Controlled Clinical Trials: Practical Knowledge You Can Use in Your Practice

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Controlled Clinical Trials Practical Knowledge
You Can Use in Your Practice

• Kyle Cheatham, O.D., F.A.A.O
• Heartland Eye Consultants
• FCO Conference, November 5, 2010

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Disclosures

• The content of this COPE Accredited CE activity
  was prepared independently without input from
  members of the ophthalmic community.
• I have no direct financial or proprietary
  interest in any companies, products or services
  mentioned in this presentation.
• The content and format of this course is
  presented without commercial bias and does not
  claim superiority of any commercial product or
  service.

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Relative Risk Reduction (RRR)

• Untreated Treated RRR
• 90/100 45/100
  50
• 40/1000 20/1000 50
• 2/1,000,000 1/1,000,000 50

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Absolute Risk Reduction

• Untreated Treated RRR ARR
• 90/100 45/100 50
  45/100
• 40/1000 20/1000 50
  20/1000
• 2/1,000,000 1/1,000,000 50
  1/Million

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Number Needed to Treat (NTT)

• ARR NTT
• 45/100 1/.45
  1.5
• 20/1000 1/.02 50
• 1/1,000,000 1/Huge gt 1,000,000

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Statistics

• There are 3 Kind of Lies
• Lies, Darn Lies Statistics
• Mark Twain

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Ocular Hypertension Treatment Trial

• Main Question.
• Does lowering IOP in patients with Ocular
  Hypertension reduce the risk of development of
  glaucoma?

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Ocular Hypertension Treatment Trial

• Answer YES
• After 5 years
• Untreated Treated
  RRR
• 9.5 4.4
  50
• Number Needed To Treat (NTT ).
• 1 / ARR 20

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Thoughts on the OHTT

• Remember, 90 of patients will NOT go on to
  develop EARLY glaucoma over 5 years.
• Recall the endpoint in this study.
• Saying 5 benefit is possibly an overstatement
  of how much we help these patients.

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Glaucoma Philosophy

• "We constantly have to remind ourselves of what
  business we're in.  We are not in the business of
  lowering intraocular pressure.  We are not in the
  business of preventing further disc damage.  We
  are not in the business of stopping visual field
  defects.   We are in the business of keeping a
  patient functioning visually at a level that
  doesn't hamper or impede the highest quality of
  life possible.  In addition, we should accomplish
  the above in the most effective and economical
  manner."
• Zimmerman, Thon, Journal of Glaucoma 1996 5 299

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QUESTIONS?....
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Diabetes What matters to us?

• What are the two threats to vision?
• Proliferative and Macular Disease
• Proliferative Preretinal/Vitreous Hemorrhage,
  NVG, Retinal Detachment
• Macular Disease Ischemia and Edema
• Which of these can you treat..

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Proliferative Diabetic Retinopathy Study (DRS)

• Question How effective is PRP in patients with
  Proliferative Diabetic Retinopathy?

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DRS Results

• -Patients with PDR and HRCs
• 26 of untreated reached endpoint
• 11 of treated reached endpoint
• 15 ARR / NTT 7
• -Patients with PDR and no HRCs
• 7 vs. 3 (4 ARR) / NTT 25

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Early Treatment Diabetic Retinopathy Study (ETDRS)

• Three Goals PRP, Macular Edema, Aspirin

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ETDRS

• How effective is PRP in patients with Severe
  NPDR?
• Answer PRP NOT effective in NPDR
• 3.7 of Untreated Patients had VA lt 5/200
• 2.6 of Treated Patients had VA lt 5/200
• ARR 1.1 / RRR 30 / NTT 91

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Results of ETDRS

• How effective is photocoagulation in preventing
  vision loss (lt3 lines) in CSME?
• PHOTOCOAGULATION FOR CSME.
• At 3 Years
• 33 Untreated Pts lost 3 or more lines of
  VA
• 13 Treated Pts lost 3 or more lines of
  VA
• ARR 20 / NTT 5

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ETDRS

• Does aspirin have any harmful or beneficial
  effects in patients with Diabetic Retinopathy?
• Aspirin does not alter the progression of
• diabetic retinopathy. It did not increase
• vitreous/preretinal hemorrhages.

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Summary of DM.

• Which threats to vision in DM are treatable?
• How does this evidence impact the way we manage
  our diabetics?

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BRVOs... What matters to us?

• What are the Threats to Vision?
• 1. MACULAR Edema, Ischemia, Intraretinal
  hemorrhage.
• 2. PROLIFERATIVE Preretinal/Vitreous
  Hemorrhage.

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BRANCHED RETINAL VEIN OCCLUSION STUDY (BVOS)

• THREE MAIN QUESTIONS
• Can PRP prevent neovascularization after a BRVO?
• Can PRP prevent vitreous hemorrhage after a BRVO?
• Can grid laser photocoagulation of the macula
  improve VA in patients with macular edema whose
  VA is 20/40 or worse.

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BVOS

• Group One 319 total eyes / Patients had
• NO current neovascularization
• Untreated 35/159 (22) developed
  neovascularization.
• Treated 19/160 (12) developed
  neovascularization

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BVOS

• 82 total eyes / Patients had Neovascularization
• Untreated 25/41 (61) developed vitreous
  hemorrhage
• Treated 12/41 (29) developed vitreous
  hemorrhage
• ARR 32 so NTT 3

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BVOS

• Should we refer for PRP right away, or can we
  wait for neovascularization before referring for
  PRP?
• (12) X (29) 3.5 get a V-heme if treated
  with PRP right away.
• (22) X (29) 6.4 get a V-heme if treated
  with PRP only after presence of
• neovascularization.

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Macular Edema from BRVO.

• 139 total eyes / Patients had macular edema with
  20/40 vision or worse and were 3 months past
  onset of BRVO.
• Control 37 improved 2 or more lines of VA at 3
  yrs
• Treated 65 improved 2 or more lines of VA at
  3 yrs
• ARR 28 so NTT 3.4

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What are Your First Thoughts?
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CRVOs What matters to us?

• What are the Threats to Vision?
• 1. MACULAR Edema, Ischemia, Intraretinal
  hemorrhage.
• 2. PROLIFERATIVE NVG, Preretinal/Vitreous
  Hemorrhage.

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Central Retinal Vein Occlusion Study (CVOS)

• Does macular grid laser therapy help macular
  edema in CRVO patients?
• Does prophylactic PRP (before the presence of
  anterior segment NV) prevent the presence of
  anterior segment NV and resultant NVG?

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Macular Edema in CRVOs

• Macular Edema 155 patients,
• all with 20/50 VA or worse.
• Grid therapy did not help. Statistical
  significance was not found at 4 months,
• 1 year, 2 years or 3 years.

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Non-Ischemic CRVOs.

• Non-ischemic 547 patients (none treated),
  followed every 4 months to see what percentage
  progressed to ischemic.
• Answer 15 became ischemic 6 of this group
  developed anterior segment NV.

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Ischemic CRVOs.

• Ischemic 181 patients (90 received immediate
  PRP, 91 followed and received PRP only if
  anterior segment NV developed).
• Prophylactic PRP reduced the risk of anterior
  segment NV from.
• 35 (untreated group) to 20 (prophylactic PRP
  group).

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Ischemic CRVOs.

• However, 2 months later, the control and treated
  groups had the same percentage (15) likelihood
  of anterior segment NV.
• And, most importantly, the groups had equal
  likelihood of developing neovascular glaucoma
  (4).

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Ischemic CRVOs.

• Based on the results of the study, is
  prophylactic PRP necessary to prevent
  neovascularization of the angle and resultant
  glaucoma?
• NO!

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What about steroid injections?

• Standard Care vs. COrticosteroid for Retinal Vein
  Occlusion (SCORE) study
• Goal Improve acuity by 15 or more letters
• Results At 12 months, 27 of patients with 1 mg
  triamcinolone acetonide intravitreal injections
  achieved goal.
• Only 7 of patients in the observation group
  achieved goal.

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CRVO SUMMARY.

• How do we use this evidence to manage our CRVO
  patients?
• Recall the threats to vision. which are
  treatable, and on what timetable?

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Summary of CRVOs and BRVOs

• Neovascularization.. when do PRP?
• Macular Edema - evidence on grid laser
  photocoagulation.

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Final Thoughts.

• --Thoughts on evidence based medicine
• --Knowing how to apply the statistics

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Recommended Trials

• ARMD TRIALS
• Visudyne
• Macugen
• AREDS
• Lucentis
• DIABETES TRIALS
• Proliferative Diabetic Retinopathy (DRS)
• Early Treatment Diabetic Retinopathy Study
  (ETDRS)

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Recommended Trials.

• GLAUCOMA TRIALS
• Advanced Glaucoma Intervention Study (AGIS)
• Collaborative Normal-Tension Glaucoma Study
  (CNTGS)
• Collaborative Initial Glaucoma Treatment Study
  (CIGTS)
• Early Manifest Glaucoma Trial (EMGT)
• Glaucoma Laser Treatment (GLT) Study
• Ocular Hypertension Treatment Study
• VEIN OCCLUSION TRIALS
• BRANCHED RETINAL VEIN OCCLUSION STUDY
• CENTRAL VEIN OCCLUSION STUDY

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More Trials.

• OTHER TRIALS
• THE OPTIC NEURITIS TREATMENT TRIAL
• HEDS -1 THE HERPETIC EYE DISEASE STUDY
• HEDS-2 HERPETIC EYE DISEASE STUDY- II

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THANK YOU!