Open angle Glaucoma

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					             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
     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
          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
                 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
            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
Study Title:
 The Collaborative Initial Glaucoma treatment study
                     (CIGTS)




          Ref: Current Opinion in Ophthalmology; 14; 106 – 111, 2003
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.
              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.
 Study’s protocol and informed consent were
  approved by human’s studies review boards at all
  participating centers..
               Study design and Methods


Inclusion criteria:
1. Diagnosis of primary open-angle, pseudoexfoliative, or
     pigmentary glaucoma in one or both eyes.
2. 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.
   •     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
                  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 < 14 days of use was 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)
               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:
   1.   Age – 25 to 54, 55 to 64, 65 to 75
   2.   Center – (14 sites)
   3.   Gender – (male, female)
   4.   Race – (African-American, white, Asian and other)
   5.   Diagnosis – (Primary, pigmentary and pseudoexfoliative forms of
        open angle glaucoma)
   Patients were randomized into either the medical or surgical arm.
                  CIGTS: Treatment Flow Sheet

Medical therapy                        Surgical therapy
1.   Medication (topical -blocker,    1.   Trabeculectomy (5 FU- optional)
     alternative monotherapy, dual,    2.   ALT
     triple and/or oral medications)   3.   Medication
2.   ALT                               4.   Trabeculectomy with
3.   Trabeculectomy (5-FU optional)         antimetabolite
4.   Medication                        5.   Medication
5.   Trabeculectomy with               6.   Ophthalmologist’s discretion
     antimetabolite
6.   Medication
7.   Ophthalmologist’s discretion
       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
                   CIGTS: Target IOP calculation

 Based on the patient’s 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
  score]xref.IOP)
                                             100
 For eg. Ref. IOP = 28 mm Hg then target IOP = (1 – [28+5]) x 28
                                                           100
          Ref. VF score = 5                       = (1 – 0.33) x 28
                                                  = 0.67 x 28 = 19 mm Hg
      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.
       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
     CIGTS Study: Outcome Assessment Methods


Progression in VF score: Increase in the VF score of 3
  units or more from the patient’s reference VF score.
Visual field score: Range from 0 (no defect) to 20 (all
  points showing a defect at the p<0.005 level)
IOP measured before Gonioscopy/ dilating agent:
  Goldmann Applanation tonometry
Visual acuity: ETDRS protocol – Patients are tested at
  4m
      CIGTS Study: Outcome Assessment Methods
                     (contd.)

Health related quality of life: An instrument was developed that
    incorporates designed questionnaire:
1. 16 questions – General health perceptions
2. 4 questions – Adaptations and social support
3. 33 item visual activities questionnaire
4. 43 item symptom and health problem list
5. 8-item center for Epidemiologic studies depression
    questionnaire
6. Full 136 – item sickness impact profile
7. Questions on a no of possible co-morbidities
8. Questions on compliance and satisfaction with their treatment
   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.
             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.
                      CIGTS Study: Follow-up
                Table. Tests performed at Study Visits
                          through Month 24
Assessment      Baseline   Month 2 Month 3 Month 6 Month 12 Month 18 Month 24
Visual field    Yes        No      Yes     Yes     Yes      Yes      Yes
Refraction      Yes        No      Yes     Yes     Yes      Yes      Yes
Visual acuity   Yes        No      Yes     Yes     Yes      Yes      Yes
Slit-lamp       Yes        No      Yes     Yes     Yes      Yes      Yes
examination
IOP             Yes        No      Yes     Yes     Yes      Yes      Yes
Gonioscopy      Yes        No      No      Yes     No       Yes      No
Dilated lens    Yes        No      Yes     No      Yes      No       Yes
examination
Dilated funds Yes          No      Yes     No      Yes      No       Yes
examination
QOL             Yes        Yes     No      Yes     Yes      Yes      Yes
interview
          CIGTS Study: Statistical analysis


 Treatment group comparisons followed the intent-
  to-treat principle.
 Time specific comparisons on mean values were
  conducted using student’s 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
    Table 1. Demographics and Ophthalmic Status
       of Enrolled patients by treatment group

Patient characteristic     Medicine    Surgery     P value*
                           (n=307)     (n=300)
Categorical variables      N (%)       N (%)
Gender female              143 (47%)   130 (43%)   0.47
Race: white                167 (54%)   170 (57%)   0.63
Immediate family history   99 (32%)    102 (34%)   0.71
of glaucoma
Hypertension               122 (40%)   103 (34%)   0.20
Diabetes                   60 (20%)    42 (14%)    0.09
Smoking history: current   62 (20%)    65 (22%)    0.73
Glaucoma type: POAG        278 (91%)   272 (91%)   0.93
                     Table 1. Demographics and Ophthalmic Status
                    of Enrolled patients by treatment group (contd.)


       Patient characteristic                   Medicine (n=307)               Surgery(n=300) P value*
       Quantitative variables                   Mean (SD)                      Mean (SD)
       Age, in years                            56.9 (11.2)                    58.1 (10.6)              0.19
       Qualifying IOP, in mmHg                  27.6 (5.5)                     27.4 (5.7)               0.71
       Reference VF score                       4.6 (4.2)                      5.0 (4.3)                0.15
       VA score                                 85.6 (5.9)                     85.8 (5.5)               0.62
       Horizontal CDR                           0.6 (0.2)                      0.6 (0.2)                0.70
       Vertical CDR                             0.7 (0.2)                      0.7 (0.2)                0.51
*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; IOP=intraocular pressure; N=number, POAG=primary open-angle glaucoma; SD=standard
deviation; VA=visual acuity; VF=visual field
RESULTS
                   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
                   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
                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)
                            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
                CIGTS: VA comparison


 Clinically substantial VA loss (defined as < 15
  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.
               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
                      CIGTS: IOP Comparison




IOP reduction 48% in the surgical group compared to 35% in the medical group
              CIGTS: Cataract Development


 Initial surgical treatment resulted in the development of
  more cataracts than initial medical treatment.
                   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:
    1.      Intraoperative bleeding – 13.5%
    2.      Shallow or flat anterior chamber – 14.2%
    3.      Encapsulated bleb – 11.9%
    4.      Ptosis – 11.9%
    5.      Serous choroidal detachment – 11.3%
    6.      Anterior chamber bleeding – 10.5%
             CIGTS: Treatment Crossover


 Treatment crossover in the medical group and
  surgical group was comparable (medical 8.5%,
  surgical 8.3%, P=0.80, 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
                             CIGTS: Quality of life Comparison


                                       2 months               12 months              60 months
                                 Medical    Surgical   Medical     Surgical   Medical     Surgical
                                 n=280 %    n=268 %    n=276 %     n=269 %    n=201 %     n=186 %

Visual Function Symptoms
Blurred vision                  31.1       34.3        22.5        29.7       13.9        17.7
Difficulty w/ bright light      38.2       48.1        32.6        43.9       32.8        34.9
Vision problems w/ steps        16.1       23.1        16.7        21.6       14.9        17.7
Local Eye Symptoms
Eye irritation, blurring        43.2       43.1        34.1        40.9       19.4        29.0
Something in eye                30.0       50.4        27.2        47.2       23.4        31.2
Red eye                         23.9       32.1        20.3        29.0       13.4        18.8
Excessive tearing               18.9       24.3        14.9        29.4       12.9        18.8
Skin sensitivity around eye     11.1       15.3        11.6        17.5       11.4        11.8
Droopy eyelid                   12.9       26.1        12.7        20.9       8.5         15.1
CIGTS: Quality of life Comparison (contd.)
              CIGTS: Quality of life Comparison (contd.)

                               2 months             12 months          60 months
                        Medical     Surgical Medical Surgical Medical Surgical
                        n=280 %     n=268 % n=276     n=269   n=201    n=186
                                               %       %        %       %
Systemic symptoms
Drowsiness              28.2       25.0      26.5        25.3   19.9        15.1
Headache/ browache      33.2       22.4      25.0        20.1   17.4        15.1
Wheezing                13.6       7.1       16.3        13.0   10.9        11.3
Weakness                15.7       11.9      11.2        12.6   10.0        8.1
Nausea                  6.1        4.1       4.3         4.1    7.0         2.7
Altered tasteor smell   7.1        2.6       3.3         5.9    1.0         3.2
Weight loss             4.6        4.1       4.3         3.3    3.5         0.5
Dizziness               15.4       9.3       14.1        10.0   7.5         9.1
                           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.
                 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 patient’s 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.
                   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.
                  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.

				
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