Scandinavian Latanoprost Study Group

In Review

Alm A, et al. "Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group.". Ophthalmology. 1995. 102(12):1743-1752.
PubMed • Full text • PDF

Clinical Question

In patients with elevated intraocular pressure (IOP) how does latanoprost compare to timolol in terms of treatment effect and side effects?

Bottom Line

The effect on diurnal lOP of latanoprost applied once daily in the evening is superior to that of timolol.

The main side effects observed are increased pigmentation of the iris induced by latanoprost and reduced heart rate by timolol.

Major Points

Prior to this study, timolol was the gold standard for treatment of ocular hypertension and glaucoma. The SSG trial was the first multicentre study comparing latanoprost to timolol and establishing latanoprost as superior.

Latanoprost has since been established as superior to timolol in a number of multicentre studies .

Latanoprost is currently first-line to manage increased IOP for glaucoma.

Guidelines

Moorfield's Eye Hospital Guidelines 2015

For open angle glaucoma and ocular hypertension a single drug should be started and its effectiveness at lowering eye pressure and any side effects should be assessed usually upon follow-up. Prostaglandin analogues (PGAs) are 1st line since they are safer than ß-Blockers and probably more effective at lowering IOP. From the PGA category: 1st line is latanoprost 0.005%, 2nd line is travoprost 0.004% and 3rd line is bimatoprost 0.01% .

NICE Guidelines 2017

Offer a generic PGA to people with IOP of 24 mmHg or more if they are at risk of visual impairment within their lifetime .

Design

• Multicenter, double-blind, randomized, controlled trial
• N =267
  • Timolol (n=84): Timolol 0.5% twice a day for 6 months
  • Latanoprost group 1 (n=89): Latanoprost 0.005% in morning followed by placebo in evening for first 3 months then regimen reversed for next 3 months
  • Latanoprost group 2 (n=94): Latanoprost 0.005% in evening preceded by placebo in morning for first 3 months then regimen reversed for next 3 months
• Setting: 13 eye clinics in Sweden, Norway, Denmark and Finland
• Mean follow-up: 6 months
• Analysis: Unclear
• Primary outcome: IOP reduction

Population

Inclusion Criteria

• 40 years or older
• Primary open-angle glaucoma, capsular glaucoma, pigmentary glaucoma, or ocular hypertension (defined as an IOP of at least 22 mm Hg)
• Unilateral or bilateral disease

Exclusion Criteria

• Current use of contact lenses
• Any systemic disease that prevented the use of beta-adrenergic blockers
• Acute angle-closure glaucoma, severe trauma or severe dry eye syndrome
• Ocular inflammation within the last 3 months
• Topical beta-adrenergic blockers within the last 6 months or longer than 3 months at any time
• Intraocular surgery or argon laser trabeculoplasty within the last 6 months
• Patients for whom the investigator judged that monotherapy would be insufficient regarding the optic nerve head and/or visual field.

Baseline Characteristics

From the timolol group

• Demographics: Age 66 years, 40% male sex
• Ocular history: primary open-angle glaucoma (POAG) 39%, capsular glaucoma 17%, OH 43%
• IOP: 24.6 mmHg

From the latanoprost group 1

• Demographics: Age 67 years, 44% male sex
• Ocular history: POAG 30%, capsular glaucoma 17%, OH 48%
• IOP: 24.8 mmHg

From the latanoprost group 2

• Demographics: Age 67 years, 46% male sex
• Ocular history: POAG 33%, capsular glaucoma 15%, OH 47%
• IOP: 25.5 mmHg

Interventions

• Randomized to timolol, latanoprost group 1 and latanoprost group 2 by computer system 

  • Timolol group received timolol 0.5% twice a day for 6 months
  • Latanoprost group 1 received latanoprost 0.005% in morning followed by placebo in evening for first 3 months with regimen reversed for next 3 months
  • Latanoprost group 2 received latanoprost 0.005% in evening followed by placebo in morning for first 3 months with regimen reversed for next 3 months
• All patients received two identical dropper bottles, labelled morning or evening
• Visits were scheduled at baseline and after 2, 6, 12, 18 and 26 weeks' treatment
• Examinations were performed at 08:00, 12:00 and 16:00 at baseline, 12 and 26 weeks. During all other timepoints, examination were performed at 08:00
• At baseline the following assessments were performed: ocular and medical history, gonioscopy, visual fields (by automated perimetry), symptomatology, visual acuity, refraction, slit-lamp examination, ophthalmoscopy, IOP determination (by Goldmann tonometry), en face and iris photography, baseline observations and blood samples
• At each subsequent visit: symptomatology, visual acuity, refraction, slit-lamp examination, evaluation of conjunctival hyperemia and IOP determination
• At the last visit in addition: visual fields, en face and iris photography, baseline observations and blood samples

Outcomes

Comparisons are timolol group vs. latanoprost group 1 vs. latanoprost group 2

Primary Outcome

Intraocular Pressure

At baseline 24.6 ± 0.3 vs. 24.8 ± 0.4 vs. 25.5 ± 0.3

At 12 weeks 17.3 ± 0.3 vs. 17.1 ± 0.3 vs. 16.4 ± 0.3 (P<0.001 compared to timolol same timepoint)

At 24 weeks 17.9 ± 0.3 (P<0.001 compared to timolol 12 weeks) vs. 16.2 ± 0.3 (P<0.001 compared to timolol same timepoint) vs. 17.7 ± 0.3

At 24 weeks 27/79 patients (34%) in timolol group vs. 58/84 (69%) patients in latanoprost group 1 had IOP of 17 mm Hg or lower

Secondary Outcomes

Ocular Side Effects

Ocular discomfort: 21/84 (25%) in timolol group vs. 12/183 (7%) in latanoprost groups

Corneal punctate erosions: 2/84 (2%) in timolol group vs. 0/183 (0%) in latanoprost groups

Increase in Iris Pigmentation: 0/84 (0%) in tim0lol groups vs. 12/183 (7%) in latanoprost groups. Of the 12 cases 9/12 (75%) were found in green-brown irides and 3/12 (25%) were found in blue/gray-brown irides

Deterioration in Visual Field: 1/84 (1%) in timolol group vs. 0/183 (0%) in latanoprost groups

Systemic Side Effects

Upper Respiratory Tract Infection: 17/84 (20%) in timolol group vs. 19/183 (10%) in latanoprost groups

Muscle and Joint pain: 12/84 (14%) in timolol group vs. 12/183 (7%) in latanoprost groups

Eczema/allergy: 7/84 (8%) in timolol group vs. 7/183 (4%) in latanoprost groups

Heart Rate: Reduction in timolol group from 72 beats per minute (bpm) at baseline to 69 bpm at 26 weeks (P<0.001)

Blood Pressure: No significant effect in blood pressure in both groups

Subgroup Analysis

For the primary outcome

There was no difference in IOP response due to sex, age, type of glaucoma or color of the iris.

Adverse Events

Serious

Any: 2/84 (2%) vs. 12/183 (7%)

Double vision: 0/84 vs. 1/183

Visual field deterioration: 1/84 vs. 0/183

Central retinal artery occlusion: 0/84 vs. 1/183

Central retinal vein occlusion: 0/84 vs. 1/183

Branch retinal vein occlusion: 1/84 vs. 0/183

Vitreous haemorrhage due to diabetes: 0/84 vs. 1/183

Cancer: 0/84 vs. 4/183

Deep vein thrombosis: 0/84 vs. 2/183

Cardiac arrhythmia: 0/84 vs. 1/183

Angina pectoris: 0/84 vs. 1/183

Criticisms

• Allocation concealment was not reported
• Not known if the statistical calculations are done on an intention to treat basis
• Number of patients remaining at end of study does not add up to figures in table listing reasons for withdrawal

Funding

• Funded by Pharmacia (now Pfizer), which manufactures latanoprost