RESEARCH ARTICLE Open Access

Long-term effect of latanoprosttimolol fixedcombination in patients with glaucoma or ocularhypertension A prospective observationalnoninterventional studyOliver Schwenn1 Barbara Heckmann2 Claudia Guzy3 Paul J Miller4

Abstract

Background Prospective observational studies that enroll large numbers of patients with few exclusion criteriamay better reflect actual ongoing clinical experience than randomized clinical trials Our purpose was to obtainefficacy and safety information from a cohort of subjects exposed to latanoprosttimolol fixed combination (FC) forge18 months using a prospective observational design

Methods In all 577 office-based ophthalmologists in Germany switched 2339 patients with glaucoma or ocularhypertension to latanoprosttimolol FC for medical reasons Follow-up visits were scheduled for every 6 monthsover 24 months physicians followed usual care routines Intraocular pressure (IOP) visual field status optic nervehead findings and adverse events were recorded Efficacy parameters were evaluated for the per protocol (PP)population the safety population included subjects receiving ge1 drop of FC Physicians rated efficacy tolerabilityand subject compliance at month 24

Results Of the 2339 subjects switched to latanoprosttimolol FC (safety population) the primary reasons for switchingwere inadequate IOP reduction (782) and desire to simplify treatment with once-daily dosing (294 multiple reasonspossible) In all 1317 (563) subjects completed the study and 1028 (440) were included in the PP population Mostdiscontinuations were due to loss to follow-up Change in mean IOP from baseline to month 6 was -40 plusmn 431 mmHga reduction that was maintained throughout (P lt 005 for change at all time points) By investigator assessments opticdisc parameters and visual field were stable over 24 months and there was no relationship between IOP reduction over24 months and development of a visual field defect More than 90 of physicians rated latanoprosttimolol FC as ldquoverygoodrdquo or ldquogoodrdquo for efficacy (PP population) tolerability and compliance The FC was safe and well tolerated Nochange in iris color was reported by most subjects (831) at month 24

Conclusions Over 24 months latanoprosttimolol FC effectively lowers IOP levels and is well tolerated in patients withglaucoma or ocular hypertension who change from their previous ocular hypotensive therapy for medical reasonsInvestigator assessments found optic disc parameters and visual field to be stable throughout 24 months of follow-up

BackgroundIn patients with glaucoma or ocular hypertension whodo not reach their target intraocular pressure (IOP)level with ocular hypotensive monotherapy the Eur-opean Glaucoma Society [1] recommends adding a sec-ond medication when the original agent showed some

effectiveness In fact many patients with these condi-tions must use more than one ocular hypotensive ther-apy to reduce IOPs to levels that may be expected toslow or stop disease progression [2] In these individualsa fixed-combination (FC) formulation may be preferredto multidrug regimens in order to maximize patientcompliance and quality of life [1]In Europe the FC of the prostaglandin analogue lata-

noprost and the beta-blocker timolol is approved for the Correspondence oschwennburgerhospital-ffmde1Buumlrgerhospital Frankfurt am Main Augenklinik Frankfurt am Main GermanyFull list of author information is available at the end of the article

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

copy 2010 Schwenn et al licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (httpcreativecommonsorglicensesby20) which permits unrestricted use distribution andreproduction in any medium provided the original work is properly cited

treatment of open-angle glaucoma or ocular hyperten-sion in patients insufficiently controlled on monother-apy Latanoprost the first prostaglandin F2a analogue tobe commercially available in Europe and the UnitedStates acts primarily by increasing outflow [34] whilethe beta-adrenergic receptor antagonist timolol lowersIOP by reducing aqueous humor production [56] Thecombination of the two agents has been shown to havean additive IOP-lowering effect [7-10] and several pro-spective randomized clinical trials have demonstratedthat latanoprosttimolol FC is effective and well toler-ated [11-16]Although such prospective randomized trials are the

gold standard for evaluating the safety and efficacy ofnew medical treatments their strict designs may notreflect community practice patterns thereby limiting thegeneralizability of findings Prospective observationalstudies that include large numbers of patients with fewexclusion criteria may better reflect actual ongoing clini-cal experience The present prospective noninterven-tional observational study was designed to obtainefficacy and tolerability information about a cohort ofsubjects exposed to the latanoprosttimolol FC for atleast 18 months

MethodsThe study was conducted in general ophthalmologypractices in Germany between August 2005 and Decem-ber 2008 The study met all standards for ethicalapproval in Germany It was planned and conductedand data were analyzed in accordance with guidelinesissued by the Bundesinstitut fuumlr Arzneimittel und Medi-zinprodukte (Federal Institute for Drugs and MedicalDevices) German law does not require patient informedconsent in observational studies in which treatment ismedically indicated by the physician regardless of studyparticipation and in which treatment use is restricted toapproved indications

Procedures and measurementsIn all 577 office-based ophthalmologists treated andprovided information for 2339 subjects with glaucomaor ocular hypertension who were being switched formedical reasons to once-daily latanoprosttimolol FCfrom another ocular hypotensive medication (monother-apy FC or unfixed combination) Participating ophthal-mologists followed their usual care practices At thebaseline visit the reason(s) for switching the subject tolatanoprosttimolol FC was noted and demographicdata medical and ocular histories visual field status(Aulhorn stage and mean defect) and optic nerve headfindings were recorded Prior to pupil dilation best-corrected visual acuity was determined and IOP level

was measured once by pulse air tonometry or calibratedGoldman applanation tonometryStudy-related follow-up visits were scheduled to occur

at approximately 6-month intervals for 24 months Ateach visit IOP was measured optic disc excavation andvisual field (Aulhorn stage) were assessed and glaucomadamageprogression was evaluated by investigators Anydecision to withdraw FC therapy before 24 months wasmade at the discretion of the treating physicianAll observed or volunteered adverse events and serious

adverse events were recorded throughout the study Ser-ious adverse events were those that were life-threaten-ing resulted in death required or prolongedhospitalization or resulted in disability or congenitalanomaly Suspected causal relationships to latanoprosttimolol FC were recorded by treating physicians Ver-sion 120 of the Medical Dictionary for RegulatoryActivities (MedDRA) was used to code diagnoses pre-viousconcomitant diseases and adverse eventsPhysicians assessed the overall efficacy and the overall

tolerability of latanoprosttimolol FC at month 24 asldquovery goodrdquo ldquogoodrdquo ldquomoderaterdquo or ldquoinsufficientrdquo Sub-ject compliance with the FC was evaluated by physiciansusing the same four categories At month 24 subjectsevaluated change in iris color from baseline as ldquononerdquoldquoslightlyrdquo ldquodistinctlyrdquo or ldquovery distinctlyrdquo and were askedwhether they wished to remain on the FC

Endpoints and analysesStatistical analyses were descriptive and exploratoryPercentages for categorical variables as well as meansstandard deviations (SDs) and where appropriate two-sided 95 confidence intervals (CIs) for continuous vari-ables were calculated based on nonmissing observationsAssociations between pairs of variables were assessedusing Pearson correlation for continuous variablesSpearman rank correlation where one or both variableswere ordinal or tetrachoric correlation for two binaryvariablesIf both eyes were treated with the FC the IOP value for

the right eye was used otherwise the value for the trea-ted eye was used If the physician did not indicate whicheye was treated it was assumed that both eyes were pre-scribed FC therapy Mean changes in IOP levels atmonths 6 12 18 and 24 and at the last visit wereassessed In the analysis of changes in IOP the last visitwas defined as the last postbaseline visit at which an IOPlevel was recorded In addition mean change in correctedIOP from baseline to last visit was assessed using the for-mula developed by Kohlhaas et al [17] (corrected IOP =raw IOP + [-00423 times central corneal thickness in μm +2328]) and for the subset of subjects in whom IOP wasmeasured using applanation tonometry and for subjects

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Page 2 of 9

stratified by diagnosis and by baseline ocular hypotensivetherapyMean changes from baseline in horizontal and vertical

cupdisc ratios were evaluated across visits Aulhornstage and mean defect at each visit and change in stagefrom baseline were summarized A stepwise analysis ofvariance (ANOVA) of mean change in visual field defect(last visit at which the parameter was recorded - base-line) included the following potential explanatory vari-ables age gender baseline mean defect change in IOP(last visit at which the parameter was recorded - base-line) number of postbaseline optic disc hemorrhagestreatment duration primary diagnosis history of hyper-tension history of hypotension and history of diabetesThe significance level for variable entry was set at 005and for retention at 010 no interaction terms werefittedA 6-item composite variable reflecting progression of

glaucomatous damage from baseline to last visit wasdefined as any of the following (a) increase in horizontalor vertical cupdisc ratio by ge02 (b) occurrence of ge1postbaseline optic disc hemorrhage (c) decrease in rimarea rim volume andor mean retinal nerve fiber layerthickness by 02 mm2 01 mm3 and 01 mm respec-tively as measured by Heidelberg Retina Tomograph(d) progressive visual field deterioration noted by thephysician at ge1 postbaseline visit (e) increase in Aul-horn stage by ge1 stage or (f) decrease in mean defectby ge25 dB A stepwise logistic regression analysis of thebinary variable presenceabsence of progression includedthe following potential predictors age gender baselineIOP change in IOP (last visit - baseline) primary diag-nosis history of hypertension history of hypotensionand history of diabetes The significance level for vari-able entry was set at 005 and for retention at 010 nointeraction terms were fitted In addition progression ofoptic disc excavation (present if either criteria [a] or [c]above was met) and progression of visual field (presentif criteria [d] and if criteria [e] andor [f] were met)were evaluatedEfficacy parameters were analyzed for the per protocol

(PP) population which included subjects treated withlatanoprosttimolol FC for ge18 months who had a base-line and ge1 postbaseline IOP measurement (ge18 monthsapart) did not have a refractive error le -8 diopters or ge+ 8 diopters at baseline and did not administer ocularhypotensive medication in addition to latanoprosttimo-lol FC medication during the study period This defini-tion of the PP population was appropriate given that theprimary objective of this noninterventional study was toobtain information about a cohort of subjects exposedto the latanoprosttimolol FC for at least 18 months Inaddition key efficacy analyses were reproduced usingthe full analysis set (FAS) population which included all

subjects with ge1 postbaseline IOP measurement inorder to evaluate the robustness of the PP analyses Thesafety population included all subjects who received ge1drop of study medication

ResultsOf the 2339 subjects switched to latanoprosttimolol FC(safety population) 1317 (563) completed the studySubject disposition is summarized in Table 1 A total of1022 subjects (437) discontinued from the study thevast majority of discontinuations (894) were unrelatedto study drug and nearly all of those (851) were attribu-table to loss to follow-up In all 1028 subjects metcriteria for inclusion in the PP population and 1934were eligible for the FAS populationIn the total study population the average age was 655

years and 10472339 (448) subjects were male (Table2) The most common primary diagnoses were open-angle glaucoma and ocular hypertension The ocularhypotensive therapies most often reported at the time ofthe switch to the FC were latanoprost (n = 343) timolol(n = 173) and timolol maleate (n = 115) (Investigatorscould report the same drug as ldquotimololrdquo or ldquotimolol mal-eaterdquo reflecting different preferences in drug terms) Themost commonly reported reasons for switching to theFC were inadequate IOP reduction on prior therapy(782) and desire to simplify treatment with once-dailydosing (294 Table 2) The median duration of latano-prosttimolol FC treatment was 708 days with 14912339 (637) subjects treated with the FC for at least18 monthsIn the PP population the mean baseline IOP was

203 plusmn 420 mmHg (Table 3) A mean change frombaseline of -40 plusmn 431 mmHg was noted at month 6this decrease was maintained and reductions were statis-tically significant throughout the follow-up period(Table 3 Figure 1 P lt 005 for each change from base-line) Similar reductions from baseline to last visit werenoted when IOP values were corrected using the for-mula proposed by Kohlhaas et al [17] in the FAS popu-lation and among the more than 600 subjects in the PPpopulation whose IOP levels were evaluated by applana-tion tonometry (Table 4) With the PP population strati-fied by primary diagnosis mean plusmn SD changes frombaseline to last visit in IOP levels were -41 plusmn 434mmHg in the open-angle glaucoma group (n = 859)-46 plusmn 404 mmHg among those with ocular hyperten-sion (n = 83) -51 plusmn 678 mmHg in pseudoexfoliationglaucoma subjects (n = 48) and -32 plusmn 375 mmHg insubjects with normal-tension glaucoma (n = 50) Strati-fied by previous ocular hypotensive medication meanchange in IOP from baseline to last visit was ge-40mmHg for those previously treated with a monotherapyor with a single FC therapy the mean plusmn SD IOP

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reduction in subjects switched to latanoprosttimolol FCfrom multiple therapies was -25 plusmn 448 mmHg (n =119) and was -45 plusmn 477 mmHg in subjects for whomthe prior ocular hypotensive therapy was not recorded(n = 586)Changes from baseline in horizontal and vertical cup

disc ratios showed a tendency toward stability and werenot considered to be clinically significant (Table 5)Among subjects in the PP population for whom infor-mation concerning whether or not they had an opticdisc hemorrhage at any postbaseline visit was availablethe percentage with a hemorrhage was lower at each fol-low-up visit than at baseline (20916 [22] at baselinevs le15 at any postbaseline visit) In all 29983 (30)reported ge1 postbaseline optic disc hemorrhage and 4983 (04) had repeated occurrences at gt1 postbaselinevisitInformation concerning mean visual field defect mea-

surement method was available for 744 subjects and themost commonly used measurement method was theHumphrey Visual Field Analyzer (n = 337) At month24 72 of the 122 subjects (590) with valid data for theAulhorn stage based on the Humphrey Visual FieldAnalyzer at both baseline and month 24 had no changein stage 156 25 and 08 of subjects increased by1 2 and 3 stages respectively whereas 156 4908 and 08 of subjects decreased by 1 2 3 and 4stages respectivelyIn the PP population there were no statistically signif-

icant changes in mean defect from baseline to months6 12 18 and 24 or to the last visit In the multivariateanalysis change in mean defect from baseline to the lastvisit was related only to baseline mean defect This

analysis only involved subjects with nonmissing data forthe response variable and all potential explanatory vari-ables (n = 355) The final model was reduced to a sim-ple linear regression with intercept -0718 and slope-0283 (95 CI -0354 -0211 P lt 00001) Hence sub-jects with a lower baseline mean defect experienced ahigher change in mean defect from baseline to last visitIn addition the correlation between changes from base-line to last visit in mean defect and in IOP was esti-mated at 00276 (95 CI -00603 01156 P = 05956n = 371) providing no evidence of a relationshipbetween IOP reduction and reduction in mean defectFewer than 18 of evaluable subjects demonstrated a

negative change in any individual progression measureby last visit or month 24 (Table 6) By the last visit pro-gression of optic disc excavation (increase in horizontalor vertical cupdisc ratio by ge02 or decrease in rimarea rim volume andor mean retinal nerve fiber layerthickness by 02 mm2 01 mm3 and 01 mm respec-tively as measured by Heidelberg Retina Tomograph)was noted in 117816 (143) subjects Visual field pro-gression (progressive visual field deterioration noted bythe physician at ge1 postbaseline visit and an increase inAulhorn stage by ge1 stage andor decrease in meandefect by ge25 dB) occurred in 46900 (51) of subjectsby the last visit Based on the six-item composite vari-able overall progression of glaucoma by the last visitwas noted in 305 (302) of the 1010 subjects in the PPpopulation who provided a response to ge1 of the sixindividual progression measures Logistic regressiondemonstrated that only age was a significant predictorof composite overall progression by the last visit (oddsratio = 0984 95 CI 0972 0996 P = 00102

Table 1 Subject disposition

No () subjects

Received latanoprosttimolol FC 2339

Completed 24 months of follow-up 1317 (563)

Discontinued prior to 24 months 1022 (437)

Per protocol population

Included 1028 (440)

Excluded 1311 (660)

Reason(s) for exclusion

Not treated for ge18 months 512

No baseline and ge1 postbaseline measure for IOP ge18 months apart 487

Additional ocular hypotensive medication during study 402

Ametropy at baseline 42

Full analysis set

Included 1934 (827)

Excluded (no postbaseline IOP measurement) 405 (173)

Safety population 2339 (1000)

FC = fixed combination IOP = intraocular pressure

More than one reason was possible If a subject was excluded from the full analysis set a separate reason for exclusion from the per protocol population is notprovided in this table

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Page 4 of 9

n = 952) From this final model there is evidence thatthe probability of experiencing overall progression ofglaucoma damage increases with ageLatanoprosttimolol FC was safe and well tolerated

Sixteen deaths were reported none of which was con-sidered by investigators to be related to study treatmentIn all 148 subjects treated with latanoprosttimolol FCexperienced 185 adverse events and 88 treatment-related adverse events were reported in 72 subjects(Table 7) Three (01) subjects experienced seriousadverse events deemed by investigators to be related tostudy treatment Fifty-two (22) subjects permanentlydiscontinued treatment with the FC due to a treatment-related adverse event Ocular adverse events were themost commonly reported adverse events Treatment-related ocular adverse events were noted in 39 (17)

subjects and 28 (12) permanently discontinued FCtherapy due to such an event Two (01) subjectsexperienced a serious treatment-related ocular adverseevent Most adverse events resulting in discontinuationwere mild or moderate in severity and resolved by theend of the studyAt month 24 the majority of responding physicians

rated the overall efficacy of latanoprosttimolol FC asldquovery goodrdquo or ldquogoodrdquo (PP population 922997 [925]FAS population 13121504 [872]) Among subjectsfor whom physicians provided evaluations at month 24the overall tolerability of the FC was assessed as either

Table 2 Baseline characteristics N = 2339

Age (years)

Mean plusmn SD 655 plusmn117

Range 10 96

Male gender n () 1047(448)

Primary diagnosisdagger

Open-angle glaucoma 1910

Ocular hypertension 177

Pseudoexfoliation glaucoma 114

Normal-tension glaucoma 111

Glaucoma NOS 41

Angle-closure glaucoma 17

Pigmentary glaucoma 12

Ocular hypotensive therapy reported by ge50 subjects

Bimatoprost 50

Brinzolamide 92

Dorzolamidetimolol FC 92

Latanoprost 343

Timolol 173

Timolol maleate 115

Travoprost 93

Reason(s) for switching to latanoprosttimolol FCDagger n ()

Inadequate IOP reduction on prior therapy 1830(782)

Desire to simplify treatment with once-daily dosing 687 (294)

Side effectshypersensitivity reactions with prior therapy 219 (94)

Prior therapy contraindicated due to subjectrsquos signssymptoms

103 (44)

Other 120 (51)

FC = fixed combination IOP = intraocular pressure NOS = not otherwisespecified SD = standard deviation

Age was missing for 57 subjects gender was missing for 48 subjectsdaggerCounts are based on diagnoses for both eyes If a subject had a differentdiagnosis for each eye these were counted twice and if a subject had morethan one diagnosis for the same eye each was countedDaggerMore than one reason could have been recorded by physicians Percentagesare based on the number of patients (N = 2339)

Table 3 Mean IOP and mean change in IOP frombaselinedagger by visit (mmHg) PP population

Visit n Mean plusmn SD(95 CI)

Change from baseline mean plusmn SD(95 CIDagger)

Baseline 1028 203 plusmn 420 na

(201 206)

Month 6 1012 164 plusmn 304 -40 plusmn 431

(162 166) (-43 -38)

Month 12 1017 164 plusmn 304 -39 plusmn 453

(162 166) (-42 -37)

Month 18 1010 164 plusmn 299 -40 plusmn 443

(162 165) (-43 -37)

Month 24 980 162 plusmn 317 -42 plusmn 469

(160 164) (-45 -39)

Last visitsect 1028 162 plusmn 316 -41 plusmn 466

(160 164) (-44 -38)

CI = confidence interval IOP = intraocular pressure na = not applicable PP =per protocol

SD = standard deviation

Raw IOP valuesdaggerMonth times - baselineDaggerP lt 005 for change from baseline at each visitsectLast visit = last postbaseline visit at which an IOP level was recorded

Figure 1 Box-plot of intraocular pressure by visit PP populationPP = per protocol Bars represent minimum and maximum valuesBoxes represent interquartile range and median Line presents themean profile over time

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ldquovery goodrdquo or ldquogoodrdquo in 15031584 (949) subjects andcompliance with the FC as ldquovery goodrdquo or ldquogoodrdquo in14391580 (911) subjects More than three-quarters(11231351 [831) of responding subjects reported nochange in iris color at month 24 and nearly 90 (n =13431520 [884]) indicated a desire to continue FCtreatment after the completion of study At month 24change in visual acuity from baseline was not statisti-cally or clinically significant

DiscussionResults of this long-term observational study of latano-prosttimolol FC demonstrate that the combinationeffectively reduces IOP levels and is well tolerated inpatients with glaucoma or ocular hypertension whochange from their previous ocular hypotensive therapyfor medical reasons The significant IOP-lowering effectof the FC was seen early at the month 6 visit and wassustained throughout the 24-month follow-up periodMoreover no significant changes in optic disc and visualfield defect were noted by investigators and structuraland functional parameters remained stable over 24months Investigator assessments revealed no significantassociation between IOP reduction over two years andchange in visual fieldPrevious research has demonstrated that progression

of glaucoma or ocular hypertension can be delayed orhalted by lowering IOP levels through the use of ocularhypotensive agents [218-21] Herein the mean IOPreduction of approximately 4 mmHg sustained over 24months was somewhat greater than reductions reportedin previous short-term observational studies of patientsswitched to the FC [2223] For example a prospectivemulticenter study [22] of patients switched to latano-prosttimolol FC and followed for at least two monthsfound mean IOP reductions from baseline of 29 mmHgin those with primary open-angle glaucoma or exfolia-tion glaucoma and of 31 mmHg among patients withocular hypertension (P lt 0001 for all) A multicenterobservational study [23] of patients with glaucoma orocular hypertension who were switched to the FC andfollowed for six months reported mean IOP reductionsfrom baseline of 33 mmHg 41 mmHg and 34 mmHgamong patients with open-angle glaucoma exfoliationglaucoma and ocular hypertension respectively (P lt0001 for all)As has been shown previously [11-16] the FC was

well tolerated In all 99185 (535) adverse events wereocular in nature half of treatment-related adverse eventsrelated to the eye and two of the three reported treat-ment-related serious adverse events were ocular Fewerthan 3 of subjects discontinued the FC due to an ocu-lar adverse event The tolerability of an ocular hypoten-sive agent is important given the negative impact of

Table 4 Mean IOP and mean change in IOP from baselineto last visit (mmHg) alternate populations

Visit n Mean plusmn SD(95 CI)

Change from baseline mean plusmn SD(95 CIdagger)

PP population corrected IOP[17]

Baseline 546 205 plusmn 394 na

(202 209)

Last visit 546 163 plusmn 330 -42 plusmn 421

(160 166) (-46 -39)

Full analysis set raw IOP

Baseline 1913 204 plusmn 425 na

(202 206)

Last visit 1934 164 plusmn 342 -39 plusmn 465Dagger

(163 166) (-42 -37)

PP population with applanation tonometry data raw IOP

Baseline 732 203 plusmn 431 na

(200 206)

Last visit 687 162 plusmn 302 -40 plusmn 459sect

(160 164) (-43 -36)

CI = confidence interval IOP = intraocular pressure na = not applicable PP =per protocol

SD = standard deviation

Last visit = last postbaseline visit at which an IOP level was recordeddaggerP lt 005 for change from baseline to last visit for each parameterDaggerN = 1913sectN = 631

Table 5 Mean change from baseline in horizontal andvertical cupdisc ratios by visit PP population

Visit n Mean plusmn SD (95 CI)

Horizontal cupdisc ratio

Month 6 645 00003 plusmn 013117

(-00099 00104)

Month 12 660 00039 plusmn 013286

(-00063 00140)

Month 18 666 00092 plusmn 013860

(-00014 00197)

Month 24 666 00041 plusmn 014078

(-00067 00148)

Last visit 783 00079 plusmn 014645

(-00024 00182)

Vertical cupdisc ratio

Month 6 600 00040 plusmn 012772

(-00062 00142)

Month 12 604 00075 plusmn 013726

(-00035 00184)

Month 18 613 00152 plusmn 014613

(00036 00268)

Month 24 615 00088 plusmn 013534

(-00019 00195)

Last visit 729 00127 plusmn 015155

(00017 00237)

CI = confidence interval PP = per protocol SD = standard deviation

Month times - baseline Last visit = last postbaseline visit at which the parameterwas recorded

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Page 6 of 9

ocular adverse events on patient continuation with ther-apy [2425]At month 24 physician evaluations of latanoprost

timolol FC were overwhelmingly positive with regard toefficacy tolerability and patient compliance In additionnearly 90 of patients expressed a desire to remain onthe FC after the end of the study These positive evalua-tions are tempered however by the fact that they weremade for and by patients who stayed on therapy for thefull follow-up period it is not known how many ofthose for whom efficacy tolerability or compliance wereissues discontinued FC therapy prior to that time pointConversely nearly 90 of discontinuations in the pre-sent study were unrelated to latanoprosttimolol FCwith the vast majority attributable to loss to follow-upMoreover a prior study [23] of patients switched tolatanoprosttimolol FC found that 97 of patients(10081042) remained on treatment after the 6-monthstudy period

Benefits of prescribing a FC agent for patients withglaucoma or ocular hypertension may include improvedadherence persistence convenience and reduced expo-sure to preservatives Improved adherence and persis-tence in particular are critical since the use of aneffective ocular hypotensive agent over the long termmay be expected to increase the likelihood of delayingor stopping glaucomatous damage Poorer compliancehas been demonstrated in those treated with more com-plex medication regimens [26-30] Comparative studiesof medication compliance in patients prescribed alterna-tive FC therapies are neededThis study has both strengths and limitations The

observational design may have better reflected actualclinical practice than controlled clinical trials but theabsence of a control group limits our ability to drawconclusions and the PP population included fewer thanhalf the number of subjects treated primarily due toloss to follow-up Given the observational design it was

Table 6 Changes in progression measures by last visit and month 24 nN () PP population

Progression measure Last visit Month 24

Increase in horizontal or vertical cupdisc ratio by ge02 (visit - baseline)dagger 98797 (123) 78676 (115)

ge1 postbaseline optic disc hemorrhageDagger 29983 (30) 23785 (29)

Decrease in ge1 rim area rim volume andor mean RNFL thickness by HRT (visit - baseline)dagger 28222 (126) 13151 (86)

Visual field deterioration rated as progression by physician at ge1 postbaseline visitDagger 137884 (155) 104630 (165)

Increase in Aulhorn stagesect by ge1 stage (visit - baseline)dagger 64370 (173) 43258 (167)

Decrease in mean defect by ge25 dBdagger 59371 (159) 45285 (158)

HRT = Heidelberg Retina Tomograph PP = per protocol RNFL = retinal nerve fiber layer

Last visit = last postbaseline visit at which the parameter was recordeddaggerTo be included in the percentage a subject must have had assessments at both the baseline and ge1 postbaseline visit for the relevant measureDaggerTo be included in the percentage a subject must have had ge1 postbaseline assessment for the relevant measuresectReflects all methods of determining Aulhorn stage

Table 7 Adverse events N = 2339

All causalitiesn ()

Treatment relatedn ()

All adverse events

Number of events 185 88

Subjects with

ge1 adverse event 148 (63) 72 (31)

ge1 serious adverse event 54 (23) 3 (01)

ge1 severe adverse event 70 (30) 15 (06)

Discontinued FC due to adverse event 69 (29) 52 (22)

Dose reducedtemporarily discontinued FC due to adverse event 22 (09) 8 (03)

All Ocular Adverse Events

Number of events 99 44

Subjects with

ge1 adverse event 84 (36) 39 (17)

ge1 serious adverse event 29 (12) 2 (01)

ge1 severe adverse event 35 (15) 5 (02)

Discontinued FC due to adverse event 41 (18) 28 (12)

Dose reducedtemporarily discontinued FC due to adverse event 19 (08) 6 (03)

FC = fixed combination

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Page 7 of 9

not possible to standardized the timing and method ofmeasuring IOP levels and visual field defects It is nota-ble however that IOP reductions from baseline to lastvisit among the 687 subjects evaluated by applanationtonometry were similar to those observed for the totalpopulation Although the design did not include a wash-out period between termination of baseline therapy andinitiation of latanoprosttimolol FC combination thiswould not be expected to impact the long-term out-comes evaluated herein The 24-month follow-up periodmay have been too short to detect changes in visualfields Moreover last visit data for individual progressionmeasures reflected a time point prior to month 24 forbetween 15 (for cupdisc ratio data) and 32 (for rimareavolumeretinal nerve fiber layer data) of evaluablesubjects Strict adherence to study procedures andreporting requirements could not be affirmed given thelarge number of participating physicians and the pro-longed follow-up period Finally while 17 of patientsreported a change in iris color from baseline to month24 evaluations relied on recollections of baseline colorThe Ocular Hypertension Treatment Study [2] foundthat 171 of subjects prescribed a prostaglandin analo-gue for at least six months and 76 of those in theobservation group reported a change in iris color dar-kening of the eyelids or growth of eyelashes

ConclusionsThis 24-month study demonstrated that latanoprosttimolol FC effectively reduces IOP levels and is well tol-erated in patients switched from other ocular hypoten-sive therapies for medical reasons Investigatorassessments showed optic disc parameters and visualfield to be stable throughout the follow-up period

AcknowledgementsThe results of this study were presented in part at the 8th InternationalSymposium on Ocular Pharmacology and Therapeutics December 3-6 2009Rome ItalyEditorial support including contributing to the first draft of the manuscriptrevising the paper based on author feedback and styling the paper forjournal submission was provided by Jane G Murphy PhD of ZolaAssociates and was funded by Pfizer Inc

Author details1Buumlrgerhospital Frankfurt am Main Augenklinik Frankfurt am Main Germany2Private practice Bruchsal Germany 3Pfizer Pharma GmbH Berlin Germany4Pfizer Limited UK Specialty Care Sandwich Kent UK

Authorsrsquo contributionsOS participated in the study concept and design analysis and interpretationof data and critical revision of the manuscript for important intellectualcontent BH participated in the study concept and design acquisition ofdata analysis and interpretation of data and critical revision of themanuscript for important intellectual content CZ participated in the analysisand interpretation of data critical revision of the manuscript for importantintellectual content and study supervision PM participated in the analysisand interpretation of data and critical revision of the manuscript forimportant intellectual content All authors read and approved the finalmanuscript

Competing interestsDr Guzy is an employee of Pfizer Pharma GmbH Mr Miller is an employeeof Pfizer Limited UK Specialty Care The research was funded by PfizerPharma GmbH

Received 15 April 2010 Accepted 8 September 2010Published 8 September 2010

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Savona Italy DOGMA II 2008 [httpwwweugsorgengEGS_guidelinesasp] Accessed September 3 2010

2 Kass MA Heuer DK Higginbotham EJ Johnson CA Keltner JL Miller JPParrish RK Wilson MR Gordon MO The Ocular Hypertension TreatmentStudy a randomized trial determines that topical ocular hypotensivemedication delays or prevents the onset of primary open-angleglaucoma Arch Ophthalmol 2002 120701-713

3 Toris CB Gabelt BT Kaufman PL Update on the mechanism of action oftopical prostaglandins for intraocular pressure reduction SurvOphthalmol 2008 53(Suppl 1)S107-120

4 Xalacomreg Summary of Product Characteristics Electronic MedicinesCompendium 2007 [httpemcmedicinesorgukmedicine7735SPCXalacom+eye+drops 2c+solution] Accessed November 16 2009

5 Coakes RL Brubaker RF The mechanism of timolol in lowering intraocularpressure in the normal eye Arch Ophthalmol 1978 962045-2048

6 Zimmerman TJ Harbin R Pett M Kaufman HE Timolol and facility ofoutflow Invest Ophthalmol Vis Sci 1977 16623-624

7 Alm A Widengaringrd I Kjellgren D Soumlderstroumlm M Fristroumlm B Heijl AStjernschantz J Latanoprost administered once daily caused amaintained reduction of intraocular pressure in glaucoma patientstreated concomitantly with timolol Br J Ophthalmol 1995 7912-16

8 Bucci MG Italian Latanoprost Study Group Intraocular pressure-loweringeffects of latanoprost monotherapy versus latanoprost or pilocarpine incombination with timolol a randomized observer-masked multicenterstudy in patients with open-angle glaucoma J Glaucoma 1999 824-30

9 Lee PY Shao H Camras CB Podos SM Additivity of prostaglandin F2alpha-1-isopropyl ester to timolol in glaucoma patients Ophthalmology1991 981079-1082

10 Rulo AH Greve EL Hoyng PF Additive effect of latanoprost aprostaglandin F2 alpha analogue and timolol in patients with elevatedintraocular pressure Br J Ophthalmol 1994 78899-902

11 Diestelhorst M Larsson LI European-Canadian Latanoprost FixedCombination Study Group A 12-week randomized double-maskedmulticenter study of the fixed combination of latanoprost and timolol inthe evening versus the individual components Ophthalmology 200611370-76

12 Diestelhorst M Larsson LI European Latanoprost Fixed Combination StudyGroup A 12 week study comparing the fixed combination of latanoprostand timolol with the concomitant use of the individual components inpatients with open angle glaucoma and ocular hypertension Br JOphthalmol 2004 88199-203

13 Higginbotham EJ Feldman R Stiles M Dubiner H Fixed CombinationInvestigative Group Latanoprost and timolol combination therapy vsmonotherapy one-year randomized trial Arch Ophthalmol 2002120915-922

14 Higginbotham EJ Olander KW Kim EE Grunden JW Kwok KK Tressler CSUnited States Fixed-Combination Study Group Fixed-combinationlatanoprosttimolol vs individual components for POAG or ocularhypertension a randomized double-masked study Arch Ophthalmol2010 128165-172

15 Pfeiffer N European Latanoprost Fixed Combination Study Group Acomparison of the fixed combination of latanoprost and timolol with itsindividual components Graefes Arch Clin Exp Ophthalmol 2002240893-899

16 Shin DH Feldman RM Sheu WP Fixed Combination LatanoprostTimololStudy Group Efficacy and safety of the fixed combinations latanoprosttimolol versus dorzolamidetimolol in patients with elevated intraocularpressure Ophthalmology 2004 111276-282

17 Kohlhaas M Boehm AG Spoerl E Puumlrsten A Grein HJ Pillunat LE Effect ofcentral corneal thickness corneal curvature and axial length onapplanation tonometry Arch Ophthalmol 2006 124471-476

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Page 8 of 9

stratified by diagnosis and by baseline ocular hypotensivetherapyMean changes from baseline in horizontal and vertical

cupdisc ratios were evaluated across visits Aulhornstage and mean defect at each visit and change in stagefrom baseline were summarized A stepwise analysis ofvariance (ANOVA) of mean change in visual field defect(last visit at which the parameter was recorded - base-line) included the following potential explanatory vari-ables age gender baseline mean defect change in IOP(last visit at which the parameter was recorded - base-line) number of postbaseline optic disc hemorrhagestreatment duration primary diagnosis history of hyper-tension history of hypotension and history of diabetesThe significance level for variable entry was set at 005and for retention at 010 no interaction terms werefittedA 6-item composite variable reflecting progression of

glaucomatous damage from baseline to last visit wasdefined as any of the following (a) increase in horizontalor vertical cupdisc ratio by ge02 (b) occurrence of ge1postbaseline optic disc hemorrhage (c) decrease in rimarea rim volume andor mean retinal nerve fiber layerthickness by 02 mm2 01 mm3 and 01 mm respec-tively as measured by Heidelberg Retina Tomograph(d) progressive visual field deterioration noted by thephysician at ge1 postbaseline visit (e) increase in Aul-horn stage by ge1 stage or (f) decrease in mean defectby ge25 dB A stepwise logistic regression analysis of thebinary variable presenceabsence of progression includedthe following potential predictors age gender baselineIOP change in IOP (last visit - baseline) primary diag-nosis history of hypertension history of hypotensionand history of diabetes The significance level for vari-able entry was set at 005 and for retention at 010 nointeraction terms were fitted In addition progression ofoptic disc excavation (present if either criteria [a] or [c]above was met) and progression of visual field (presentif criteria [d] and if criteria [e] andor [f] were met)were evaluatedEfficacy parameters were analyzed for the per protocol

(PP) population which included subjects treated withlatanoprosttimolol FC for ge18 months who had a base-line and ge1 postbaseline IOP measurement (ge18 monthsapart) did not have a refractive error le -8 diopters or ge+ 8 diopters at baseline and did not administer ocularhypotensive medication in addition to latanoprosttimo-lol FC medication during the study period This defini-tion of the PP population was appropriate given that theprimary objective of this noninterventional study was toobtain information about a cohort of subjects exposedto the latanoprosttimolol FC for at least 18 months Inaddition key efficacy analyses were reproduced usingthe full analysis set (FAS) population which included all

subjects with ge1 postbaseline IOP measurement inorder to evaluate the robustness of the PP analyses Thesafety population included all subjects who received ge1drop of study medication

ResultsOf the 2339 subjects switched to latanoprosttimolol FC(safety population) 1317 (563) completed the studySubject disposition is summarized in Table 1 A total of1022 subjects (437) discontinued from the study thevast majority of discontinuations (894) were unrelatedto study drug and nearly all of those (851) were attribu-table to loss to follow-up In all 1028 subjects metcriteria for inclusion in the PP population and 1934were eligible for the FAS populationIn the total study population the average age was 655

years and 10472339 (448) subjects were male (Table2) The most common primary diagnoses were open-angle glaucoma and ocular hypertension The ocularhypotensive therapies most often reported at the time ofthe switch to the FC were latanoprost (n = 343) timolol(n = 173) and timolol maleate (n = 115) (Investigatorscould report the same drug as ldquotimololrdquo or ldquotimolol mal-eaterdquo reflecting different preferences in drug terms) Themost commonly reported reasons for switching to theFC were inadequate IOP reduction on prior therapy(782) and desire to simplify treatment with once-dailydosing (294 Table 2) The median duration of latano-prosttimolol FC treatment was 708 days with 14912339 (637) subjects treated with the FC for at least18 monthsIn the PP population the mean baseline IOP was

203 plusmn 420 mmHg (Table 3) A mean change frombaseline of -40 plusmn 431 mmHg was noted at month 6this decrease was maintained and reductions were statis-tically significant throughout the follow-up period(Table 3 Figure 1 P lt 005 for each change from base-line) Similar reductions from baseline to last visit werenoted when IOP values were corrected using the for-mula proposed by Kohlhaas et al [17] in the FAS popu-lation and among the more than 600 subjects in the PPpopulation whose IOP levels were evaluated by applana-tion tonometry (Table 4) With the PP population strati-fied by primary diagnosis mean plusmn SD changes frombaseline to last visit in IOP levels were -41 plusmn 434mmHg in the open-angle glaucoma group (n = 859)-46 plusmn 404 mmHg among those with ocular hyperten-sion (n = 83) -51 plusmn 678 mmHg in pseudoexfoliationglaucoma subjects (n = 48) and -32 plusmn 375 mmHg insubjects with normal-tension glaucoma (n = 50) Strati-fied by previous ocular hypotensive medication meanchange in IOP from baseline to last visit was ge-40mmHg for those previously treated with a monotherapyor with a single FC therapy the mean plusmn SD IOP

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Page 3 of 9

reduction in subjects switched to latanoprosttimolol FCfrom multiple therapies was -25 plusmn 448 mmHg (n =119) and was -45 plusmn 477 mmHg in subjects for whomthe prior ocular hypotensive therapy was not recorded(n = 586)Changes from baseline in horizontal and vertical cup

disc ratios showed a tendency toward stability and werenot considered to be clinically significant (Table 5)Among subjects in the PP population for whom infor-mation concerning whether or not they had an opticdisc hemorrhage at any postbaseline visit was availablethe percentage with a hemorrhage was lower at each fol-low-up visit than at baseline (20916 [22] at baselinevs le15 at any postbaseline visit) In all 29983 (30)reported ge1 postbaseline optic disc hemorrhage and 4983 (04) had repeated occurrences at gt1 postbaselinevisitInformation concerning mean visual field defect mea-

surement method was available for 744 subjects and themost commonly used measurement method was theHumphrey Visual Field Analyzer (n = 337) At month24 72 of the 122 subjects (590) with valid data for theAulhorn stage based on the Humphrey Visual FieldAnalyzer at both baseline and month 24 had no changein stage 156 25 and 08 of subjects increased by1 2 and 3 stages respectively whereas 156 4908 and 08 of subjects decreased by 1 2 3 and 4stages respectivelyIn the PP population there were no statistically signif-

icant changes in mean defect from baseline to months6 12 18 and 24 or to the last visit In the multivariateanalysis change in mean defect from baseline to the lastvisit was related only to baseline mean defect This

analysis only involved subjects with nonmissing data forthe response variable and all potential explanatory vari-ables (n = 355) The final model was reduced to a sim-ple linear regression with intercept -0718 and slope-0283 (95 CI -0354 -0211 P lt 00001) Hence sub-jects with a lower baseline mean defect experienced ahigher change in mean defect from baseline to last visitIn addition the correlation between changes from base-line to last visit in mean defect and in IOP was esti-mated at 00276 (95 CI -00603 01156 P = 05956n = 371) providing no evidence of a relationshipbetween IOP reduction and reduction in mean defectFewer than 18 of evaluable subjects demonstrated a

negative change in any individual progression measureby last visit or month 24 (Table 6) By the last visit pro-gression of optic disc excavation (increase in horizontalor vertical cupdisc ratio by ge02 or decrease in rimarea rim volume andor mean retinal nerve fiber layerthickness by 02 mm2 01 mm3 and 01 mm respec-tively as measured by Heidelberg Retina Tomograph)was noted in 117816 (143) subjects Visual field pro-gression (progressive visual field deterioration noted bythe physician at ge1 postbaseline visit and an increase inAulhorn stage by ge1 stage andor decrease in meandefect by ge25 dB) occurred in 46900 (51) of subjectsby the last visit Based on the six-item composite vari-able overall progression of glaucoma by the last visitwas noted in 305 (302) of the 1010 subjects in the PPpopulation who provided a response to ge1 of the sixindividual progression measures Logistic regressiondemonstrated that only age was a significant predictorof composite overall progression by the last visit (oddsratio = 0984 95 CI 0972 0996 P = 00102

Table 1 Subject disposition

No () subjects

Received latanoprosttimolol FC 2339

Completed 24 months of follow-up 1317 (563)

Discontinued prior to 24 months 1022 (437)

Per protocol population

Included 1028 (440)

Excluded 1311 (660)

Reason(s) for exclusion

Not treated for ge18 months 512

No baseline and ge1 postbaseline measure for IOP ge18 months apart 487

Additional ocular hypotensive medication during study 402

Ametropy at baseline 42

Full analysis set

Included 1934 (827)

Excluded (no postbaseline IOP measurement) 405 (173)

Safety population 2339 (1000)

FC = fixed combination IOP = intraocular pressure

More than one reason was possible If a subject was excluded from the full analysis set a separate reason for exclusion from the per protocol population is notprovided in this table

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Page 4 of 9

n = 952) From this final model there is evidence thatthe probability of experiencing overall progression ofglaucoma damage increases with ageLatanoprosttimolol FC was safe and well tolerated

Sixteen deaths were reported none of which was con-sidered by investigators to be related to study treatmentIn all 148 subjects treated with latanoprosttimolol FCexperienced 185 adverse events and 88 treatment-related adverse events were reported in 72 subjects(Table 7) Three (01) subjects experienced seriousadverse events deemed by investigators to be related tostudy treatment Fifty-two (22) subjects permanentlydiscontinued treatment with the FC due to a treatment-related adverse event Ocular adverse events were themost commonly reported adverse events Treatment-related ocular adverse events were noted in 39 (17)

subjects and 28 (12) permanently discontinued FCtherapy due to such an event Two (01) subjectsexperienced a serious treatment-related ocular adverseevent Most adverse events resulting in discontinuationwere mild or moderate in severity and resolved by theend of the studyAt month 24 the majority of responding physicians

rated the overall efficacy of latanoprosttimolol FC asldquovery goodrdquo or ldquogoodrdquo (PP population 922997 [925]FAS population 13121504 [872]) Among subjectsfor whom physicians provided evaluations at month 24the overall tolerability of the FC was assessed as either

Table 2 Baseline characteristics N = 2339

Age (years)

Mean plusmn SD 655 plusmn117

Range 10 96

Male gender n () 1047(448)

Primary diagnosisdagger

Open-angle glaucoma 1910

Ocular hypertension 177

Pseudoexfoliation glaucoma 114

Normal-tension glaucoma 111

Glaucoma NOS 41

Angle-closure glaucoma 17

Pigmentary glaucoma 12

Ocular hypotensive therapy reported by ge50 subjects

Bimatoprost 50

Brinzolamide 92

Dorzolamidetimolol FC 92

Latanoprost 343

Timolol 173

Timolol maleate 115

Travoprost 93

Reason(s) for switching to latanoprosttimolol FCDagger n ()

Inadequate IOP reduction on prior therapy 1830(782)

Desire to simplify treatment with once-daily dosing 687 (294)

Side effectshypersensitivity reactions with prior therapy 219 (94)

Prior therapy contraindicated due to subjectrsquos signssymptoms

103 (44)

Other 120 (51)

FC = fixed combination IOP = intraocular pressure NOS = not otherwisespecified SD = standard deviation

Age was missing for 57 subjects gender was missing for 48 subjectsdaggerCounts are based on diagnoses for both eyes If a subject had a differentdiagnosis for each eye these were counted twice and if a subject had morethan one diagnosis for the same eye each was countedDaggerMore than one reason could have been recorded by physicians Percentagesare based on the number of patients (N = 2339)

Table 3 Mean IOP and mean change in IOP frombaselinedagger by visit (mmHg) PP population

Visit n Mean plusmn SD(95 CI)

Change from baseline mean plusmn SD(95 CIDagger)

Baseline 1028 203 plusmn 420 na

(201 206)

Month 6 1012 164 plusmn 304 -40 plusmn 431

(162 166) (-43 -38)

Month 12 1017 164 plusmn 304 -39 plusmn 453

(162 166) (-42 -37)

Month 18 1010 164 plusmn 299 -40 plusmn 443

(162 165) (-43 -37)

Month 24 980 162 plusmn 317 -42 plusmn 469

(160 164) (-45 -39)

Last visitsect 1028 162 plusmn 316 -41 plusmn 466

(160 164) (-44 -38)

CI = confidence interval IOP = intraocular pressure na = not applicable PP =per protocol

SD = standard deviation

Raw IOP valuesdaggerMonth times - baselineDaggerP lt 005 for change from baseline at each visitsectLast visit = last postbaseline visit at which an IOP level was recorded

Figure 1 Box-plot of intraocular pressure by visit PP populationPP = per protocol Bars represent minimum and maximum valuesBoxes represent interquartile range and median Line presents themean profile over time

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ldquovery goodrdquo or ldquogoodrdquo in 15031584 (949) subjects andcompliance with the FC as ldquovery goodrdquo or ldquogoodrdquo in14391580 (911) subjects More than three-quarters(11231351 [831) of responding subjects reported nochange in iris color at month 24 and nearly 90 (n =13431520 [884]) indicated a desire to continue FCtreatment after the completion of study At month 24change in visual acuity from baseline was not statisti-cally or clinically significant

DiscussionResults of this long-term observational study of latano-prosttimolol FC demonstrate that the combinationeffectively reduces IOP levels and is well tolerated inpatients with glaucoma or ocular hypertension whochange from their previous ocular hypotensive therapyfor medical reasons The significant IOP-lowering effectof the FC was seen early at the month 6 visit and wassustained throughout the 24-month follow-up periodMoreover no significant changes in optic disc and visualfield defect were noted by investigators and structuraland functional parameters remained stable over 24months Investigator assessments revealed no significantassociation between IOP reduction over two years andchange in visual fieldPrevious research has demonstrated that progression

of glaucoma or ocular hypertension can be delayed orhalted by lowering IOP levels through the use of ocularhypotensive agents [218-21] Herein the mean IOPreduction of approximately 4 mmHg sustained over 24months was somewhat greater than reductions reportedin previous short-term observational studies of patientsswitched to the FC [2223] For example a prospectivemulticenter study [22] of patients switched to latano-prosttimolol FC and followed for at least two monthsfound mean IOP reductions from baseline of 29 mmHgin those with primary open-angle glaucoma or exfolia-tion glaucoma and of 31 mmHg among patients withocular hypertension (P lt 0001 for all) A multicenterobservational study [23] of patients with glaucoma orocular hypertension who were switched to the FC andfollowed for six months reported mean IOP reductionsfrom baseline of 33 mmHg 41 mmHg and 34 mmHgamong patients with open-angle glaucoma exfoliationglaucoma and ocular hypertension respectively (P lt0001 for all)As has been shown previously [11-16] the FC was

well tolerated In all 99185 (535) adverse events wereocular in nature half of treatment-related adverse eventsrelated to the eye and two of the three reported treat-ment-related serious adverse events were ocular Fewerthan 3 of subjects discontinued the FC due to an ocu-lar adverse event The tolerability of an ocular hypoten-sive agent is important given the negative impact of

Table 4 Mean IOP and mean change in IOP from baselineto last visit (mmHg) alternate populations

Visit n Mean plusmn SD(95 CI)

Change from baseline mean plusmn SD(95 CIdagger)

PP population corrected IOP[17]

Baseline 546 205 plusmn 394 na

(202 209)

Last visit 546 163 plusmn 330 -42 plusmn 421

(160 166) (-46 -39)

Full analysis set raw IOP

Baseline 1913 204 plusmn 425 na

(202 206)

Last visit 1934 164 plusmn 342 -39 plusmn 465Dagger

(163 166) (-42 -37)

PP population with applanation tonometry data raw IOP

Baseline 732 203 plusmn 431 na

(200 206)

Last visit 687 162 plusmn 302 -40 plusmn 459sect

(160 164) (-43 -36)

CI = confidence interval IOP = intraocular pressure na = not applicable PP =per protocol

SD = standard deviation

Last visit = last postbaseline visit at which an IOP level was recordeddaggerP lt 005 for change from baseline to last visit for each parameterDaggerN = 1913sectN = 631

Table 5 Mean change from baseline in horizontal andvertical cupdisc ratios by visit PP population

Visit n Mean plusmn SD (95 CI)

Horizontal cupdisc ratio

Month 6 645 00003 plusmn 013117

(-00099 00104)

Month 12 660 00039 plusmn 013286

(-00063 00140)

Month 18 666 00092 plusmn 013860

(-00014 00197)

Month 24 666 00041 plusmn 014078

(-00067 00148)

Last visit 783 00079 plusmn 014645

(-00024 00182)

Vertical cupdisc ratio

Month 6 600 00040 plusmn 012772

(-00062 00142)

Month 12 604 00075 plusmn 013726

(-00035 00184)

Month 18 613 00152 plusmn 014613

(00036 00268)

Month 24 615 00088 plusmn 013534

(-00019 00195)

Last visit 729 00127 plusmn 015155

(00017 00237)

CI = confidence interval PP = per protocol SD = standard deviation

Month times - baseline Last visit = last postbaseline visit at which the parameterwas recorded

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Page 6 of 9

ocular adverse events on patient continuation with ther-apy [2425]At month 24 physician evaluations of latanoprost

timolol FC were overwhelmingly positive with regard toefficacy tolerability and patient compliance In additionnearly 90 of patients expressed a desire to remain onthe FC after the end of the study These positive evalua-tions are tempered however by the fact that they weremade for and by patients who stayed on therapy for thefull follow-up period it is not known how many ofthose for whom efficacy tolerability or compliance wereissues discontinued FC therapy prior to that time pointConversely nearly 90 of discontinuations in the pre-sent study were unrelated to latanoprosttimolol FCwith the vast majority attributable to loss to follow-upMoreover a prior study [23] of patients switched tolatanoprosttimolol FC found that 97 of patients(10081042) remained on treatment after the 6-monthstudy period

Benefits of prescribing a FC agent for patients withglaucoma or ocular hypertension may include improvedadherence persistence convenience and reduced expo-sure to preservatives Improved adherence and persis-tence in particular are critical since the use of aneffective ocular hypotensive agent over the long termmay be expected to increase the likelihood of delayingor stopping glaucomatous damage Poorer compliancehas been demonstrated in those treated with more com-plex medication regimens [26-30] Comparative studiesof medication compliance in patients prescribed alterna-tive FC therapies are neededThis study has both strengths and limitations The

observational design may have better reflected actualclinical practice than controlled clinical trials but theabsence of a control group limits our ability to drawconclusions and the PP population included fewer thanhalf the number of subjects treated primarily due toloss to follow-up Given the observational design it was

Table 6 Changes in progression measures by last visit and month 24 nN () PP population

Progression measure Last visit Month 24

Increase in horizontal or vertical cupdisc ratio by ge02 (visit - baseline)dagger 98797 (123) 78676 (115)

ge1 postbaseline optic disc hemorrhageDagger 29983 (30) 23785 (29)

Decrease in ge1 rim area rim volume andor mean RNFL thickness by HRT (visit - baseline)dagger 28222 (126) 13151 (86)

Visual field deterioration rated as progression by physician at ge1 postbaseline visitDagger 137884 (155) 104630 (165)

Increase in Aulhorn stagesect by ge1 stage (visit - baseline)dagger 64370 (173) 43258 (167)

Decrease in mean defect by ge25 dBdagger 59371 (159) 45285 (158)

HRT = Heidelberg Retina Tomograph PP = per protocol RNFL = retinal nerve fiber layer

Last visit = last postbaseline visit at which the parameter was recordeddaggerTo be included in the percentage a subject must have had assessments at both the baseline and ge1 postbaseline visit for the relevant measureDaggerTo be included in the percentage a subject must have had ge1 postbaseline assessment for the relevant measuresectReflects all methods of determining Aulhorn stage

Table 7 Adverse events N = 2339

All causalitiesn ()

Treatment relatedn ()

All adverse events

Number of events 185 88

Subjects with

ge1 adverse event 148 (63) 72 (31)

ge1 serious adverse event 54 (23) 3 (01)

ge1 severe adverse event 70 (30) 15 (06)

Discontinued FC due to adverse event 69 (29) 52 (22)

Dose reducedtemporarily discontinued FC due to adverse event 22 (09) 8 (03)

All Ocular Adverse Events

Number of events 99 44

Subjects with

ge1 adverse event 84 (36) 39 (17)

ge1 serious adverse event 29 (12) 2 (01)

ge1 severe adverse event 35 (15) 5 (02)

Discontinued FC due to adverse event 41 (18) 28 (12)

Dose reducedtemporarily discontinued FC due to adverse event 19 (08) 6 (03)

FC = fixed combination

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 7 of 9

not possible to standardized the timing and method ofmeasuring IOP levels and visual field defects It is nota-ble however that IOP reductions from baseline to lastvisit among the 687 subjects evaluated by applanationtonometry were similar to those observed for the totalpopulation Although the design did not include a wash-out period between termination of baseline therapy andinitiation of latanoprosttimolol FC combination thiswould not be expected to impact the long-term out-comes evaluated herein The 24-month follow-up periodmay have been too short to detect changes in visualfields Moreover last visit data for individual progressionmeasures reflected a time point prior to month 24 forbetween 15 (for cupdisc ratio data) and 32 (for rimareavolumeretinal nerve fiber layer data) of evaluablesubjects Strict adherence to study procedures andreporting requirements could not be affirmed given thelarge number of participating physicians and the pro-longed follow-up period Finally while 17 of patientsreported a change in iris color from baseline to month24 evaluations relied on recollections of baseline colorThe Ocular Hypertension Treatment Study [2] foundthat 171 of subjects prescribed a prostaglandin analo-gue for at least six months and 76 of those in theobservation group reported a change in iris color dar-kening of the eyelids or growth of eyelashes

ConclusionsThis 24-month study demonstrated that latanoprosttimolol FC effectively reduces IOP levels and is well tol-erated in patients switched from other ocular hypoten-sive therapies for medical reasons Investigatorassessments showed optic disc parameters and visualfield to be stable throughout the follow-up period

AcknowledgementsThe results of this study were presented in part at the 8th InternationalSymposium on Ocular Pharmacology and Therapeutics December 3-6 2009Rome ItalyEditorial support including contributing to the first draft of the manuscriptrevising the paper based on author feedback and styling the paper forjournal submission was provided by Jane G Murphy PhD of ZolaAssociates and was funded by Pfizer Inc

Author details1Buumlrgerhospital Frankfurt am Main Augenklinik Frankfurt am Main Germany2Private practice Bruchsal Germany 3Pfizer Pharma GmbH Berlin Germany4Pfizer Limited UK Specialty Care Sandwich Kent UK

Authorsrsquo contributionsOS participated in the study concept and design analysis and interpretationof data and critical revision of the manuscript for important intellectualcontent BH participated in the study concept and design acquisition ofdata analysis and interpretation of data and critical revision of themanuscript for important intellectual content CZ participated in the analysisand interpretation of data critical revision of the manuscript for importantintellectual content and study supervision PM participated in the analysisand interpretation of data and critical revision of the manuscript forimportant intellectual content All authors read and approved the finalmanuscript

Competing interestsDr Guzy is an employee of Pfizer Pharma GmbH Mr Miller is an employeeof Pfizer Limited UK Specialty Care The research was funded by PfizerPharma GmbH

Received 15 April 2010 Accepted 8 September 2010Published 8 September 2010

References1 European Glaucoma Society Terminology and Guidelines for Glaucoma

Savona Italy DOGMA II 2008 [httpwwweugsorgengEGS_guidelinesasp] Accessed September 3 2010

2 Kass MA Heuer DK Higginbotham EJ Johnson CA Keltner JL Miller JPParrish RK Wilson MR Gordon MO The Ocular Hypertension TreatmentStudy a randomized trial determines that topical ocular hypotensivemedication delays or prevents the onset of primary open-angleglaucoma Arch Ophthalmol 2002 120701-713

3 Toris CB Gabelt BT Kaufman PL Update on the mechanism of action oftopical prostaglandins for intraocular pressure reduction SurvOphthalmol 2008 53(Suppl 1)S107-120

4 Xalacomreg Summary of Product Characteristics Electronic MedicinesCompendium 2007 [httpemcmedicinesorgukmedicine7735SPCXalacom+eye+drops 2c+solution] Accessed November 16 2009

5 Coakes RL Brubaker RF The mechanism of timolol in lowering intraocularpressure in the normal eye Arch Ophthalmol 1978 962045-2048

6 Zimmerman TJ Harbin R Pett M Kaufman HE Timolol and facility ofoutflow Invest Ophthalmol Vis Sci 1977 16623-624

7 Alm A Widengaringrd I Kjellgren D Soumlderstroumlm M Fristroumlm B Heijl AStjernschantz J Latanoprost administered once daily caused amaintained reduction of intraocular pressure in glaucoma patientstreated concomitantly with timolol Br J Ophthalmol 1995 7912-16

8 Bucci MG Italian Latanoprost Study Group Intraocular pressure-loweringeffects of latanoprost monotherapy versus latanoprost or pilocarpine incombination with timolol a randomized observer-masked multicenterstudy in patients with open-angle glaucoma J Glaucoma 1999 824-30

9 Lee PY Shao H Camras CB Podos SM Additivity of prostaglandin F2alpha-1-isopropyl ester to timolol in glaucoma patients Ophthalmology1991 981079-1082

10 Rulo AH Greve EL Hoyng PF Additive effect of latanoprost aprostaglandin F2 alpha analogue and timolol in patients with elevatedintraocular pressure Br J Ophthalmol 1994 78899-902

11 Diestelhorst M Larsson LI European-Canadian Latanoprost FixedCombination Study Group A 12-week randomized double-maskedmulticenter study of the fixed combination of latanoprost and timolol inthe evening versus the individual components Ophthalmology 200611370-76

12 Diestelhorst M Larsson LI European Latanoprost Fixed Combination StudyGroup A 12 week study comparing the fixed combination of latanoprostand timolol with the concomitant use of the individual components inpatients with open angle glaucoma and ocular hypertension Br JOphthalmol 2004 88199-203

13 Higginbotham EJ Feldman R Stiles M Dubiner H Fixed CombinationInvestigative Group Latanoprost and timolol combination therapy vsmonotherapy one-year randomized trial Arch Ophthalmol 2002120915-922

14 Higginbotham EJ Olander KW Kim EE Grunden JW Kwok KK Tressler CSUnited States Fixed-Combination Study Group Fixed-combinationlatanoprosttimolol vs individual components for POAG or ocularhypertension a randomized double-masked study Arch Ophthalmol2010 128165-172

15 Pfeiffer N European Latanoprost Fixed Combination Study Group Acomparison of the fixed combination of latanoprost and timolol with itsindividual components Graefes Arch Clin Exp Ophthalmol 2002240893-899

16 Shin DH Feldman RM Sheu WP Fixed Combination LatanoprostTimololStudy Group Efficacy and safety of the fixed combinations latanoprosttimolol versus dorzolamidetimolol in patients with elevated intraocularpressure Ophthalmology 2004 111276-282

17 Kohlhaas M Boehm AG Spoerl E Puumlrsten A Grein HJ Pillunat LE Effect ofcentral corneal thickness corneal curvature and axial length onapplanation tonometry Arch Ophthalmol 2006 124471-476

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 8 of 9

reduction in subjects switched to latanoprosttimolol FCfrom multiple therapies was -25 plusmn 448 mmHg (n =119) and was -45 plusmn 477 mmHg in subjects for whomthe prior ocular hypotensive therapy was not recorded(n = 586)Changes from baseline in horizontal and vertical cup

disc ratios showed a tendency toward stability and werenot considered to be clinically significant (Table 5)Among subjects in the PP population for whom infor-mation concerning whether or not they had an opticdisc hemorrhage at any postbaseline visit was availablethe percentage with a hemorrhage was lower at each fol-low-up visit than at baseline (20916 [22] at baselinevs le15 at any postbaseline visit) In all 29983 (30)reported ge1 postbaseline optic disc hemorrhage and 4983 (04) had repeated occurrences at gt1 postbaselinevisitInformation concerning mean visual field defect mea-

surement method was available for 744 subjects and themost commonly used measurement method was theHumphrey Visual Field Analyzer (n = 337) At month24 72 of the 122 subjects (590) with valid data for theAulhorn stage based on the Humphrey Visual FieldAnalyzer at both baseline and month 24 had no changein stage 156 25 and 08 of subjects increased by1 2 and 3 stages respectively whereas 156 4908 and 08 of subjects decreased by 1 2 3 and 4stages respectivelyIn the PP population there were no statistically signif-

icant changes in mean defect from baseline to months6 12 18 and 24 or to the last visit In the multivariateanalysis change in mean defect from baseline to the lastvisit was related only to baseline mean defect This

analysis only involved subjects with nonmissing data forthe response variable and all potential explanatory vari-ables (n = 355) The final model was reduced to a sim-ple linear regression with intercept -0718 and slope-0283 (95 CI -0354 -0211 P lt 00001) Hence sub-jects with a lower baseline mean defect experienced ahigher change in mean defect from baseline to last visitIn addition the correlation between changes from base-line to last visit in mean defect and in IOP was esti-mated at 00276 (95 CI -00603 01156 P = 05956n = 371) providing no evidence of a relationshipbetween IOP reduction and reduction in mean defectFewer than 18 of evaluable subjects demonstrated a

negative change in any individual progression measureby last visit or month 24 (Table 6) By the last visit pro-gression of optic disc excavation (increase in horizontalor vertical cupdisc ratio by ge02 or decrease in rimarea rim volume andor mean retinal nerve fiber layerthickness by 02 mm2 01 mm3 and 01 mm respec-tively as measured by Heidelberg Retina Tomograph)was noted in 117816 (143) subjects Visual field pro-gression (progressive visual field deterioration noted bythe physician at ge1 postbaseline visit and an increase inAulhorn stage by ge1 stage andor decrease in meandefect by ge25 dB) occurred in 46900 (51) of subjectsby the last visit Based on the six-item composite vari-able overall progression of glaucoma by the last visitwas noted in 305 (302) of the 1010 subjects in the PPpopulation who provided a response to ge1 of the sixindividual progression measures Logistic regressiondemonstrated that only age was a significant predictorof composite overall progression by the last visit (oddsratio = 0984 95 CI 0972 0996 P = 00102

Table 1 Subject disposition

No () subjects

Received latanoprosttimolol FC 2339

Completed 24 months of follow-up 1317 (563)

Discontinued prior to 24 months 1022 (437)

Per protocol population

Included 1028 (440)

Excluded 1311 (660)

Reason(s) for exclusion

Not treated for ge18 months 512

No baseline and ge1 postbaseline measure for IOP ge18 months apart 487

Additional ocular hypotensive medication during study 402

Ametropy at baseline 42

Full analysis set

Included 1934 (827)

Excluded (no postbaseline IOP measurement) 405 (173)

Safety population 2339 (1000)

FC = fixed combination IOP = intraocular pressure

More than one reason was possible If a subject was excluded from the full analysis set a separate reason for exclusion from the per protocol population is notprovided in this table

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 4 of 9

n = 952) From this final model there is evidence thatthe probability of experiencing overall progression ofglaucoma damage increases with ageLatanoprosttimolol FC was safe and well tolerated

Sixteen deaths were reported none of which was con-sidered by investigators to be related to study treatmentIn all 148 subjects treated with latanoprosttimolol FCexperienced 185 adverse events and 88 treatment-related adverse events were reported in 72 subjects(Table 7) Three (01) subjects experienced seriousadverse events deemed by investigators to be related tostudy treatment Fifty-two (22) subjects permanentlydiscontinued treatment with the FC due to a treatment-related adverse event Ocular adverse events were themost commonly reported adverse events Treatment-related ocular adverse events were noted in 39 (17)

subjects and 28 (12) permanently discontinued FCtherapy due to such an event Two (01) subjectsexperienced a serious treatment-related ocular adverseevent Most adverse events resulting in discontinuationwere mild or moderate in severity and resolved by theend of the studyAt month 24 the majority of responding physicians

rated the overall efficacy of latanoprosttimolol FC asldquovery goodrdquo or ldquogoodrdquo (PP population 922997 [925]FAS population 13121504 [872]) Among subjectsfor whom physicians provided evaluations at month 24the overall tolerability of the FC was assessed as either

Table 2 Baseline characteristics N = 2339

Age (years)

Mean plusmn SD 655 plusmn117

Range 10 96

Male gender n () 1047(448)

Primary diagnosisdagger

Open-angle glaucoma 1910

Ocular hypertension 177

Pseudoexfoliation glaucoma 114

Normal-tension glaucoma 111

Glaucoma NOS 41

Angle-closure glaucoma 17

Pigmentary glaucoma 12

Ocular hypotensive therapy reported by ge50 subjects

Bimatoprost 50

Brinzolamide 92

Dorzolamidetimolol FC 92

Latanoprost 343

Timolol 173

Timolol maleate 115

Travoprost 93

Reason(s) for switching to latanoprosttimolol FCDagger n ()

Inadequate IOP reduction on prior therapy 1830(782)

Desire to simplify treatment with once-daily dosing 687 (294)

Side effectshypersensitivity reactions with prior therapy 219 (94)

Prior therapy contraindicated due to subjectrsquos signssymptoms

103 (44)

Other 120 (51)

FC = fixed combination IOP = intraocular pressure NOS = not otherwisespecified SD = standard deviation

Age was missing for 57 subjects gender was missing for 48 subjectsdaggerCounts are based on diagnoses for both eyes If a subject had a differentdiagnosis for each eye these were counted twice and if a subject had morethan one diagnosis for the same eye each was countedDaggerMore than one reason could have been recorded by physicians Percentagesare based on the number of patients (N = 2339)

Table 3 Mean IOP and mean change in IOP frombaselinedagger by visit (mmHg) PP population

Visit n Mean plusmn SD(95 CI)

Change from baseline mean plusmn SD(95 CIDagger)

Baseline 1028 203 plusmn 420 na

(201 206)

Month 6 1012 164 plusmn 304 -40 plusmn 431

(162 166) (-43 -38)

Month 12 1017 164 plusmn 304 -39 plusmn 453

(162 166) (-42 -37)

Month 18 1010 164 plusmn 299 -40 plusmn 443

(162 165) (-43 -37)

Month 24 980 162 plusmn 317 -42 plusmn 469

(160 164) (-45 -39)

Last visitsect 1028 162 plusmn 316 -41 plusmn 466

(160 164) (-44 -38)

CI = confidence interval IOP = intraocular pressure na = not applicable PP =per protocol

SD = standard deviation

Raw IOP valuesdaggerMonth times - baselineDaggerP lt 005 for change from baseline at each visitsectLast visit = last postbaseline visit at which an IOP level was recorded

Figure 1 Box-plot of intraocular pressure by visit PP populationPP = per protocol Bars represent minimum and maximum valuesBoxes represent interquartile range and median Line presents themean profile over time

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 5 of 9

ldquovery goodrdquo or ldquogoodrdquo in 15031584 (949) subjects andcompliance with the FC as ldquovery goodrdquo or ldquogoodrdquo in14391580 (911) subjects More than three-quarters(11231351 [831) of responding subjects reported nochange in iris color at month 24 and nearly 90 (n =13431520 [884]) indicated a desire to continue FCtreatment after the completion of study At month 24change in visual acuity from baseline was not statisti-cally or clinically significant

DiscussionResults of this long-term observational study of latano-prosttimolol FC demonstrate that the combinationeffectively reduces IOP levels and is well tolerated inpatients with glaucoma or ocular hypertension whochange from their previous ocular hypotensive therapyfor medical reasons The significant IOP-lowering effectof the FC was seen early at the month 6 visit and wassustained throughout the 24-month follow-up periodMoreover no significant changes in optic disc and visualfield defect were noted by investigators and structuraland functional parameters remained stable over 24months Investigator assessments revealed no significantassociation between IOP reduction over two years andchange in visual fieldPrevious research has demonstrated that progression

of glaucoma or ocular hypertension can be delayed orhalted by lowering IOP levels through the use of ocularhypotensive agents [218-21] Herein the mean IOPreduction of approximately 4 mmHg sustained over 24months was somewhat greater than reductions reportedin previous short-term observational studies of patientsswitched to the FC [2223] For example a prospectivemulticenter study [22] of patients switched to latano-prosttimolol FC and followed for at least two monthsfound mean IOP reductions from baseline of 29 mmHgin those with primary open-angle glaucoma or exfolia-tion glaucoma and of 31 mmHg among patients withocular hypertension (P lt 0001 for all) A multicenterobservational study [23] of patients with glaucoma orocular hypertension who were switched to the FC andfollowed for six months reported mean IOP reductionsfrom baseline of 33 mmHg 41 mmHg and 34 mmHgamong patients with open-angle glaucoma exfoliationglaucoma and ocular hypertension respectively (P lt0001 for all)As has been shown previously [11-16] the FC was

well tolerated In all 99185 (535) adverse events wereocular in nature half of treatment-related adverse eventsrelated to the eye and two of the three reported treat-ment-related serious adverse events were ocular Fewerthan 3 of subjects discontinued the FC due to an ocu-lar adverse event The tolerability of an ocular hypoten-sive agent is important given the negative impact of

Table 4 Mean IOP and mean change in IOP from baselineto last visit (mmHg) alternate populations

Visit n Mean plusmn SD(95 CI)

Change from baseline mean plusmn SD(95 CIdagger)

PP population corrected IOP[17]

Baseline 546 205 plusmn 394 na

(202 209)

Last visit 546 163 plusmn 330 -42 plusmn 421

(160 166) (-46 -39)

Full analysis set raw IOP

Baseline 1913 204 plusmn 425 na

(202 206)

Last visit 1934 164 plusmn 342 -39 plusmn 465Dagger

(163 166) (-42 -37)

PP population with applanation tonometry data raw IOP

Baseline 732 203 plusmn 431 na

(200 206)

Last visit 687 162 plusmn 302 -40 plusmn 459sect

(160 164) (-43 -36)

CI = confidence interval IOP = intraocular pressure na = not applicable PP =per protocol

SD = standard deviation

Last visit = last postbaseline visit at which an IOP level was recordeddaggerP lt 005 for change from baseline to last visit for each parameterDaggerN = 1913sectN = 631

Table 5 Mean change from baseline in horizontal andvertical cupdisc ratios by visit PP population

Visit n Mean plusmn SD (95 CI)

Horizontal cupdisc ratio

Month 6 645 00003 plusmn 013117

(-00099 00104)

Month 12 660 00039 plusmn 013286

(-00063 00140)

Month 18 666 00092 plusmn 013860

(-00014 00197)

Month 24 666 00041 plusmn 014078

(-00067 00148)

Last visit 783 00079 plusmn 014645

(-00024 00182)

Vertical cupdisc ratio

Month 6 600 00040 plusmn 012772

(-00062 00142)

Month 12 604 00075 plusmn 013726

(-00035 00184)

Month 18 613 00152 plusmn 014613

(00036 00268)

Month 24 615 00088 plusmn 013534

(-00019 00195)

Last visit 729 00127 plusmn 015155

(00017 00237)

CI = confidence interval PP = per protocol SD = standard deviation

Month times - baseline Last visit = last postbaseline visit at which the parameterwas recorded

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 6 of 9

ocular adverse events on patient continuation with ther-apy [2425]At month 24 physician evaluations of latanoprost

timolol FC were overwhelmingly positive with regard toefficacy tolerability and patient compliance In additionnearly 90 of patients expressed a desire to remain onthe FC after the end of the study These positive evalua-tions are tempered however by the fact that they weremade for and by patients who stayed on therapy for thefull follow-up period it is not known how many ofthose for whom efficacy tolerability or compliance wereissues discontinued FC therapy prior to that time pointConversely nearly 90 of discontinuations in the pre-sent study were unrelated to latanoprosttimolol FCwith the vast majority attributable to loss to follow-upMoreover a prior study [23] of patients switched tolatanoprosttimolol FC found that 97 of patients(10081042) remained on treatment after the 6-monthstudy period

Benefits of prescribing a FC agent for patients withglaucoma or ocular hypertension may include improvedadherence persistence convenience and reduced expo-sure to preservatives Improved adherence and persis-tence in particular are critical since the use of aneffective ocular hypotensive agent over the long termmay be expected to increase the likelihood of delayingor stopping glaucomatous damage Poorer compliancehas been demonstrated in those treated with more com-plex medication regimens [26-30] Comparative studiesof medication compliance in patients prescribed alterna-tive FC therapies are neededThis study has both strengths and limitations The

observational design may have better reflected actualclinical practice than controlled clinical trials but theabsence of a control group limits our ability to drawconclusions and the PP population included fewer thanhalf the number of subjects treated primarily due toloss to follow-up Given the observational design it was

Table 6 Changes in progression measures by last visit and month 24 nN () PP population

Progression measure Last visit Month 24

Increase in horizontal or vertical cupdisc ratio by ge02 (visit - baseline)dagger 98797 (123) 78676 (115)

ge1 postbaseline optic disc hemorrhageDagger 29983 (30) 23785 (29)

Decrease in ge1 rim area rim volume andor mean RNFL thickness by HRT (visit - baseline)dagger 28222 (126) 13151 (86)

Visual field deterioration rated as progression by physician at ge1 postbaseline visitDagger 137884 (155) 104630 (165)

Increase in Aulhorn stagesect by ge1 stage (visit - baseline)dagger 64370 (173) 43258 (167)

Decrease in mean defect by ge25 dBdagger 59371 (159) 45285 (158)

HRT = Heidelberg Retina Tomograph PP = per protocol RNFL = retinal nerve fiber layer

Last visit = last postbaseline visit at which the parameter was recordeddaggerTo be included in the percentage a subject must have had assessments at both the baseline and ge1 postbaseline visit for the relevant measureDaggerTo be included in the percentage a subject must have had ge1 postbaseline assessment for the relevant measuresectReflects all methods of determining Aulhorn stage

Table 7 Adverse events N = 2339

All causalitiesn ()

Treatment relatedn ()

All adverse events

Number of events 185 88

Subjects with

ge1 adverse event 148 (63) 72 (31)

ge1 serious adverse event 54 (23) 3 (01)

ge1 severe adverse event 70 (30) 15 (06)

Discontinued FC due to adverse event 69 (29) 52 (22)

Dose reducedtemporarily discontinued FC due to adverse event 22 (09) 8 (03)

All Ocular Adverse Events

Number of events 99 44

Subjects with

ge1 adverse event 84 (36) 39 (17)

ge1 serious adverse event 29 (12) 2 (01)

ge1 severe adverse event 35 (15) 5 (02)

Discontinued FC due to adverse event 41 (18) 28 (12)

Dose reducedtemporarily discontinued FC due to adverse event 19 (08) 6 (03)

FC = fixed combination

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 7 of 9

not possible to standardized the timing and method ofmeasuring IOP levels and visual field defects It is nota-ble however that IOP reductions from baseline to lastvisit among the 687 subjects evaluated by applanationtonometry were similar to those observed for the totalpopulation Although the design did not include a wash-out period between termination of baseline therapy andinitiation of latanoprosttimolol FC combination thiswould not be expected to impact the long-term out-comes evaluated herein The 24-month follow-up periodmay have been too short to detect changes in visualfields Moreover last visit data for individual progressionmeasures reflected a time point prior to month 24 forbetween 15 (for cupdisc ratio data) and 32 (for rimareavolumeretinal nerve fiber layer data) of evaluablesubjects Strict adherence to study procedures andreporting requirements could not be affirmed given thelarge number of participating physicians and the pro-longed follow-up period Finally while 17 of patientsreported a change in iris color from baseline to month24 evaluations relied on recollections of baseline colorThe Ocular Hypertension Treatment Study [2] foundthat 171 of subjects prescribed a prostaglandin analo-gue for at least six months and 76 of those in theobservation group reported a change in iris color dar-kening of the eyelids or growth of eyelashes

ConclusionsThis 24-month study demonstrated that latanoprosttimolol FC effectively reduces IOP levels and is well tol-erated in patients switched from other ocular hypoten-sive therapies for medical reasons Investigatorassessments showed optic disc parameters and visualfield to be stable throughout the follow-up period

AcknowledgementsThe results of this study were presented in part at the 8th InternationalSymposium on Ocular Pharmacology and Therapeutics December 3-6 2009Rome ItalyEditorial support including contributing to the first draft of the manuscriptrevising the paper based on author feedback and styling the paper forjournal submission was provided by Jane G Murphy PhD of ZolaAssociates and was funded by Pfizer Inc

Author details1Buumlrgerhospital Frankfurt am Main Augenklinik Frankfurt am Main Germany2Private practice Bruchsal Germany 3Pfizer Pharma GmbH Berlin Germany4Pfizer Limited UK Specialty Care Sandwich Kent UK

Authorsrsquo contributionsOS participated in the study concept and design analysis and interpretationof data and critical revision of the manuscript for important intellectualcontent BH participated in the study concept and design acquisition ofdata analysis and interpretation of data and critical revision of themanuscript for important intellectual content CZ participated in the analysisand interpretation of data critical revision of the manuscript for importantintellectual content and study supervision PM participated in the analysisand interpretation of data and critical revision of the manuscript forimportant intellectual content All authors read and approved the finalmanuscript

Competing interestsDr Guzy is an employee of Pfizer Pharma GmbH Mr Miller is an employeeof Pfizer Limited UK Specialty Care The research was funded by PfizerPharma GmbH

Received 15 April 2010 Accepted 8 September 2010Published 8 September 2010

References1 European Glaucoma Society Terminology and Guidelines for Glaucoma

Savona Italy DOGMA II 2008 [httpwwweugsorgengEGS_guidelinesasp] Accessed September 3 2010

2 Kass MA Heuer DK Higginbotham EJ Johnson CA Keltner JL Miller JPParrish RK Wilson MR Gordon MO The Ocular Hypertension TreatmentStudy a randomized trial determines that topical ocular hypotensivemedication delays or prevents the onset of primary open-angleglaucoma Arch Ophthalmol 2002 120701-713

3 Toris CB Gabelt BT Kaufman PL Update on the mechanism of action oftopical prostaglandins for intraocular pressure reduction SurvOphthalmol 2008 53(Suppl 1)S107-120

4 Xalacomreg Summary of Product Characteristics Electronic MedicinesCompendium 2007 [httpemcmedicinesorgukmedicine7735SPCXalacom+eye+drops 2c+solution] Accessed November 16 2009

5 Coakes RL Brubaker RF The mechanism of timolol in lowering intraocularpressure in the normal eye Arch Ophthalmol 1978 962045-2048

6 Zimmerman TJ Harbin R Pett M Kaufman HE Timolol and facility ofoutflow Invest Ophthalmol Vis Sci 1977 16623-624

7 Alm A Widengaringrd I Kjellgren D Soumlderstroumlm M Fristroumlm B Heijl AStjernschantz J Latanoprost administered once daily caused amaintained reduction of intraocular pressure in glaucoma patientstreated concomitantly with timolol Br J Ophthalmol 1995 7912-16

8 Bucci MG Italian Latanoprost Study Group Intraocular pressure-loweringeffects of latanoprost monotherapy versus latanoprost or pilocarpine incombination with timolol a randomized observer-masked multicenterstudy in patients with open-angle glaucoma J Glaucoma 1999 824-30

9 Lee PY Shao H Camras CB Podos SM Additivity of prostaglandin F2alpha-1-isopropyl ester to timolol in glaucoma patients Ophthalmology1991 981079-1082

10 Rulo AH Greve EL Hoyng PF Additive effect of latanoprost aprostaglandin F2 alpha analogue and timolol in patients with elevatedintraocular pressure Br J Ophthalmol 1994 78899-902

11 Diestelhorst M Larsson LI European-Canadian Latanoprost FixedCombination Study Group A 12-week randomized double-maskedmulticenter study of the fixed combination of latanoprost and timolol inthe evening versus the individual components Ophthalmology 200611370-76

12 Diestelhorst M Larsson LI European Latanoprost Fixed Combination StudyGroup A 12 week study comparing the fixed combination of latanoprostand timolol with the concomitant use of the individual components inpatients with open angle glaucoma and ocular hypertension Br JOphthalmol 2004 88199-203

13 Higginbotham EJ Feldman R Stiles M Dubiner H Fixed CombinationInvestigative Group Latanoprost and timolol combination therapy vsmonotherapy one-year randomized trial Arch Ophthalmol 2002120915-922

14 Higginbotham EJ Olander KW Kim EE Grunden JW Kwok KK Tressler CSUnited States Fixed-Combination Study Group Fixed-combinationlatanoprosttimolol vs individual components for POAG or ocularhypertension a randomized double-masked study Arch Ophthalmol2010 128165-172

15 Pfeiffer N European Latanoprost Fixed Combination Study Group Acomparison of the fixed combination of latanoprost and timolol with itsindividual components Graefes Arch Clin Exp Ophthalmol 2002240893-899

16 Shin DH Feldman RM Sheu WP Fixed Combination LatanoprostTimololStudy Group Efficacy and safety of the fixed combinations latanoprosttimolol versus dorzolamidetimolol in patients with elevated intraocularpressure Ophthalmology 2004 111276-282

17 Kohlhaas M Boehm AG Spoerl E Puumlrsten A Grein HJ Pillunat LE Effect ofcentral corneal thickness corneal curvature and axial length onapplanation tonometry Arch Ophthalmol 2006 124471-476

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 8 of 9

n = 952) From this final model there is evidence thatthe probability of experiencing overall progression ofglaucoma damage increases with ageLatanoprosttimolol FC was safe and well tolerated

Sixteen deaths were reported none of which was con-sidered by investigators to be related to study treatmentIn all 148 subjects treated with latanoprosttimolol FCexperienced 185 adverse events and 88 treatment-related adverse events were reported in 72 subjects(Table 7) Three (01) subjects experienced seriousadverse events deemed by investigators to be related tostudy treatment Fifty-two (22) subjects permanentlydiscontinued treatment with the FC due to a treatment-related adverse event Ocular adverse events were themost commonly reported adverse events Treatment-related ocular adverse events were noted in 39 (17)

subjects and 28 (12) permanently discontinued FCtherapy due to such an event Two (01) subjectsexperienced a serious treatment-related ocular adverseevent Most adverse events resulting in discontinuationwere mild or moderate in severity and resolved by theend of the studyAt month 24 the majority of responding physicians

rated the overall efficacy of latanoprosttimolol FC asldquovery goodrdquo or ldquogoodrdquo (PP population 922997 [925]FAS population 13121504 [872]) Among subjectsfor whom physicians provided evaluations at month 24the overall tolerability of the FC was assessed as either

Table 2 Baseline characteristics N = 2339

Age (years)

Mean plusmn SD 655 plusmn117

Range 10 96

Male gender n () 1047(448)

Primary diagnosisdagger

Open-angle glaucoma 1910

Ocular hypertension 177

Pseudoexfoliation glaucoma 114

Normal-tension glaucoma 111

Glaucoma NOS 41

Angle-closure glaucoma 17

Pigmentary glaucoma 12

Ocular hypotensive therapy reported by ge50 subjects

Bimatoprost 50

Brinzolamide 92

Dorzolamidetimolol FC 92

Latanoprost 343

Timolol 173

Timolol maleate 115

Travoprost 93

Reason(s) for switching to latanoprosttimolol FCDagger n ()

Inadequate IOP reduction on prior therapy 1830(782)

Desire to simplify treatment with once-daily dosing 687 (294)

Side effectshypersensitivity reactions with prior therapy 219 (94)

Prior therapy contraindicated due to subjectrsquos signssymptoms

103 (44)

Other 120 (51)

FC = fixed combination IOP = intraocular pressure NOS = not otherwisespecified SD = standard deviation

Age was missing for 57 subjects gender was missing for 48 subjectsdaggerCounts are based on diagnoses for both eyes If a subject had a differentdiagnosis for each eye these were counted twice and if a subject had morethan one diagnosis for the same eye each was countedDaggerMore than one reason could have been recorded by physicians Percentagesare based on the number of patients (N = 2339)

Table 3 Mean IOP and mean change in IOP frombaselinedagger by visit (mmHg) PP population

Visit n Mean plusmn SD(95 CI)

Change from baseline mean plusmn SD(95 CIDagger)

Baseline 1028 203 plusmn 420 na

(201 206)

Month 6 1012 164 plusmn 304 -40 plusmn 431

(162 166) (-43 -38)

Month 12 1017 164 plusmn 304 -39 plusmn 453

(162 166) (-42 -37)

Month 18 1010 164 plusmn 299 -40 plusmn 443

(162 165) (-43 -37)

Month 24 980 162 plusmn 317 -42 plusmn 469

(160 164) (-45 -39)

Last visitsect 1028 162 plusmn 316 -41 plusmn 466

(160 164) (-44 -38)

CI = confidence interval IOP = intraocular pressure na = not applicable PP =per protocol

SD = standard deviation

Raw IOP valuesdaggerMonth times - baselineDaggerP lt 005 for change from baseline at each visitsectLast visit = last postbaseline visit at which an IOP level was recorded

Figure 1 Box-plot of intraocular pressure by visit PP populationPP = per protocol Bars represent minimum and maximum valuesBoxes represent interquartile range and median Line presents themean profile over time

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 5 of 9

ldquovery goodrdquo or ldquogoodrdquo in 15031584 (949) subjects andcompliance with the FC as ldquovery goodrdquo or ldquogoodrdquo in14391580 (911) subjects More than three-quarters(11231351 [831) of responding subjects reported nochange in iris color at month 24 and nearly 90 (n =13431520 [884]) indicated a desire to continue FCtreatment after the completion of study At month 24change in visual acuity from baseline was not statisti-cally or clinically significant

DiscussionResults of this long-term observational study of latano-prosttimolol FC demonstrate that the combinationeffectively reduces IOP levels and is well tolerated inpatients with glaucoma or ocular hypertension whochange from their previous ocular hypotensive therapyfor medical reasons The significant IOP-lowering effectof the FC was seen early at the month 6 visit and wassustained throughout the 24-month follow-up periodMoreover no significant changes in optic disc and visualfield defect were noted by investigators and structuraland functional parameters remained stable over 24months Investigator assessments revealed no significantassociation between IOP reduction over two years andchange in visual fieldPrevious research has demonstrated that progression

of glaucoma or ocular hypertension can be delayed orhalted by lowering IOP levels through the use of ocularhypotensive agents [218-21] Herein the mean IOPreduction of approximately 4 mmHg sustained over 24months was somewhat greater than reductions reportedin previous short-term observational studies of patientsswitched to the FC [2223] For example a prospectivemulticenter study [22] of patients switched to latano-prosttimolol FC and followed for at least two monthsfound mean IOP reductions from baseline of 29 mmHgin those with primary open-angle glaucoma or exfolia-tion glaucoma and of 31 mmHg among patients withocular hypertension (P lt 0001 for all) A multicenterobservational study [23] of patients with glaucoma orocular hypertension who were switched to the FC andfollowed for six months reported mean IOP reductionsfrom baseline of 33 mmHg 41 mmHg and 34 mmHgamong patients with open-angle glaucoma exfoliationglaucoma and ocular hypertension respectively (P lt0001 for all)As has been shown previously [11-16] the FC was

well tolerated In all 99185 (535) adverse events wereocular in nature half of treatment-related adverse eventsrelated to the eye and two of the three reported treat-ment-related serious adverse events were ocular Fewerthan 3 of subjects discontinued the FC due to an ocu-lar adverse event The tolerability of an ocular hypoten-sive agent is important given the negative impact of

Table 4 Mean IOP and mean change in IOP from baselineto last visit (mmHg) alternate populations

Visit n Mean plusmn SD(95 CI)

Change from baseline mean plusmn SD(95 CIdagger)

PP population corrected IOP[17]

Baseline 546 205 plusmn 394 na

(202 209)

Last visit 546 163 plusmn 330 -42 plusmn 421

(160 166) (-46 -39)

Full analysis set raw IOP

Baseline 1913 204 plusmn 425 na

(202 206)

Last visit 1934 164 plusmn 342 -39 plusmn 465Dagger

(163 166) (-42 -37)

PP population with applanation tonometry data raw IOP

Baseline 732 203 plusmn 431 na

(200 206)

Last visit 687 162 plusmn 302 -40 plusmn 459sect

(160 164) (-43 -36)

CI = confidence interval IOP = intraocular pressure na = not applicable PP =per protocol

SD = standard deviation

Last visit = last postbaseline visit at which an IOP level was recordeddaggerP lt 005 for change from baseline to last visit for each parameterDaggerN = 1913sectN = 631

Table 5 Mean change from baseline in horizontal andvertical cupdisc ratios by visit PP population

Visit n Mean plusmn SD (95 CI)

Horizontal cupdisc ratio

Month 6 645 00003 plusmn 013117

(-00099 00104)

Month 12 660 00039 plusmn 013286

(-00063 00140)

Month 18 666 00092 plusmn 013860

(-00014 00197)

Month 24 666 00041 plusmn 014078

(-00067 00148)

Last visit 783 00079 plusmn 014645

(-00024 00182)

Vertical cupdisc ratio

Month 6 600 00040 plusmn 012772

(-00062 00142)

Month 12 604 00075 plusmn 013726

(-00035 00184)

Month 18 613 00152 plusmn 014613

(00036 00268)

Month 24 615 00088 plusmn 013534

(-00019 00195)

Last visit 729 00127 plusmn 015155

(00017 00237)

CI = confidence interval PP = per protocol SD = standard deviation

Month times - baseline Last visit = last postbaseline visit at which the parameterwas recorded

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 6 of 9

ocular adverse events on patient continuation with ther-apy [2425]At month 24 physician evaluations of latanoprost

timolol FC were overwhelmingly positive with regard toefficacy tolerability and patient compliance In additionnearly 90 of patients expressed a desire to remain onthe FC after the end of the study These positive evalua-tions are tempered however by the fact that they weremade for and by patients who stayed on therapy for thefull follow-up period it is not known how many ofthose for whom efficacy tolerability or compliance wereissues discontinued FC therapy prior to that time pointConversely nearly 90 of discontinuations in the pre-sent study were unrelated to latanoprosttimolol FCwith the vast majority attributable to loss to follow-upMoreover a prior study [23] of patients switched tolatanoprosttimolol FC found that 97 of patients(10081042) remained on treatment after the 6-monthstudy period

Benefits of prescribing a FC agent for patients withglaucoma or ocular hypertension may include improvedadherence persistence convenience and reduced expo-sure to preservatives Improved adherence and persis-tence in particular are critical since the use of aneffective ocular hypotensive agent over the long termmay be expected to increase the likelihood of delayingor stopping glaucomatous damage Poorer compliancehas been demonstrated in those treated with more com-plex medication regimens [26-30] Comparative studiesof medication compliance in patients prescribed alterna-tive FC therapies are neededThis study has both strengths and limitations The

observational design may have better reflected actualclinical practice than controlled clinical trials but theabsence of a control group limits our ability to drawconclusions and the PP population included fewer thanhalf the number of subjects treated primarily due toloss to follow-up Given the observational design it was

Table 6 Changes in progression measures by last visit and month 24 nN () PP population

Progression measure Last visit Month 24

Increase in horizontal or vertical cupdisc ratio by ge02 (visit - baseline)dagger 98797 (123) 78676 (115)

ge1 postbaseline optic disc hemorrhageDagger 29983 (30) 23785 (29)

Decrease in ge1 rim area rim volume andor mean RNFL thickness by HRT (visit - baseline)dagger 28222 (126) 13151 (86)

Visual field deterioration rated as progression by physician at ge1 postbaseline visitDagger 137884 (155) 104630 (165)

Increase in Aulhorn stagesect by ge1 stage (visit - baseline)dagger 64370 (173) 43258 (167)

Decrease in mean defect by ge25 dBdagger 59371 (159) 45285 (158)

HRT = Heidelberg Retina Tomograph PP = per protocol RNFL = retinal nerve fiber layer

Last visit = last postbaseline visit at which the parameter was recordeddaggerTo be included in the percentage a subject must have had assessments at both the baseline and ge1 postbaseline visit for the relevant measureDaggerTo be included in the percentage a subject must have had ge1 postbaseline assessment for the relevant measuresectReflects all methods of determining Aulhorn stage

Table 7 Adverse events N = 2339

All causalitiesn ()

Treatment relatedn ()

All adverse events

Number of events 185 88

Subjects with

ge1 adverse event 148 (63) 72 (31)

ge1 serious adverse event 54 (23) 3 (01)

ge1 severe adverse event 70 (30) 15 (06)

Discontinued FC due to adverse event 69 (29) 52 (22)

Dose reducedtemporarily discontinued FC due to adverse event 22 (09) 8 (03)

All Ocular Adverse Events

Number of events 99 44

Subjects with

ge1 adverse event 84 (36) 39 (17)

ge1 serious adverse event 29 (12) 2 (01)

ge1 severe adverse event 35 (15) 5 (02)

Discontinued FC due to adverse event 41 (18) 28 (12)

Dose reducedtemporarily discontinued FC due to adverse event 19 (08) 6 (03)

FC = fixed combination

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 7 of 9

not possible to standardized the timing and method ofmeasuring IOP levels and visual field defects It is nota-ble however that IOP reductions from baseline to lastvisit among the 687 subjects evaluated by applanationtonometry were similar to those observed for the totalpopulation Although the design did not include a wash-out period between termination of baseline therapy andinitiation of latanoprosttimolol FC combination thiswould not be expected to impact the long-term out-comes evaluated herein The 24-month follow-up periodmay have been too short to detect changes in visualfields Moreover last visit data for individual progressionmeasures reflected a time point prior to month 24 forbetween 15 (for cupdisc ratio data) and 32 (for rimareavolumeretinal nerve fiber layer data) of evaluablesubjects Strict adherence to study procedures andreporting requirements could not be affirmed given thelarge number of participating physicians and the pro-longed follow-up period Finally while 17 of patientsreported a change in iris color from baseline to month24 evaluations relied on recollections of baseline colorThe Ocular Hypertension Treatment Study [2] foundthat 171 of subjects prescribed a prostaglandin analo-gue for at least six months and 76 of those in theobservation group reported a change in iris color dar-kening of the eyelids or growth of eyelashes

ConclusionsThis 24-month study demonstrated that latanoprosttimolol FC effectively reduces IOP levels and is well tol-erated in patients switched from other ocular hypoten-sive therapies for medical reasons Investigatorassessments showed optic disc parameters and visualfield to be stable throughout the follow-up period

AcknowledgementsThe results of this study were presented in part at the 8th InternationalSymposium on Ocular Pharmacology and Therapeutics December 3-6 2009Rome ItalyEditorial support including contributing to the first draft of the manuscriptrevising the paper based on author feedback and styling the paper forjournal submission was provided by Jane G Murphy PhD of ZolaAssociates and was funded by Pfizer Inc

Author details1Buumlrgerhospital Frankfurt am Main Augenklinik Frankfurt am Main Germany2Private practice Bruchsal Germany 3Pfizer Pharma GmbH Berlin Germany4Pfizer Limited UK Specialty Care Sandwich Kent UK

Authorsrsquo contributionsOS participated in the study concept and design analysis and interpretationof data and critical revision of the manuscript for important intellectualcontent BH participated in the study concept and design acquisition ofdata analysis and interpretation of data and critical revision of themanuscript for important intellectual content CZ participated in the analysisand interpretation of data critical revision of the manuscript for importantintellectual content and study supervision PM participated in the analysisand interpretation of data and critical revision of the manuscript forimportant intellectual content All authors read and approved the finalmanuscript

Competing interestsDr Guzy is an employee of Pfizer Pharma GmbH Mr Miller is an employeeof Pfizer Limited UK Specialty Care The research was funded by PfizerPharma GmbH

Received 15 April 2010 Accepted 8 September 2010Published 8 September 2010

References1 European Glaucoma Society Terminology and Guidelines for Glaucoma

Savona Italy DOGMA II 2008 [httpwwweugsorgengEGS_guidelinesasp] Accessed September 3 2010

2 Kass MA Heuer DK Higginbotham EJ Johnson CA Keltner JL Miller JPParrish RK Wilson MR Gordon MO The Ocular Hypertension TreatmentStudy a randomized trial determines that topical ocular hypotensivemedication delays or prevents the onset of primary open-angleglaucoma Arch Ophthalmol 2002 120701-713

3 Toris CB Gabelt BT Kaufman PL Update on the mechanism of action oftopical prostaglandins for intraocular pressure reduction SurvOphthalmol 2008 53(Suppl 1)S107-120

4 Xalacomreg Summary of Product Characteristics Electronic MedicinesCompendium 2007 [httpemcmedicinesorgukmedicine7735SPCXalacom+eye+drops 2c+solution] Accessed November 16 2009

5 Coakes RL Brubaker RF The mechanism of timolol in lowering intraocularpressure in the normal eye Arch Ophthalmol 1978 962045-2048

6 Zimmerman TJ Harbin R Pett M Kaufman HE Timolol and facility ofoutflow Invest Ophthalmol Vis Sci 1977 16623-624

7 Alm A Widengaringrd I Kjellgren D Soumlderstroumlm M Fristroumlm B Heijl AStjernschantz J Latanoprost administered once daily caused amaintained reduction of intraocular pressure in glaucoma patientstreated concomitantly with timolol Br J Ophthalmol 1995 7912-16

8 Bucci MG Italian Latanoprost Study Group Intraocular pressure-loweringeffects of latanoprost monotherapy versus latanoprost or pilocarpine incombination with timolol a randomized observer-masked multicenterstudy in patients with open-angle glaucoma J Glaucoma 1999 824-30

9 Lee PY Shao H Camras CB Podos SM Additivity of prostaglandin F2alpha-1-isopropyl ester to timolol in glaucoma patients Ophthalmology1991 981079-1082

10 Rulo AH Greve EL Hoyng PF Additive effect of latanoprost aprostaglandin F2 alpha analogue and timolol in patients with elevatedintraocular pressure Br J Ophthalmol 1994 78899-902

11 Diestelhorst M Larsson LI European-Canadian Latanoprost FixedCombination Study Group A 12-week randomized double-maskedmulticenter study of the fixed combination of latanoprost and timolol inthe evening versus the individual components Ophthalmology 200611370-76

12 Diestelhorst M Larsson LI European Latanoprost Fixed Combination StudyGroup A 12 week study comparing the fixed combination of latanoprostand timolol with the concomitant use of the individual components inpatients with open angle glaucoma and ocular hypertension Br JOphthalmol 2004 88199-203

13 Higginbotham EJ Feldman R Stiles M Dubiner H Fixed CombinationInvestigative Group Latanoprost and timolol combination therapy vsmonotherapy one-year randomized trial Arch Ophthalmol 2002120915-922

14 Higginbotham EJ Olander KW Kim EE Grunden JW Kwok KK Tressler CSUnited States Fixed-Combination Study Group Fixed-combinationlatanoprosttimolol vs individual components for POAG or ocularhypertension a randomized double-masked study Arch Ophthalmol2010 128165-172

15 Pfeiffer N European Latanoprost Fixed Combination Study Group Acomparison of the fixed combination of latanoprost and timolol with itsindividual components Graefes Arch Clin Exp Ophthalmol 2002240893-899

16 Shin DH Feldman RM Sheu WP Fixed Combination LatanoprostTimololStudy Group Efficacy and safety of the fixed combinations latanoprosttimolol versus dorzolamidetimolol in patients with elevated intraocularpressure Ophthalmology 2004 111276-282

17 Kohlhaas M Boehm AG Spoerl E Puumlrsten A Grein HJ Pillunat LE Effect ofcentral corneal thickness corneal curvature and axial length onapplanation tonometry Arch Ophthalmol 2006 124471-476

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 8 of 9

ldquovery goodrdquo or ldquogoodrdquo in 15031584 (949) subjects andcompliance with the FC as ldquovery goodrdquo or ldquogoodrdquo in14391580 (911) subjects More than three-quarters(11231351 [831) of responding subjects reported nochange in iris color at month 24 and nearly 90 (n =13431520 [884]) indicated a desire to continue FCtreatment after the completion of study At month 24change in visual acuity from baseline was not statisti-cally or clinically significant

DiscussionResults of this long-term observational study of latano-prosttimolol FC demonstrate that the combinationeffectively reduces IOP levels and is well tolerated inpatients with glaucoma or ocular hypertension whochange from their previous ocular hypotensive therapyfor medical reasons The significant IOP-lowering effectof the FC was seen early at the month 6 visit and wassustained throughout the 24-month follow-up periodMoreover no significant changes in optic disc and visualfield defect were noted by investigators and structuraland functional parameters remained stable over 24months Investigator assessments revealed no significantassociation between IOP reduction over two years andchange in visual fieldPrevious research has demonstrated that progression

of glaucoma or ocular hypertension can be delayed orhalted by lowering IOP levels through the use of ocularhypotensive agents [218-21] Herein the mean IOPreduction of approximately 4 mmHg sustained over 24months was somewhat greater than reductions reportedin previous short-term observational studies of patientsswitched to the FC [2223] For example a prospectivemulticenter study [22] of patients switched to latano-prosttimolol FC and followed for at least two monthsfound mean IOP reductions from baseline of 29 mmHgin those with primary open-angle glaucoma or exfolia-tion glaucoma and of 31 mmHg among patients withocular hypertension (P lt 0001 for all) A multicenterobservational study [23] of patients with glaucoma orocular hypertension who were switched to the FC andfollowed for six months reported mean IOP reductionsfrom baseline of 33 mmHg 41 mmHg and 34 mmHgamong patients with open-angle glaucoma exfoliationglaucoma and ocular hypertension respectively (P lt0001 for all)As has been shown previously [11-16] the FC was

well tolerated In all 99185 (535) adverse events wereocular in nature half of treatment-related adverse eventsrelated to the eye and two of the three reported treat-ment-related serious adverse events were ocular Fewerthan 3 of subjects discontinued the FC due to an ocu-lar adverse event The tolerability of an ocular hypoten-sive agent is important given the negative impact of

Table 4 Mean IOP and mean change in IOP from baselineto last visit (mmHg) alternate populations

Visit n Mean plusmn SD(95 CI)

Change from baseline mean plusmn SD(95 CIdagger)

PP population corrected IOP[17]

Baseline 546 205 plusmn 394 na

(202 209)

Last visit 546 163 plusmn 330 -42 plusmn 421

(160 166) (-46 -39)

Full analysis set raw IOP

Baseline 1913 204 plusmn 425 na

(202 206)

Last visit 1934 164 plusmn 342 -39 plusmn 465Dagger

(163 166) (-42 -37)

PP population with applanation tonometry data raw IOP

Baseline 732 203 plusmn 431 na

(200 206)

Last visit 687 162 plusmn 302 -40 plusmn 459sect

(160 164) (-43 -36)

CI = confidence interval IOP = intraocular pressure na = not applicable PP =per protocol

SD = standard deviation

Last visit = last postbaseline visit at which an IOP level was recordeddaggerP lt 005 for change from baseline to last visit for each parameterDaggerN = 1913sectN = 631

Table 5 Mean change from baseline in horizontal andvertical cupdisc ratios by visit PP population

Visit n Mean plusmn SD (95 CI)

Horizontal cupdisc ratio

Month 6 645 00003 plusmn 013117

(-00099 00104)

Month 12 660 00039 plusmn 013286

(-00063 00140)

Month 18 666 00092 plusmn 013860

(-00014 00197)

Month 24 666 00041 plusmn 014078

(-00067 00148)

Last visit 783 00079 plusmn 014645

(-00024 00182)

Vertical cupdisc ratio

Month 6 600 00040 plusmn 012772

(-00062 00142)

Month 12 604 00075 plusmn 013726

(-00035 00184)

Month 18 613 00152 plusmn 014613

(00036 00268)

Month 24 615 00088 plusmn 013534

(-00019 00195)

Last visit 729 00127 plusmn 015155

(00017 00237)

CI = confidence interval PP = per protocol SD = standard deviation

Month times - baseline Last visit = last postbaseline visit at which the parameterwas recorded

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 6 of 9

ocular adverse events on patient continuation with ther-apy [2425]At month 24 physician evaluations of latanoprost

timolol FC were overwhelmingly positive with regard toefficacy tolerability and patient compliance In additionnearly 90 of patients expressed a desire to remain onthe FC after the end of the study These positive evalua-tions are tempered however by the fact that they weremade for and by patients who stayed on therapy for thefull follow-up period it is not known how many ofthose for whom efficacy tolerability or compliance wereissues discontinued FC therapy prior to that time pointConversely nearly 90 of discontinuations in the pre-sent study were unrelated to latanoprosttimolol FCwith the vast majority attributable to loss to follow-upMoreover a prior study [23] of patients switched tolatanoprosttimolol FC found that 97 of patients(10081042) remained on treatment after the 6-monthstudy period

Benefits of prescribing a FC agent for patients withglaucoma or ocular hypertension may include improvedadherence persistence convenience and reduced expo-sure to preservatives Improved adherence and persis-tence in particular are critical since the use of aneffective ocular hypotensive agent over the long termmay be expected to increase the likelihood of delayingor stopping glaucomatous damage Poorer compliancehas been demonstrated in those treated with more com-plex medication regimens [26-30] Comparative studiesof medication compliance in patients prescribed alterna-tive FC therapies are neededThis study has both strengths and limitations The

observational design may have better reflected actualclinical practice than controlled clinical trials but theabsence of a control group limits our ability to drawconclusions and the PP population included fewer thanhalf the number of subjects treated primarily due toloss to follow-up Given the observational design it was

Table 6 Changes in progression measures by last visit and month 24 nN () PP population

Progression measure Last visit Month 24

Increase in horizontal or vertical cupdisc ratio by ge02 (visit - baseline)dagger 98797 (123) 78676 (115)

ge1 postbaseline optic disc hemorrhageDagger 29983 (30) 23785 (29)

Decrease in ge1 rim area rim volume andor mean RNFL thickness by HRT (visit - baseline)dagger 28222 (126) 13151 (86)

Visual field deterioration rated as progression by physician at ge1 postbaseline visitDagger 137884 (155) 104630 (165)

Increase in Aulhorn stagesect by ge1 stage (visit - baseline)dagger 64370 (173) 43258 (167)

Decrease in mean defect by ge25 dBdagger 59371 (159) 45285 (158)

HRT = Heidelberg Retina Tomograph PP = per protocol RNFL = retinal nerve fiber layer

Last visit = last postbaseline visit at which the parameter was recordeddaggerTo be included in the percentage a subject must have had assessments at both the baseline and ge1 postbaseline visit for the relevant measureDaggerTo be included in the percentage a subject must have had ge1 postbaseline assessment for the relevant measuresectReflects all methods of determining Aulhorn stage

Table 7 Adverse events N = 2339

All causalitiesn ()

Treatment relatedn ()

All adverse events

Number of events 185 88

Subjects with

ge1 adverse event 148 (63) 72 (31)

ge1 serious adverse event 54 (23) 3 (01)

ge1 severe adverse event 70 (30) 15 (06)

Discontinued FC due to adverse event 69 (29) 52 (22)

Dose reducedtemporarily discontinued FC due to adverse event 22 (09) 8 (03)

All Ocular Adverse Events

Number of events 99 44

Subjects with

ge1 adverse event 84 (36) 39 (17)

ge1 serious adverse event 29 (12) 2 (01)

ge1 severe adverse event 35 (15) 5 (02)

Discontinued FC due to adverse event 41 (18) 28 (12)

Dose reducedtemporarily discontinued FC due to adverse event 19 (08) 6 (03)

FC = fixed combination

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 7 of 9

not possible to standardized the timing and method ofmeasuring IOP levels and visual field defects It is nota-ble however that IOP reductions from baseline to lastvisit among the 687 subjects evaluated by applanationtonometry were similar to those observed for the totalpopulation Although the design did not include a wash-out period between termination of baseline therapy andinitiation of latanoprosttimolol FC combination thiswould not be expected to impact the long-term out-comes evaluated herein The 24-month follow-up periodmay have been too short to detect changes in visualfields Moreover last visit data for individual progressionmeasures reflected a time point prior to month 24 forbetween 15 (for cupdisc ratio data) and 32 (for rimareavolumeretinal nerve fiber layer data) of evaluablesubjects Strict adherence to study procedures andreporting requirements could not be affirmed given thelarge number of participating physicians and the pro-longed follow-up period Finally while 17 of patientsreported a change in iris color from baseline to month24 evaluations relied on recollections of baseline colorThe Ocular Hypertension Treatment Study [2] foundthat 171 of subjects prescribed a prostaglandin analo-gue for at least six months and 76 of those in theobservation group reported a change in iris color dar-kening of the eyelids or growth of eyelashes

ConclusionsThis 24-month study demonstrated that latanoprosttimolol FC effectively reduces IOP levels and is well tol-erated in patients switched from other ocular hypoten-sive therapies for medical reasons Investigatorassessments showed optic disc parameters and visualfield to be stable throughout the follow-up period

AcknowledgementsThe results of this study were presented in part at the 8th InternationalSymposium on Ocular Pharmacology and Therapeutics December 3-6 2009Rome ItalyEditorial support including contributing to the first draft of the manuscriptrevising the paper based on author feedback and styling the paper forjournal submission was provided by Jane G Murphy PhD of ZolaAssociates and was funded by Pfizer Inc

Author details1Buumlrgerhospital Frankfurt am Main Augenklinik Frankfurt am Main Germany2Private practice Bruchsal Germany 3Pfizer Pharma GmbH Berlin Germany4Pfizer Limited UK Specialty Care Sandwich Kent UK

Authorsrsquo contributionsOS participated in the study concept and design analysis and interpretationof data and critical revision of the manuscript for important intellectualcontent BH participated in the study concept and design acquisition ofdata analysis and interpretation of data and critical revision of themanuscript for important intellectual content CZ participated in the analysisand interpretation of data critical revision of the manuscript for importantintellectual content and study supervision PM participated in the analysisand interpretation of data and critical revision of the manuscript forimportant intellectual content All authors read and approved the finalmanuscript

Competing interestsDr Guzy is an employee of Pfizer Pharma GmbH Mr Miller is an employeeof Pfizer Limited UK Specialty Care The research was funded by PfizerPharma GmbH

Received 15 April 2010 Accepted 8 September 2010Published 8 September 2010

References1 European Glaucoma Society Terminology and Guidelines for Glaucoma

Savona Italy DOGMA II 2008 [httpwwweugsorgengEGS_guidelinesasp] Accessed September 3 2010

2 Kass MA Heuer DK Higginbotham EJ Johnson CA Keltner JL Miller JPParrish RK Wilson MR Gordon MO The Ocular Hypertension TreatmentStudy a randomized trial determines that topical ocular hypotensivemedication delays or prevents the onset of primary open-angleglaucoma Arch Ophthalmol 2002 120701-713

3 Toris CB Gabelt BT Kaufman PL Update on the mechanism of action oftopical prostaglandins for intraocular pressure reduction SurvOphthalmol 2008 53(Suppl 1)S107-120

4 Xalacomreg Summary of Product Characteristics Electronic MedicinesCompendium 2007 [httpemcmedicinesorgukmedicine7735SPCXalacom+eye+drops 2c+solution] Accessed November 16 2009

5 Coakes RL Brubaker RF The mechanism of timolol in lowering intraocularpressure in the normal eye Arch Ophthalmol 1978 962045-2048

6 Zimmerman TJ Harbin R Pett M Kaufman HE Timolol and facility ofoutflow Invest Ophthalmol Vis Sci 1977 16623-624

7 Alm A Widengaringrd I Kjellgren D Soumlderstroumlm M Fristroumlm B Heijl AStjernschantz J Latanoprost administered once daily caused amaintained reduction of intraocular pressure in glaucoma patientstreated concomitantly with timolol Br J Ophthalmol 1995 7912-16

8 Bucci MG Italian Latanoprost Study Group Intraocular pressure-loweringeffects of latanoprost monotherapy versus latanoprost or pilocarpine incombination with timolol a randomized observer-masked multicenterstudy in patients with open-angle glaucoma J Glaucoma 1999 824-30

9 Lee PY Shao H Camras CB Podos SM Additivity of prostaglandin F2alpha-1-isopropyl ester to timolol in glaucoma patients Ophthalmology1991 981079-1082

10 Rulo AH Greve EL Hoyng PF Additive effect of latanoprost aprostaglandin F2 alpha analogue and timolol in patients with elevatedintraocular pressure Br J Ophthalmol 1994 78899-902

11 Diestelhorst M Larsson LI European-Canadian Latanoprost FixedCombination Study Group A 12-week randomized double-maskedmulticenter study of the fixed combination of latanoprost and timolol inthe evening versus the individual components Ophthalmology 200611370-76

12 Diestelhorst M Larsson LI European Latanoprost Fixed Combination StudyGroup A 12 week study comparing the fixed combination of latanoprostand timolol with the concomitant use of the individual components inpatients with open angle glaucoma and ocular hypertension Br JOphthalmol 2004 88199-203

13 Higginbotham EJ Feldman R Stiles M Dubiner H Fixed CombinationInvestigative Group Latanoprost and timolol combination therapy vsmonotherapy one-year randomized trial Arch Ophthalmol 2002120915-922

14 Higginbotham EJ Olander KW Kim EE Grunden JW Kwok KK Tressler CSUnited States Fixed-Combination Study Group Fixed-combinationlatanoprosttimolol vs individual components for POAG or ocularhypertension a randomized double-masked study Arch Ophthalmol2010 128165-172

15 Pfeiffer N European Latanoprost Fixed Combination Study Group Acomparison of the fixed combination of latanoprost and timolol with itsindividual components Graefes Arch Clin Exp Ophthalmol 2002240893-899

16 Shin DH Feldman RM Sheu WP Fixed Combination LatanoprostTimololStudy Group Efficacy and safety of the fixed combinations latanoprosttimolol versus dorzolamidetimolol in patients with elevated intraocularpressure Ophthalmology 2004 111276-282

17 Kohlhaas M Boehm AG Spoerl E Puumlrsten A Grein HJ Pillunat LE Effect ofcentral corneal thickness corneal curvature and axial length onapplanation tonometry Arch Ophthalmol 2006 124471-476

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 8 of 9

ocular adverse events on patient continuation with ther-apy [2425]At month 24 physician evaluations of latanoprost

timolol FC were overwhelmingly positive with regard toefficacy tolerability and patient compliance In additionnearly 90 of patients expressed a desire to remain onthe FC after the end of the study These positive evalua-tions are tempered however by the fact that they weremade for and by patients who stayed on therapy for thefull follow-up period it is not known how many ofthose for whom efficacy tolerability or compliance wereissues discontinued FC therapy prior to that time pointConversely nearly 90 of discontinuations in the pre-sent study were unrelated to latanoprosttimolol FCwith the vast majority attributable to loss to follow-upMoreover a prior study [23] of patients switched tolatanoprosttimolol FC found that 97 of patients(10081042) remained on treatment after the 6-monthstudy period

Benefits of prescribing a FC agent for patients withglaucoma or ocular hypertension may include improvedadherence persistence convenience and reduced expo-sure to preservatives Improved adherence and persis-tence in particular are critical since the use of aneffective ocular hypotensive agent over the long termmay be expected to increase the likelihood of delayingor stopping glaucomatous damage Poorer compliancehas been demonstrated in those treated with more com-plex medication regimens [26-30] Comparative studiesof medication compliance in patients prescribed alterna-tive FC therapies are neededThis study has both strengths and limitations The

observational design may have better reflected actualclinical practice than controlled clinical trials but theabsence of a control group limits our ability to drawconclusions and the PP population included fewer thanhalf the number of subjects treated primarily due toloss to follow-up Given the observational design it was

Table 6 Changes in progression measures by last visit and month 24 nN () PP population

Progression measure Last visit Month 24

Increase in horizontal or vertical cupdisc ratio by ge02 (visit - baseline)dagger 98797 (123) 78676 (115)

ge1 postbaseline optic disc hemorrhageDagger 29983 (30) 23785 (29)

Decrease in ge1 rim area rim volume andor mean RNFL thickness by HRT (visit - baseline)dagger 28222 (126) 13151 (86)

Visual field deterioration rated as progression by physician at ge1 postbaseline visitDagger 137884 (155) 104630 (165)

Increase in Aulhorn stagesect by ge1 stage (visit - baseline)dagger 64370 (173) 43258 (167)

Decrease in mean defect by ge25 dBdagger 59371 (159) 45285 (158)

HRT = Heidelberg Retina Tomograph PP = per protocol RNFL = retinal nerve fiber layer

Last visit = last postbaseline visit at which the parameter was recordeddaggerTo be included in the percentage a subject must have had assessments at both the baseline and ge1 postbaseline visit for the relevant measureDaggerTo be included in the percentage a subject must have had ge1 postbaseline assessment for the relevant measuresectReflects all methods of determining Aulhorn stage

Table 7 Adverse events N = 2339

All causalitiesn ()

Treatment relatedn ()

All adverse events

Number of events 185 88

Subjects with

ge1 adverse event 148 (63) 72 (31)

ge1 serious adverse event 54 (23) 3 (01)

ge1 severe adverse event 70 (30) 15 (06)

Discontinued FC due to adverse event 69 (29) 52 (22)

Dose reducedtemporarily discontinued FC due to adverse event 22 (09) 8 (03)

All Ocular Adverse Events

Number of events 99 44

Subjects with

ge1 adverse event 84 (36) 39 (17)

ge1 serious adverse event 29 (12) 2 (01)

ge1 severe adverse event 35 (15) 5 (02)

Discontinued FC due to adverse event 41 (18) 28 (12)

Dose reducedtemporarily discontinued FC due to adverse event 19 (08) 6 (03)

FC = fixed combination

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

Page 7 of 9

not possible to standardized the timing and method ofmeasuring IOP levels and visual field defects It is nota-ble however that IOP reductions from baseline to lastvisit among the 687 subjects evaluated by applanationtonometry were similar to those observed for the totalpopulation Although the design did not include a wash-out period between termination of baseline therapy andinitiation of latanoprosttimolol FC combination thiswould not be expected to impact the long-term out-comes evaluated herein The 24-month follow-up periodmay have been too short to detect changes in visualfields Moreover last visit data for individual progressionmeasures reflected a time point prior to month 24 forbetween 15 (for cupdisc ratio data) and 32 (for rimareavolumeretinal nerve fiber layer data) of evaluablesubjects Strict adherence to study procedures andreporting requirements could not be affirmed given thelarge number of participating physicians and the pro-longed follow-up period Finally while 17 of patientsreported a change in iris color from baseline to month24 evaluations relied on recollections of baseline colorThe Ocular Hypertension Treatment Study [2] foundthat 171 of subjects prescribed a prostaglandin analo-gue for at least six months and 76 of those in theobservation group reported a change in iris color dar-kening of the eyelids or growth of eyelashes

ConclusionsThis 24-month study demonstrated that latanoprosttimolol FC effectively reduces IOP levels and is well tol-erated in patients switched from other ocular hypoten-sive therapies for medical reasons Investigatorassessments showed optic disc parameters and visualfield to be stable throughout the follow-up period

AcknowledgementsThe results of this study were presented in part at the 8th InternationalSymposium on Ocular Pharmacology and Therapeutics December 3-6 2009Rome ItalyEditorial support including contributing to the first draft of the manuscriptrevising the paper based on author feedback and styling the paper forjournal submission was provided by Jane G Murphy PhD of ZolaAssociates and was funded by Pfizer Inc

Author details1Buumlrgerhospital Frankfurt am Main Augenklinik Frankfurt am Main Germany2Private practice Bruchsal Germany 3Pfizer Pharma GmbH Berlin Germany4Pfizer Limited UK Specialty Care Sandwich Kent UK

Authorsrsquo contributionsOS participated in the study concept and design analysis and interpretationof data and critical revision of the manuscript for important intellectualcontent BH participated in the study concept and design acquisition ofdata analysis and interpretation of data and critical revision of themanuscript for important intellectual content CZ participated in the analysisand interpretation of data critical revision of the manuscript for importantintellectual content and study supervision PM participated in the analysisand interpretation of data and critical revision of the manuscript forimportant intellectual content All authors read and approved the finalmanuscript

Competing interestsDr Guzy is an employee of Pfizer Pharma GmbH Mr Miller is an employeeof Pfizer Limited UK Specialty Care The research was funded by PfizerPharma GmbH

Received 15 April 2010 Accepted 8 September 2010Published 8 September 2010

References1 European Glaucoma Society Terminology and Guidelines for Glaucoma

Savona Italy DOGMA II 2008 [httpwwweugsorgengEGS_guidelinesasp] Accessed September 3 2010

2 Kass MA Heuer DK Higginbotham EJ Johnson CA Keltner JL Miller JPParrish RK Wilson MR Gordon MO The Ocular Hypertension TreatmentStudy a randomized trial determines that topical ocular hypotensivemedication delays or prevents the onset of primary open-angleglaucoma Arch Ophthalmol 2002 120701-713

3 Toris CB Gabelt BT Kaufman PL Update on the mechanism of action oftopical prostaglandins for intraocular pressure reduction SurvOphthalmol 2008 53(Suppl 1)S107-120

4 Xalacomreg Summary of Product Characteristics Electronic MedicinesCompendium 2007 [httpemcmedicinesorgukmedicine7735SPCXalacom+eye+drops 2c+solution] Accessed November 16 2009

5 Coakes RL Brubaker RF The mechanism of timolol in lowering intraocularpressure in the normal eye Arch Ophthalmol 1978 962045-2048

6 Zimmerman TJ Harbin R Pett M Kaufman HE Timolol and facility ofoutflow Invest Ophthalmol Vis Sci 1977 16623-624

7 Alm A Widengaringrd I Kjellgren D Soumlderstroumlm M Fristroumlm B Heijl AStjernschantz J Latanoprost administered once daily caused amaintained reduction of intraocular pressure in glaucoma patientstreated concomitantly with timolol Br J Ophthalmol 1995 7912-16

8 Bucci MG Italian Latanoprost Study Group Intraocular pressure-loweringeffects of latanoprost monotherapy versus latanoprost or pilocarpine incombination with timolol a randomized observer-masked multicenterstudy in patients with open-angle glaucoma J Glaucoma 1999 824-30

9 Lee PY Shao H Camras CB Podos SM Additivity of prostaglandin F2alpha-1-isopropyl ester to timolol in glaucoma patients Ophthalmology1991 981079-1082

10 Rulo AH Greve EL Hoyng PF Additive effect of latanoprost aprostaglandin F2 alpha analogue and timolol in patients with elevatedintraocular pressure Br J Ophthalmol 1994 78899-902

11 Diestelhorst M Larsson LI European-Canadian Latanoprost FixedCombination Study Group A 12-week randomized double-maskedmulticenter study of the fixed combination of latanoprost and timolol inthe evening versus the individual components Ophthalmology 200611370-76

12 Diestelhorst M Larsson LI European Latanoprost Fixed Combination StudyGroup A 12 week study comparing the fixed combination of latanoprostand timolol with the concomitant use of the individual components inpatients with open angle glaucoma and ocular hypertension Br JOphthalmol 2004 88199-203

13 Higginbotham EJ Feldman R Stiles M Dubiner H Fixed CombinationInvestigative Group Latanoprost and timolol combination therapy vsmonotherapy one-year randomized trial Arch Ophthalmol 2002120915-922

14 Higginbotham EJ Olander KW Kim EE Grunden JW Kwok KK Tressler CSUnited States Fixed-Combination Study Group Fixed-combinationlatanoprosttimolol vs individual components for POAG or ocularhypertension a randomized double-masked study Arch Ophthalmol2010 128165-172

15 Pfeiffer N European Latanoprost Fixed Combination Study Group Acomparison of the fixed combination of latanoprost and timolol with itsindividual components Graefes Arch Clin Exp Ophthalmol 2002240893-899

16 Shin DH Feldman RM Sheu WP Fixed Combination LatanoprostTimololStudy Group Efficacy and safety of the fixed combinations latanoprosttimolol versus dorzolamidetimolol in patients with elevated intraocularpressure Ophthalmology 2004 111276-282

17 Kohlhaas M Boehm AG Spoerl E Puumlrsten A Grein HJ Pillunat LE Effect ofcentral corneal thickness corneal curvature and axial length onapplanation tonometry Arch Ophthalmol 2006 124471-476

Schwenn et al BMC Ophthalmology 2010 1021httpwwwbiomedcentralcom1471-24151021

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not possible to standardized the timing and method ofmeasuring IOP levels and visual field defects It is nota-ble however that IOP reductions from baseline to lastvisit among the 687 subjects evaluated by applanationtonometry were similar to those observed for the totalpopulation Although the design did not include a wash-out period between termination of baseline therapy andinitiation of latanoprosttimolol FC combination thiswould not be expected to impact the long-term out-comes evaluated herein The 24-month follow-up periodmay have been too short to detect changes in visualfields Moreover last visit data for individual progressionmeasures reflected a time point prior to month 24 forbetween 15 (for cupdisc ratio data) and 32 (for rimareavolumeretinal nerve fiber layer data) of evaluablesubjects Strict adherence to study procedures andreporting requirements could not be affirmed given thelarge number of participating physicians and the pro-longed follow-up period Finally while 17 of patientsreported a change in iris color from baseline to month24 evaluations relied on recollections of baseline colorThe Ocular Hypertension Treatment Study [2] foundthat 171 of subjects prescribed a prostaglandin analo-gue for at least six months and 76 of those in theobservation group reported a change in iris color dar-kening of the eyelids or growth of eyelashes

ConclusionsThis 24-month study demonstrated that latanoprosttimolol FC effectively reduces IOP levels and is well tol-erated in patients switched from other ocular hypoten-sive therapies for medical reasons Investigatorassessments showed optic disc parameters and visualfield to be stable throughout the follow-up period

AcknowledgementsThe results of this study were presented in part at the 8th InternationalSymposium on Ocular Pharmacology and Therapeutics December 3-6 2009Rome ItalyEditorial support including contributing to the first draft of the manuscriptrevising the paper based on author feedback and styling the paper forjournal submission was provided by Jane G Murphy PhD of ZolaAssociates and was funded by Pfizer Inc

Author details1Buumlrgerhospital Frankfurt am Main Augenklinik Frankfurt am Main Germany2Private practice Bruchsal Germany 3Pfizer Pharma GmbH Berlin Germany4Pfizer Limited UK Specialty Care Sandwich Kent UK

Authorsrsquo contributionsOS participated in the study concept and design analysis and interpretationof data and critical revision of the manuscript for important intellectualcontent BH participated in the study concept and design acquisition ofdata analysis and interpretation of data and critical revision of themanuscript for important intellectual content CZ participated in the analysisand interpretation of data critical revision of the manuscript for importantintellectual content and study supervision PM participated in the analysisand interpretation of data and critical revision of the manuscript forimportant intellectual content All authors read and approved the finalmanuscript

Competing interestsDr Guzy is an employee of Pfizer Pharma GmbH Mr Miller is an employeeof Pfizer Limited UK Specialty Care The research was funded by PfizerPharma GmbH

Received 15 April 2010 Accepted 8 September 2010Published 8 September 2010

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Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1471-24151021prepub

doi1011861471-2415-10-21Cite this article as Schwenn et al Long-term effect of latanoprosttimolol fixed combination in patients with glaucoma or ocularhypertension A prospective observational noninterventional studyBMC Ophthalmology 2010 1021

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