Intervention Review

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Interventions for improving adherence to ocular hypotensive therapy

  1. Heather Waterman1,*,
  2. Jennifer R Evans2,
  3. Trish A Gray3,
  4. David Henson3,
  5. Robert Harper4

Editorial Group: Cochrane Eyes and Vision Group

Published Online: 30 APR 2013

Assessed as up-to-date: 26 JUN 2012

DOI: 10.1002/14651858.CD006132.pub3


How to Cite

Waterman H, Evans JR, Gray TA, Henson D, Harper R. Interventions for improving adherence to ocular hypotensive therapy. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD006132. DOI: 10.1002/14651858.CD006132.pub3.

Author Information

  1. 1

    University of Manchester, School of Nursing, Midwifery and Social Work, Manchester, UK

  2. 2

    London School of Hygiene & Tropical Medicine, Cochrane Eyes and Vision Group, ICEH, London, UK

  3. 3

    Manchester Royal Eye Hospital, Academic Department of Ophthalmology, Manchester, UK

  4. 4

    Central Manchester & Manchester Children's NHS Trust, Optometry Department, Manchester, UK

*Heather Waterman, School of Nursing, Midwifery and Social Work, University of Manchester, Room 6.31a, University Place, Oxford Road, Manchester, M13 9PL, UK. heather.waterman@manchester.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 30 APR 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Gray 2011

MethodsRandomised, single-centre, observer masked, parallel-group study

Duration: 24 months


ParticipantsCountry: UK

Setting: hospital outpatient clinic

Target number of participants: 127

Gender: 64 men, 63 women

Age range: 30 to 91, mean age 66 years

Ethnicity: 114 (90%) white, 8 (6%) black, 5 (4%) other

Inclusion criteria: patients newly prescribed ocular hypotensive eye drops with a diagnosis of OAG, normal tension glaucoma, pseudo-exfoliation glaucoma, pigment dispersion glaucoma or OHT

Exclusion criteria: patients unable to give informed consent or patients already prescribed a complicated drop regime for another eye condition


InterventionsIntervention group: individualised programme of care carried out by an ophthalmic-trained nurse based on an assessment that takes into account factors such as other medical conditions, additional medications, independence with daily living activities, potential problems managing an eye drop regime and beliefs about medications. Patients also continue to receive the information, advice and training they would normally be given within the outpatients department.

Control group: usual care; patients receive the information, advice and training they would normally be given within the outpatients department

Follow-up: 1 year


OutcomesPersistence of therapy measured by counting prescription and dispensing data

Adherence to therapy assessed through self report via interviewer-administered questionnaire

Beliefs about illness and medicines assessed through self report via previously validated, interviewer-administered questionnaires

Patient enablement assessed through self report via previously validated, interviewer-administered questionnaires

Intraocular pressure


NotesFunding sources: part-funded by Pfizer

http://www.controlled-trials.com/ISRCTN13706134


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“Computer-generated randomisation was conducted by a statistician with no involvement in data collection.  Patients were allocated to receive either individualised patient care in addition to standard care or standard care alone.  Stratified random sampling ensured equal proportions of patients within each arm from specialist glaucoma and general ophthalmic clinics, to reduce the risk of confounding factors from potential clinical management inequalities” Page 257

Allocation concealment (selection bias)Low risk"Allocations were concealed in opaque sealed envelopes by personnel with no involvement in the study.  Envelopes were then passed onto a study coordinator with minimal involvement in the study.  The study coordinator was responsible for opening envelopes as patients were recruited and contacting the intervention nurse to inform her as new patients were randomised to the intervention-arm.” Page 257

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The researcher and outcome assessor were masked to allocations until study completion." Figure 1 page 409

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes at 12 months: data for 63/64 of intervention group and 60/63 of control group. Reasons for incomplete outcome data supplied. Figure 2 page 412

Selective reporting (reporting bias)Low riskThere were some modifications from the protocol but this was additional data collection (clinical outcomes data and knowledge and self report adherence measures). All data collected were available for this review.

Hermann 2011a

MethodsRandomised, single-centre, observer masked, parallel-group study

Duration: 4 weeks


ParticipantsCountry: Greece

Setting: hospital outpatient clinic

Number of participants: 36

Gender: 11 men, 25 women

Age range: 26 to 76, mean age 55.1 +/- 14

Ethnicity: Caucasian

61% ocular hypertension

Inclusion criteria: age more than 18 years; diagnosis of primary open-angle glaucoma or ocular hypertension; established topical hypotensive therapy with brimonidine; no history of ocular surgery in the past 6 months

Exclusion criteria: none


InterventionsOpen or masked monitoring and brimonidine twice daily or 3 times daily


OutcomesDosing interval, applications per day, adherence rate, coverage. Assessed using an electronic monitoring device.


NotesFunding sources: not reported. This statement was included in the published paper "The authors did not receive support from a for-profit organization."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“Patients were then assigned to open or masked monitoring and to brimonidine BID or TID using permuted block randomization and randomization envelopes.” Page e301

Allocation concealment (selection bias)Unclear risk“Patients were then assigned to open or masked monitoring and to brimonidine BID or TID using permuted block randomization and randomization envelopes.” Page e301

Not enough detail about the envelopes reported

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk“Subjects received the study medication with attached monitoring devices free of charge and were familiarized with the usage of the bottles. Patients with masked monitoring were not informed about the electronic adherence monitoring. Instead, these patients were told, the electronic devices would continuously record the temperature of the medication. Patients assigned to open monitoring were fully informed about the monitoring of adherence to topical therapy.” Page e301

 

It is not clear if the personnel or participants were masked

Blinding of outcome assessment (detection bias)
All outcomes
Low risk“Subjects received the study medication with attached monitoring devices free of charge and were familiarized with the usage of the bottles. Patients with masked monitoring were not informed about the electronic adherence monitoring. Instead, these patients were told, the electronic devices would continuously record the temperature of the medication. Patients assigned to open monitoring were fully informed about the monitoring of adherence to topical therapy.” Page e301

 

The above statement suggests the participants might have been masked, but not clear as to personnel or outcome assessors. However, as the outcome measures were based on electronic recording, lack of masking was considered not to be a source of bias here.

Incomplete outcome data (attrition bias)
All outcomes
Low risk36/37 participants completed the study

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern.

Hermann 2011b

MethodsRandomised, single-centre, observer masked, parallel-group study

Duration: 4 weeks


ParticipantsCountry: France

Setting: hospital outpatient clinic

Number of participants: 75

Gender: 44 men, 31 women

Age range: 42 to 89 years, mean age 70.0 +/- 11.2 years

Ethnicity: 100% white

Inclusion criteria: 18 years of age or older taking topical therapy for open-angle glaucoma, chronic angle-closure glaucoma, or ocular hypertension; no history of ocular surgery in the past 3 months; minimum of 12 months experience with topical glaucoma therapy

Exclusion criteria: none


InterventionsBrimonidine twice daily and 3 times daily


OutcomesElectronic monitoring

Dosing interval

Applications per day

Adherence rate %

Coverage %

Medication used per dosing

Drops per dosing


NotesFunding sources: "The authors did not receive support from a for-profit organization."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were then randomly assigned to brimonidine bid or tid using permuted block randomization with randomization envelopes and received the study medication with attached monitoring devices free of charge." Page 503

Allocation concealment (selection bias)Low risk"Patients were then randomly assigned to brimonidine bid or tid using permuted block randomization with randomization envelopes and received the study medication with attached monitoring devices free of charge." Page 503

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"According to the study protocol electronic adherence monitoring was accomplished in a masked fashion. Patients were informed about the electronic monitoring only to the point that the temperature of the medication would be recorded." Page 502

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"According to the study protocol electronic adherence monitoring was accomplished in a masked fashion. Patients were informed about the electronic monitoring only to the point that the temperature of the medication would be recorded." Page 502

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"A total of 75 patients [...] were enrolled in the study; 67 (89%) completed the study and were included in the statistical analysis. Seven patients (9.3%) did not complete the study owing to adverse effects (migraine, dry eye, redness, allergy). One bottle (1.3%) was not recollected." Unclear which group 7 patients were in. Page 504.

Selective reporting (reporting bias)Unclear riskDifficult to assess with information available

I-SIGHT

MethodsRandomised, multi-centre, observer masked, parallel-group study

Duration: 12 months


ParticipantsCountry: USA

Setting: outpatient clinic

Number of participants: 312

Gender: 195 men, 117 women

Age range: 18 to 80 years, mean age 62.6 years

Study participants were patients with glaucoma considered to non-adherent "because they did not take their medication, refill their medication, and/or keep their appointments"

Inclusion criteria: receive treatment for their eye condition at 1 of the 2 participating eye clinics; be between the ages of 18 and 80 years; be white or black/African American; have a home or cellular telephone; speak and understand English; be diagnosed with glaucoma or ocular hypertension for at least 1 year; be prescribed daily doses of topical glaucoma treatments for at least the past year; not have had eye surgery within the past 3 months; have better than 20/200 vision in at least 1 eye; and be able to read or have someone who can help them with reading printed materials

Patients also had to acknowledge non-adherence in the past year with medication taking, obtaining refills or clinic appointments


InterventionsIntervention group: 12 telephone calls over 9 months delivered automatically including tailored information on adherence and glaucoma. The intervention was "individually tailored to a participant’s knowledge, attitudes, and behaviors; psychosocial predictors of adherence; health literacy; race and culture; and prescribed medication regimen."

Control group: usual care


OutcomesAdherence (self report of missed doses)

Prescription refills (pharmacy records)

Appointment keeping
Sources of information: interviews, medical record review, appointment records and pharmacy data


Noteshttp://clinicaltrials.gov/ct2/show/NCT00794170


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"After completing the baseline interview, each participant was randomized into either the control or intervention group (with a 1:1 ratio). A random number generator was used in Excel (Microsoft), and participants were randomized in blocks of 10. The sequence was generated in advance by the research project manager, and participants were assigned in the order that they were enrolled. Randomization was stratified by clinical site because of expected differences in sex, race, and educational level between the sites." Page E2

Allocation concealment (selection bias)Unclear risk"Research interviewers were not masked to assignment because it was necessary to determine treatment group participants’ preferences for intervention delivery (eg, preferred telephone number and time of day)" Page E2

Unclear if this applies to recruitment as well as outcome assessment

Blinding of outcome assessment (detection bias)
All outcomes
High risk"Adherence data from data abstractions were coded independently by 2 raters who met in cases of disagreement to resolve discrepancies" Page E3

"Research interviewers were not masked to assignment because it was necessary to determine treatment group participants’ preferences for intervention delivery (eg, preferred telephone number and time of day)" Page E2

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntervention group: 150/157 (96%) interviewed at 12 months

Intervention group: 152/155 (98%) interviewed at 12 months

Figure page E4

Selective reporting (reporting bias)Low riskInvestigator confirmed that all outcome data specified in protocol and collected in the study were published

Laibovitz 1996

MethodsRandomised, single-centre, observer masked, 2-period cross-over study

Duration: 4 weeks


ParticipantsCountry: USA

Setting: outpatient clinic

Number of participants: 75

Gender: 36 men, 39 women

Age range: 24 to 88 years, mean age 55.7 years

Ethnicity: white: 29/312 (9.3%), black 283/312 (90.7%)

Inclusion criteria: men and women aged 18 years or older with OAG or OHT who were clinically suitable for adjunctive therapy. Patients treated with an ophthalmic beta-blocker for at least 3 weeks prior to randomisation.

Exclusion criteria: patients prescribed dorzolamide or pilocarpine in the past, visual acuity of worse than 20/80 in both eyes, history or evidence of acute or chronic ACG, insufficient pupillary dilation for an adequate retinal examination, history or presence of uveitis or retinal detachment. Patients with asthma or chronic obstructive pulmonary disease, clinically significant renal disease, severe physical disability or any contraindication to the use of dorzolamide, timolol or pilocarpine ophthalmic solution.


InterventionsGroup A: 2% dorzolamide 3 times daily during period 1 and 2% pilocarpine 4 times daily during period 2

Group B: 2% pilocarpine 4 times daily during period 1 and 2% dorzolamide 3 times daily during period 2

Both groups continued to receive 0.5% timolol twice daily throughout the study

Follow-up: short-term; 14 days per period


OutcomesAdherence assessed through self report via interviewer-administered questionnaire using previously validated tool (COMTol). Patients were asked how often they missed eye drops. Responses were marked on a scale of 0 to 6: 0 = never, 6 = always.

Quality of life assessed via interviewer-administered questionnaire (COMTol). Patients asked whether quality of life was interfered with by side effects or activity limitations. Responses were marked on a scale of 0 to 5: 0 = not at all, 5 = extremely.

IOP reduction assessed with Goldmann applanation tonometer

Visual field defects assessed with Humphrey Field Analyser 24-2 programme


NotesFunding Sources: Sponsored by Merck & Co


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised random number generator used

Allocation concealment (selection bias)Low riskCentral allocation used

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“Because one purpose of our study was to determine patient preference between the two ophthalmic medications, and dosing regimen is an integral part of such preference, we deliberately did not mask the treatment regimens to the patients or study physician. However, the interviewer administering the COMTol questionnaire was masked to the patient’s regimen, interviews were conducted in a brightly lit room (to induce miosis in all patients), and patients were instructed not to disclose their dosing frequency to the interviewer.” Page 823

Blinding of outcome assessment (detection bias)
All outcomes
Low risk“Because one purpose of our study was to determine patient preference between the two ophthalmic medications, and dosing regimen is an integral part of such preference, we deliberately did not mask the treatment regimens to the patients or study physician. However, the interviewer administering the COMTol questionnaire was masked to the patient’s regimen, interviews were conducted in a brightly lit room (to induce miosis in all patients), and patients were instructed not to disclose their dosing frequency to the interviewer.” Page 823

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Of the 75 patients who entered the study, 51 completed both treatment periods (Table III). A total of 21 patients discontinued therapy due to adverse experiences while receiving pilocarpine (12 from group A and 9 from group B), whereas only 2 patients discontinued therapy due to adverse experiences while receiving dorzolamide (both from group B).[...] Only 1 patient, who was lost to follow-up during the first period, discontinued dorzolamide
and did not enter the second period."
Page 825

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

Laster 1996

MethodsRandomised, single-centre, 2-period cross-over study

Duration: 60 days


ParticipantsCountry: USA

Setting: university-based glaucoma clinic

Number of participants: 13

Gender: 2 men, 11 women

Age range and mean age: data unavailable

Ethnicity: data unavailable

Inclusion criteria: patients diagnosed with OAG who were prescribed pilocarpine solution 4 times a day

Exclusion criteria: not stated


InterventionsGroup 1: pre-weighed bottle of pilocarpine of appropriate concentration (according to prescription) in a medication vial fitted with the Prescript TimeCap in period 1 and pre-weighed bottle of pilocarpine of appropriate concentration (according to prescription) without the vial or cap in period 2

Group 2: pre-weighed bottle of pilocarpine of appropriate concentration (according to prescription) without the vial or cap in period 1 and pre-weighed bottle of pilocarpine of appropriate concentration (according to prescription) in a medication vial fitted with the TimeCap in period 2

Follow-up: short-term; 30 days per period


OutcomesAdherence assessed by weighing the drop bottle at the end of each 30-day period and also through self report via a patient questionnaire completed at the end of each period


NotesFunding sources: non-commercially funded


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskDrawing of lots (each participant was randomly given a number using a statistical table then numbers were drawn to assign to either group 1 or group 2)

Allocation concealment (selection bias)High riskOpen random allocation schedule used

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and personnel were not masked

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskOutcome assessors were not masked. The effects may vary with outcome.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskA total of 13 patients were [..] able to complete the study” Page 655

This suggests that more people could have been enrolled and not reported

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

Muir 2012

MethodsRandomised, single-centre, parallel-group study

Duration: 6 months


ParticipantsCountry: USA

Setting: medical centre

Number of participants: 127 (131 enrolled, 4 withdrew)

Gender: 126 men, 1 woman

Age range 43 to 87 years; mean age: 66 years (SD 9.6)

Ethnicity: 29% white, 80% African American, 1% other

Inclusion criteria: score of 18 or higher on Mini Mental State Examination patients diagnosed with OAG who were prescribed pilocarpine solution 4 times a day

Exclusion criteria: best-corrected visual acuity in the better seeing eye < 20/200; eye surgery in the past month


InterventionsEducational intervention lasting 20 minutes (one-on-one session) including "informational video". Language of video varied according to participants' tested health literacy level.

Standard care


OutcomesNumber of days without medication

Medication possession ratio

Self reported disease knowledge

Satisfaction with care


NotesFunding sources: non-commercially funded


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Subjects were randomized in a one-to-one fashion to standard care or an educational intervention." Page 161

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk131 enrolled, 4 withdrew, no other information on follow-up

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

Nakakura 2012

MethodsRandomised, multi-centre, parallel-group study

Duration: 12 weeks


ParticipantsCountry: Japan

Setting: hospital

Number of participants: 36 (39 enrolled, 3 withdrew)

Gender: 19 men, 17 women

Average age: 71 years

Ethnicity: not reported, assumed Japanese

Inclusion criteria: primary open-angle glaucoma; exhibition of a stable intraocular pressure for more than 3 months; no history of fixed-combination therapy; treated with 3 antiglaucoma eye drops (various preparations of prostaglandin F2-alpha analogues + beta-blockers + carbonic anhydrase inhibitors)
Exclusion criteria: congenital or narrow-angle glaucoma; ocular surgery including laser surgery within the previous 6 months; any previous glaucoma surgery; ocular inflammation, neovascular glaucoma or steroid-induced glaucoma; any other conditions that prevent use of the Goldmann applanation tonometer; at risk of visual acuity and visual fields worsening during this study; allergy to preservatives


InterventionsLatanoprost 0.005%/timolol 0.5% plus brinzolamide 1%
Dorzolamide 1%/timolol 0.5% plus latanoprost 0.005%


OutcomesIntraocular pressure

Questionnaire including question "How often do you forget administration per week?"

Adverse effects

If both eyes included, right eye analysed


NotesFunding not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported

Blinding of outcome assessment (detection bias)
All outcomes
High riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Low risk20/21 participants in latanoprost/timolol plus brinzolamide group followed up compared to 16/18 in dorzolamide/timolol plus latanoprost

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

Norell 1979

MethodsRandomised, single-centre, 2-period, parallel-group study. Randomisation stratified by age.

Duration: 40 days


ParticipantsCountry: Sweden

Setting: hospital outpatient clinic

Number of participants: 73 (82 recruited, 9 excluded from analysis)

Gender: 45 men, 37 women

Age range: 50 to 90 years, median age 73 years

Ethnicity: not stated

Inclusion criteria: patients with chronic simple glaucoma, glaucomatous visual field defect, cupping of optic disc, raised IOP and prescribed pilocarpine eye drops 3 times a day in an eye with visual acuity of least 2/60

Exclusion criteria: not stated


InterventionsExperimental group: no intervention for the first 20-day monitoring period, then 30-minute education and tailoring programme implemented at clinic appointment and monitoring continued for a further 20 days. Education involved basic information on glaucoma and its treatment, supplied by a tape-slide show and leaflet. Patients' knowledge and understanding was then checked by ophthalmology assistant and insufficiently mastered information re-emphasised. Patients were encouraged to ask questions and discuss problems with medication. Tailoring involved patient interview with an ophthalmology assistant to ascertain daily routine and to advise on best times to instil eye drops within daily routine. Advice given re: storage of drops. Times and drop routine written for each patient.

Control group: monitoring for 2 x 20-day periods, no intervention

Follow-up: short-term; 20 days per period


OutcomesAdherence to therapy assessed with a medication monitor which recorded the date and hour each time the medication bottle was opened


NotesFunding sources: not stated


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk“They were stratified for age and randomly allocated to an experimental group or a control group.” Page 1031

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of outcome assessment (detection bias)
All outcomes
Low risk“Patients were not told the purpose of the monitor until we had finished collecting all the data.” Page 1032

Electronic outcome monitoring considered at low risk of bias

Incomplete outcome data (attrition bias)
All outcomes
Low risk73/82 (89%) participants provided complete data

 

“The second monitor record was lost in nine cases-one patient suffered acute heart disease, two were admitted to hospital for long-term care, in two cases the monitor was lost or broken, and in four no record was obtained because the monitor battery was defective." Page 1032

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

Okeke 2009

MethodsRandomised, 2-centre, 2-period, parallel-group study

Duration: 3 months


ParticipantsCountry: USA

Setting: Glaucoma Services of the Wilmer Eye Institute and the Scheie Eye Institute

Number of participants: 66

Gender:3 6 men, 30 women

Age range: mean age 66.1 in intervention group; 63.8 in the control group

Ethnicity: 40 black, 25 white, 1 Asian

Inclusion criteria: people with glaucoma being treated with a prostaglandin analogue in 1 or both eyes

Exclusion criteria: people were excluded if they were unable to understand the study, they did not put in their own drops, or they could not use the dosing aid


InterventionsThe intervention consisted of the following:

  • 10-minute educational video
  • structured discussion
  • reminder telephone calls
  • activation of the audible and visible alarms on the dosing aid


People in the control group received usual care, i.e. were told that it is important to take their eye drops as prescribed but had no other intervention


OutcomesAdherence rate as measured by a dosing aid device and a questionnaire

Intraocular pressure


NotesFunding sources: supported in part by the National Institutes of Health, charitable grants and Alcon

http://clinicaltrials.gov/ct2/show/NCT00333463


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"To perform the randomization procedure, a string of random numbers was selected from a random numbers table...." Page 2287

Allocation concealment (selection bias)Low risk"...The numbers were placed into envelopes and then sealed and initialed across the seal. The envelopes were numbered consecutively starting with 1. When an eligible patient was identified, an envelope was opened; if the envelope contained an even number then the participant received the intervention." Page 2287

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMasking was not described and intervention/control group received very different interventions

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll 66 patients randomised were apparently assessed for adherence at 3 months, however the following statement implies there were some dropouts in the intervention group. "For the 35 patients randomized to the intervention group, telephone calls were made at weeks 1 to 5, 7, 9, and 11. The number of patients contacted was highest at week 1 (100%), and over the remaining weeks there was a decline in the number successfully contacted (week 11, 63%). Reasons for the decline included early dropout from study, inability to contact patients, and early final visit." Page 2289

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

Ring 2011

MethodsQuasi-experimental, single-centre study

Duration: 3 months


ParticipantsCountry: UK

Setting: hospital outpatient clinic

Number of participants: 124 (127 recruited, 2 withdrew and 1 died)

Gender: 47 men, 77 women

Age range: 40 to over 80, mean age = 71 years (calculated from frequencies on table 5, page 32), median age 73 years

Ethnicity: 101 white, 12 Asian, 8 black, 3 other

Inclusion criteria: people diagnosed with open-angle glaucoma, ocular hypertension, normal tension glaucoma on ocular hypotensive drops

Exclusion criteria: people who were unable to understand and sign and informed consent form, people who could not see the film clearly


InterventionsEducational intervention: specially developed film


OutcomesQuestionnaire

Weight of eye drop bottles


NotesFunding Sources: International Glaucoma Association


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk“The participants were randomly allocated to either the control group or the intervention group. The allocation can be referred to as random because the film was shown on various days and no prior knowledge of when the participants were attending their routine clinic appointment was known.” Page 27

Further information from investigator:

"The participants were allocated into each group purely by attending an outpatient appointment on different days. The control or test intervention was set for different days and the participants arrived according to their outpatient appointment. This was considered random allocation as the student researcher had no influence over which participant arrived on which day."

Allocation concealment (selection bias)High riskInformation from investigator:

"The person recruiting the participants was the student researcher as outlined in the dissertation.  This person was aware of which group the participant was allocated to."

Blinding of outcome assessment (detection bias)
All outcomes
High riskNot masked

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk“A total of 127 participants were enrolled into the study over a four week period; 2 participants withdrew without a specific reason and 1 participant died before the 3 month data was collected. All results are based on a cohort of responding participants (n=124). 110 participants completed the study (88.7%). 14 of the original cohort did not respond to the 3 month postal questionnaire (non-response rate of 11.3%).” Page 32

Selective reporting (reporting bias)Low riskInvestigator confirmed all data collected were reported

Sakai 2005

MethodsQuasi-randomised, single-centre, parallel-group study

Duration: 12 weeks


ParticipantsCountry: Japan

Setting: university-based ophthalmology clinic

Number of participants: 36 (40 recruited, 2 withdrew after randomisation, 2 excluded after washout period as IOP < 20 mmHg and, therefore, no longer met criteria)

Gender: 14 men, 22 women

Age range: 45 to 75 years, mean age 64 years

Ethnicity: Asian 100%

Inclusion criteria: patients with primary ACG diagnosed by indentation gonioscopy and UBM, existence of synechial angle closure, released pupillary block by LPI at least 3 months before the study and a history of elevated IOP > 21 mmHg without any treatment with antiglaucoma medications

Exclusion criteria: previous ocular surgery other than LPI, acute PAC, use of oral acetazolamide because of poor IOP control, suspected secondary angle closure related to uveal effusion, uveitis, lens subtractions or trauma. Patients who were already scheduled for surgery that would affect IOP such as trabeculectomy or phacoemulsification. Patients prescribed medicines for hypertension, cardiovascular disease, bronchial asthma and allergy to any of the study medication.


InterventionsLatanoprost (L) group: monotherapy with latanoprost once daily

Timolol/dorzolamide (T/D) group: unfixed combination therapy with 0.5% timolol maleate twice daily and 1% dorzolamide 3 times daily

Follow-up: short-term; 12 weeks


OutcomesAdherence assessed though self report via patient questionnaire at 12 weeks. Patients were asked how many times they had forgotten to apply their drops. Pre-defined responses were; less than once a week, once a week, 2 or 3 times a week and 4 or more times a week.

IOP reduction assessed with Goldmann applanation tonometer

Visual field defects assessed with Humphrey Field Analyser, automated perimetry full-threshold 30-2 programme


NotesFunding sources: none


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High risk“All but 1 of the remaining 36 patients were randomly allocated to ...”

Page 484

Assigned by rotation. 1 patient not randomised but assigned to latanoprost group to minimise possible side effects of timolol administration due to a pulse rate of 59/min at first evaluation.

Allocation concealment (selection bias)High riskOpen random allocation schedule used

"One patient was assigned.. to the latanoprost group to eliminate the risk of side effects."

Correspondence with investigator: "It was open labelled and allocation schedule was not concealed prior to the assignment to the subjects. Two subjects were dropped out by their own will, may be because of the allocation."

Blinding of participants and personnel (performance bias)
All outcomes
High riskDifficult to mask participants as dosing frequency differed

Blinding of outcome assessment (detection bias)
All outcomes
High riskCorrespondence with investigator: "It was open labelled, and the number of the eye drop(s) was different."

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo data available for 4 patients; 2o withdrew after randomisation and 2 were excluded after washout period
Attrition rate: 10%

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

Schenker 1999

MethodsRandomised, multi-centre, 2-period, cross-over study

Duration: 12 weeks


ParticipantsCountry: USA

Setting: hospital outpatient clinic

Number of participants: 202

Gender: 77 men, 125 women

Mean age: 59.4 years

Ethnicity: white 142 (70%), black 47 (23%), Hispanic 13 (6%)

Inclusion criteria: patients with a diagnosis of OAG or OHT. IOP ≥ 22 mmHg in at least 1 eye after a 3-week washout period

Exclusion criteria: contact lens use within 3 weeks of study start, a history of acute or chronic ACG, occludable angles, a history of recent ocular inflammation or foreign body, a history of uveitis, concomitant use of systemic medications known to affect IOP, contraindications to beta-blockers and existing renal disease


InterventionsGroup A: timolol gel once daily during period 1 followed by timolol solution twice daily during period 2

Group B: timolol solution twice daily during period 1 followed by timolol gel once daily during period 2

Follow-up: short-term; 6 weeks per period


OutcomesAdherence assessed through self report via interviewer-administered questionnaire. Patients were asked how often they missed 1 or 2 doses of test medication during the last 2 weeks. Pre-defined responses were scored on a scale of 1 to 5: never = 1, rarely = 2, occasionally = 3, frequently = 4, always = 5.

IOP reduction assessed with Goldmann applanation tonometer


NotesFunding sources: sponsored by Merck & Co.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“... were enrolled in this 12-week, randomized observer-masked, two-period cross-over study.” Page 138

 

“This was an open-label, multicenter, randomized, observer-masked, two-period crossover study ...“ Page 139

Correspondence with investigators: "Subjects were randomized 1:1 to one of two sequences of treatment (tgel/ts or ts/tgel); randomization done within each center in blocks of 4."

Allocation concealment (selection bias)Low riskCorrespondence with investigators: "Allocation completed by use of sealed envelopes opened at the time of enrollment"

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and care providers deliberately not masked. Difficult to mask participants as dosing frequencies were different.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk“A member of the clinic staff who was masked to the treatment the patient was receiving administered an anti-glaucoma patient-preference questionnaire.” Page 139

Correspondence with investigators: "Investigator office staff was blinded until after the analysis was reported."

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk10 patients did not complete both periods, a further 8 patients were excluded from the questionnaire analysis because of other protocol violations. Attrition rate: 9%. A further 4 patients (11%) did not respond to the adherence question.

99/102 group A and 93/100 group B completed the study. Reasons for non-completion described well and summarised here:

Adverse event: n = 5, 4 probably related to medication, 1 unrelated

Other reason: 3 lost to follow-up, 1 withdrew consent, 1 for personal reasons

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

Sheppard 2003

MethodsRandomised, single-centre, parallel-group study

Duration: 3 months


ParticipantsCountry: UK

Setting: hospital outpatient clinic

Number of participants: 73 (92 recruited, 19 withdrew)

Gender: not stated

Mean age 73 years (SD 11.6)

Ethnicity: not stated

Inclusion criteria: patients with a diagnosis of long-term chronic stable glaucoma

Exclusion criteria: no telephone access, difficulties using the phone, diagnosis of cognitive impairment


InterventionsIntervention: glaucoma monitoring nurse-led clinic involving consultations of 15 minutes duration divided into 2 parts. The first part was a standard assessment designed to monitor and record health details, such as current health status and recent ocular history. Eye examinations included visual acuity, visual field test and IOP test using Goldmann's applanation tonometry. The second part was a semi-structure educational session tailored to individual patient needs.

Control: general ophthalmic clinic involving consultations of 10 minutes duration which included the standard assessment, a fundus examination and remainder of time utilised according to each individual clinician


OutcomesAdherence assessed through self report patient questionnaire during a structured telephone interview


NotesFunding sources: not stated


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“The patients who consented to take part were allocated [...] using a computerised randomisation table". Page 17

Allocation concealment (selection bias)Unclear riskNot described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk92 participants: 36/42 (86%) nurse-led and 37/50 (74%) doctor clinic

 

“There was no difference in age, length of time diagnosed with glaucoma or the questionnaire measures between the participants who dropped out and those who remained in the study.” Page 18

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

Sverrisson 1999 Europe

MethodsRandomised, multi-centre, observer masked, 2-period, cross-over study

Duration: 38 days


ParticipantsCountries: 8 sites in 5 European countries: Belgium, Denmark, Iceland, Sweden and Switzerland

Setting: outpatient clinics

Number of participants: 93

Gender: 35 men, 58 women

Age range: 44 to 87 years, mean age: 69.5

Ethnicity: white 92 (98.9%), other 1 (1.1%)

Inclusion criteria: patients 18+ years with a diagnosis of OAG or OHT in both eyes. IOP of ≥ 22 mmHg 2 hrs after the morning dose of timolol maleate on study day 1 after run-in

Exclusion criteria: patients previously treated with dorzolamide or pilocarpine. Visual acuity of worse than 20/80 in both eyes, evidence of ACG, current use of contact lenses, intraocular surgery or significant trauma within 6 months or intraocular laser surgery within 3 months of initiation of the study, history or presence of retinal detachment or other conditions for which pilocarpine might be appropriate. Asthma, chronic obstructive pulmonary disease, renal disease, severe physical disabilities or any contraindications to the use of pilocarpine, dorzolamide or timolol ophthalmic solutions.


InterventionsGroup A: 2% dorzolamide/0.5% timolol combination twice daily during period 1 and 2% pilocarpine 4 times daily plus 0.5% timolol twice daily during period 2

Group B: 2% pilocarpine 4 times daily plus 0.5% timolol twice daily during period 1 and 2% dorzolamide/0.5% timolol combination twice daily during period 2

Follow-up: short-term; 14 days per period


OutcomesAdherence assessed through self report via interviewer-administered questionnaire using previously validated tool (COMTol). Patients were asked how often they missed their drops. Responses were marked on a scale of 0 to 6: 0 = never, 6 = always.

Quality of life assessed via interviewer-administered questionnaire (COMTol). Patients asked whether quality of life was interfered with by side effects or activity limitations. Responses were marked on a scale of 0 to 5: 0 = not at all, 5 = extremely.

IOP reduction assessed with Goldman applanation tonometer

Visual field defects assessed with Humphrey Field Analyser at all US sites and some European sites. The other European sites used an Octopus perimeter.


NotesFunding sources: sponsored by Merck & Co.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised random number generator used

Allocation concealment (selection bias)Low riskCentral allocation used

Blinding of participants and personnel (performance bias)
All outcomes
High risk“Because the purpose of the studies was to determine patient preference between two therapeutic regimes and dose regimen is an integral part of such preference, the treatment regimens were deliberately not masked to the patients or the study physician. However, the interviewer administering the COMTol questionnaire was masked to the patient’s regimen, interviews were conducted in a brightly lit room (to induce miosis in all patients), and patients were instructed not to disclose their dose frequency to the interviewer.” Page 823

Blinding of outcome assessment (detection bias)
All outcomes
Low risk“Because the purpose of the studies was to determine patient preference between two therapeutic regimes and dose regimen is an integral part of such preference, the treatment regimens were deliberately not masked to the patients or the study physician. However, the interviewer administering the COMTol questionnaire was masked to the patient’s regimen, interviews were conducted in a brightly lit room (to induce miosis in all patients), and patients were instructed not to disclose their dose frequency to the interviewer.” Page 823

Incomplete outcome data (attrition bias)
All outcomes
High riskInsufficient information to permit judgement. Difficult to assess attrition rate from paper and following contact with author. 18 patients (19%) were excluded from the adherence analysis, 19 (20%) from quality of life analysis concerning side effects and 22 (24%) from quality of life analysis concerning activity limitations. Numbers of patients involved in IOP and visual field test analysis were not published and could not be obtained from authors.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Sverrisson 1999 USA

MethodsRandomised, multi-centre, observer masked, 2-period cross-over study

Duration: 38 days


ParticipantsCountries: USA (10 sites)

Setting: outpatient clinics

Number of participants: 97

Gender: 41 men, 56 women

Age range: 27 to 83 years, mean age 60.4 years

Ethnicity: white 70 (72.2%), black 18 (18.6%), other 9 (9.3%)

Inclusion criteria: patients 18+ years with a diagnosis of OAG or OHT in both eyes. IOP of ≥ 22 mmHg 2 hours after the morning dose of timolol maleate on study day 1 after run-in.

Exclusion criteria: patients previously treated with dorzolamide or pilocarpine. Visual acuity of worse than 20/80 in both eyes, evidence of ACG, current use of contact lenses, intraocular surgery or significant trauma within 6 months or intraocular laser surgery within 3 months of initiation of the study, history or presence of retinal detachment or other conditions for which pilocarpine might be appropriate. Asthma, chronic obstructive pulmonary disease, renal disease, severe physical disabilities or any contraindications to the use of pilocarpine, dorzolamide or timolol ophthalmic solutions.


InterventionsGroup A: 2% dorzolamide/0.5% timolol combination twice daily during period 1 and 2% pilocarpine 4 times daily plus 0.5% timolol twice daily during period 2

Group B: 2% pilocarpine 4 times daily plus 0.5% timolol twice daily during period 1 and 2% dorzolamide/0.5% timolol combination twice daily during period 2

Follow-up: short-term; 14 days per period


OutcomesAdherence assessed through self report via interviewer-administered questionnaire using previously validated tool (COMTol). Patients were asked how often they missed their drops. Responses were marked on a scale of 0 to 6: 0 = never, 6 = always.

Quality of life assessed via interviewer-administered questionnaire (COMTol). Patients asked whether quality of life was interfered with by side effects or activity limitations. Responses were marked on a scale of 0 to 5: 0 = not at all, 5 = extremely.

IOP reduction assessed with Goldman applanation tonometer

Visual field defects assessed with Humphrey Field Analyser at all US sites and some European sites. The other European sites used an Octopus perimeter.


NotesFunding sources: sponsored by Merck & Co.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised random number generator used (contact with trialists)

“[...] patients who met the inclusion criteria and who had none of the exclusion criteria on study day 1 were randomly assigned to group A or group B.” Page 316

Allocation concealment (selection bias)Low riskCentral allocation used (contact with trialists)

Blinding of participants and personnel (performance bias)
All outcomes
High risk“Because the purpose of the studies was to determine patient preference between two therapeutic regimes and dose regimen is an integral part of such preference, the treatment regimens were deliberately not masked to the patients or the study physician. However, the interviewer administering the COMTol questionnaire was masked to the patient’s regimen, interviews were conducted in a brightly lit room (to induce miosis in all patients), and patients were instructed not to disclose their dose frequency to the interviewer.” Page 823

Blinding of outcome assessment (detection bias)
All outcomes
Low risk“Because the purpose of the studies was to determine patient preference between two therapeutic regimes and dose regimen is an integral part of such preference, the treatment regimens were deliberately not masked to the patients or the study physician. However, the interviewer administering the COMTol questionnaire was masked to the patient’s regimen, interviews were conducted in a brightly lit room (to induce miosis in all patients), and patients were instructed not to disclose their dose frequency to the interviewer.” Page 823

Incomplete outcome data (attrition bias)
All outcomes
High riskInsufficient information to permit judgement. Difficult to assess attrition rate from paper and following contact with author. 12 patients (13%) were excluded from the adherence analysis, 8 (8%) from the quality of life analysis concerning side effects and 9 (9%) from the quality of life analysis concerning activity limitations. Numbers of patients involved in IOP and visual field test analysis were not published and could not be obtained from authors.

See table 5. Lower follow-up in timolol plus pilocarpine group (63%) compared to combination group (97%), however, in international study good follow-up, 95% and 92%, in both groups

Selective reporting (reporting bias)Unclear riskDifficult to judge without access to protocol; no immediate cause for concern

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Akafo 1995Did not measure adherence

Amon 1990Not a randomised study

Bayer 2004Not a randomised study, adherence not measured

Bhojwani 1981Not a randomised study, adherence not measured

Blair 2001Not a randomised study

Blair 2004Not a randomised study

Bron 2004Measured adherence but did not publish results. Author contacted and gave reason, "such an evaluation of compliance is not reliable".

Chang 1991Not a randomised study

Derick 1992Adherence not measured

Dunker 2007Not a randomised study

Flowers 2006Single-arm study

Ghinato 1996Unclear whether participants were randomised to 1 of 2 groups. No reply from author.

Goni 2005Did not measure adherence

Granstrom 1982Not a randomised study

Gulkilik 2011Did not measure adherence

Hasegawa 2005Not a randomised study

Hughes 2005Did not measure adherence

Hunter 1999Very little information available, no paper, no other evidence of study found. Several attempts made to contact author without success.

Inoue 2011Not a controlled trial

Inoue 2012Not a controlled trial

Kass 1987Not a randomised study

Klein 2003Not a randomised study, adherence not measured

Konstas 2001Did not measure adherence

Kurtz 2004Did not measure adherence

Lorenz 2011Did not measure adherence

March 2000Did not measure adherence

NCT00230763Non-randomised study

NCT00262626Non-randomised study

NCT00328835Non-randomised study not assessing adherence

NCT00329095Non-randomised study

NCT00348062Non-randomised study

NCT01415401Non-randomised

Novack 1988Did not measure adherence

Rolle 2012Not a controlled trial

Rossi 2011Not a controlled trial

Sanchez-Pulgarin 2011Not a controlled trial

Sclar 1991Not a randomised study, adherence not measured

Shibuya 2003Adherence measured although the 2 types of drops being compared were instilled with the same dosage frequency of once daily

Wandel 1986Not a randomised study, adherence not measured

Yie 2000Not a randomised study, adherence not measured

 
Characteristics of ongoing studies [ordered by study ID]
ISRCTN25754048

Trial name or titleGlaucoma compliance aids research project

MethodsRandomised, single-centre, parallel-group study

ParticipantsCountry: UK

Setting: hospital outpatient clinic

Target number of participants: 100

Inclusion criteria: patients with a diagnosis of OAG, using anti-glaucoma eye drops, able to instil drops independently

Exclusion criteria: patients prescribed more than 1 eye drop, patients with other eye problems, patients unable to give informed consent, patients < 40 years

InterventionsIntervention group: adherence aid and usual care which involves glaucoma assessment followed by assessment for appropriate adherence aid with instruction on how to use it; patients also continue to receive the usual care normally provided within the outpatients department

Control group: glaucoma assessment and usual care normally provided within the outpatients department

OutcomesAdherence to therapy assessed through self report via patient questionnaire

Starting dateSeptember 2006

Contact informationSee trial register entry

Noteshttp://www.controlled-trials.com/ISRCTN25754048

ISRCTN31673586

Trial name or titleComparing the after-use sensation and safety of long acting (LA) carteolol 2 % versus timolol LA 0.5 % in simple intra-ocular hypertension and glaucoma

MethodsRandomised controlled trial, parallel-group

ParticipantsPeople with unilateral or bilateral ocular hypertension or primary open-angle glaucoma and intra-ocular pressure controlled with beta-blocker monotherapy: pressure < 21mmHg and visual field stable

InterventionsCarteolol long-acting 2%: daily, 1 drop at 8 am in the eye(s) to be treated over 3 months
Timolol long-acting 0.5%: daily, 1 drop at 8 am in the eye(s) to be treated over 3 months

OutcomesCompliance, reported at 1 and 3 months was one of the secondary outcomes for this study

Starting dateDecember 2007

Contact informationSee trial register entry

Noteshttp://www.controlled-trials.com/ISRCTN31673586

ISRCTN89683704

Trial name or titleHelping adherence with glaucoma treatment

MethodsRandomised, single-centre, parallel-group study

Duration: 2 years

ParticipantsCountry: UK

Setting: hospital outpatient clinic

Target number of patients: 200

Inclusion criteria: newly diagnosed or previously untreated glaucoma patients (using established standard criteria as documented in the European Glaucoma Society Guidelines), prescribed travoprost only, male or female, > 18 years of age

Exclusion criteria: those who cannot speak English fluently (to eliminate any potential bias by poor interpretation of information by a translator), those whose drops will be applied by care home staff/carers/home-helpers

InterventionsIntervention group: the intervention group will spend time with a Glaucoma Support Assistant (GSA) who will discuss/provide general aspects relating to glaucoma and anti-glaucomatous therapy, advice and practical help with drop application techniques, advice on taking eye drops within their own schedule/routine and an invitation for the participant to ask any questions about anything they are unsure of. In addition, patients will be asked to discuss their normal routine and a mutually agreeable time and place will be decided upon for patients to administer their drops. Patients will be advised to take their drops before a given point in their routine, to leave their drops where this "event" normally happens (e.g. by their toothbrush holder). A helpline number will also be given so that participants or their carers can call the on-call GSA at any time during clinic hours for additional information about glaucoma and drop application. The initial intervention group appointment is expected to last about 30 minutes.

Standard care group/control group: the control group will receive information in the form of our expected standard care and a leaflet about glaucoma with their ophthalmologist. Expected standard care consists of a brief explanation about glaucoma and the degree to which the particular patient has the condition, a summary of the proposed future management for that patient, including how frequently and when drop administration should be carried out and the importance of the condition with respect to driving and future vision. In addition, they will receive a contact telephone number for the glaucoma research unit in case of any problems with the electronic device or adverse events.

Follow-up: 32 weeks

OutcomesPatient adherence, measured by an electronic dosing monitor to give a % adherence and persistence score

Self perception of adherence will be measured using self rating questionnaires

Level of knowledge about glaucoma will be measured using self rating questionnaires

The individual components of the intervention will be assessed using questionnaires so as to identify which components are in most demand for a given population

A cost-effectiveness approach will determine the additional cost associated with the additional benefits. In this way, the 'fixed' (staff, overheads etc) and 'variable' costs of the intervention protocol will be estimated per patient. Resource utilisation and variance by individual patient will be monitored prospectively. 

Social demographic and medical history data recorded will be used in the socio-economic and health analyses

Starting dateNovember 2009

Contact informationSee trial register entry

Noteshttp://www.controlled-trials.com/ISRCTN89683704

NCT00376974

Trial name or titleThe effect of education on patient compliance

MethodsRandomised controlled trial, parallel-group

ParticipantsPeople with glaucoma attending for routine examination

InterventionsEducational video

OutcomesIntraocular pressure

Score on glaucoma educational test

Starting dateMarch 2005

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/ct2/show/NCT00376974

NCT00454922

Trial name or titleEffect of glaucoma educators on adherence to prescribed therapeutic regimens in glaucoma patients

MethodsAllocation: randomised
Endpoint classification: efficacy study
Intervention model: parallel assignment
Masking: single-blind (outcomes assessor)
Primary purpose: prevention

Participants100

InterventionsEducation versus standard care

OutcomesPrimary outcome measures: primary outcome is adherence (time frame: 6 months)
Secondary outcome measures: differences between patients randomised to standard of care and education intervention (time frame: 6 months)
Differences between dropouts and non-dropouts (time frame: 6 months)

Starting dateFrom clinical trals.gov

Start date: October 2007; end date: May 2008

From contact with investigators December 2011

"Our study evaluating the “Effect of Glaucoma Educators on Adherence to Prescribed Therapeutic Regimens in Glaucoma Patients” (http://clinicaltrials.gov/show/NCT00454922) just started a few months ago and is still recruiting participants. We won't have outcomes to report for another 12-18 months."

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/show/NCT00454922

NCT00465803

Trial name or titleCompliance study comparing DuoTrav to TRAVATAN plus timolol using the dosing aid

MethodsRandomised controlled trial, parallel-group

ParticipantsPeople with open-angle glaucoma or ocular hypertension

InterventionsDuoTrav

Travatan/timolol

OutcomesPatient compliance

Starting dateMarch 2007

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/ct2/show/NCT00465803

NCT00508469

Trial name or titleAdherence assessment with Travalert dosing aid

MethodsParallel-group randomised controlled trial

ParticipantsPeople diagnosed with glaucoma or ocular hypertension

InterventionsDosing aid device

OutcomesFrom ClinicalTrials.gov

Primary outcome measures: the primary objective is to compare patients adherence using Travalert® device in the different treatment groups (time frame: use) (designated as safety issue: no)
Secondary outcome measures: safety and satisfaction (time frame: use) (designated as safety issue: no)

Starting dateJuly 2007

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/ct2/show/NCT00508469

NCT00573638

Trial name or titleEffects of Xal-Ease on patient compliance with Xalatan

MethodsIntervention model: single group assignment
Masking: open label
Primary purpose: treatment

Participants50

InterventionsDevice: Xal-Ease device to be used with Xalatan eye drops

OutcomesPrimary outcome measures: the primary outcome measure is compliance with the medication Xalatan using and not using the Xal-Ease delivery aid for their glaucoma treatment (time frame: 6 months)
Secondary outcome measures: to determine if any of the other factors mentioned in the survey affect compliance to their medical regimen (time frame: 6 months)
To see whether or not the Xal-Ease device helps patients conserve medication, i.e. - aids in drops not distilled in the eye (time frame: 6 months)

Starting dateFebruary 2005

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/ct2/show/NCT00573638

NCT00626067

Trial name or titleStudy of patient use and perception of the Travatan dosing aid

Pilot study of patient acceptance and impact of the new Travatan™ compliance monitoring dispenser (Travatan™ dosing aid)

MethodsAllocation: randomised
Endpoint classification: efficacy study
Intervention model: single group assignment (but has 3 interventions)
Masking: double-blind (subject, investigator)
Primary purpose: supportive care

Participants45

InterventionsTravatan compliance monitoring dispenser

Fully functioning, partially functioning and non-functioning

OutcomesFrom clinicatrials.gov

Primary outcome measures: assess patients' opinions regarding new Travatan compliance monitoring dispenser (time frame: 6 weeks) (designated as safety issue: no)
Secondary outcome measures: pilot study of the impact of physician monitoring of compliance on patient compliance (time frame: 6 weeks) (designated as safety issue: no) 

Starting dateSeptember 2006

Investigator indicates manuscript in preparation

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/show/NCT00626067

NCT00676637

Trial name or titleGAS - Glaucoma Adherence Study

MethodsAllocation: non-randomised
Intervention model: single group assignment
Masking: open-label

Participants100

InterventionsTravAlert dosing aid

OutcomesMean change from baseline in intraocular pressure at 4 months

Starting dateMay 2008

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/show/NCT00676637%20%C2%A0

NCT00756184

Trial name or title1-year randomized control trial investigating the value of an intervention to enhance adherence in glaucoma patients receiving prostaglandin monotherapy and in patients who are candidates for adjunctive therapy

MethodsParallel-group randomised controlled trial

ParticipantsPeople with newly diagnosed open-angle glaucoma, or ocular hypertensive subjects naive to medical therapy and people who have failed monotherapy with any prostaglandin analogue

InterventionsIntensive glaucoma adherence and education during the course of 1 year compared to intensive, equal-time eye care education without any direct adherence or glaucoma specific education

OutcomesAdherence rate (% of days patient used the medication) as monitored by a dosing aid electronic device, intraocular pressure (morning) and persistency to therapy
Follow-up time: 1, 3, 6, 9 and 12 months

Starting dateSeptember 2007

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/ct2/show/NCT00756184

NCT00767793

Trial name or titleA multi-center, double-masked, randomized, placebo-controlled, ascending dose study of INS117548 ophthalmic solution in subjects with bilateral ocular hypertension or early primary open angle glaucoma

MethodsRandomised controlled trial, parallel-group

ParticipantsPeople with primary open-angle glaucoma or ocular hypertension

InterventionsINS117548 at various concentrations

Placebo

OutcomesInclude compliance and rate of discontinuation

Starting dateSeptember 2008

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/ct2/show/NCT00767793

NCT00887029

Trial name or titleA 12 week comparison of DuoTrav and Xalacom at 24 hours post-dose in the treatment of open-angle glaucoma (the DVX study)

MethodsRandomised controlled trial, cross-over

ParticipantsPeople with primary open-angle glaucoma or ocular hypertension

InterventionsDuoTrav

Xalacom

OutcomesIntraocular pressure

Compliance and patient preference

Starting dateJanuary 2009

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/ct2/show/NCT00887029

NCT01125306

Trial name or titleEfficiency of Xal-Ease device in glaucoma and/or ocular hypertension (OHT) patients, treated with Xalatan or Xalacom

MethodsIntervention model: single group assignment
Masking: open-label
Primary purpose: supportive care

Participants50

InterventionsDevice: Xal-Ease

OutcomesPrimary outcome measures: consumption of Xalatan/Xalacom bottles per year per patient (time frame: 12 months)
Secondary outcome measures: evaluating cost of Xalatan/Xalacom eye drops use per year with Xal-Ease (time frame: 12 months)
Characterising the optimal conditions for proper usage of the Xal-Ease device (time frame: 12 months)

Starting dateJune 2009

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/ct2/show/NCT01125306

NCT01409421

Trial name or titleResearch protocol: glaucoma treatment adherence and persistence

MethodsParallel-group randomised controlled trial

ParticipantsPeople with glaucoma

InterventionsMotivational interviewing, reminder calls and standard care

OutcomesFrom ClinicalTrials.gov

Primary outcome measures: MEMS-based medication adherence and persistence (time frame: 1 month) (designated as safety issue: no) comparing adherence and persistence between the intervention and control groups. Medication Event Monitoring Systems record the date and time a pill bottle is opened, evaluating the percentage of prescribed doses taken during one-week intervals, but will augment it by also considering a more fine-grained percentage of prescribed doses taken in required dosing window (defined as within 3 hours before or after the scheduled time) as a second primary outcome measure.

Secondary outcome measures: counsellor-rated medication adherence (time frame: 1 month) (designated as safety issue: no). Will supplement MEMS-based adherence metrics with a counsellor rating of adherence completed by the glaucoma educator during each in-person or telephone contact with intervention group participants. The interview also measures patients' perceived reasons for non-adherence, including treatment cost, lack of commitment based on low perceived benefits of treatment and fear of potential adverse drug events (ADEs)

Starting dateApril 2011

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/show/NCT01409421

NCT01417689

Trial name or titleEyedrop Instillation Technique

MethodsParallel-group randomised controlled trial

ParticipantsPeople with glaucoma or suspected glaucoma

InterventionsStandard eye drop instillation compared to experimental technique of eye drop instillation

OutcomesFrom ClinicalTrials.gov

Primary outcome measures: complete success (time frame: day 1, immediately after intervention) (designated as safety issue: no). Total success is defined as: patient manages to instil 1 eye drop into the eye spending only 1 eye drop. Difference in the proportion of patients achieving successful eye drop instillation in each of the 2 groups. For the main analysis the results of the first eye (right or left randomly determined will be used) a mixed model with both eyes in the analysis will also be presented for sensitivity analysis.

Secondary outcome measures: qualified success (time frame: day 1, same day as intervention) (designated as safety issue: no). Qualified success is defined as: patient manages to instil 1 eye drop into the eye regardless of the amount of drops spent. Difference in the proportion of patients achieving successful eye drop instillation in each of the 2 groups. For the main analysis the results of the first eye (right or left randomly determined will be used) a mixed model with both eyes in the analysis will also be presented for sensitivity analysis.
Number of drops (time frame: day 1) (designated as safety issue: no). Number of eye drops spent on attempted instillation in the first eye (randomly assigned). The average number of drops spent on each of the groups will be compared. Mixed models with data from both eyes will also be presented for sensitivity analysis.

Starting dateAugust 2011

Contact informationSee trial register entry

Noteshttp://clinicaltrials.gov/show/NCT01417689

 
Summary of findings for the main comparison. Summary of findings: education and individualised care planning

Education and individualised care planning compared with standard care for improving adherence to ocular hypotensive therapy

Patient or population: people with glaucoma or ocular hypertension

Settings: outpatients

Intervention: education and individualised care planning

Comparison: standard care

OutcomesNo of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Adherence902

(7)
⊕⊕⊝⊝
low1
3 studies found that people given education and individualised care planning were more adherent. Substantial improvements in adherence were observed in these studies. 4 studies did not find a difference, in these studies the intervention was less detailed. Different measures of adherence meant it was difficult to estimate overall treatment effect.

Persistence127
(1)
⊕⊕⊝⊝
low2
Only 1 trial reported this outcome in which 17/127 patients discontinued therapy (risk ratio for persistence 1.14, 95% CI 0.99 to 1.41)

Intraocular pressure193
(2)
⊕⊕⊝⊝
low3
Only 2 trials reported this outcome. One trial reported this at 12 and 24 months and found no difference between the intervention groups. 1 trial reported at 3 months follow-up which may be too short a time period to observe an effect on intraocular pressure.

Visual field defectsNo data on this outcome

Quality of lifeNo data on this outcome

Adverse effectsNo data on this outcome

Patient knowledge390

(4)
⊕⊝⊝⊝
low4
In Gray 2011 intervention improved patient knowledge (median knowledge score was 14 (range 2 to 18) for the intervention group and 6 (range 0 to 17) for the control group (Mann–Whitney P < 0.001). 3 other studies reported no differences in patient knowledge between groups.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1We downgraded to low because (i) the majority of the trials were not masked , (ii) there was inconsistency in trial results.
2We downgraded to low because (i) only one trial, (ii) imprecision in the estimate.
3We downgraded to low because (i) only one trial measured at reasonable length of follow-up, (ii) no pooled estimate so not enough numbers to detect moderate effects.
4We downgraded to low because (i) inconsistency in trial results, (ii) the majority of the trials were not masked.
 
Summary of findings 2. Summary of findings: drug regimen

Simplified drug regimen for improving adherence to ocular hypotensive therapy

Patient or population: people with glaucoma or ocular hypertension

Settings: outpatients

Intervention: simplified drug regimen

Comparison: standard care

OutcomesNo of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Adherence650

(8)
⊕⊝⊝⊝
very low1
All studies reported a better adherence rate in the group with the simpler drug regimen; in 3 studies this difference was statistically significant. Different measures of adherence meant it was difficult to estimate overall treatment effect.

Persistence265

(3)
⊕⊝⊝⊝
very low1
2 out of 3 studies found that the people using the simpler drug regimen had a higher persistence, however all 3 studies were short-term cross-over studies and time periods were not reported

Intraocular pressure503
(5)
⊕⊝⊝⊝
very low1
Overall there was little evidence of any effect on IOP

Visual field defects301

(4)
⊕⊝⊝⊝
very low1
None of the studies found significant effects on visual fields but were of short duration

Quality of life265

(3)
⊕⊝⊝⊝
very low1
In all 3 studies quality of life was assessed using the COMTol questionnaire. There were more reported activity limitations when the frequency of drop instillation increased.

Adverse effects650

(8)
⊕⊝⊝⊝
very low1
Interventions too different to come to a consensus as to adverse effects

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1We downgraded to very low because (i) trials were at risk of performance and other biases, (ii) data from cross-over trials had not been analysed appropriately, and (iii) there was inconsistency in trial results.
 
Table 1. Study design, interventions and outcomes in included studies

 StudyRCT typeInterventionControl groupLength of follow-upMain outcome measuresComments

1Gray 2011Parallel-groupEducation and tailoring programmeUsual care12 months and 24 monthsAdherence (prescription data and questionnaire)

Persistence (prescription and dispensing data)

Intraocular pressure

Patient knowledge
-

2Hermann 2011Parallel-group, factorialBrimonidine twice daily

Masked monitoring

 
Brimonidine 3 times daily

 

Open monitoring
1 monthAdherence (electronic monitoring device)

 
-

3Herman 2011aParallel-groupBrimonidine twice dailyBrimonidine 3 times daily4 weeksAdherence (electronic monitoring)-

4I-SIGHTParallel-groupTelephone automated education and tailoring programmeUsual care12 monthsAdherence (self report of missed doses)

Prescription refills (pharmacy records)

Appointment keeping
Sources of information: interviews, medical record review, appointment records, and pharmacy data
-

5Laibovitz 1996Cross-over2% dorzolamide three times daily2% pilocarpine four times daily during period 114 days per periodAdherence (questionnaire – COMTol)

Persistence (number of patients who continued treatment)

Quality of life (questionnaire – COMTol)

Intraocular pressure (Goldmann applanation tonometer)

Visual field defects (Humphrey Field Analyser) 
Both groups continued to receive 0.5% timolol twice daily throughout the study

 

6Laster 1996Cross-overPre-weighed bottle of pilocarpine in a medication vial fitted with the Prescript TimeCapPre-weighed bottle of pilocarpine in a medication vial fitted with the TimeCap

 
30 days per period

 
Adherence (weighing the drop bottle and questionnaire) -

7Muir 2012Parallel-groupEducational intervention lasting 20 minutes (one-on-one session) including "informational video" delivered at varying literacy levelsStandard care6 monthsAdherence (number of days without medication)

Self reported disease knowledge

Satisfaction with care
Language of video varied according to participants' tested health literacy level

8Nakakura 2012Parallel-groupLatanoprost 0.005%/timolol 0.5% plus brinzolamide 1%Dorzolamide 1%/timolol 0.5% plus latanoprost 0.005%12 weeksIntraocular pressure

Adherence (self reported)
-

9Norell 1979Parallel-groupEducation and tailoring programmeNo intervention20 daysAdherence (medication monitor) -

10Okeke 2009Parallel-groupEducation and tailoring programmeNo intervention3 monthsAdherence rate (dosing aid device)

Intraocular pressure

 
 -

12Ring 2011Quasi-experimentalEducational intervention (film)No intervention3 monthsAdherence (return of bottles)

Patient knowledge (questionnaire)
 -

12Sakai 2005Quasi-experimentalLatanoprost once daily

 
0.5% timolol maleate twice daily and 1% dorzolamide 3 times daily

 
3 monthsAdherence (questionnaire)

Intraocular pressure (Goldmann applanation tonometer)

Visual field defects (Humphrey Field Analyser)
 -

13Schenker 1999Cross-overTimolol gel once daily

 
Timolol solution twice daily6 weeks per periodAdherence (questionnaire)

Intraocular pressure (Goldmann applanation tonometer)

 
 -

14Sheppard 2003Parallel-groupEducation and tailoringUsual care3 monthsAdherence (questionnaire)

Patient knowledge (questionnaire)
 -

15Sverrisson 1999 EuropeCross-over2% dorzolamide/0.5% timolol combination twice daily2% pilocarpine four times daily plus 0.5% timolol twice daily14 days per periodAdherence (questionnaire COMTol)

Persistence (number of patients who completed treatment)

Quality of life (questionnaire COMTol)

Intraocular pressure (Goldman applanation tonometer)

Visual field defects (Humphrey Field Analyser/ Octopus perimeter)

 
 -

16Sverrisson USACross-over2% dorzolamide/0.5% timolol combination twice daily2% pilocarpine 4 times daily plus 0.5% timolol twice daily14 days per periodAdherence (questionnaire COMTol)

Persistence (number of patients who completed treatment)

Quality of life (questionnaire COMTol)

Intraocular pressure (Goldman applanation tonometer)

Visual field defects (Humphrey Field Analyser)
 -

 COMTol: Comparison of Ophthalmic Medications for Tolerability
 
Table 2. Effect of education and tailoring on adherence

StudyOutcome measure  Follow-up periodOutcome measure variable typeIntervention

n/N (%)

or

mean (SD)
Control

n/N(%)

or

mean (SD)
Reported P valueComments

Gray 2011Number of people who were adherent12 monthsDichotomous45/64 (70%)27/63 (43%)0.002Data from page 185 of Gray PhD thesis

“Refill adherence” measured by contacting GPs and pharmacists for prescription and dispensing information during the 1-year follow-up. People who collected 100% of prescriptions were defined as adherent.

I-SIGHTSelf reported medication adherence: number of people not reporting missing drops in 1 month"last visit" which could be 6, 9 or 12 monthsDichotomous30.2%27.0%"treatment x visit" interaction 0.18Also reported a number of other measures of adherence (see table 3, page E5) including self reported refill adherence, self reported appointment adherence, chart report medication adherence, chart report refill adherence, chart report appointment adherence, none of which showed statistically significant differences between groups

Muir 2012Days without medication6 monthsContinuous63 (198) n = 6765 (198) n = 600.955 (calculated from data t-test)-

Norell 1979% of time exceeding 8-hour dose intervals

 

% (number of missed doses)
20 daysDichotomous  (denominator not reported)

 

 

 
13%

 

 

6% (120)
24%

 

 

15% (338)
< 0.001

 

 

 
Table page 1032

Measured using a medication monitor

Unit of analysis not same as unit of randomisation

Reported P value tests difference in change between first time period (before intervention) and second time period (after intervention)

Okeke 2011Adherence rate

 

Change between pre-intervention 3 months and post-intervention 3 months 
3 monthsContinuous

 

 

Continuous
0.73 (0.22)

 

 

0.19 (0.20)
0.51 (0.30)

 

 

0.06 (0.30)
0.001

 

 

0.01
Table 3 page 2289

Adherence rate measured using Travatan dosing aid device

*Ring 2011Number of people who were adherent3 monthsDichotomous18/54 (33.3)19/56 (33.9)0.947 (calculated from data)Page 44 of Ring MSc thesis

People who returned bottles within 10% of target weight were defined as adherent

Sheppard 2003Adherence3 monthsContinuousNo differences were found between the two groups on adherence using an ANCOVA with the pre-appointment score as a covariatePage 19

Adherence measured by questionnaire using an 11-point response scale: 0 “I never use my eye drops” to 10 “I always use my eye drops”. Reported as a continuous variable in the paper but only pre-appointment mean (SD) reported. Also reported “significantly fewer of the [intervention] group reported [specific problems with adherence] compared to [control group].”

 Adherence: taking medicine as prescribed
See text for description of education and tailoring packages in each study.
*Ring 2011 did not include any tailoring.
 
Table 3. Effect of drug regimen on adherence

StudyOutcome measure  Follow-up periodOutcome measure variable typeIntervention*

n/N (%)

or

mean (SD)
Control

n/N(%)

or

mean (SD)
Reported P valueComments

Hermann 2011

 
Adherence rate (%)4 weeksContinuous73.3 (13)

n = 18

 
64.0 (12)

n = 18
0.02Table 3 page e302

Adherence rate defined as “Ratio of recorded dosing events to intended dosing events for the observed time period.” A recorded dosing event was application of 1 or more drops within 30 minutes following the first application.

Herman 2011aAdherence rate (%)4 weeksContinuous72.2 (19)

n = 33
62.1 (16)

n = 34
0.04Text pages 504 and 505
Adherence rate defined as for Herman 2011 above

Laibovitz 1996Reported missed doses4 weeksContinuous0.8 (SE 0.18)

 
2.3 (SE 0.18)

 
< 0.001COMTol questionnaire: “How often did you miss one or more doses?” Graded 0 (never) to 6 (always). Data are from cross-over study but data from 2 time periods appear to have been pooled.

Nakakura 2012Forgot administration12 weeksDichotomous2/192/160.855 (calculated)Question "How often do you forget administration per week?" Never/within 2 times per week/more than 3 times per week

Sakai 2005Reported missed doses3 monthsDichotomous16/18 (88.9)13/18 (72.2)0.207 (calculated)“How many times patient has forgotten to apply the eye drop?” Answer less than once a week defined as adherent

Schenker 1999Reported never missed dose3 monthsDichotomous141/180 (78.3)123/182 (67.6)0.021 (calculated)Table V Page 144

Frequency of missed doses: never, rarely, occasionally, frequently, always
Analysis ignores cross-over design

Sverrisson 1999 EuropeReported missed doses14 daysContinuous0.1   (0.1)1.4 (0.1) -COMTol questionnaire: “How often did you miss one or more doses?” Graded 0 (never) to 6 (always). Data are from cross-over study but data from 2 time periods appears to have been pooled.

Sverrisson 1999 USAReported missed doses14 daysContinuous0.2 (0.1)1.2 (0.1) -

 COMTol: Comparison of Ophthalmic Medications for Tolerability
SE: standard error