Open angle Glaucoma

1
Open angle Glaucoma

• Open angle glaucoma, one of the major causes of
  impaired vision worldwide, is a condition
  characterized by damage to and loss of optic
  nerve axons, resulting most commonly in loss of
  peripheral aspect of the visual field, which may
  progress to loss of central vision.
• Ref Ophthalmology 1999 106 653 - 663

2
Open angle Glaucoma Treatment

• Methods to reduce IOP include
• Use of systemic or topical medications
• Use of laser energy applied to the trabecular
  meshwork to improve aqueous outflow.
  
• Use of filtration surgery to produce an alternate
  route for aqueous outflow.
  
• Ref Ophthalmology 1999 106 653 - 663

3
Open angle Glaucoma Medical therapy

• The expanded pharmacologic armamentarium in the
  last decade has greatly increased the efficacy
  and tolerability of medical therapy.
  
• Medical treatment is costly, lifelong and is a
  daily reminder for patients that they have
  potentially vision threating disorder.
  
• Ref Curr Opin Ophthalmol 2003 14 106 - 111

4
Open angle Glaucoma Surgical Option

• European Ophthalmology community has advocated
  early incision surgery and demonstrated better
  IOP control compared with patients treated with
  eye drops.
• Retrospective study demonstrated that 60 of eyes
  initially treated with medications required
  surgical interventions.
  
• Surgery can be more cost-effective than a
  lifetime of medications.
  
• Less inconvenience, patients do not have the
  daily psychological burden of treating the
  disease.
  
• Surgical side effects ptosis, chronic
  dysesthesia, surgical related visual compromise
  and risk of blebitis.
  
• Ref Current Opinion Ophthalmol, 2003 14 106 -
  111

5
BACKGROUND

• Recent studies have challenged the
  conventional wisdom of treating all newly
  diagnosed open-angle glaucoma with eye drops
  rather, these studies suggest more effective
  control of glaucomatous damage can be obtained by
  immediate filtration surgery. In addition,
  increased attention to the impact of therapy on
  health-related quality of life has added another
  consideration in deciding upon appropriate
  treatment of such patients.
• Ref http//www/net.nih-gov

6

• Study Title
• The Collaborative Initial Glaucoma treatment
  study (CIGTS)
  
• Ref Current Opinion in Ophthalmology 14 106
  111, 2003

7

• Objective
• CIGTS is a randomized, controlled clinical trial
  
  
• designed to determine whether patients with newly
  
  
• diagnosed POAG are better treated by initial
  treatment
  
• with medications or by immediate filtration
  surgery.

8
Study design and Methods

• Organization
• Randomized controlled clinical trial
• Duration of the study 5 years
• 14 clinical centers enrolled patients from
  October 1993 April 1997.
  
• Studys protocol and informed consent were
  approved by humans studies review boards at all
  participating centers..

9
Study design and Methods

• Inclusion criteria
• Diagnosis of primary open-angle,
  pseudoexfoliative, or pigmentary glaucoma in one
  or both eyes.
  
• One of three combinations of qualifying IOP,
  visual field changes, and optic disc findings as
  follows
  
• IOP of 20 mm Hg or higher, Humphrey 24-2 visual
  field result with 3 contiguous points on the
  total deviation plot at the less than 2 level
  and glaucoma hemifield test result that is
  outside normal limits and optic disc compatible
  with glaucoma.

10

• IOP between 20-26 mm Hg or higher, Humphrey 24-2
  visual field result with 2 contiguous points on
  the total deviation plot at the less than 2
  level and glaucomatous optic disc damage.
• IOP greater than 26 mm Hg and glaucomatous optic
  disc damage
  
• 3. Visual acuity equal to or better than 20/40 on
  ETDRS chart.
  
• 4. Age between 25 and 75 years
• 5. Ability to meet the follow-up requirements for
  a minimum of 5 years
  
• 6. Written informed consent

11
Study design and Methods

• Exclusion criteria
• Use of glaucoma medication for more than 14 days
  
  
• Use of glaucoma medication within 3 weeks of
  baseline visit (washout from permitted)
  
• CIGTS visual field score 16
• Ocular disease that might affect measurement of
  IOP, visual field testing
  
• Diabetic retinopathy with more than 10 micro
  aneurysms
  
• Previous ocular surgery
• Significant cataract
• Use of corticosteroids (oral or ophthalmic)

12
Study design and Methods (contd.)

• Enrollment and Randomization
• After two baseline visits (which measured visual
  field and IOP taken at each visit), other
  eligibility criteria confirmed ,patients were
  randomized.
• Adaptive randomization used resulted in optimal
  balance across 5 strata
  
• Age 25 to 54, 55 to 64, 65 to 75
• Center (14 sites)
• Gender (male, female)
• Race (African-American, white, Asian and
  other)
  
• Diagnosis (Primary, pigmentary and
  pseudoexfoliative forms of open angle glaucoma)
  
• Patients were randomized into either the medical
  or surgical arm.

13
CIGTS Treatment Flow Sheet
14
CIGTS Criteria for intervention failure

• Criteria for intervention failure had to be met
  each time that a further treatment step was
  initiated.
  
• Criteria include
• Failure to meet a target IOP that was established
  at the time of randomization
  
• Evidence of progressive visual field loss
• Or both

15
CIGTS Target IOP calculation

• Based on the patients reference IOP (ie., the
  mean of six separate IOP measurements taken in
  the course of the 2 baseline visits)
  
• Reference visual field score (ie., the mean of at
  least 2 visual fields taken during 2 baseline
  visits)
  
• Formula for target IOP (1-reference IOP
  visual field scorexref.IOP)
  
• 100
• For eg. Ref. IOP 28 mm Hg then target IOP
  (1 285) x 28
  
• 100
• Ref. VF score 5 (1 0.33)
  x 28
  
• 0.67 x 28 19 mm Hg

16
CIGTS Criteria for Intervention Failure

• IOP related intervention failure If on a
  follow-up visit, the IOP was 1 mm Hg above the
  target IOP and this confirmed on another visit.
  
• Visual field related intervention Visual field
  score failure was 3 or more units above the
  reference visual field score on 3 consecutive
  tests performed at separate clinic visits.

17
CIGTS Study Main outcome measures

• Primary outcome variable Progression in visual
  field score
  
• Secondary outcome variable
• Health related quality of life
• Visual acuity
• Intraocular pressure

18
CIGTS Study Outcome Assessment Methods

• Progression in VF score Increase in the VF
  score of 3 units or more from the patients
  reference VF score.
  
• Visual field score Range from 0 (no defect) to
  20 (all points showing a defect at the plevel)
  
• IOP measured before Gonioscopy/ dilating agent
  Goldmann Applanation tonometry
  
• Visual acuity ETDRS protocol Patients are
  tested at 4 m
  

19
CIGTS Study Outcome Assessment Methods (contd.)

• Health related quality of life An instrument
  was developed that incorporates designed
  questionnaire
  
• 16 questions General health perceptions
• 4 questions Adaptations and social support
• 33 item visual activities questionnaire
• 43 item symptom and health problem list
• 8-item center for Epidemiologic studies
  depression questionnaire
  
• Full 136 item sickness impact profile
• Questions on a no of possible co-morbidities
• Questions on compliance and satisfaction with
  their treatment
  

20
CIGTS Study Outcome Assessment Methods (contd.)

• The instrument is administered by telephone
• contact with the patient in his or her home at a
  pre
  
• arranged time and requires approximately 45
• minutes to administer.

21
CIGTS Study Follow-up

• Patients followed up 3 months after treatment
  has begun, after a 6 month visit, subsequent
  visits are conducted at 6 month interval.
  
• Health related quality of life interviews at 2
  months, 6 months and then at 6 months
  intervalsafter treatment initiation.

22
CIGTS Study Follow-upTable. Tests performed at
Study Visits through Month 24
23
CIGTS Study Statistical analysis

• Treatment group comparisons followed the
  intent-to-treat principle.
  
• Time specific comparisons on mean values were
  conducted using students t test.
  
• Repeated measures logistic regression, to
  investigate VF loss and VA loss
  
• SAS proc mixed and SAC Proc Genmod was used
• Study 90 power

24
Table 1. Demographics and Ophthalmic Status of
Enrolled patients by treatment group
25
Table 1. Demographics and Ophthalmic Status of
Enrolled patients by treatment group (contd.)
P values result from either Yates corrected
chi-square tests contrasting proportions or
independent two-sided Student's tests contrasting
means in the medical and surgical groups.
Immediate parents, siblings, children
CDR Cup/disc ratio IOPintraocular pressure
Nnumber, POAGprimary open-angle glaucoma
SDstandard deviation VAvisual acuity
VFvisual field
26
RESULTS
27
CIGTS Study VF comparison

• Clinically substantial VF loss 10.7 - medically
  treated
  
• 13.5 - surgically treated
• Initial surgery resulted in 0.36 unit worst VF
  score than initial medical treatment

28
CIGTS Study Results
Patients in the medical arm initially had
improvements in visual field scores , but at 5
years both groups converged towards similar
scores
29
CIGTS Study Visual Field Loss

• Logistic regression analysis revealed significant
  associations of a 3 unit or more VF score
  increase with age, race, history of diabetes and
  time in study.
• Older age (every 10 yr increment in age increased
  the risk of VF loss by 40)
  
• Nonwhites had a 50 increased risk relative to
  whites (adjusted OR, 1.50, 95 CI 1.08, 2.07)
  
• Diabetic patients had a 59 increased risk
  relative to non-diabetics (adjusted OR, 1.59, 95
  CI, 1.07, 2.38)
  
• Patients with cataract were at increased risk of
  vf loss(adjusted OR, 4.71, 95 CI, 3.34, 6.65)
  
• Initial surgery had a marginally positive
  association with the risk of VF loss (adjusted
  OR, 4.71, 95 CI, 3.34, 6.65)

30
CIGTS VA comparison
Surgery resulted in a 3 letter loss of VA (about
½ a line) evident at month 3 whereas in the
medicine groups showed essentially no change
31
CIGTS VA comparison

• Clinically substantial VA loss (defined as letters in VA from baseline) during 5 years of
  follow-up in 3.9 of medically treated patients
  and 7.2 of surgically treated patients.

32
CIGTS IOP Comparison

• The decrease in IOP was significantly greater in
  the surgery group compared to medical group.
  
• Surgery Baseline 27 mm Hg
• After 5 years 17-18 mm Hg
• Medical Baseline 28 mm Hg
• After 5 years 17-18 mm Hg

33
CIGTS IOP Comparison
IOP reduction 48 in the surgical group compared
to 35 in the medical group
34
CIGTS Cataract Development

• Initial surgical treatment resulted in the
  development of more cataracts than initial
  medical treatment.

35
CIGTS Surgical Complications

• 525 trabeculectomies were performed in 300
  patients randomized to the surgery arm.
  
• Incidence of complication occuring during the
  first post-operative month
  
• Intraoperative bleeding 13.5
• Shallow or flat anterior chamber 14.2
• Encapsulated bleb 11.9
• Ptosis 11.9
• Serous choroidal detachment 11.3
• Anterior chamber bleeding 10.5

36
CIGTS Treatment Crossover

• Treatment crossover in the medical group and
  surgical group was comparable (medical 8.5,
  surgical 8.3, P0.80, log rank test)
  
• By 1 year after treatment initiation,
  Kaplan-Meier estimates show
  
• 23.6 of medicine group patients underwent ALT
• 11.8 of surgical group patients underwent ALT

37
CIGTS Quality of life Comparison
38
CIGTS Quality of life Comparison (contd.)
39
CIGTS Quality of life Comparison (contd.)
40
CIGTS Discussion

• Both medications and surgery significantly reduce
  IOP.
  
• Over 5 years, both groups of patients had similar
  low rates of VF progression.
  
• Target IOP achieved in 90 of patients in both
  groups.
  
• Medically treated patients less likely to develop
  cataracts, suffer non-cataract VA loss or
  complain of ocular side effects.
  
• Medically treated patients were less likely to
  develop VF loss.
  
• Pertaining to QOL, 5 higher scores for surgical
  group on VAQ Acuity subscale to approximately 22
  higher scores on symptom impact glaucoma total
  score.
• Local eye subscale higher with surgical group
• Less impact on QOL with initial medical treatment
  than initial surgical treatment.

41
CIGTS Study Strengths

• Unlike other trials like AGIS, the CIGTS
  randomization unit was patient and not the eye.
  
• To assess treatment effects in patients rather
  than eyes.
  
• Effective randomization to provide 90 power
• Thorough assessment of the patients health
  related quality of life.
  
• Protocol allowed inclusion of new medications
  like topical CAIs, PG analogues.
  
• Provides directly applicable and germane guidance
  to clinicians on how best to begin treating a
  patient who is diagnosed with open angle
  glaucoma.
• First long term study involving a large number of
  patients.

42
CIGTS Weakness

• Laser trabeculoplasty as initial therapy not
  studied in CIGTS.
  
• Baseline demographics do not mention the no of
  patients with cataract.
  
• Cost accounting of the two forms of therapy not
  studied.

43
CIGTS Conclusion

• Over the period to follow up to date, both
  initial medication
  
• or surgery were equally effective in minimizing
  visual field
  
• loss. This can be attributed to an aggressive
  IOP
  
• lowering treatment approach.