Standard threshold laser versus subthreshold micropulse laser for adults with diabetic macular oedema - the DIAMONDS non-inferiority RCT

At a Glance

Metadata	Details
Publication Date	2022-12-01
Journal	Health Technology Assessment
Authors	Noemi Lois, Christina Campbell, Norman Waugh, Augusto Azuara‐Blanco, Mandy Maredza
Institutions	Hull and East Yorkshire Hospitals NHS Trust, Royal Victoria Hospital
Citations	7
Analysis	Full AI Review Included

Executive Summary

The DIAMONDS non-inferiority Randomized Controlled Trial (RCT) compared Standard threshold Laser (SL) versus Subthreshold Micropulse Laser (SML) for treating Diabetic Macular Oedema (DMO) in adults with Central Retinal Subfield Thickness (CRT) less than 400 µm.

Clinical Equivalence: SML was found to be clinically equivalent to SL in maintaining or improving Best-Corrected Visual Acuity (BCVA) at 24 months. The mean difference was -1.84 ETDRS letters (favoring SL), which fell well within the pre-defined non-inferiority margin of ±5 ETDRS letters.
Safety Profile: SML, which operates without creating a visible retinal burn, demonstrated a safety profile comparable to SL. Neither treatment showed statistically significant differences in the occurrence of Adverse Events (AEs) or Serious Adverse Events (SAEs).
Treatment Load: SML required a slightly higher mean number of laser treatments (2.4 sessions) compared to SL (1.9 sessions) over the 2-year period (p = 0.002).
Anatomical and Functional Outcomes: There were no statistically significant differences between SML and SL in secondary outcomes, including mean change in CRT, binocular BCVA, visual field mean deviation (MD), or patient-reported quality of life (EQ-5D-5L, NEI-VFQ-25).
Cost-Effectiveness: The economic analysis suggested SML was cost-effective (SML dominant in the base-case analysis, meaning lower cost and marginally higher Quality-Adjusted Life-Years or QALYs), although the cost difference was not statistically significant due to wide confidence intervals.
Implications for Practice: The equivalence of SML and SL, coupled with SML’s non-destructive nature, supports its continued use and suggests potential for training allied non-medical staff (e.g., nurses, optometrists) to deliver this therapy, thereby increasing NHS capacity.

Technical Specifications

Parameter	Value	Unit	Context
Trial Duration	24	Months	Follow-up period for primary outcome (BCVA change).
DMO Inclusion Criteria (CRT)	< 400	µm	Central Retinal Subfield Thickness (SD-OCT measurement).
SML Laser Type	577	nm	Optically pumped diode laser (IRIDEX IQ 577™ system).
SL Laser Type	532	nm	Argon or frequency-doubled Nd:YAG laser.
SML Spot Size	200	µm	Used for confluent grid application.
SML Duty Cycle	5	%	Ratio of ‘on’ time (0.1 ms pulses) to total time.
SML Pulse Duration (On Time)	200	ms	Total duration of active laser during one treatment spot.
SML Mean Power (Micropulse)	256.1 (SD 63.3)	mW	Power set at 4x the visible threshold power.
SL Mean Power	120.7 (SD 37.8)	mW	Power used to achieve a mild grey-white burn.
Mean Laser Treatments (SML)	2.4 (SD 1.7)	Sessions	Mean number of retreatments over 24 months.
Mean Laser Treatments (SL)	1.9 (SD 1.2)	Sessions	Mean number of retreatments over 24 months.
Non-Inferiority Margin (BCVA)	5	ETDRS letters	Maximum permitted difference for clinical relevance.
Mean BCVA Change (SML)	-2.43 (SD 8.20)	ETDRS letters	Change from baseline to month 24 (PP analysis).
Mean BCVA Change (SL)	-0.45 (SD 6.72)	ETDRS letters	Change from baseline to month 24 (PP analysis).
Mean CRT Change (SML)	-17.45 (SE 4.84)	µm	Change from baseline to month 24.
Mean CRT Change (SL)	-16.81 (SE 4.84)	µm	Change from baseline to month 24.
Mean Total Cost (SML)	897.83	£ (2020)	Total NHS and PSS costs over 24 months (complete cost data).
Mean Total Cost (SL)	1125.66	£ (2020)	Total NHS and PSS costs over 24 months (complete cost data).
Cost-Effectiveness Ratio (ICER)	SML Dominant	-	SML was lower cost and marginally higher QALYs (ITT analysis).

Key Methodologies

The DIAMONDS trial employed a pragmatic, double-masked, non-inferiority RCT design across 16 UK hospital eye services (HES).

Patient Cohort Definition: Participants were selected based on centre-involving DMO with mild fluid accumulation (CRT < 400 µm via SD-OCT) and good baseline visual acuity (> 24 ETDRS letters).
Randomization and Masking: Patients were randomized 1:1 to SML or SL. The allocation was concealed from participants and all outcome assessors (optometrists, technicians, photographers) to minimize bias.
Standard Threshold Laser (SL) Protocol (Modified ETDRS):
- Laser Type: Typically 532 nm (Argon or Nd:YAG).
- Targeting: Applied to areas of retinal thickening, non-perfusion, and leaking microaneurysms, guided by Fundus Fluorescein Angiography (FFA) and SD-OCT.
- Endpoint: Treatment intensity was set to achieve a mild grey-white burn.
- Sparing: Central 500 µm of the fovea was intentionally spared to prevent central vision loss.
Subthreshold Micropulse Laser (SML) Protocol (577 nm Diode Laser):
- Threshold Titration: Power was titrated upwards (starting at 50 mW, 10 mW increments) until a barely visible tissue reaction was observed (or 50 mW if reaction was immediate).
- Micropulse Setting: Laser switched to micropulse mode at 4x the determined threshold power.
- Application: Confluent application using three 7 x 7 spot grids above and below the fovea (500 µm from center) and one 7x7 grid temporally/nasally.
- Non-Destructive Goal: The micropulse mode utilized a 5% duty cycle (200 µm spot size, 200 ms duration) to allow retinal cooling, preventing a visible burn and preserving the Retinal Pigment Epithelium (RPE).
Retreatment and Rescue: Laser treatments could be repeated as needed. Rescue therapy (intravitreal anti-VEGF or steroids) was initiated if CRT increased to > 400 µm or if there was a loss of ≥ 10 ETDRS letters due to DMO.
Primary Outcome Measurement: Mean change in BCVA (ETDRS letters) in the study eye from baseline to 24 months.
Economic Evaluation: A cost-utility analysis was performed from the NHS and Personal Social Services (PSS) perspective, calculating cost per QALY gained using EQ-5D-5L data and accounting for direct intervention costs, retreatments, rescue treatments (anti-VEGF), and outpatient care.

Commercial Applications

The findings of the DIAMONDS trial have direct implications for the following commercial and clinical sectors:

Ophthalmic Laser Device Market:
- Validation of 577 nm diode SML systems (e.g., IRIDEX IQ 577™) as clinically equivalent to traditional SL systems for mild DMO.
- Marketing focus on the safety advantage (no retinal burn) of SML technology.
Diabetic Retinopathy Management:
- Supports clinical guidelines (NICE) recommending macular laser for DMO with CRT < 400 µm, confirming SML as a viable, non-inferior alternative to SL.
- Potential reduction in the long-term need for expensive anti-VEGF rescue therapies, impacting pharmaceutical market dynamics for DMO treatment.
Healthcare Service Delivery and Training:
- Facilitates the development of training programs for allied non-medical staff (nurses, optometrists) to administer SML, leveraging its inherent safety (no risk of foveal burn).
- Supports models of care aimed at increasing capacity and efficiency in hospital eye services (HES) by delegating laser procedures.
Health Technology Assessment (HTA):
- Provides robust, long-term (24-month) cost-effectiveness data, confirming SML dominance (lower cost, comparable or better outcomes) in the base-case analysis, influencing future procurement decisions and clinical recommendations in the UK NHS.

View Original Abstract

Background The National Institute for Health and Care Excellence recommends macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm on optical coherence tomography. The DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial compared standard threshold macular laser with subthreshold micropulse laser to treat diabetic macular oedema suitable for macular laser. Objectives Determining the clinical effectiveness, safety and cost-effectiveness of subthreshold micropulse laser compared with standard threshold macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm. Design A pragmatic, multicentre, allocation-concealed, double-masked, randomised, non-inferiority, clinical trial. Setting Hospital eye services in the UK. Participants Adults with diabetes and centre-involving diabetic macular oedema with a central retinal subfield thickness of < 400 µm, and a visual acuity of > 24 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent > 20/320) in one/both eyes. Interventions Participants were randomised 1 : 1 to receive 577 nm subthreshold micropulse laser or standard threshold macular laser (e.g. argon laser, frequency-doubled neodymium-doped yttrium aluminium garnet 532 nm laser); laser treatments could be repeated as needed. Rescue therapy with intravitreal anti-vascular endothelial growth factor therapies or steroids was allowed if a loss of ≥ 10 Early Treatment Diabetic Retinopathy Study letters between visits occurred and/or central retinal subfield thickness increased to > 400 µm. Main outcome measures The primary outcome was the mean change in best-corrected visual acuity in the study eye at 24 months (non-inferiority margin 5 Early Treatment Diabetic Retinopathy Study letters). Secondary outcomes included the mean change from baseline to 24 months in the following: binocular best-corrected visual acuity; central retinal subfield thickness; the mean deviation of the Humphrey 10-2 visual field in the study eye; the percentage of people meeting driving standards; and the EuroQol-5 Dimensions, five-level version, National Eye Institute Visual Function Questionnaire - 25 and Vision and Quality of Life Index scores. Other secondary outcomes were the cost per quality-adjusted life-years gained, adverse effects, number of laser treatments and additional rescue treatments. Results The DIAMONDS trial recruited fully ( n = 266); 87% of participants in the subthreshold micropulse laser group and 86% of participants in the standard threshold macular laser group had primary outcome data. Groups were balanced regarding baseline characteristics. Mean best-corrected visual acuity change in the study eye from baseline to month 24 was -2.43 letters (standard deviation 8.20 letters) in the subthreshold micropulse laser group and -0.45 letters (standard deviation 6.72 letters) in the standard threshold macular laser group. Subthreshold micropulse laser was deemed to be not only non-inferior but also equivalent to standard threshold macular laser as the 95% confidence interval (-3.9 to -0.04 letters) lay wholly within both the upper and lower margins of the permitted maximum difference (5 Early Treatment Diabetic Retinopathy Study letters). There was no statistically significant difference between groups in any of the secondary outcomes investigated with the exception of the number of laser treatments performed, which was slightly higher in the subthreshold micropulse laser group (mean difference 0.48, 95% confidence interval 0.18 to 0.79; p = 0.002). Base-case analysis indicated no significant difference in the cost per quality-adjusted life-years between groups. Future work A trial in people with ≥ 400 µm diabetic macular oedema comparing anti-vascular endothelial growth factor therapy alone with anti-vascular endothelial growth factor therapy and macular laser applied at the time when central retinal subfield thickness has decreased to < 400 µm following anti-vascular endothelial growth factor injections would be of value because it could reduce the number of injections and, subsequently, costs and risks and inconvenience to patients. Limitations The majority of participants enrolled had poorly controlled diabetes. Conclusions Subthreshold micropulse laser was equivalent to standard threshold macular laser but required a slightly higher number of laser treatments. Trial registration This trial is registered as EudraCT 2015-001940-12, ISRCTN17742985 and NCT03690050. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 50. See the NIHR Journals Library website for further project information.

Tech Support

Original Source

DOI: https://doi.org/10.3310/szki2484

References

2016 - The progress in understanding and treatment of diabetic retinopathy [Crossref]
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2010 - Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema [Crossref]
2009 - Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema [Crossref]
2016 - Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial [Crossref]
2011 - Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema [Crossref]
2010 - Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation [Crossref]