Clinical uncertainties in Glaucoma treatment and priorities for

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Clinical uncertainties in Glaucoma treatment and priorities for research Richard Wormald Pune December 2015

Clinical uncertainties in Glaucoma treatment and priorities for research Richard Wormald Pune December 2015

with gratitude ○ ○ ○ ○ 2 Richard Wormald is funded with financial support

with gratitude ○ ○ ○ ○ 2 Richard Wormald is funded with financial support from the UK's Department of Health through the award made by the National Institute for Health Research (NIHR) to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this presentation are those of the author and not necessarily those of the Department of Health. I have no commercial conflicts of interest I am a board member and trustee for Vision 2020 (UK) and Fred Hollows UK I am a grant holder for research from the NIHR I am joint Co-ordinating Editor of Cochrane Eyes and Vision with Jennifer Evans, based at the London School of Hygiene & Medicine's International Centre for Eye Health and Centre for Evidence and Disability I am an editorial board member for Ophthalmic Epidemiology, Journal of Community Eye Health, Bio. Med Central Ophthalmology and the Indian Journal of Ophthalmology. I recently stepped down from Ophthalmology after 12 years

The Cochrane Collaboration ○ ○ 3 Cochrane is a global independent network of health

The Cochrane Collaboration ○ ○ 3 Cochrane is a global independent network of health practitioners, researchers, patient advocates and others, responding to the challenge of making the vast amounts of evidence generated through research useful for informing decisions about health. We are a not-for-profit organisation with collaborators from over 120 countries working together to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest. The Cochrane Library is published but not owned by John Wiley on a renewable contract

EVOLUTION

EVOLUTION

Ho·mo me·di·cus noun ˌhō-(ˌ)mō-ˈmē-di-kus/ : eminence-based doctor. Read a paper once and didn’t like

Ho·mo me·di·cus noun ˌhō-(ˌ)mō-ˈmē-di-kus/ : eminence-based doctor. Read a paper once and didn’t like it. Homo medicus

Ho·mo e·vi·dence noun ˌhō-(ˌ)mō-ˈē-vi-dēns/ : evidence-based doctor. Make research-informed decisions, and thinks research is

Ho·mo e·vi·dence noun ˌhō-(ˌ)mō-ˈē-vi-dēns/ : evidence-based doctor. Make research-informed decisions, and thinks research is useful but complicated Homo evidence

Ho·mo sin·the·sys noun ˌhō-(ˌ)mo- sin-ˈtē-sis-/ : a mutation of the homo evidence that sparkled

Ho·mo sin·the·sys noun ˌhō-(ˌ)mo- sin-ˈtē-sis-/ : a mutation of the homo evidence that sparkled interest in synthesing research in order to help others. Homo synthesis

Ho·mo Co·chra·ne noun ˌhō-(ˌ)mō-ˈcō-krēn, especially British / : the species of human that are

Ho·mo Co·chra·ne noun ˌhō-(ˌ)mō-ˈcō-krēn, especially British / : the species of human that are able to complete a high quality Cochrane review on time

Models for developing capacity: inside or out? Gabriel Rada (@radagabriel) radagabriel@epistemonikos. org Evidence-based Health

Models for developing capacity: inside or out? Gabriel Rada (@radagabriel) radagabriel@epistemonikos. org Evidence-based Health Care Program, Pontificia Universidad Católica de Chile Epistemonikos Foundation (@epistemonikos) Santiago, Chile

What is a clinical uncertainty? Clinical uncertainties resolved by systematic reviews and meta-analysis Or

What is a clinical uncertainty? Clinical uncertainties resolved by systematic reviews and meta-analysis Or Uncertainties confirmed and used for research prioritisation

an example of a clinical certainty 11

an example of a clinical certainty 11

an example of a clinical certainty 12

an example of a clinical certainty 12

Lens Extraction in Angle closure glaucoma ○ ○ Jen Burr and Augusto Azuara Blanco

Lens Extraction in Angle closure glaucoma ○ ○ Jen Burr and Augusto Azuara Blanco Aberdeen Clinical Trials Unit £ 1. 1 million MRC

Network Meta-Analysis of Glaucoma Medical Treatment Trials Tianjing Li, MD, MHS, Ph. D Center

Network Meta-Analysis of Glaucoma Medical Treatment Trials Tianjing Li, MD, MHS, Ph. D Center for Clinical Trials Department of Epidemiology, JHBSPH April 5, 2014 17

Network Graph for 114 Trials on First-line Medications for OAG # of total studies

Network Graph for 114 Trials on First-line Medications for OAG # of total studies =114 Carteolol # of participants =20, 275 Betaxolol Levobunolol Timolol Brimonidine Color coding: Apraclonidine Levobetaxolol Grey Placebo/vehicle/no treatment Gold Alpha-2 adrenergic agonist Green Beta-blocker Placebo Brinzolamide Red Carbonic anhydrase inhibitor Blue Prostaglandin analog Unoprostone Dorzolamide Tafluprost Bimatoprost Latanoprost Li et al. Ophthalmology 2015 Travoprost 18

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○ NMA is often needed to address comparative effectiveness research questions. Indirect comparisons help

○ NMA is often needed to address comparative effectiveness research questions. Indirect comparisons help to assess the validity of direct comparisons. ○ Based on our analysis, as a single agent, bimatoprost seems to be the most effective first-line treatment in lowering IOP at 3 months; as a class, prostaglandins seems to be best. However, the quality of evidence is low. ○ Next steps: analyze other outcomes, including visual fields, cup/disc ratio, visual acuity, and harms. ○ I went through all trials that reported visual field data, which Kristina and Sueko helped with data abstraction (n=~70). ○ There are 6 trials that reported analyzable visual field data as mean deviation, and 10 trials reported analyzable improvement or worsening of visual field. However, none of these trials were those trials we included in the IOP analysis. 20

Maier et al. BMJ April 06 prevention of progression of glaucoma in OAG 21

Maier et al. BMJ April 06 prevention of progression of glaucoma in OAG 21

The UKGTS, Lancet 2015, now provides the first report in the literature for a

The UKGTS, Lancet 2015, now provides the first report in the literature for a single treatment on VF outcomes 22

UK Glaucoma Treatment Study 23

UK Glaucoma Treatment Study 23

Maier ‘ 06 + UKGTS 24

Maier ‘ 06 + UKGTS 24

The Low Tension Glaucoma treatment study - Lo. GTS ○ ○ ○ 25 Krupin

The Low Tension Glaucoma treatment study - Lo. GTS ○ ○ ○ 25 Krupin et Al. AJO… Is Brimonidine neuroprotective compared to Timolol (standard treatment) - in low(er) tension glaucoma Primary outcome: visual field progression after 4 years of treatment

The Low Tension Glaucoma treatment study - Lo. GTS 26

The Low Tension Glaucoma treatment study - Lo. GTS 26

The Low Tension Glaucoma treatment study - Lo. GTS Of the 190 adults enrolled

The Low Tension Glaucoma treatment study - Lo. GTS Of the 190 adults enrolled in the study, 12 (6. 3%) were excluded after randomization and 77 (40. 5%) did not complete four years of follow up. The rate of attrition was unbalanced between groups with more participants dropping out of the brimonidine group (55%) than the timolol group (29%). High Risk of Bias 27

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ANSWERS “…Furthermore, the spatial correlation utilised in ANSWERS was shown to improve the ability

ANSWERS “…Furthermore, the spatial correlation utilised in ANSWERS was shown to improve the ability to detect deterioration, compared to equivalent models without spatial correlation, especially in short follow-up series. ANSWERS is a new efficient method for detecting changes in retinal function. It allows for better detection of change, more efficient endpoints and can potentially shorten the time in clinical trials for new therapies. ” 32

CONCLUSION ○ ○ ○ 33 Now we are ready to design the definitive trial

CONCLUSION ○ ○ ○ 33 Now we are ready to design the definitive trial for comparing the actual effectiveness of modern first line treatments for preventing progression in glaucoma - in different populations Prostaglandin analogues, Beta Blockers and Alpha agonists Great opportunities for collaborative multi-centre multinational trials