Combination therapy ofers several maFor advantages or patients not reachingtheir target ')( *ith single drug treatment/ #hese advantages include enhancedpatient compliance1 a reduction o the number o drops instilled during a day1and a reduced e&posure to preservatives/??1?> #he current data con2rm avariety o previous studies indicating that both 2&ed combinations $# and !#induce a pronounced decrease in ')(/ 'n addition1 the data o the current studyindicate that neither $# nor !# change ocular hemodynamics ater a :-*eektreatment period to a relevant degree/

Modern combination therapy usually combines a badrenoceptor antagonist *ith

another class o ocular hypotensives such as carbonic anhydrase inhibitors1prostaglandins1 or an a-receptor agonist/ %or most o the mentionedmonosubstances1 the efect on ocular blood .o* has been studied/ As a detaileddiscussion o all monosubstances is beyond the scope o this article1 readers arereerred to e&cellent revie* articles covering this issue/9?1?4 #he blood .o*efect o timolol has been the ocus o a variety o e&periments1 but data are notconsistent/ 0hereas most o the studies report no change in ocularhemodynamics ater short and long term treatment *ith timolol1?:1?G somee&periments indicate that timolol may lead to an increase in ocularhemodynamic parameters/?=

 #he same holds true or the treatment *ith prostaglandins/ Animal and human

studies have provided little evidence or an efect o topical latanoprost on ocular

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hemodynamics/?=@>4 #here is1 ho*ever1 evidence that latanoprost increasespulsatile choroidal blood .o* in patients *ith glaucoma/>:@>=

 #he data o the current study indicate that neither the 2&ed combination !# northe 2&ed combination $# in.uences ocular hemodynamic variables ater a :-*eek treatment/ #his is in keeping *ith the maFority o the abovementionedstudies1 *here no consistent efect o any o the substances used in the currentstudy on ocular blood .o* has been reported/ 'n addition1 it has to be mentionedthat the current study *as designed to detect changes o 945 or more in ocularblood .o*/ As such1 *e cannot ans*er the uestion *hether the administereddrugs e&ert blood .o* efects smaller than this/ 0hich degree o blood .o*change is relevant or the progression o glaucomatous damage is1 ho*ever1unkno*n/ !ongitudinal studies are necessary to clariy *hether changes o 945or less are o clinical relevance to patients *ith glaucoma/

Due to the pronounced decrease in ')(1 *e observed an increase in )(( in bothtreatments groups/ Since )(( is the driving orce o blood .o* in the human eye1one may *onder *hy it did not translate into changes in blood .o* in thepresent study/ 'n healthy subFects1 blood .o* in the human eye sho*sautoregulation over a *ide range o )((s/ 'n glaucoma patients1 there is1ho*ever1 evidence o vascular dysregulation41> associated *ith abnormalautoregulation/43 Along this line o thought1 changes in ')( may be associated*ith changes in ocular blood .o* in glaucoma patients due to reducedautoregulatory capacity/>149 'nterestingly1 this *as not seen in our studypopulation in *hich none o the administered combinations altered ocularperusion/ 0hether our results indicate that the increase in )(( o N845 *as stillin the autoregulatory range in the group o our patients is1 ho*ever1 unclearbecause a clinically applicable test to assess autoregulation is currently notavailable/

)nly e* data are available rom head to head studies comparing the efect o !#2&ed combination and $# 2&ed combination on ')(/ #*o studies have compared!# 2&ed combination and brimonidine"timolol concomitant 8 times daily/4814? 'ncontrast to the data o the current study1 these studies report a signi2cantlybetter ')( reduction in patients treated *ith the 2&ed combination !#/ 't has1ho*ever1 been mentioned that these studies considerably difer in sample size1study population1 and study design/

Some limitations have to be considered *hen interpreting the data o the currentstudy/ %irst1 both treatment periods o the crossover study *ere limited to :*eeks/ #his is shorter than in the above-mentioned studies comparing the ocular

hypotensive efect o !# and $#/4814? 't is also not entirely clear *hether the*ashout period or prior antiglaucoma medication *as suOcient to omit potentialvasomotor efects o the previous study medication1 because no data on thistopic are available/ !onger *ashout periods may1 ho*ever1 be hampered byethical considerations/ #his also holds true or the absence o a *ashout beorepatients crossed over to the alternative treatment/ +iven that none o thetreatments induced any changes in ocular hemodynamic parameters1 thislimitation is not considered severe in the present study/ 'n addition1 both patients*ith ()A+ and subFects *ith ),# *ere included in the study/ +iven that1 rom aclinical point o vie*1 the therapy or the 8 groups does not difer1 it seemsreasonable to include ocular hypertensives as *ell as ()A+ patients/ 'n addition1there is no evidence that potential vasomotor efects o antiglaucoma drugs may

difer bet*een patients *ith ()A+ and subFects *ith ),#/

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A urther limitation is related to the techniues used or blood .o*measurement/ nortunately1 there is currently no gold standard or blood .o*measurement in humans available/ #hus1 all techniues available are onlycapable o measuring certain aspects o ocular blood .o* and sufer romdiferent limitations/ $lood .o* measurement at the optic nerve head blood by

the means o !D% provides only a relative measure o perusion1 *hich may alsodepend on the scattering o the tissue and thereore on the anatomicalproperties o the optic never head/ 'n addition1 only e* studies have related);, blood .o* *ith glaucoma although one study indicates that lo*er bloodvolume values as assessed *ith !D% are associated to glaucoma progression/ 4>,o*ever1 given that in a 8-*ay crossover1 every subFect acts as its o*n control1this does not interere *ith our study results/ %urthermore1 the CD' techniue isonly capable o measuring blood .o* velocities1 *hich might not necessarilyre.ect volumetric blood .o* o the retrobulbar vessels/

'n conclusion1 *e report that both !# and $# 2&ed combination lead to apronounced decrease in ')( *ithout any observable diference in their ')(

lo*ering potential/ ;one o the 8 treatment regimen afected );, blood .o* orretrobulbar .o* velocities/

Ackno*ledgment

%inancial support by an unrestricted research grant o Allergan is grateullyackno*ledged/

Author Disclosure Statement

;o competing 2nancial interests e&ist/