CNTGS

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Clinical Question

In patients diagnosed with normal tension glaucoma, does IOP reduction reduce glaucomatous progression?

Bottom Line

For patients with normal tension glaucoma, reduction of IOP by at least 30% is associated with a reduction of the incidence of glaucomatous visual field progression at 5 years from 35% to 12%.

Major Points

Primary open-angle glaucoma (POAG) is a major cause of blindness both in the United States and worldwide. Historically, glaucoma was believed to be tightly linked with elevated IOP, and glaucomatous progression in individuals with normal IOP was often attributed a failure to capture episodes of ocular hypertension. True normal tension glaucoma was believed to be rare. Furthermore, in patients with normal IOP readings but optic nerve and visual field changes suggestive of glaucoma, it was unclear to what degree lowering IOP would reduce the progression of the disease.

This study demonstrated that substantial and sustained IOP lowering in eyes with normal tension glaucoma is effective in reducing glaucomatous visual field progression. Filtration surgery was frequently required to achieve IOP goals in the experimental group, and was significantly associated with cataract formation. For many eyes, greater than 6 months of treatment was necessary to obtain target IOP reduction. The majority of eyes without treatment did not undergo any glaucomatous progression.

As a result of this study, IOP lowering medications and surgery were established as the mainstay of treatment for normal tension glaucoma. However, the risks of treatment, such as cataract formation associated with drainage surgery, must be weighed against the relatively low rate of progression in the natural course of the disease. Treatment plans are often individualized based on a patient-by-patient basis.


Guidelines

American Academy of Ophthalmology Preferred Practice Patterns for Primary Open Angle Glaucoma in 2016
  • Primary open-angle glaucoma with consistently normal IOP is common, especially in certain populations. Lowering pressure in these patients can be beneficial.
  • Clinical trials have shown that lowering IOP reduces the risk of developing POAG and slows the progression of POAG, including normal-tension OAG.


Design

  • Prospective, multicenter, unmasked, randomized, controlled trial with 2 groups: Treated eyes with target IOP reduction of 30% via medical or surgical therapy vs. control group with no IOP lowering treatment
  • N=140
    • Treatment group (n=61)
    • Control group (n=71)
  • Setting: 24 centers in North America and Europe
  • Enrollment: Not specified
  • Follow-up 5+ years
  • Analysis: Survival, Intention-to-treat
  • Primary outcome: Visual field progression, worsening glaucomatous progression of optic disc, or both

Population

Inclusion Criteria

  • Unilateral or bilateral normal-tension glaucoma
    • Defined as optic disk changes and visual fields consistent with glaucoma as judged by the patient's ophthalmologist
  • Age > 20 years
  • Age < 90 years
  • Never recorded IOP > 24 mmHg in either eye
  • 10 baseline IOP readings with the following characteristics:
    • The median is < 20 mmHg
    • No more than one reading 23 or 24 mmHg
  • 3 consistent, reliable visual fields within 1 month of each other; performed prior to treatment

Exclusion Criteria

  • Patients taking systemic beta-blockers
  • Patients taking systemic clonidine
  • Eyes with previous laser treatment
  • Eyes with previous ocular surgery (except strabismus surgery)
  • Cyclodestructive procedures
  • Eyes with visual fields defects secondary to diseases other than glaucoma (e.g. choroidal rupture)
  • Narrow anterior chamber angles deemed to be occludable
  • Corneal abnormalities
  • Eyes with best corrected visual acuity worse than 20/30
  • Eyes with visual fields too advanced to detect further glaucomatous progression

Baseline Characteristics

Mean ± SD

From the control group (n=79)

  • Mean age: 72 (± 9.6) years
  • 30 Males, 49 Females
  • 65 White, 9 Asian, 2 Black, 2 Hispanic
  • Refraction: -0.66 ± 2.86
  • Visual Acuity: 0.89 ± 2.86
  • Mean defect: -7.54 ± 4.31
  • IOP (mmHg): 16.1 ± 2.3

From the IOP-lowering group (n=61)

  • Mean age: 66.3 (± 10.3) years
  • 17 Males, 44 Females
  • 51 White, 3 Asian, 5 Black, 1 Hispanic
  • Refraction: -1.09 ± 3.3
  • Visual Acuity: 0.89 ± 0.15
  • Mean Deviation: -8.38 ± 5.26
  • IOP (mmHg): 16.9 ± 2.1
- Baseline IOP difference was statistically significant (p=0.0224)

Interventions

  • Each patient was randomized to 30% IOP lowering treatment by medical or surgical means, or to no no treatment
    • IOP lowering treatment plan was determined by the patient's ophthalmologist
    • If the patient received a filtration surgery, a 20% IOP reduction was accepted without requiring a second procedure
    • No more than 3 surgical procedures were performed
    • To prevent confounding cardiovascular effects, beta-adrenergic blockers and adrenergic blockers could not be used

Outcomes

Comparisons are IOP-lowering therapy vs. Untreated controls

Primary Outcomes

Survival analysis (Optic disc or visual field progression as independently judged by consistent 2 member reading committee)
2,688 ± 123 days vs. 1,695 ± 143 days (p < 0.0001)
Survival analysis (Visual field progression in 4 of 5 consecutive follow-up fields as judged by software)
2,255 ± 118 days vs. 1,837 ± 168 days (p = 0.0116)
Survival analysis (Visual field progression in 4 of 5 consecutive follow-up fields as judged by software, after the control group underwent statistical thinning to account for more frequent follow-up visits)
2,049 ± 129 days vs. 1,427 ± 139 days (p = 0.0050)
Survival analysis (Visual field progression in 4 of 5 consecutive follow-up fields as judged by software, after eyes which developed cataracts were censored)
2,242 ± 108 days vs. 1,783 ± 185 days (p = 0.0034)


Additional Data

Comparisons are IOP-lowering therapy vs. Untreated controls

Glaucomatous progression 5 years after reaching new IOP baseline (as independently judged by consistent 2 member reading committee)

p-values not reported

7/61 (12%) vs. 28/79 (35%)
Glaucomatous progression 5 years after reaching new IOP baseline (as determined on 4 of 5 consecutive follow-up visual fields judge by software)

p-values not reported

11/61 (18%) vs. 24/79 (30%)
Group characteristics after IOP reduction was achieved

Mean ± SD

From the Control Group (n=79)

  • Mean defect at stabilization: -7.54 ± 4.31
  • IOP during follow-up (mmHg): 16.0 ± 2.1
  • Mean defect during follow-up: -8.08 ± 4.28
  • Mean defect slope during follow-up (dB per year): -0.4018 ± 3.65

From the IOP-lowering group (n=61)

  • Mean defect at stabilization: -9.42 ± 4.82 (p=0.02)
  • IOP during follow-up (mmHg): 10.6 ± 2.7 (p<0.0001)
  • Mean defect during follow-up: -9.62 ± 4.53 (p=0.05)
  • Mean defect slope during follow-up (dB per year): -0.4992 ± 1.97 (p=0.85)


Intention-to-treat analysis

  • N=145
    • Treatment group (n=66)
    • Control group (n=71)

Comparisons are IOP-lowering therapy vs. Untreated controls

Survival analysis (Visual field progression in 4 of 5 consecutive follow-up fields as judged by software)
1,796 ± 151 days vs. 1,525 ± 152 days (p=0.21)
Survival analysis (Visual field progression in 4 of 5 consecutive follow-up fields as judged by software, after the control group underwent statistical thinning to account for more frequent follow-up visits)
1,899 ± 146 days vs. 1,659 ± 161 days (p=0.19)
Survival analysis (Visual field progression in 4 of 5 consecutive follow-up fields as judged by software, after censoring visual fields taken at the time of cataract diagnosis)
2,101 ± 122 days vs. 1,476 ± 155 days (p=0.0018)
Survival analysis (Visual field progression in 4 of 5 consecutive follow-up fields as judged by software, after censoring visual fields taken at the time of cataract diagnosis and after the control group underwent statistical thinning to account for more frequent follow-up visits)
2,161 ± 119 days vs. 1,724 ± 186 days (p=0.013)

Comparisons are IOP-lowering therapy vs. Untreated controls

Glaucomatous progression 5 years after reaching new IOP baseline (as determined on 4 of 5 consecutive follow-up visual fields judge by software, after censoring visual fields taken at the time of cataract diagnosis)

p-values not reported

20% vs. 60%


Risk factors for glaucomatous progression

Reported as Relative risk

Migraine: 2.58 (p=0.0058)
Disk hemorrhage: 2.72 (p=0.0036)
Female Gender: 1.85 (p=0.0622)
  • Although migraines and disc hemorrhages are each known to be associated with female gender, multivariate analyses showed that each was also an independent risk factor for visual field progression in normal tension glaucoma.


Adverse Events

IOP-lowering therapy vs. Untreated controls

Survival analysis (Time from randomization until cataract formation)
1,200 ± 694 days vs. 1,443 ± 785 days (p=0.031)


IOP-lowering therapy group only

Survival analysis (Time from IOP stabilization at new baseline until cataract formation)
822 ± 687.2 days


IOP-lowering therapy with medical treatment vs. IOP-lowering therapy with surgical treatment

Survival analysis (Time from randomization until cataract formation)
1,266 ± 648 days vs. 1,168 ± 732 days (p=0.75)

Criticisms

  • During the study, the authors changed visual field requirements from 1 to 3 consistent visual fields, in an attempt to reduce false-positives.
  • Did not account for central corneal thickness, a known risk factor for POAG
  • Inclusion of individuals with occasional IOP up to 24 mmHg, compared to the common definition of normal tension glaucoma as universal IOP <= 21mmHg
  • Optic disc hemorrhage was defined as glaucomatous progression and used as criteria for inclusion into the study, but new optic disc hemorrhage was not used as an indicator of progression as an outcome
  • Intent-to-treat analysis was not able to demonstrate a protective effect of IOP-lowering therapy until after adjusting for the effect of cataracts, which had a higher incidence in the IOP-lowering group
  • The patient population studied was predominantly White, other groups were underrepresented

Funding

The CNTGS study was funded by the Glaucoma Research Foundation, with special grants from the Oxnard Foundation and the Edward J. Daly Foundation, San Francisco, California.

Further Reading

Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressure. Am J Ophthalmol. 1998; 126: 487–497. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998; 126(4):498-505.

Drance S, et al. Risk Factors for Progression of Visual Field Abnormalities in Normal-tension Glaucoma. Am J Ophthalmol. 2001; 131:699-708.

Prum B, et al. Primary open-angle glaucoma preferred practice pattern® guidelines. Ophthalmology. 2016; 123(1): 41-111.

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