Combination therapy as initial treatment in glaucoma andsuspected glaucomaFrederick S. Mikelberg, MD, FRCSC*, Mahyar Etminan, PharmD, MSc†

ABSTRACT ● RÉSUMÉ

Objective: We hypothesize that there may be an inappropriate overuse of initial combination therapy in patients with glaucoma and inthose who are glaucoma suspects. To test this hypothesis, we examined the British Columbia Population DataBase to determine thefrequency of prescription of combination eye drops as initial therapy in glaucoma patients or glaucoma suspects.

Design: Cohort study.Participants: The study cohort included all those who visited an ophthalmologist’s office between 2004 and 2007. Within the cohort we

identified all those who were newly prescribed any ocular hypotensive eye drop. Specifically, we identified those who had been newlyprescribed any ocular hypotensive eye drop within 60 days of receiving diagnoses of glaucoma, as defined by having received aninternational classification for disease code ICD-9 for glaucoma 365.

Methods: We used the Population Data British Columbia (POP Data BC) as the main data source for this study. POP Data BC is aprovincially linkable database that captures the physician visits (including inpatient procedures); hospital admissions; demographics;and prescription drug use of 4.5 million residents of British Columbia.

Results: Between 2004 and 2007, the percentage of combination therapy as the first ocular hypotensive prescription rose from 12.29%to 18.63%.

Conclusions: The high percentage of combination therapy as initial therapy suggests that ophthalmologists either require additionaleducation in principles of pharmacologic therapy or are unduly influenced by their interaction with the pharmaceutical industry.

Objet : Nous avons émis l’hypothèse qu’il pourrait y avoir une surutilisation inappropriée d’une thérapie combinée initiale pour lespatients atteints ou soupçonnés de glaucome. Pour vérifier cette hypothèse, nous avons examiné la Base de données de lapopulation de Colombie-Britannique afin d’établir la fréquence des gouttes ophtalmiques combinées, prescrites comme thérapieinitiale pour les patients atteints ou soupçonnés de glaucome.

Méthodes : Nous avons utilisé la Base de données de la population de Colombie-Britannique (POP Data BC) comme source principalede données pour cette étude. POP Data BC est la basse provinciale de données qui peuvent être associées, notamment les visiteschez le médecin (y compris les procédures), les hospitalisations, les données démographiques et les ordonnances médicales pourles 4,5 millions de résidents de la Colombie-Britannique.

Résultats : Entre 2004 et 2007, le pourcentage des gouttes ophtalmiques combinées comme premières thérapies oculaires hypoten-sives a augmenté de 12,29 % à 18,63 %.

Conclusions : Le pourcentage élevé de la combinaison thérapeutique comme thérapie initiale suggère que les ophtalmologistes ontbesoin d’une formation additionnelle sur les principes de la thérapie pharmacologique ou sont trop influencés par leur interaction avecl’industrie pharmaceutique.

It is a basic principle of medical therapeutics that ininitiating therapy, the lowest dose of a single agent is pref-erable for achieving the targeted effect.1 Target intraocularpressure is often achieved and maintained by using a singleagent. In the Ocular Hypertension Treatment Study, 51%of patients achieved and maintained target intraocularpressure with a single agent for the full 60 months of ob-servation.2 Patient variability in response to a particularclass of medication exists and can be determined only bythe trial of a single agent. Side effects of medication areimportant and are minimized by the use of a single class ofmedication. As well, the medication responsible for a givenside effect is more easily differentiated when using a singletherapy.

Combination therapies have been developed for pa-tients in whom both medications are required to achievethe therapeutic goal. These combinations increase the easeof use for patients and often increase adherence.3 Also,

From the *Department of Ophthalmology and Visual Sciences and the†Department of Medicine, University of British Columbia, Vancouver, B.C.

Originally received Sep. 17, 2011. Final revision Dec. 23, 2011. AcceptedJan. 25, 2012Correspondence to Frederick S. Mikelberg, 2550 Willow St., Vancouver BC

V5Z 3N9; fsm@mail.ubc.ca

240 CAN J OPHTHALMOL—VOL. 47, NO. 3, JUNE 2012

there is often a cost saving as compared to the 2 agents’being used separately.4 Another determinant of drug usageis the effect of drug representative “detailing” of physi-cians.5 We hypothesize that there may be an inappropriateoveruse of combination therapy as the initial therapy inpatients with glaucoma and in glaucoma suspects. To testthis hypothesis, we examined the British Columbia Popu-lation DataBase to determine the frequency of combina-tion eye drops prescribed as initial therapy for glaucomapatients or glaucoma suspects.

METHODS

We used the British Columbia Linked Health Database(BCLHD) as the main source of data for this study. Allhealth services information for all residents of BritishColumbia are captured in the BCLHD. The database con-tains linkable data files concerning patient demographics;

Can J Ophthalmol 2012;47:240–2420008-4182/11/$-see front matter © 2012 Canadian Ophthalmological Society.Published by Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.jcjo.2012.03.023

in

Combination therapy as initial treatment in glaucoma—Mikelberg & Etminan

hospital admissions6 and discharges (including all hospitalprocedures); physician visits7 (including all in-office pro-cedures); and a comprehensive prescription drug database,PharmaNet.8 PharmaNet captures information about allprescription drugs dispensed in the province, includingdrug strength, quantity, and day supply. The prescriptiondrug data cover both children and adults. The data arelinkable through a unique identifier. The BCLHD is oneof the largest available longitudinal databases containingthe health care data of approximately 4.5 million residentsof the province. The database has been used in numeroushealth services and epidemiologic studies.9,10

The study cohort included all those who visited an oph-thalmologist’s office between 2004 and 2007. The 2004,2005, and 2006 databases include 12 months per year; the2007 database includes the first 8 months of the year.Within the cohort we identified all those who were newlyprescribed any ocular hypotensive eye drop. Specifically,we identified those who had been newly prescribed anyocular hypotensive eye drop within 60 days of receiving adiagnosis of glaucoma, as defined by having received aninternational classification for disease code ICD-9 for glau-coma 365. We ensured that only new users of a study drug

Table 1—Number of initial prescriptions (percent)

2004

Beta blockersbetaxolol 106 (4.11)levobunolol 61 (2.36)timolol 354 (13.72)

Subtotal 521 (20.19)Prostaglandins

bimatoprost 315 (12.21)latanaprost 702 (27.21)travaprost 319 (12.36)

Subtotal 1336 (51.78)Alpha adrenergics

dipivefrine 2 (0.08)brimonidine 251 (9.73)Iopidine 0 (0.0)

Subtotal 253 (9.81)Carbonic anhydrase inhibitors

brinzolamide 17 (0.66)dorzolamide 41 (1.59)

Subtotal 58 (2.25)Cholinergic agonists

carbachol 1 (0.04)pilocarpine 94 (3.64)

Subtotal 95 (3.68)Combination medications

Combigan 41 (1.59)Cosopt 234 (9.07)DuoTrav 0 (0.0)Xalacom 17 (0.66)Timpilo 25 (0.97)

Subtotal 317 (12.29)Total 2580 (100)Combination therapy initially prescribed

as individual prescription*Two medications 149 (5.77)Three medications 8 (0.31)

*Combination therapy initially prescribed as individual prescription percentage is

were included in the cohort by going back 1 year from the

date of cohort entry and checking for previous dispensedmedications of a study drug. If 2 separate medications wereprescribed at the same time as initial therapy, the databasecaptured the first medication listed by PharmaNet. Weused descriptive statistics to examine the number of newprescriptions for each study drug dispensed in each year.

RESULTS

Combination drops were prescribed as initial therapywith increasing frequency, from 12.29% of initial therapyin 2004 to 18.63% of initial therapy in 2007. As well, by2004, 3.8% of patients received 2 medications prescribedseparately as initial therapy (Table 1). Most of the increasein combination therapy usage involved Combigan (Aller-gan, Irvine, CA), which increased from 1.59% to 10.27%as initial therapy. To further assess the scope of combina-tion therapy as initial treatment we analyzed the data toevaluate the percentage of use of particular combinationsas compared to their 2 components used individually be-cause the choice of the particular combination would log-ically be selected when one or the other of the componentswas deemed appropriate. By 2007, 43% of the total of first

2005 2006 2007

71 (2.81) 38 (1.56) 26 (2.24)36 (1.43) 30 (1.23) 16 (1.38)

284 (11.26) 201 (8.23) 92 (7.94)391 (15.50) 269 (11.02) 134 (11.56)

352 (13.95) 291 (11.92) 180 (15.53)651 (25.80) 597 (24.45) 290 (25.02)348 (13.79) 504 (20.64) 186 (16.05)

1351 (53.54) 1392 (57.01) 656 (56.60)

2 (0.08) 0 (0.0) 0 (0.0)230 (9.12) 179 (7.33) 66 (5.69)

0 (0.0) 2 (0.08) 0 (0.0)232 (9.20) 181 (7.41) 66 (5.69)

21 (0.83) 46 (1.88) 18 (1.55)38 (1.51) 20 (0.82) 12 (1.04)59 (2.34) 66 (2.70) 30 (2.54)

4 (0.16) 2 (0.08) 0 (0.0)102 (4.04) 96 (3.93) 57 (4.92)106 (4.20) 98 (4.01) 57 (4.92)

140 (5.55) 206 (8.44) 119 (10.27)223 (8.84) 160 (6.55) 58 (5.00)

0 (0.0) 7 (0.29) 8 (0.69)20 (0.79) 63 (2.58) 31 (2.67)

1 (0.04) 0 (0.0) 0 (0.0)384 (15.22) 436 (17.86) 216 (18.63)

2523 (100) 2442 (100) 1159 (100)

112 (4.44) 92 (3.77) 44 (3.80)6 (0.24) 5 (0.20) 1 (0.09)

addition to 100% total because of double counting.

prescriptions for timolol, brimonidine, or Combigan were

CAN J OPHTHALMOL—VOL. 47, NO. 3, JUNE 2012 241

Combination therapy as initial treatment in glaucoma—Mikelberg & Etminan

for Combigan. By 2007, 36% of the total initial prescrip-tions for timolol, dorzolamide, or Cosopt (Merck, White-house Station, NJ) were for Cosopt. By 2007, 8% of thetotal initial prescriptions for timolol, latanaprost, or Xala-com were for Xalacom (Pfizer, New York, NY).

DISCUSSION

It is accepted standard practice that initial therapyshould be a single agent in an attempt to achieve the tar-geted effect. Target pressure is commonly achieved initiallyby the use of a single agent. In the Ocular HypertensionTreatment Study, 51% of patients achieved and main-tained target intraocular pressure via a single agent for thefull 60 months of observation.2 Response to a particularclass of medication can be assessed initially only by single-agent therapy. Side effects of medications are minimizedby using single therapy. As well, the medication responsi-ble for a given side effect is more easily differentiatedthrough single therapy. In patients with glaucoma and inglaucoma suspects, other than in rare exceptions in pa-tients who have exceptionally high intraocular pressure,such as acute angle closure, uveitic glaucoma, and otheracute situations, combination therapy in not indicated asinitial therapy.

Prostaglandins as a class are the most commonly pre-scribed ocular hypotensive medication; in 2007, they were56% of the initial therapeutic agents for patients with glau-coma and in glaucoma suspects. Nevertheless, combina-tion therapy was prescribed as initial therapy in 18.63% ofpatients. After prostaglandins, the most common initialtherapy was Combigan, which was prescribed 10.27% ofthe time.

By 2007, of all patients started on timolol or brimoni-dine, Combigan was the first prescribed therapy in 43% ofpatients. By 2007, of all patients started on timolol or

dorzolamide, Cosopt was the first prescribed therapy for

242 CAN J OPHTHALMOL—VOL. 47, NO. 3, JUNE 2012

36%. Although it is difficult to predict the percent of pa-tients on timolol or brimonidine, or on timolol or dorzo-lamide, who subsequently required a combination of both,one would expect that as an initial therapy, Combigan orCosopt use should be minimal.

These findings suggest that ophthalmologists either re-quire additional education in principles of clinical pharma-cology or that they are unduly influenced by their interac-tions with the pharmaceutical industry.

Disclosure: The authors have no proprietary or commercial interestin any materials in this article.

Funding for this study was provided by the Department of Oph-thalmology and Visual Sciences, University of British Columbia,Vancouver, BC.

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