Objective assessment of compliance and persistence among patients treated for glaucoma and ocular hypertension: a systematic review

Figures & data

Figure 1 Reviewed studies by publication year.

Table 1 Mean of compliance and persistence endpoints

Source	Endpoint	Mean of studiesa	SD	Range	Number of studies
Rx fills	Percentage persistent at 1 year until discontinuation of therapy^Citation1,Citation5,Citation30^–^Citation41	31%	17%	10%–68%	14
Rx fills	Percentage persistent at 1 year until discontinuation or change of therapy^Citation32,Citation36^–^Citation38,Citation40^–^Citation47	40%	19%	14%–67%	12
Rx fills	Medication possession at end of 1st year^Citation5,Citation48,Citation49	51%	7%	44%–59%	3
Rx fills	Medication possession ratio or proportion of days covered over 1st year^Citation1,Citation12,Citation13,Citation31,Citation49,Citation51	56%	19%	37%–92%	6
Rx fills	Rate of total non-adherence (no refills following start of therapy in 1st year)^Citation12,Citation13	24%	1%	23%–25%	2
Medical chart	Percentage persistent at 1 year until change (or change/discontinuation) of therapy^Citation11,Citation61^–^Citation64	67%	7%	62%–78%	5

a Notes: Mean across studies for those endpoints that were reported in two or more reviewed studies (within-study means were derived by n-weighting drug cohorts if a total-sample mean was not available). The denominator for mean of studies estimate is the total number studies within the source category, except for two studies that reported findings for two separate cohorts: diagnosed glaucoma and glaucoma suspect⁵ and primary open-angle glaucoma and ocular hypertension.⁵¹ For these exceptions, both cohorts were included in both the numerator and denominator when calculating the mean of studies estimates. For Tingey et al⁶⁴ persistence findings include only the Phase 1 cohort (those starting first-line glaucoma treatment) but exclude the Phase II cohort (those who previously failed beta blocker therapy).

Abbreviation: Rx, prescription.

Table S1 Measurement of compliance – electronic monitoring studies

Study group	Design/cohorts	Endpoint	Patient/setting	Study year	Findings
Granstrom^Citation10	Retrospective observational E lectronic medication monitor data Chart review. Subjects were blinded from the purpose of the monitor. Single cohort: pilocarpine (TID)	See description of endpoints below in Norell/Granstrom	56 of 82 subjects from Norell^Citation16 who were followed for 2 years before and after the electronic monitor observation period	Not specified	Compared with those having no progression, those with progression of visual field defects during the 2-year pre-monitor period had a lower rate of “goodintermediate” (50%) vs “poor” compliance (58%) during the 20-day monitor assessment. In the noninterventional group (n = 26) followed for 2 years after monitor observation, those with progression of visual field defects, in the post-monitor period had a higher rate of “good-intermediate” (63%) vs “poor” compliance (30%) observed at the time of the monitor. Neither finding was significant. There was a statistically significant association between type of glaucoma, stage of visual field defects, and mean IOP. When these factors were adjusted for, the difference in proportion of patients with visual field defect progression in those with “good” vs “poor” compliance was reduced for both 2-year pre- and post-monitor periods
Hermann^Citation27	Prospective observational. Electronic medication monitor data. Subjects were randomly assigned to masked (ie, blinded) and unmasked monitoring. Random assignment to BID or TID dosing. Single cohort: brimonidine	Over 4 weeks, Number of recorded application events per 24-hour period Time interval between doses Ratio of recorded to intended dose events (adherence) Proportion of time for which recorded dose was not exceeding intended dose by >3 hours (coverage)	36 subjects who were 18+ years with diagnosis of POAG or OHT, prescribed brimonidine BID to TID at university glaucoma clinic [Greece]	Not specified	BID mean = 1.47 (SD = 0.3), TID 1.92 (0.4) Sig BID 17.5 (4.4) hours, TID 13.2 (2.5) hours Sig BID 73.3% (13%), TID 64.0% (12%) Sig BID 71.8% (12%), TID 69.3% (9.5%) NS Differences between means of masked vs unmasked monitoring for 1–4 were not significant when stratified by regimen (BID, TID)
Hermann^Citation28	Prospective observational. Electronic medication monitor data. All subjects were masked from purpose of the monitor. Random assignment to BID or TID dosing. Single cohort: brimonidine	Over 4 weeks, Number of recorded application events per 24-hour period Time interval between doses Ratio of recorded to intended dose events (adherence) Proportion of time for which recorded dose was not exceeding intended dose by >3 hours (coverage) Amount of medication used per dosing event Mean number of drops applied per dosing event	75 subjects who were 18+ years with diagnosis of OAG, angle closure or OHT, receiving topical glaucoma therapy [France]	Not specified	BID mean = 1.44 (SD = 0.4), TID 1.86 (0.5) Sig BID 18.5 (5.9) hours, TID 14.8 (7.1) hours Sig. 35% of all dosing intervals in BID group and >20% in TID group were >16 hours BID 72.2% (19%), TID 62.1% (16%) Sig BID 69.9% (14%), TID 67.2% (15%) NS Treat 1 eye 69 (3.1) mg, treat both eyes 97 (3.3) mg Sig Treat 1 eye 1.7 (0.7), treat both eyes 2.4 (1.5) Sig. On average 20% of medication was wasted due to using >1 drop per eye per dosing
Kass^Citation23,Citation24	Prospective observational E lectronic medication monitor data Post-monitor subject interview Pre-monitor physicianpredicted estimate of compliance W eight difference of vial between pre- and post-monitor visits Daily log of compliance [n = 32 subset sample] for additional 30-day period. All subjects were masked from purpose of the monitor. Single cohort: pilocarpine	Percentage of doses taken as recorded by the monitor over 30 days One or more questions on compliance behavior at the end of the 30-day period E stimated number of doses that subject would omit over next 30 days Pre- vs post-observation difference in vial weight Subject daily diary of administration times	184 subjects who were 18+ years, currently prescribed pilocarpine QID for IOP reduction, from private practices of university faculty [Washington in US]	1981–1984	For all subjects, mean of 76.0% (SD = 24.3%) of prescribed doses. 15.2% of all patients took < 50% of prescribed doses, 34.2% took < 75% of doses.^Citation22 Mean rate of compliance was higher (87.6% [27.8%] Sig) in the 24-hour period preceding the return appointment than over the entire 30-day observation period.^Citation22 IOP on day 30 return visit did not significantly correlate with compliance Subjects reported that they were taking a mean of 97.1% (5.9%) of prescribed doses. Correlation between patient-reported compliance and monitor data was modest (r = 0.203) Sig^Citation23 Mean physician estimate of compliance was 79.4% (15.9%). Correlation between physician estimates of compliance and medication monitor estimates was modest, with a correlation coefficient of r = 0.20 Sig^Citation23 Modest correlation (r = 0.18) Sig occurred between vial weight difference and monitor estimates^Citation23 Mean reported rate of compliance was 98.9% (1.8%). Correlation between daily log and monitor data was modest (r = 0.24, NS)^Citation23
Kass^Citation25	Prospective observational. Electronic medication monitor data. All subjects were masked from purpose of the monitor. Single cohort: timolol (BID, with or without other agents)	Compliance was defined as the percentage of timolol doses taken, as recorded by the monitor over 30-day period	110 subjects who were 18+ years, prescribed timolol BID for IOP reduction, from private practices of university faculty [Washington in US]	1984–1985	The entire group administered a mean of of 82.7% (SD = 19.0%) of prescribed doses. 8.2% of all patients took less than 50% of prescribed doses, and 27.3% took < 75% of doses. 60 of the 110 patients were receiving pilocarpine or another agent along with timolol. The rate of compliance with timolol was lower among patients receiving timolol alone vs those receiving timolol plus another agent NS
Norell-Granstrom^Citation16^–^Citation22	Prospective observational E lectronic medication monitor data Post-monitor patient interview Post-monitor physician and assistant estimates of compliance Only findings prior to second, 20-day interventional phase of study are reported here. All subjects were masked from purpose of the monitor. Single cohort: pilocarpine (TID)	1A) Number of days where <3 doses were self-administered over 20-day period 1B) Proportion of missed doses (of 60 possible) over 20 days 1C) Proportion of extra doses (of 60 possible) over 20 days 1D) Proportion of time over 20-day period for which scheduled dosing time was exceeded 2) Immediate post-monitor subject estimate of compliance during past 7 days compared with medication monitor data 3) Immediate post-monitor physician and assistant estimates of estimates of compliance independent of knowledge from 1) and 2) above	82 subjects, aged 56–90 years, treated at eye clinic at Huddlinge University Hospital, with POAG, visual defects, cupping, IOP 21+ mmHg, visual acuity 2/60, and currently using pilocarpine TID [Sweden]	1977–1978	1A) Patients missed at least 1 dose during 23% of all days. Of these, 19% occurred at the 1st, 54% at the 2nd, and 27% at the 3rd scheduled dose during the day 1B) 10% of the doses prescribed were missed.^Citation16 Patients missed at least 1 dose during 23% of all days.^Citation17 Of all 60 expected doses, 59% of patients missed 0%–9% (had good compliance), 20% missed 10%–19% (had intermediate compliance), and 20% missed 20+% (had poor compliance) 1C) 1% of doses were extra doses^Citation16 1D) For a median of 17.2% (range 3%–8%) of the observed time, the time since the previous dose had exceeded 8 hours^Citation16 2) 4% of patients said they missed 2+ doses over past week, compared to medication monitor results showing that 33% missed 2+ doses^Citation18 3) Correlation between physician estimates of compliance and medication monitor estimates was poor, with a correlation coefficient of r = 0.19 NS
Robin^Citation26	Prospective, single-site, open-label, non-randomized, parallel design. Electronic medication monitor data. Subjects were not masked from purpose of the monitor. Cohorts: prostaglandin (QD) as monotherapy (1-drug group), prostaglandin with an adjunctive medication (2-drug group)	Over a 60-day observation period Over/underadherence of the number of doses per 24-hour period, compared to nominal dosing: adherers (0–2 errors), marginal (3–5 dosing errors), and poor (>5 errors) Proportion of time for which interval between doses was <2 hours more than nominal dosing interval (coverage) Interval between doses (interdose interval) Number of doses divided by the number of days in study, times the prescribed dosing frequency (% of doses taken)	62 subjects at a private, subspecialty glaucoma practice, 18+ years with OAG or OHT, stable IOP for 30+ days, using either a single prostaglandin or prostaglandin plus adjunctive agent	Not specified	Overall, 20% of all subjects were in the poor category. For subjects in the 1-drug group, only 3.3% were in the poor category. For subjects in the 2-drug group, 10.0% were in the poor category for the prostaglandin and 30.0% were in the poor category for adjunctive therapy For the prostaglandin, the mean coverage was 97.2% (SD = 6.1%). It was similar in both the 1-drug group (97.5% [3.9%]) and the 2-drug group (96.8% [6.2%]). For adjunctive medications, the mean coverage was slightly less: 93.0% (8.3%) For the prostaglandin, the mean interval between doses was 24.4 (1.2) hours. When stratified by number of medications, the 2 groups were similar, 24.3 (1.2) hours for the 1-drug group vs 24.4 hours (1.3) for the 2-drug group. For adjunctive medications, the mean interval between doses was 22.7 (2.1) hours for QD dosing, 12.4 (1.4) hours for BID dosing, and 8.2 (0.2) hours for TID dosing For the prostaglandin, subjects took 97.0% (6.7%) of doses prescribed. The proportion of doses taken was similar when stratified by 1-drug [96.5% (4.7%)] or 2-drug [97.5% (8.2%)] groups. For the adjunctive medications (2-drug subjects only), subjects took 99.9% (13.0%) of doses prescribed

Abbreviations: BID, twice daily; IOP, intraocular pressure; NS, not significant at 95% confidence; OAG, open-angle glaucoma; OHT, ocular hypertension; POAG, primary open-angle glaucoma; QD, once daily; QID, 4 times daily; r, correlation coefficient; SD, standard deviation; Sig, significant at 95% confidence; TID, 3 times daily.

Table S2 Measurement of compliance and persistence – prescription fill record studies

Study group	Design/cohorts	Endpoint	Patient/setting	Study year	Findings
Bhosle^Citation31	Retrospective observation using Rx claims. Cohorts: latanoprost, non-latanprost agents	Persistence: time to Tx DC (60-day [1 bottle], 120-day [2 bottle] gaps) Adherence: MPR was calculated as the total days supply divided by the number of days between the index date and the dispensing date of the last prescription in the first Tx year	268 patients, 65+ years, new to glaucoma therapy, with POAG diagnosis in a Medicaid HMO [Southeastern US]	2000–2002	Mean (range) of persistence of cohorts at 1 yeara: 25% (18%–29%) Mean (range) of adherence of cohorts at 1 year: 44% (0.40%–0.51%)
Dasgupta^Citation32	Retrospective observation using Rx claims. Cohorts: beta blockers, brimonidine, carbonic anhydrase inhibitors, latanoprost	Time to Tx DC [120-day gap] Time to DC or change	1330 patients, <65 years and newly treated for glaucoma, in various health plans [US]	1999–2000	Mean (range) of persistence of cohorts at 1 yeara: 68% (51%–79%) 55% (33%–64%)
De Natale^Citation42	Retrospective observation using Rx records and electronic medical record. Cohorts: travoprost, latanoprost + timolol	Time to treatment failure, defined as prescription change (replace or DC initial therapy or add another agent) or receiving laser therapy or glaucoma surgery	815 patients in GPRD database. Had glaucoma diagnosis or glaucoma surgery, follow-up duration of 6 months, and first-line treatment with study agent [United Kingdom]	2002–2005	Mean (range) of non-failure rate of cohorts at 1 year: 67% (61%–69%)
Denis^Citation43	Retrospective observation using Rx records and electronic medical record. Cohorts: alpha-2 agonists + prostaglandin, carbonic anhydrase inhibitor + prostaglandin	Treatment failure, defined as prescription change (replace or DC initial therapy or add another agent) or receiving laser therapy or glaucoma surgery	6176 patients in GPRD database. Had glaucoma or OHT diagnosis, glaucoma surgery or glaucoma medication; follow-up duration of 6 months, and new to a cohort Tx [United Kingdom]	Not specified	Mean (range) of non-failure rate of cohorts at 1 year: 40% (34%–41%)
Djafari^Citation52	Retrospective observation using Rx utilization data Patient interview Treating ophthalmologist assessment Cohorts: prostaglandins, beta blockers, carbonic anhydrase inhibitors, adrenergic agents, miotics, beta blocker combinations	Adherent if number of days covered was ≥75% over 2 years Single question on adherence Perceived adherence status of treated patient	181 patients at ophthalmology clinic treated for POAG, OHT or were glaucoma suspects, and covered by RAMQ provincial insurance program [Quebec in Canada]	2004	71.8% of patients were adherent (across all cohorts) 88.3% of patients reported being adherent to glaucoma treatment (when asked if they used their medication as prescribed [recall period not specified]) 74.6% of patients were described by ophthalmologist as being at least 75% adherent. Although 72.1% of patients thought by physician to be adherent were actually adherent, 71.1% of patients thought by physician to be non-adherent were actually adherent
Friedman^Citation48	GAPS [This article is the reference source for the GAPS methodology] Retrospective observation using Rx claims Phone interviews with ophthalmologists Phone interviews with patients Chart review: compliance findings reported only for 1) above. No drug cohorts	1A) MPR as linear score and 1B) Gap analysis (60-day [2.5 mL], 90-day [5 mL], 120-day [>5 mL]) 1C) Medical possession at 12 months	13,977 patients, 40+ years, with OAG and new to glaucoma Tx, seen by surveyed physician [US]	1999–2005	Over a mean follow-up period of 22 months, 1A) Mean MPR of 0.64 (range 0.01–3.7) 1B) 10% used the originally prescribed prostaglandin without any gaps (were continually persistent) in refilling the prescription. Slightly more than half (54%) of the subjects had a gap in refilling the index drug but restarted after the gap. 16% switched from the index drug to another drug, and 20% discontinued all glaucoma medications without adding, switching, or restarting 1C) 59% had an ocular hypotensive in hand at the end of first Tx year. Despite required absence of glaucoma medication in the medical and pharmacy claims database in the pre-index period, 31% of subjects whose charts were surveyed had actually been treated with ocular hypotensive agents
Friedman^Citation54	See study above	1A) MPR as linear score, 1B) MPR as categorical variable [low 0–0.36, moderate 0.37–0.88, high 0.89–2.18]	300 patients from GAPS who also had completed interview, 40+ years, seen by surveyed physician, with OAG and new to glaucoma therapy [US]	1999–2005	1A) Mean not reported. Eight variables obtained from interview were associated independently with a lower MPR (P < 0.05): (1) hearing all of what you know about glaucoma from your doctor (compared with some or nothing); (2) not believing that reduced vision is a risk of not taking medication as recommended; (3) having a problem paying for medications; (4) difficulty while traveling or away from home; (5) not acknowledging stinging and burning; (6) being non-white; (7) receiving samples; and (8) not receiving a phone call visit reminder 1B) Frequency distribution not reported
Gurwitz^Citation12	Retrospective observation using Medicaid Management Information System database. No drug cohorts	Total non-adherence, defined as no filled Rx for any Tx (topical or systemic) during the 12 months following first Rx for a topical Tx Days without therapy, defined as cumulative number of days during which patient did not have glaucoma medication available in the 12 months following first Rx	2440 patients, 65+ years of age, newly initiated on ocular hypotensive for glaucoma, enrolled in Medicaid [New Jersey in US]	1980–1987	23.3% (95% CI = 21.6%, 25.0%) of patients were non-adherent within the first 12 months after initial fill Mean number of days without therapy in the 12-month observation period was 112 (SD = 111.6)
Gurwitz^Citation13	Retrospective observation using Rx claims. No drug cohorts	Same endpoints described above	616 patients newly initiated on therapy to treat OAG. Had at least 1 prescription fill of a topical medication and 15 months of eligibility in group HMO [Massachusetts in US]	1987–1990	24.7% (95% CI = 21.3%, 28.1%) of patients were non-adherent within the first 12 months after initial fill. Mean number of days without therapy in the 12-month observation period was 30.7 (SD = 57.0)
Higginbotham^Citation55	Retrospective observation using Rx fills. Cohorts: single-bottle dorzolamide/timolol fixed combination, 2-bottle combination of beta blocker and second agent, 3-bottle combination of any 3 agents	Persistence: time until a prescription for an additional agent occurred during 12-month follow-up period (all cohorts) or 1 of agents in multiple-bottle cohorts was no longer dispensed	37,979 patients identified from national retail pharmacy database who had any prescription fill during a single month that matched 1 of the 3 study cohorts [US]	2004	Mean (range) of persistence of cohorts at 1 year: 30% (24%–35%)
Jayawant^Citation33	Retrospective observation using Rx claims. No drug cohorts	Persistence: time to DC, for prostaglandins (60 days [≤2.5 mL], 90 days [>2.5 to ≤5 mL], 120 days [>5 mL]), for other medications (60 days [≤10 mL], 90 days [>10 to ≤15 mL], 120 days [>15 mL])	268 subjects, aged 65+ years in a Medicare HMO with 2+ years of follow-up with POAG diagnosis and receiving glaucoma prescription [US]	2000–2002	Mean of persistence of cohorts at 1 year:a 34%
Lafuma^Citation44	Retrospective observation using Rx records and electronic medical record. Cohorts: travoprost, dorzolamide + timolol	Treatment failure, defined as prescription change (replace or DC initial therapy or add another agent) or receiving laser therapy or glaucoma surgery	1026 patients in GPRD database. Had glaucoma diagnosis or glaucoma surgery, follow-up duration of 6 months, and new to antiglaucoma Tx [United Kingdom]	Not specified	Mean (range) of non-failure rate of cohorts at 1 year: 67% (62%–70%)
Lafuma^Citation45	Retrospective observation using Rx records and electronic medical record. Cohorts: carbonic anhydrase inhibitor + beta blocker, alpha-2 adrenergic agonist + beta blocker	Same endpoints described above	6745 patients in GPRD database. Had glaucoma diagnosis or glaucoma surgery, follow-up duration of 6 months, and new to antiglaucoma Tx [United Kingdom]	Not specified	Mean (range) of non-failure rate of cohorts at 1 year: 42% (36%–43%)
Lafuma^Citation46	Retrospective observation using Rx records and electronic medical record. Cohorts: brimonidine, brinzolamide	Same endpoints described above	2657 patients in GPRD database. Had OAG diagnosis or glaucoma surgery, follow-up duration of 6 months, and receiving antiglaucoma therapy (may not be Tx-naïve) [United Kingdom]	Not specified	Mean (range) of non-failure rate of cohorts at 1 year: 46% (44%–52%)
Lee^Citation53	Retrospective observation using pharmacy database. No drug cohorts	Proportion of patients who had a gap during during the first year (45-day, 60-day, or 120-day gaps)	95,417 patients at retail pharmacies, had single fill of 2.5 mL size prostaglandin during 4Q2002 and had same product and 2.5 mL size filled 4Q2003 [US]	2002	Percentages of patients with no annual gaps in therapy at 365 days were 10.6%, 28.6%, and 77.5% for refill periods of 45, 60, and 120 days, respectively
Muir^Citation56,Citation57	Retrospective observation using Rx claims Personal interviews with subjects. No drug cohorts	Refill rates over 6-month period prior to subject recruitment	142 subjects with a diagnosis of OAG from the Duke University Eye Center treated at practices of four glaucoma specialists [North Carolina in US]	2000–2001	Mean number of refills requested over 6 months for each prescribed medication was 2.5 (SD = 1.8). There was no significant association between Trust in Physician Score and the number of refills. There was a significant positive relationship between the Health Literacy Score (Rapid Assessment of Adult Literacy in Medicine) and the number of refills
Nordstrom^Citation5	Retrospective observational using Rx claims. Cohorts: beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, prostaglandins	Persistence: time to DC (60-day [≤10 mL], 90-day [>10 to ≤15 mL], 120-day [>15 mL] gaps) or change Adherence: having current refill of index Tx at 6-month intervals	5300 patients, 30+ years, newly diagnosed with OAG or glaucoma suspect, new to therapy, United Healthcare [US]	1995–2001	Mean (range) of persistence of cohorts at 1 yeara: 20% (10%–38%) for diagnosed glaucoma, 16% (10%–33%) for glaucoma suspect Mean (range) of adherence at 1 year:a 53% (38%–65%) for diagnosed glaucoma, 44% (32%–56%) for glaucoma suspect
Owen^Citation34	Retrospective observational using using Rx records and electronic medical record. Cohorts: beta blockers, prostaglandins	Time to DC 90 days (any ocular hypotensive)	5670 patients in DIN-LINK database, started on treatment for glaucoma or OHT and new to therapy [United Kingdom]	1994–2004	Across all cohorts and study years (1994–2004), persistence was 67%. The mean percentage persistent at 1 year rose after 1997 when prostaglandins were introduced, from 61% in 1994–1996 to 70% in 2002–2004
Quigley^Citation66	GAPS Retrospective observation using Rx claims Phone interviews with ophthalmologists Phone interviews with patients Chart review. Compliance findings reported only for 1) above. No drug cohorts.	MPR as linear score	300 patients who had available pharmacy and chart data, 40+ years, seen by surveyed physician, with OAG and new to glaucoma therapy [US]	2000–2005	This article reports demographics and clinical characteristics for a subset of GAPS study participants who had both pharmacy and chart data. MPR findings were not reported. See Friedman 2007^Citation48 study group above for MPR findings from the larger GAPS sample
Rait^Citation35	Retrospective observational using Rx claims. Cohorts: prostaglandins, dorzolamidetimolol, beta-blockers, alpha-agonists or carbonic anhydrase inhibitors	Time to DC (90-day gap)	357,099 patients comprising 2 cohorts: Population new to this ocular hypotensive agent and New to any agent [Australia]	1999–2005	New to any eyedrop mean (range) of persistence of cohorts at 1 year: 36% (22%–56%) in year 2002, 39% (20%–55%) in year 2003 New to this eyedrop mean (range) of persistence of cohorts at 1 year: 29% (6%–50%) in year 2002, 30% (6%–51%) in year 2003
Reardon^Citation29,Citation36	Retrospective observational using Rx claims. Cohorts: bimatoprost, latanoprost, travoprost	Time to DC (90-day [1 bottle] and 180-day gap [2 bottles]) Time to DC or Tx change	4356 patients, 20+ years, new to Tx, enrolled in commercial HMO, PPO, or Medicare-risk plans [US]	2001–2002	Mean (range) of persistence of cohorts at 1 year:a 19% (14%–23%); 14% (10%–17%)^Citation35 Of a subset of 2503 patients who had not changed ocular hypotensive therapy or disenrolled from the health plan at day 180, 65% were estimated to have discontinued therapy before the end of the year. Of these, 51% failed to restart any ocular hypotensive therapy before the end of the study at day 360 or their plan enrollment^Citation28
Reardon^Citation37	Retrospective observational using Rx claims. Cohorts: betaxolol, bromonidine, dorzolamide, latanoprost, timolol	Time to DC (120-day [1 bottle] and 180-day [2 bottles] gap) Time to DC or Tx change	2850 patients, 20+ years, new to Tx, covered by large New England insurer [US]	1999–2001	Mean (range) of persistence of cohorts at 1 year:a 40% (28%–55%); 29% (17%–40%)
Reardon^Citation41	Retrospective observational using Rx claims. Cohorts: betaxolol, bimatoprost, brimonidine, dorzolamide, latanoprost, timolol, travoprost	Time to DC (90-day [1 bottle] and 180-day gap [2 bottles]) Time to DC or Tx change	28,741 patients, 20+ years, new to Tx, enrolled in commercial HMO, PPO, or Medicare-risk plans [US]	1996–2002	Mean (range) of persistence of cohorts at 1 year:a 22% (8%–33%); 15% (6%–23%)
Reardon^Citation49	Retrospective observational using Rx claims. Cohorts: bimatoprost, latanoprost, travoprost	Medication possession at the end of year (currently taking Tx) Days covered in first therapy year (sum of adjusted days supply all 1st-year Rxs)	7873 patients new to Tx, glaucoma-related condition in commercial and Medicare-risk plans in HMO or PPO [US]	2004	Medication possession at the end of year was 28% (unadjusted pharmacy-reported days supply) and 47%–48% (adjusted days supply) Days covered in first therapy year was 131 (unadjusted days supply) and 228–236 (adjusted days supply)
Robin^Citation14	Retrospective observational using Rx claims. Cohorts: latanoprost users who remained on monotherapy, latanoprost users who added a second medication	For each patient, the mean number of days between latanoprost refills was calculated for both the period before and that subsequent to the addition of the second medication (if any). The difference in means between the 2 periods was calculated	1784 patients who were persistent for 1 year on latanoprost from index date, received 2+ fills of latanoprost then 2+ fills of 2nd agent, and were enrolled 12+ months in a large national health plan [US]	2001–2002	Mean refill intervals were 40.6 (SD = 21.8) days for latanoprost before the addition of a 2nd medication and 47.4 (24.4) days after the addition of a 2nd medication, with a significant mean increase of 6.7 (25.6) days. The latter interval was longer than that found for the 3146 patients who continued on latanoprost monotherapy, who had a mean refill interval of 41 (24) days
Rotchford^Citation58	Retrospective observational and survey design. Rx fills review Self-administered mailed questionnaire. Cohort: timolol	How frequently and what volume of monthly repeat prescriptions for timolol were dispensed over 12-month period Single question on compliance	86 respondents, 55+ years, in 3 large dispensing practices in Cambridgeshire, receiving repeat prescription for timolol [United Kingdom]	Not specified	Of the 55 subjects for whom dispensing information was available, 51% did not have sufficient timolol to medicate as prescribed. The average shortfall was 85 days over 12 months. 24% of patients admitted to omitting treatment either frequently or occasionally
Schwartz^Citation38	Retrospective observational using Rx claims. Cohorts: latanoprost, timolol	Time to DC (90-day [1 bottle] and 180-day gap [2 bottles]) Time to DC or Tx change	1474 patients who were 20+ years, were glaucoma suspects, were new to Tx, in commercial and Medicare-risk plans in HMO or PPO [US]	1997–2002	Mean (range) of persistence of cohorts at 1 year: 31% (25%–39%) 23% (18%–30%)
Shaya^Citation39	Retrospective observational using Rx claims. Cohorts: brimonidine, latanoprost, timolol	Time to DC (120-day gap)	2283 patients, 20–64 years, enrolled in Care First BCBS managed care plans, new to glaucoma Tx [Maryland in US]	1999–2001	Mean (range) of persistence of cohorts at 1 yeara: 18% (11%–25%)
Spooner^Citation40	Retrospective observational using Rx claims. Cohorts: betaxolol, brimonidine, latanoprost, timolol	Time to DC (120-day [2.5, 5, 10 mL] and 180-day gap [15 mL]) Time to DC or Tx change	1006 patients, 20 to 64 years, enrolled in Blue Cross of California, new to glaucoma Tx [California in US]	1998–1999	Mean (range) of persistence of cohorts at 1 year:a 29% (21%–44%) 22% (15%–36%)
Stryker^Citation59	Prospective observational using prescription records chart review patient interview. Cohorts: none	Non-adherent with taking medication: had both a physician note about non-adherence and self-report of missing at least 1 dose of medication in a week Refill non-adherence: had both Rx record of at least1 month lag in refill time, and self-report of running out of medication before getting a refill Non-adherent with respect to keeping clinical appointments if review of clinic records or self-report revealed any missed appointments in past year	80 participants, 18–80 years, white or African-American, with OAG, glaucoma suspect or OHT, at 2 VA hospital-based eye clinics, had Tx since at least the past year [Southeast US]	2007	60% of the sample was classified as non-adherent (were non-adherent with taking medication, had refill non-adherence, or missed any visit appointment in past year). Of these, 67% were non-adherent with taking medication as prescribed 50% had refill non-adherence 29% were non-adherent for appointment keeping
Traverso^Citation51	Retrospective observational using Rx claims. Cohorts: Patients with OHT, POAG	Coverage: percentage of days during which a patient was in possession of any glaucoma medication during 1st year Compliance: the 75th percentile of coverage (for both cohorts) served as the compliance/non-compliance cutoff	57,803 patients, 18+ years in multiple managed care database, with OHT or POAG diagnosis, following Rx for IOP-lowering medication within 12 months, and 12+ months follow-up [US]	1998–2005	Mean medication coverage was significantly higher for the POAG cohort 50% (SD = 0.26) than for the OHT cohort 40% (0.25) The 75th percentile of coverage for all medicated patients (OHT and POAG) was 71.3%
Wilensky^Citation50	Retrospective observational using Rx claims. Cohorts: bimatoprost, latanoprost, travoprost	Days persistent was measured from the date of the first claim through the end of the adjusted days supply of the last claim during the 12-month observation period Adherence was determined as the percentage of days for which the patient possessed medication	2424 patients in indemnity and PPO health plans, new to IOP-lowering medication, who continued for at least 3 months of therapy and took only a single Tx during the observation period [US]	2001–2002	69.3% were persistent for 1 year or longer Mean adherence (had medication available for use) was 76.3% (278 days) during the 1st year
Yeaw^Citation1	Retrospective observational using Rx claims. Cohorts: prostaglandin analogs, statins, bisphosphonates, oral antidiabetics, angiotensin II receptor blockers (ARBs), overactive bladder (OAB) medications	Persistence (on any prostaglandin rather than on specific agents) was defined as time to DC (30-day, 60-day, and 90-day gaps) Adherence (on any prostaglandin rather than on specific agents) was defined as proportion of days covered (PDC) over during the first 12 months of observation	3310 patients (prostaglandin cohort) in multiple managed care database, with glaucoma diagnosis, and new to prostaglandinTx [US]	2005–2007	Persistence at 1 year: 32% (60-day gap) Mean adherence (SD) at 1 year was 37% (26%)
Yousuf^Citation60	Retrospective observational using inpatient prescriptions	Adherence defined as ratio of doses administered in the hospital to doses expected (based upon the dosing regimen identified from the outpatient prescription noted on admission)	184 patients discharged with a diagnosis of glaucoma at 2 community hospitals and receiving ocular hypotensive therapy [Pennsylvania in US]	2006–2009	In the hospital setting mean adherence rate was 67.3% (SD = 29.4%). 51.6% of patients received < 75% of expected doses while 20.6% received < 50% of doses. Knowing (P < 0.01) and prescribing (P < 0.01) the complete outpatient regimen upon admission was associated with adherence. Neither class of topical glaucoma medication nor the number of medications was significantly associated with adherence
Zhou^Citation47	Retrospective observation using Rx records and electronic medical record. Cohorts: beta blockers, prostaglandins	Time to failure [change in Tx or surgery] Time to DC (2 × days supply duration or 60 days) or failure	2001 newly diagnosed OAG patients new to Tx in the GPRD database [United Kingdom]	1997–1999	Mean (range) of persistence of cohorts at 1 yeara: 72% (55%–86%) 56% (37%–69%)
Zimmerman^Citation30	GAPS Retrospective observation using Rx claims Phone interviews with ophthalmologists Phone interviews with patients Chart review. Compliance findings reported only for 1) above. Cohorts: bimatoprost, latanoprost, travoprost	Descriptive tree of multiple endpoints, including: proportion persistent (60– day [2.5 mL bottle], 90-day [5 mL bottle], and 120-day gap [>5 mL]) during 1st year (includes monotherapy, add-on therapy) Proportion persistent or restarting index therapy during 1st year Proportion switching therapy during 1st year Proportion discontinuing and no longer using any medication at end of year Any adherence-related comment entered in the chart was recorded as positive (eg,, “Patient compliant with drops”) or negative (eg, “Patient not compliant with regimen”) [DC of index medication was considered a switch]. Reported starting then discontinuing a previously prescribed medication	6271 patients age 40+ years, with diagnosis of OAG and new to Tx and receiving monotherapy, with 12+ months follow-up, enrolled in health network [US]	1999–2005	Mean (range) of cohorts at 1 year: 10% (5%–11%) 65% (58%–68%) 16% (14%–21%) 19% (18%–21%) Index medication was continued for the duration of the chart-reviewed time frame (mean 4.1 years) in only 37% of patients. 63% had their medication regimens changed with either a switch or an addition of medication. Of the latter, 43% of changes were efficacy related (due to insufficient IOP reduction) and 31% were adverse-event related. Among the 37% of patients who reported starting and then discontinuing a previously prescribed medication, adverse effects were by far the most common (44%) reason reported for stopping the medication, followed by perceived lack of efficacy (19%)

a Note: Engage Digitizer 4.1 (www.digitizer.sourceforge.net) was used to translate the plot line for each cohort to a spreadsheet of persistence values.

Abbreviations: BCBS, Blue Cross Blue Shield; DC, discontinuation; DIN-LINK, a primary care/family practice electronic medical record database in the United Kingdom; GAPS, Glaucoma Adherence and Persistency Study; GPRD, General Practice Research Database (a primary care/family practice electronic medical record database in the United Kingdom); HMO, health maintenance organization; IOP, intraocular pressure; MPR, medication possession ratio; OAG, open-angle glaucoma; OHT, ocular hypertension; POAG, primary open-angle glaucoma; PPO, preferred provider organization; RAMQ, Régie de l’assurance maladie du Québec; Rx, prescription; SD, standard deviation; Tx, therapy; VA, Veterans Affairs.

Table S3 Measurement of persistence – medical chart review studies

Study group	Design/cohorts	Endpoint	Patient/setting	Study year	Findings
Arias^Citation61	Retrospective observational using chart review. Cohorts: latanoprost, bimatoprost, travoprost, timolol	Time to Tx DC or change, or referral to surgery	191 patients, 18+ years, seen at hospital clinic with glaucoma or OHT, initiated with monotherapy, not required to be new to Tx [Madrid, Spain]	2003–2004	Mean (range) of persistence of cohorts at 1 yeara: 78% (50%–91%)
Day^Citation62	Retrospective multicenter observation using chart review. Cohorts: latanoprost, bimatoprost, beta blockers	Time to Tx change	1182 patients, 18+ years, diagnosis of POAG or OHT at ophthalmologist practices, may/ may not be new to Tx [South Carolina, Georgia, Florida in US]	1996–2002	Mean (range) of persistence of cohorts at 1 yeara: 64% (57%–71%)
Diestelhorst^Citation63	Retrospective multicenter observation using chart review. Cohorts: beta blockers, latanoprost	Time to Tx DC	260 patients, 18+ years, with diagnosis of POAG, were treatment-naïve, at ophthalmology practices and clinics [Germany, Italy, Spain, United Kingdom]	1996–2000	Mean (range) of persistence of cohorts at 1 yeara: 62% (46%–83%)
Hahn^Citation11	GAPS. Retrospective observation using Rx claims, Phone interviews with ophthalmologists, Phone interviews with patients, Chart review. [Persistence findings reported for 4) above] Cohorts: bimatoprost, latanoprost, travoprost	4) Time to DC or Tx change	223 patients from database cited in Zimmerman et al^Citation30 who also had chart review data, age 40+ years, with diagnosis of OAG and new to Tx and receiving monotherapy, with 12+ months follow-up, enrolled in health network [US]	1999–2005	Mean (range) of persistence of cohorts at 1 yeara: 63% (58%–71%)
Kashiwagi^Citation65	Retrospective observation using patient registry. Cohorts: latanoprost, prostaglandins, beta-blockers, carbonic anhydrase inhibitors, pilocarpine, epinephrine, bunazosin	Persistence for ophthalmic solutions prescribed in 2001 [not further described]	1955 glaucoma patients in clinical registry at university glaucoma clinic who were newly prescribed an antiglaucoma agent for 1+ months [Japan]	2000–2008	Mean (range) of persistence of cohorts at 1 year: not reported
Tingey^Citation64	Retrospective observational using chart review. Cohorts: Phase 1 – patients starting first-line glaucoma treatment, Phase 2 – patients in whom first-line monotherapy with a β-blocker had failed and a second-line agent was being added or substituted (Phase 2)	Time persistent defined as the proportion of patients remaining on that therapy each month after initiation. Change in therapy defined as the addition of a medication, a switch to an alternative medication or a referral to surgery	115 patients, 18+ years with who had begun therapy for newly diagnosed POAG or OHT, at private ophthalmology practices and outpatient clinic [Alberta in Canada]	1998–1999	Mean (range) of persistence of cohorts at 1 yeara: Phase 1 was 69% (63%–87%); Phase 2 was 65% (64%–69%)

a Note: Engage Digitizer 4.1 (www.digitizer.sourceforge.net) was used to translate the plot line for each cohort to a spreadsheet of persistence values.

Abbreviations: DC, discontinuation; GAPS, Glaucoma Adherence and Persistency Study; MPR, Medication Possession Ratio; OAG, open-angle glaucoma; OHT, ocular hypertension; POAG, primary open-angle; Rx, prescription; Tx, therapy.

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