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	Frimley Health NHS Foundation Trust, Manchester Royal Eye Hospital
Citations	7
Analysis	Full AI Review Included

Technical Documentation: MPCVD Diamond for Advanced Ophthalmic Laser Systems

This document analyzes the technical requirements derived from the DIAMONDS Randomized Controlled Trial (RCT), which compared Standard Threshold Laser (SL) and Subthreshold Micropulse Laser (SML) for Diabetic Macular Oedema (DMO). The findings confirm the clinical equivalence of SML, highlighting the ongoing need for high-precision, thermally stable optical components in next-generation ophthalmic laser delivery systems.

Executive Summary

Clinical Equivalence Confirmed: The DIAMONDS trial established that Subthreshold Micropulse Laser (SML) is non-inferior and clinically equivalent to Standard Threshold Laser (SL) for treating DMO with Central Retinal Subfield Thickness (CRT) < 400 µm.
Laser Technology Focus: The study utilized high-precision ophthalmic lasers, specifically a 577 nm optically pumped diode laser (SML) and 532 nm frequency-doubled Nd:YAG or Argon lasers (SL).
Thermal Management Criticality: SML relies on a micropulse mode (5% duty cycle) to prevent thermal damage (“burn”) to the Retinal Pigment Epithelium (RPE), emphasizing the extreme thermal stability required in the laser delivery optics.
Increased Treatment Frequency: SML required a slightly higher mean number of laser treatments (2.4 sessions vs. 1.9 for SL) over 24 months, necessitating robust, long-lifetime optical components capable of repeated high-power operation.
High-Precision Optics Demand: The use of small spot sizes (down to 50 µm) and precise energy delivery at visible wavelengths (532 nm, 577 nm) demands ultra-low absorption, high-purity optical materials.
6CCVD Value Proposition: MPCVD Single Crystal Diamond (SCD) and Polycrystalline Diamond (PCD) are ideally suited for manufacturing the critical optical windows, output couplers, and high-efficiency heat sinks required to maximize performance and longevity in these advanced ophthalmic laser systems.

Technical Specifications

The following parameters define the operational environment and performance metrics relevant to the optical components within the tested laser systems:

Parameter	Value	Unit	Context
SML Wavelength	577	nm	Optically pumped diode laser (IRIDEX IQ 577™)
SL Wavelength (Example)	532	nm	Frequency-doubled Nd:YAG or Argon laser
SML Spot Size	200	µm	Applied confluently in 7 x 7 grids
SL Spot Size (Range)	50 to 200	µm	Standard threshold macular laser
SML Duty Cycle	5	%	Ratio of ‘on’ time to total pulse duration
SML Pulse Duration (‘On’)	0.1	ms	Individual pulse duration
SML Total Duration	200	ms	Total ‘on’ duration (sum of multiple 0.1 ms pulses)
SML Power (Example)	200	mW	Set at 4x the visible reaction threshold
Primary Outcome Metric	BCVA (Best-Corrected Visual Acuity)	ETDRS letters	Mean change from baseline to 24 months
Non-Inferiority Margin	±5	ETDRS letters	Equivalence margin for clinical relevance
Mean CRT (Baseline)	329.2 (SD 37.3)	µm	Central Retinal Subfield Thickness
Mean Treatments (SML)	2.4 (SD 1.7)	Sessions	Required over 24 months
Mean Treatments (SL)	1.9 (SD 1.2)	Sessions	Required over 24 months

Key Methodologies

The DIAMONDS trial utilized highly specific laser delivery protocols, emphasizing the need for precise beam control and thermal stability in the laser hardware:

SML System and Wavelength: Subthreshold micropulse laser was delivered using a 577 nm optically pumped diode laser (IRIDEX IQ 577™).
Standard Laser Systems: Standard Threshold Laser (SL) utilized conventional continuous wave lasers, such as Argon or frequency-doubled Nd:YAG (532 nm).
SML Power Titration: Power was titrated upwards, starting from 50 mW in 10 mW increments, until a barely visible tissue reaction was observed (threshold). The SML treatment power was then set at 4x this threshold (e.g., 200 mW).
Micropulse Mode Parameters: The SML was delivered using a 200 µm spot size, a 5% duty cycle, and a 200 ms total ‘on’ duration (composed of multiple 0.1 ms ‘on’ pulses separated by 1.9 ms ‘off’ time for retinal cooling).
SML Application Pattern: Applied confluently in three 7 x 7 spot grids 500 µm from the foveal center, plus additional treatment to areas of thickening.
SL Application Goal: Applied to achieve a mild grey-white burn beneath leaking microaneurysms, intentionally sparing the central 500 µm of the fovea.
Retreatment Protocol: Laser treatments could be repeated as needed, allowing retreatment of areas within 300-500 µm from the foveal center.

6CCVD Solutions & Capabilities

The DIAMONDS trial confirms the clinical viability of high-precision, thermally managed laser systems operating in the visible spectrum (532 nm and 577 nm) for DMO treatment. 6CCVD’s MPCVD diamond materials provide the essential foundation for optimizing the performance, reliability, and miniaturization of these advanced ophthalmic lasers.

Applicable Materials for Ophthalmic Laser Systems

The high thermal conductivity and broad optical transparency of MPCVD diamond are critical for managing the heat generated by high-power diode and Nd:YAG lasers, ensuring stable output and beam quality.

Application Requirement	6CCVD Material Recommendation	Key Benefit
High-Power Laser Windows/Optics	Optical Grade SCD (Single Crystal Diamond)	Ultra-low absorption at 532 nm and 577 nm, preventing thermal lensing and maintaining beam quality.
Diode Laser Heat Sinks	Thermal Grade PCD (Polycrystalline Diamond)	Unmatched thermal conductivity (> 2000 W/mK) for rapid heat dissipation, crucial for stabilizing 577 nm diode laser performance.
Output Couplers/Beam Splitters	Optical Grade SCD or High-Purity PCD	Excellent surface finish (Ra < 1 nm achievable) and high damage threshold for reliable long-term operation.
Miniaturized Systems	Thin SCD/PCD Wafers	Enables compact, high-efficiency laser modules required for portable or integrated ophthalmic devices.

Customization Potential for Laser Manufacturers

6CCVD provides bespoke manufacturing services tailored to the stringent requirements of medical laser engineering:

Custom Dimensions: We supply diamond plates and wafers up to 125mm in diameter (PCD) and large-area SCD, allowing for scalable production of optical components and heat sinks.
Precision Thickness Control: We offer SCD and PCD materials ranging from 0.1 µm to 500 µm for thin optical windows, and substrates up to 10 mm for robust thermal spreaders.
Advanced Polishing: Our internal capabilities ensure optical surfaces meet demanding specifications, achieving Ra < 1 nm for SCD optics and Ra < 5 nm for inch-size PCD heat sinks, minimizing scatter and absorption losses.
Integrated Metalization: We offer in-house metalization services (Au, Pt, Pd, Ti, W, Cu) for direct bonding of diamond heat sinks to active laser elements (e.g., 577 nm diode arrays) or for creating patterned electrodes on optical surfaces.

Engineering Support

The DIAMONDS trial highlights the trend toward non-ablative, high-repetition-rate laser therapies. This shift increases the demand for precise thermal management to ensure consistent pulse delivery and prevent component drift.

Thermal and Optical Design Consultation: 6CCVD’s in-house PhD team specializes in the thermal and optical properties of CVD diamond. We can assist engineers in selecting the optimal diamond material grade and geometry for high-power 532 nm and 577 nm ophthalmic laser projects, ensuring maximum efficiency and reliability.
Material Selection for Repeatability: Given that SML requires repeated sessions (mean 2.4 treatments), the long-term stability of the laser source is paramount. We provide materials engineered for superior thermal cycling resistance, ensuring consistent performance across the device lifetime.

For custom specifications or material consultation, visit 6ccvd.com or contact our engineering team directly.

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]
1985 - Photocoagulation for diabetic macular edema: early treatment diabetic retinopathy report number 1 [Crossref]
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]