Evidence Table 13Separate combination vs. single medications

Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Bucci, 199913

Study design:
RCT

Evidence level:
1+

Duration of follow-up:
6 months
Patient group: COAG

Setting: Multi-centre centre, Italy

Inclusion criteria: Exclusion criteria: All patients
N: 99

Group 1
N: 49
Age (mean ± SD): 63 ± 12
M/F: 21/28
POAG: 43
PXF: 6
Drop outs: 4

Group 2
N: 50
Age (mean ± SD): 59 ± 13
M/F: 28/22
POAG: 50
PXF: 1*
Drop outs: 4
* patient had different diagnosis in each eye
Group 1
Latanoprost 0.005% 1/day + Timolol 0.5% 2/day

Group 2
Latanoprost 0.005% 1/day

Examination methods:
IOP measured at baseline, 2 weeks, 3 months and 6 months using a Goldmann tonometer. 3 (9am, 12 pm and 4pm) measurements were taken in each eye and mean value used in statistical analysis.
Mean ± SD baseline diurnal IOP mmHgGroup 1: NR
Group 2: NR
Funding:
Not reported.
Conducted at Clinica Oculistica, Universita di Roma Tor Vergata
Limitations: Additional outcomes:
Timolol + pilocarpine study arm

Notes:
If 2 eyes used in study, mean IOP was taken.
Mean ± SD end point diurnal IOP at 6 mthsGroup 1: NR
Group 2: NR
Mean ± SD reduction in IOP mmHg at 6mths (baseline – end point)
SD = SE*√n
Group 1: 6.1 ± 2.10
Group 2: 5.5 ± 2.12
P between arm difference = not signif (using ANCOVA)**
% patients achieving an acceptable 30% reduction in IOP
<20% reduction from baseline (~21 mmHg) is approx <18 mmHg
Group 1: 30/45 (not ITT)
Group 2: 32/46 (not ITT)
Total number of local ocular side effects by groupGroup 1: 21
Group 2: 17
Includes itching, stinging, conjunctivitis, vision disturbance and conjunctival hyperaemia
Total number of systemic side effects by groupGroup 1: 1
Group 2: 4
Total number of patients with hyperaemiaGroup 1: 8/49
Group 2: 4/50
Reasons for withdrawalsGroup 1: Group 2:
Manni et al., 200491

Study design:
RCT
Single masked

Evidence level:
1+

Duration of follow-up:
6 months
Patient group: COAG

Setting: Single centre, Italy

Inclusion criteria: Exclusion criteria:
  • Uncontrolled systemic diseases
  • Allergy to treatment medications
  • Severe trauma
  • Previous ocular surgery in last 6 months
  • Any condition affecting IOP measurement such as corneal abnormalities
  • Pregnant, nursing or patients considering pregnancy
All patients
N: 61
Age (mean ± SD): 59.4 ± 14.1

Group 1
N: 30
Age (mean ± SD): 59.7 ± 13.5
M/F: 16/14
Drop outs: 4

Group 2
N: 31
Age (mean ± SD): 59.2 ± 14.7
M/F: 14/17
Drop outs: 7
Group 1
Latanoprost 0.005% (pm) 1/day + Timolol 0.5% (am) 1/day

Group 2
Bimatoprost 0.03% 1/day evening

Examination methods:
IOP measured at baseline, 2 weeks and every month months using a Goldmann tonometer. 3 (8am, 12 pm, 4pm) measurements were taken in each eye and mean value used in statistical analysis.
Photographs of lids and periocular area were taken at baseline to compare to end point
Mean ± SD baseline diurnal IOP mmHgGroup 1: 24.1 ± 4.6
Group 2: 23.5 ± 3.2
Funding:
Not reported.
Conducted at Clinica Oculistica, Universita di Roma Tor Vergata

Limitations:
  • No washout period for bimatoprost monotherapy.
  • Patients were selected for inadequate IOP control on timolol 0.5%
  • *Significance testing between arms does not appear to be on an ITT basis – only 28 patients counted per group
Additional outcomes:
Occurrence of hyperaemia and eyelash growth

Notes:
Investigators were masked to treatment allocation and randomisation performed using computer generated sequence.

**Standard Deviations were estimated using the precise p values reported in the study following the method detailed in the Cochrane Handbook
Mean ± SD end point diurnal IOP at 6 mthsGroup 1: 16.8 ± 1.4
Group 2: 17.0 ± 2.1
Mean ± SD reduction in IOP mmHg at 6mths (baseline – end point)Group 1: 7.3 ± 5.59**
Group 2: 6.5 ± 3.98**
P = not significant*
Total number of patients reporting ocular side effectsGroup 1: NR
Group 2: NR
Total number of cardiovascular systemic side effects by groupGroup 1: NR
Group 2: NR
6 patients in group 1 reported a headache
Reasons for withdrawalsGroup 1:
  • Inadequate IOP control = 2
  • Ocular allergy = 2
Group 2:
  • Inadequate IOP control = 2
  • Ocular allergy = 3
  • Self-withdrawal = 2
Hyeperaemia at baselineGroup 1: 10/30
Group 2: 9/31
P value: 0.20
Hyeperaemia at 90 daysGroup 1: 24/30
Group 2: 14/31
P value: 0.004
Hyeperaemia at 180 daysGroup 1: 19/30
Group 2: 14/31
P value: 0.08
Orengo-Nania et al, 2001114

Study design:
RCT, masked (subjects, investigators and study staff)

Evidence level:
1+

Duration of follow-up:
6 months
Patient group: COAG or OHT

Setting: Multi-centre, USA

Inclusion criteria: Exclusion criteria: All patients
N: 271
Group 1
N: 145
Age (mean): 63.9 +11.1
M/F: 65/72
Drop outs: 8
Black/Non-black: 35/105
COAG/OHT: 123/14

Group 2
N: 139
Age (mean): 63.3 +11.3
M/F: 56/78
Drop outs: 5
Black/Non-black: 32/102
COAG/OHT: 121/13
Group 1
Travoprost 0.004% 1/day + timolol 0.5% 2/day *

Group 2
Placebo 1/day and timolol 0.5% 2/day *

Examination methods:
Mean IOP measured by calibrated Goldmann applanation tonometer at 8am, 10am and 4pm for the patient’s eye with the highest reading.

Hyperaemia measured by comparing photographs of subjects’ eyes with a standard set of photographs depicting ocular hyperaemia. Hyperaemia and iris and eyelash changes were assessed by masked ophthalmologists.
Mean ± SD baseline diurnal IOP (mmHg)Group 1: 25.0 ± NR
Group 2: 25.2 ± NR
P value: not significant
Funding:
Alcon Research Ltd, manufacturers of travoprost

Limitations:
Reporting of discontinuations was not clear for each group. 24 discontinued due to inadequate IOP control 21 in timolol group and 3 across both travoprost groups.
Standard deviations were not provided with the IOP data.
*Timolol was open label

Additional outcomes:
Data for travoprost 0.0015% not included in study (dosage not in BNF)

Eye lash changes also mentioned, no patient stopped treatment due to these.
No reported iris pigmentation changes or clinical visible cystoid macular oedema reported

Notes:
All subjects who qualified stopped any ocular hypotensive medication (other than timolol) and were placed on timolol 0.05% 2/day for 3 weeks. Run in phase

Randomisation sequence was computer generated. Allocation concealment in sealed but not necessarily opaque envelopes.
Mean IOP at end point (6 months)Group 1: 19.6 (8am), 18.3 (10am), 18.9 (4pm)
Group 2: 23.8 (8am), 23.0 (10am), 23.1 (4pm)
Mean diurnal IOP at end point (6 months)Group 1: 18.9 ± NR
Group 2: 23.3 ± NR (calculated as mean across 3 times)
Mean change in IOP from baseline mmHg at 6 months (end point – baselineGroup 1: 6.1 ± NR
Group 2: 1.9 ± NR
P = 0.0001 (ANOVA – repeated measures)
Percent of patients with6mmHg decrease in IOP OR20mmHg at 6 mthsGroup1: 73.0–86.9%
Group 2: 23.1–43.3% (per protocol data)
Percent of patients with acceptable decrease30% in IOP OR17mmHg at 6 mthsGroup 1: 55/114 (47.8%)
Group 2: 11/112 (9.9%)
P value groups 1 to 2: <0.0001 (per protocol data)
No. of ocular adverse events by group seen in2% of any treatment group (NB some patients may have had more than one adverse eventGroup 1: 78
Group 2: 34
Includes: aqueous flare, anterior chamber cells, blurred vision, discomfort, dry eye, foreign body sensation, hyperaemia, keratitis, lid disorder, pain, photophobia, pruritus, tearing, visual acuity decreased
No. of non-ocular adverse events by group seen in2% of any treatment group (NB some patients may have had more than one adverse event)Group 1: 19
Group 2: 13
Includes: cold syndrome, infection, sinusitis, surgical/medical procedure, urinary tract infection.
Number of patients with hyperaemia (assessed on a scale. 1=none/trace, 2=mild, 3=moderate, 4=severe. Mean hyperaemia score in all groups <0.50)Group 1: 52/145
Group 2: 13/139
P value groups 1 to 2: <0.001
Reasons for withdrawalsGroup 1:
  • NR
Group 2:
  • Inadequate IOP control = 21
Polo et al., 2005117

Study design:
RCT

Evidence level:
1 +

Duration of follow-up:
24 months
Patient group: COAG

Setting: Single centre, Italy

Inclusion criteria: Exclusion criteria: All patients
N: 61

Group 1
N: 30
Age (mean ± SD): 67.9 ± 11.2
M/F: 60%/40% eyes
1 eye/2eyes: 2/28
Family history: 24% eyes
POAG/PXF: 23/8
Drop outs: 26/58 eyes (45%)

Group 2
N: 31
Age (mean ± SD): 64.6 ± 19.1
M/F: 64%/36% eyes
1 eye/2eyes: 3/28
Family history: 29% eyes
POAG/PXF: 25/5
Drop outs: 14/59 eyes (24%)
Group 1
Dorzolamide 2% 2/day + Timolol 0.5% 2/day

Group 2
Latanoprost 0.005% 1/day

Examination methods:
At eligibility testing, automated perimetry (Humphrey 30-II STATPAC 2) was used to measure visual field, stereo photographs used to assess glaucomatous damage (neuroretinal rim loss, haemorrhage etc), visual acuity, refraction, slit lamp examination also performed and IOP measurement technique was not specified. Examination schedule was at baseline, 2 wks and every 3 months.
Mean ± SD baseline diurnal IOP mmHgGroup 1: 23.8 ± 2.3
Group 2: 23.9 ± NR
Funding:
Not reported.
Conducted at Department of Ophthalmology, “Miguel Servet” University Hospital, Zaragoza, Spain

Limitations: Additional outcomes:

Notes:
Data analyses use data per eye rather than patient.

** Standard deviations (SD) for fixed v monotherapy calculated using the Cochrane method for imputed SDs from the mean correlation coefficients calculated from Ozturk 2007115 (CAI + BB v PGA)
Mean ± SD end point diurnal IOP at 6 mthsGroup 1: 18.2 ± 3.2
Group 2: 17.1 ± 2.4
Mean ± SD end point diurnal IOP at 24 mthsGroup 1: 18.4 ± 1.9
Group 2: 15.9 ± 2.04
Mean ± SD reduction in IOP mmHg at 6 mths (baseline – end point)Group 1: 5.6 ± 2.53**
Group 2: 6.8 ± 1.94**
Mean ± SD reduction in IOP mmHg at 24 mths (baseline – end point)Group 1: 5.4 ± 1.87**
Group 2: 8.0 ± 1. 81**
P < 0.05
Eyes reaching acceptable IOP of20% reduction from baseline after 24 mths (<21 mmHg)
Figures estimated from Kaplan-Meier graph
Group 1: 17/30 (56%)
Group 2: 37/45 (82%)
Total number of patients reporting ocular side effectsGroup 1: NR
Group 2: NR
Total number of patients reporting cardiovascular systemic side effectsGroup 1: NR
Group 2: NR
Reasons for withdrawalsGroup 1: NR
Group 2: NR
Rismanchian et al, 2008121

Study design:
RCT
Observer masked

Evidence level:
1+

Duration of follow-up:
6 months
Patient group: Newly diagnosed bilateral POAG

Setting: single centre, ophthalmology department, Isfahan University of Medical Science, Feiz Hospital, Isfahan, Iran

Inclusion criteria: Exclusion criteria: All patients
N: 120
Age (mean ± SD): 57.3 ± 13.15 (range 21–80)
M/F: 60/60
Drop outs: NR

Group 1
N: 60
Age (mean ± SD): 54.8 ± 15.49 (range 21–80)
M/F: 28/32
Drop outs: NR
Mean Cup disc ratio ± SD: 0.60 ± 0.15
Mean baseline IOP ± SD mmHg: 30.4 ± 6.58

Group 2
N: 60
Age (mean ± SD): 52.7 ± 10.84 (range 35–80)
M/F: 32/28
Drop outs: NR
Mean Cup disc ratio ± SD: 0.60 ± 0.08
Mean baseline IOP ± SD mmHg: 29.6 ± 5.81
Group 1
Dorzolamide 2% 3/day* & timolol 0.5% 2/day.

*Note: normal dosage of dorzolamide if used with timolol is 2/day (BNF)
Group 2
Latanoprost 0.005% 1/day

Examination methods:
At baseline best corrected visual acuity, refraction, visual field testing, ophthalmoscopy, IOP measurement and slit lamp examination were performed.

Goldmann applanation tonometry was used to measure IOP at 1, 3 and 6 months by same masked observer
Mean ± SD IOP at 6 mths mmHgGroup 1: 22.9 ± 5.81
Group 2: 22.4 ± 5.42
Funding:
Not reported

Limitations:
Randomisation method and allocation concealment not reported
Dropouts were not reported so unclear if all patients completed study

Notes:
If both eyes qualified for study worse eye was used.

No serious adverse events were observed.
Mean ± SD change in IOP from baseline at 6 mths mmHgGroup 1: 7.4 ± 2.32
Group 2: 7.1 ± 2.71
p value: 0.52
(calculated by NCC- AC team using t test with equal variances and ITT analysis)

Abbreviations: NR=not reported, M/F=male/female, NA=not applicable, N=total number of patients randomised, SD=Standard Deviation, CI95%= 95% Confidence Interval, ITT=Intention to Treat

From: Appendix D, Evidence tables

Cover of Glaucoma
Glaucoma: Diagnosis and Management of Chronic Open Angle Glaucoma and Ocular Hypertension.
NICE Clinical Guidelines, No. 85.
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