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

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 13/142/04. The contractual start date was in April 2016. The draft report began editorial review in January 2022 and was accepted for publication in May 2022. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

Copyright © 2022 Lois et al. This work was produced by Lois et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2022 Lois et al.

Background

People with diabetes are at risk of experiencing permanent sight loss because of complications of diabetic retinopathy, including diabetic macular oedema (DMO), proliferative diabetic retinopathy (PDR), and macular ischaemia. 1

In DMO (Figure 1) fluid, and at times blood and lipid (fat), leaks from the retinal blood vessels, damaged by the chronically high glucose environment and its consequences, and builds up in the centre of the retina, the macula, the area responsible for central vision. As a result, the macular function is compromised, and the person’s sight is reduced.

FIGURE 1.

Infrared and optical coherence tomography (OCT) images of patients with and without diabetic macular oedema (DMO). (a) Infrared image and (b) optical coherence tomography (OCT) scan of the macula (left eye) of a patient with DMO. Fluid is observed as areas or reduced reflectance (arrows) on the OCT scan. For comparison, (c) infrared image and (d) OCT scan of the macula (right eye) of another patient in whom DMO cleared following treatment. The normal depression at the centre of the macula (fovea) is present (arrowhead).

Currently, depending on the amount of fluid present [this can be measured using a diagnostic technology called optical coherence tomography (OCT) (Figures 1b and 1d)], different treatment options are recommended for patients with DMO. If the amount of fluid is considerable [i.e. people with a central retinal subfield thickness (CRT), as measured with OCT, of ≥ 400 µm], the National Institute for Health and Care Excellence (NICE) recommends treatment with intravitreal eye injections of drugs; this is known as anti-vascular endothelial growth factor (anti-VEGF) therapy. 2,3 Anti-VEGF therapy is required monthly during the first year of treatment for most patients and at less frequent intervals thereafter, until the fluid clears. If the amount of fluid in DMO is less severe (a CRT of < 400 µm on OCT) macular laser treatment is recommended by NICE as the treatment of choice as, for this group, macular laser is as clinically effective as anti-VEGF therapy but less costly. 1,2,4 Macular laser is applied in a single session with topical anaesthetic drops; injections of local anaesthetic are not required as it causes no discomfort/pain to patients. The topical anaesthesia is used as to apply the laser, a viewing contact lens needs to be placed on the surface of the eye, so an appropriately magnified and sharp view of the macula is obtained to perform the treatment. Laser sessions may need to be repeated every 3–4 months until the fluid clears.

The first randomised clinical trial (RCT) that showed a benefit of laser treatment for people with diabetes and macular oedema was the Early Treatment Diabetic Retinopathy Study (ETDRS). 5 The ETDRS demonstrated that macular laser reduced the risk of visual loss (≥ 3 ETDRS line loss) by 50% at 3 years in patients with what was defined as clinically significant diabetic macular oedema (CSMO). 5 The definition of CSMO was based on the presence of the following characteristics on clinical examination (slit-lamp biomicroscopy): (1) thickening of the retina at or within 500 µm from the centre of the macula, (2) hard exudation at or within 500 µm from the centre of the macula provided that it was associated with adjacent retinal thickening or (3) thickening of the retina of the size of the optic nerve head or larger within one disc diameter from the centre of the macula. In the ETDRS only 3% of patients had improvement in vision of ≥ 15 letters, but 85% of eyes included in the study had excellent vision at baseline (Snellen equivalent ≥ 20/40) which may have accounted for the limited visual improvement observed. More recent RCTs on laser treatment for centre-involving DMO showed laser can indeed improve vision, with improvements of ≥ 10 ETDRS letters observed in 32% of eyes at 2 years and in 44% of eyes at 3 years. 6,7

It is important to note that centre-involving DMO may not necessarily mean CSMO. In regards to this, trials conducted comparing anti-VEGF therapy with macular laser included people with centre-involving DMO. Centre-involving DMO is defined based on OCT findings. The natural history of centre-involving DMO diagnosed by OCT is less clear than that of CSMO.

Macular laser is also used in patients with DMO who do not fully respond to anti-VEGF therapy. In a randomised trial comparing different anti-VEGF drugs to treat centre-involving DMO, 41–64% of eyes receiving anti-VEGF therapy required macular laser by 2 years following treatment initiation to control the disease. 8

In the ETDRS study,5 laser treatment was undertaken using a continuous wave laser. This laser [referred to as ‘threshold’ laser, and here, throughout this report, as standard threshold macular laser (SL)] produces a visible burn in the retina and is considered the ‘standard’ manner in which to perform macular laser. The laser energy when using this SL is predominantly absorbed by one of the layers of the retina, the retinal pigment epithelium (RPE), and converted into heat. Although the mechanism of action of macular laser is not completely understood, it is believed that it has its effect, at least partly, by acting on still viable RPE cells around the area of the burn. Given that heat spreads by conduction, there could be damage to the retinal layers overlying the RPE, including photoreceptor cells (i.e. the cones and rods which are the visual cells of the retina). SL can ‘burn’ the retina and, if applied to the centre of the fovea (the centre of the macula, which is the area of the retina that provides maximal central vision) could cause marked central sight loss. Therefore, this form of laser requires considerable expertise by the clinician administering it as the fovea may not be easily identifiable when thickened by DMO. Ideally, as advised by the ETDRS,5 a fundus fluorescein angiogram (FFA) would be performed to identify areas of leakage that should be aimed at by the laser treatment. However, clinicians may opt to use SL to treat areas of macular thickening as observed on OCT. 6,7 Side effects of SL, besides the potential burning of the fovea as explained above, could include paracentral scotomas (areas of loss of sight around the centre) which can potentially affect driving ability, colour vision deficits and formation of scarring over or under the retina (i.e. epiretinal membrane/subretinal fibrosis, respectively). If strong laser is applied close to the centre of the macula, the size of the ‘burn’ (i.e. the area where retinal cells are lost) could expand over time and, even if initially the centre is not affected, central loss of vision could occur over time.

Macular laser treatment can also be delivered using what is called ‘subthreshold’ micropulse laser (SML). In SML, a series of repetitive, very short pulses of laser are delivered, with each pulse of active ‘on’ laser separated by a long ‘off’ time. This ‘off’ time allows for cooling of the retina, preventing the development of a ‘burn’ and, thus, leaving the RPE and overlying neurosensory retina, including photoreceptors, intact. It is believed SML acts by directly stimulating the RPE. As there is no destruction of the retina, this treatment could be applied to larger areas of the retina (not only those with ‘leaking’ blood vessels or thickened by DMO) in a standardised fashion and repeated as many times as needed.

Although the lack of a ‘burn’ in the retina would appear to be of clear advantage, the absence of clinically objective changes in the retina following SML has led to some clinicians/researchers being sceptical of SML having equally beneficial effects as SL. Earlier studies, however, including small RCTs, have shown comparable or superior results using SML. Lavinsky et al. 9 showed superiority regarding improvement in vision and reduction in CRT at 12 months following high-density SML in a three-arm trial that included 123 participants with CSMO (n = 42 and n = 39 randomised to high-density and low-density SML, respectively; and n = 42 to SL). Similarly, in a smaller RCT which included 62 eyes from 50 patients with centre-involving CSMO (32 eyes received SML and 30 eyes received SL) Vujosevic et al. 10 found no statistically significant differences in vision or CRT between laser groups, but a statistically significant increased retinal sensitivity (i.e. better retinal function) on microperimetry testing following SML. Other trials by Figueira et al. (n = 53 patients with CSMO according to the ETDRS definition),11 Venkatesh et al. 12 (n = 33 patients with CSMO), Kumar et al. 13 (n = 20 patients with CSMO according to ETDRS criteria) and Laursen et al. 14 (n = 16 patients with CSMO), with follow-up of 18 weeks and 8, 12 and 5 months, respectively, found no statistically significant differences in vision and CRT between both types of laser. A more recent RCT by Xie et al. 15 which included 84 patients (99 eyes) receiving standard argon laser (n = 49 eyes) or SML (n = 50 eyes) also found comparable results between laser groups.

In a systematic review and meta-analysis by Chen et al. ,16 which included all but one (Kumar et al. 13) of the RCTs mentioned above, and based on data from 398 eyes (203 eyes in the SML group and 195 in the SL group), SML was found to be statistically significantly superior to SL in terms of mean change of best-corrected visual acuity (BCVA) at 3, 9 and 12 months following treatment, with no statistically significant difference in change in CRT. The largest difference in BCVA between laser arms was observed at 12 months (0.1 log-MAR) favouring SML, but this seemed to be due to the effect of one trial (Lavinsky et al. 9), and to the high-density arm of this trial; the difference would not be considered, in any case, clinically important (0.1 log-MAR, equivalent to 5 ETDRS letters).

Qaio et al. 17 subsequently published another systematic review comparing SML laser with SL, which included seven RCTs, all six included in Chen et al. ’s review16 and, in addition, the study by Kumar et al. ,13 with a total of 467 eyes from 379 participants. The primary outcomes were change in BCVA and CRT. Secondary outcomes included contrast sensitivity and retinal damage; neither quality of life nor cost-effectiveness of the treatments were evaluated. Meta-analysis found no statistically significant differences in outcomes at any time point (longest follow-up was 12 months). There was comparable preservation of contrast sensitivity with SML with less retinal damage. The review authors concluded that SML was as good as SL but caused less retinal damage.

The results of the review by Qiao et al. 17 differ somewhat from those of Chen et al. 16 owing to the choice of arm and outcome from the RCT conducted by Lavinsky et al. 9 The review by Qiao et al. 17 reported mean BCVA at 12 months with three trials, Figueira et al.,11 Lavinsky et al.,9 and Vujosevic et al.,10 whereas the review by Chen et al. 16 reported change from baseline with only two trials at 12 months, Lavinsky et al. 9 and Vujosevic et al. 10 The Lavinsky et al. 9 RCT had two SML arms, one with normal and another with high-density SML treatment, and reported better results with the latter. The Chen et al. 16 meta-analysis used only the high-density arm whereas the Qiao et al. 17 meta-analysis used only the normal density arm. Their different conclusions were due to the Lavinsky et al. trial,9 deemed to give a significant result in Chen et al. 16 (based on change from baseline) but not in Qiao et al. 17 (based on mean BCVA at 12 months).

A Bayesian network meta-analysis by Wu et al. 18 found no significant difference in mean change in BCVA and CRT between SL and SML. A 2018 Cochrane systematic review19 and meta-analysis by Jorge et al. concluded SML may be as effective as SL, but the GRADE (Grading of Recommendations Assessment, Development and Evaluation) assessment was of low certainty.

All conducted meta-analyses were limited by the inherent limitations of the available RCTs, including the short follow-up (longest follow-up of 12 months). Furthermore, it is unclear what the proportion of participants with a CRT of < 400 µm was in the RCTs included, which based on NICE guidelines would be the participants most likely to respond to macular laser. 1,2,4

Recently (and thus not included in any of the systematic reviews mentioned above) a small (68 participants, 34 in each group), very short-term (4 months) RCT by Fazel et al. 20 compared SML with SL in people with CSMO and with a CRT of less than 450 µm. Changes in CRT were statistically significantly higher in the SML group than the SL group. Changes in macular volume and visual acuity were only significant in the SML group but not in the SL group.

In summary, published data suggest that SML is comparable, and potentially even superior, to SL, but stronger evidence is required. None of the trials conducted comparing SML and SL included patient-reported outcome measures (PROMs) or the cost-effectiveness of the treatments. Furthermore, outcomes were measured, at the longest, at 12 months. Given the lack of destruction of retinal tissue, SML can be given to larger areas of the macula and repeated as needed, potentially indefinitely. SML may allow for a more standardised delivery of treatment (e.g. using set grids that cover the entire macula), which could, in turn, minimise variability in the quality of treatment delivered, with successful delivery being less dependent on the surgeon’s skills. The lack of deleterious effects when used over the fovea21 makes SML very safe (i.e. sight loss as a result of an inadvertent foveal burn is obviated), potentially facilitating training on its application to junior ophthalmologists and ophthalmic-allied non-medical staff. This would be highly advantageous considering the major problems with capacity currently faced in ophthalmic clinics throughout the world.

On this basis, the DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial was designed as a non-inferiority trial of the efficacy of SML when compared with SL, although the trial was also powered to test equivalence and superiority (if this were to exist). We chose central vision as the primary outcome, as this is very important to people with diabetes and DMO, and set the non-inferiority margin at 5 ETDRS letters (equivalence margin as ± 5 ETDRS letters), as visual changes of this size should not be clinically relevant to patients and could even be due to test/re-test variability.

Aims

The DIAMONDS trial aimed to evaluate the clinical effectiveness and cost-effectiveness of SML when compared with SL for the treatment of patients with centre-involving DMO with a CRT on spectral domain optical coherence tomography (SD-OCT) of < 400 µm.

Primary objective

The primary objective of the trial was to determine whether or not SML is non-inferior (or equivalent) to SL at improving or preserving vision 24 months after treatment in patients with centre-involving DMO with a CRT of < 400 µm. The non-inferiority margin was set at 5 ETDRS letters (and the equivalence margin at ± 5 ETDRS letters), as a difference of this size is not considered to be clinically relevant and could even be due to test/re-test variability. 2,3,8,24–26

Secondary objectives

The secondary objectives of the trial were to determine whether or not SML is superior to SL at improving or preserving binocular vision and visual field; reducing or clearing DMO; allowing treated patients to achieve driving standards; and improving their health- and vision-related quality of life 24 months after treatment. The relative cost-effectiveness of SML when compared with SL was also evaluated, as well as the side effects of these treatments, the number of laser treatments required and the need for additional treatments (other than laser).

Trial design

The protocol for the DIAMONDS trial was published in February 2019. 22 The DIAMONDS trial was a pragmatic, multicentre, allocation-concealed, non-inferiority, randomised, double-masked (participants and outcome assessors), prospective clinical trial set within specialist hospital eye services (HES) (n = 16) in the UK.

Patient eligibility and recruitment

Potential participants were identified at each of the participating sites through electronic databases, through referrals to HES or while in the clinic. Patients identified through electronic databases or referrals were approached by telephone or invitation letter. Verbal and written information about the study was given to potential participants. Informed consent was obtained from patients willing to take part in the trial and they were subsequently recruited. Patients identified while in the clinic were verbally informed about the study and given a patient information leaflet. They were given time to think about their participation and ask questions. If they wished to be enrolled on the same day, they were recruited into the trial following informed consent. If they wanted more time to think about their potential participation, a further visit was organised and, if they were willing to participate at this visit, they were recruited.

Inclusion criteria

Inclusion criteria for the trial were centre-involving DMO, as determined by slit-lamp biomicroscopy and SD-OCT, in one or both eyes, with either (1) a CRT of > 300 µm but < 400 µm in the central subfield (central 1 mm) owing to DMO as determined by SD-OCT, or (2) a CRT of < 300 µm provided that intraretinal and/or subretinal fluid was present in the central subfield (central 1 mm) owing to DMO.

The following conditions also had to be met:

• visual acuity of > 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent > 20/320)

• amenable to laser treatment, as judged by the treating ophthalmologist

• aged ≥ 18 years.

Exclusion criteria

A patient’s eyes were not eligible for the study if their macular oedema was owing to causes other than DMO or if their eyes met the following criteria:

• ineligible for macular laser, as judged by the treating ophthalmologist

• DMO with a CRT of ≥ 400 µm

• active PDR requiring treatment

• received intravitreal anti-VEGF therapy within the previous 2 months

• received macular laser treatment within the previous 12 months

• received intravitreal injection of steroids

• cataract surgery within the previous 6 weeks

• panretinal photocoagulation (PRP) within the previous 3 months.

In addition, patients who were otherwise eligible were not included in the study if they met the following criteria:

• on pioglitazone (Actos^®, Takeda UK Ltd.), and the drug could not be stopped 3 months before joining the trial and for its entire duration (because this drug could be responsible for the presence of macular oedema)

• chronic renal failure requiring dialysis or kidney transplant

• any other condition that in the opinion of the investigator would preclude participation in the study (such as unstable medical status or severe disease that would make it difficult for the patient to complete the study)

• very poor glycaemic control that required their starting intensive therapy within the previous 3 months

• using an investigational drug.

If both eyes were eligible, both eyes would receive the same type of laser but one was designated as the ‘study eye’. This was the eye with the best BCVA at randomisation or, if vision was the same in both eyes, the eye with the lesser CRT.

If the fellow eye was not eligible, baseline data and information on whether or not participants developed DMO or PDR in this eye during the study and about treatments administered to it were recorded in the patient’s case report form (CRF) at months 12 and 24 to determine any possible effects of these events on outcomes.

The DIAMONDS trial participants were similar to those enrolled in the original ETDRS5 in that, like those enrolled in ETDRS, they had mild to moderate non-proliferative diabetic retinopathy and had a visual acuity of 20/200 or better. As mentioned above, ETDRS was the first trial demonstrating the clinical effectiveness of macular laser for the treatment of DMO. However, unlike in ETDRS, DIAMONDS trial participants did not necessarily have to have CSMO to be enrolled, as per ETDRS definition, and they could have only centre-involving DMO as determined using SD-OCT, a technology not available at the time ETDRS was conducted. This follows standard clinical practice.

Ethics approval and consent

The protocol for the DIAMONDS trial22 was approved by the Office for Research Ethics Committees Northern Ireland (ORECNI) (15/NI/0197). A Clinical Trial Authorisation (CTA) was obtained from the Medicines and Healthcare products Regulatory Agency (MHRA) (32485/0029/001–0001). The trial was registered with the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database (2015-001940-12), in the International Standard Randomised Controlled Trial Number (ISRCTN) register (ISRCTN16962255), and at clinicaltrials.gov (NCT03690050).

Interventions

Patients were randomised to one of two groups: (1) 577 nm SML or (2) SL [e.g. argon, frequency-doubled neodymium-doped yttrium aluminium garnet (Nd:YAG) 532 nm laser]. Application of the allocated laser was in accordance with the processes described in Micropulse laser and Standard laser. Information on laser type, parameters used and time spent applying the treatment was recorded in the patient’s CRF. In participants with both eyes eligible and included in the trial, both study eye and fellow eye received the same type of laser (i.e. the type randomly allocated).

Randomisation and masking

Patient assessments

Patients were assessed during the study according to the schedule of assessments shown in Table 1.

Participants’ BCVA was measured in both eyes using ETDRS visual acuity charts at 4 m at baseline and at months 4, 8, 12, 16, 20 and 24. BCVA was obtained following refraction at baseline and at 12 and 24 months by optometrists masked to treatment allocation. At all other visits, BCVA could be obtained by other masked staff using the most recently obtained refraction. Binocular BCVA was obtained to give an indication of the person’s vision ‘in real life’, using both eyes (i.e. with both eyes opened simultaneously). It was obtained by masked optometrists using the ETDRS visual acuity charts at 4 m at baseline and at 12 and 24 months. A refraction protocol was followed by the optometrists to obtain BCVA. ETDRS visual acuity scores were recorded for study and fellow eyes in the patient’s CRF at each study visit.

Testing of the 10–2 Humphrey visual field was performed in the study eye (and the fellow eye if this was included in the trial) by a visual field technician masked to the allocated treatment at baseline at 12 and 24 months. An Esterman binocular visual field (to determine the patient’s ability to fulfil driving standards) was obtained at the same time points. Visual fields eligible for analysis had to achieve pre-defined reliability criteria (false positives < 15%). If the visual fields were not reliable, they were repeated. The mean deviation (MD) value for the 10–2 Humphrey visual fields and the number of points seen and missed for the Esterman binocular visual fields were recorded in the patient’s CRF.

Participants’ CRT, as determined using SD-OCT, was obtained in both eyes at baseline and at months 4, 8, 12, 16, 20 and 24. SD-OCT was obtained by technicians, photographers or nurses, as per standard clinical practice at each of the participating centres, who were masked to the treatment allocation. The measure of thickness at the central 1 mm (i.e. CRT) was recorded in the patient’s CRF and used for analysis. Total and maximal macular volume were also recorded in the CRF. Presence or absence of intraretinal or subretinal fluid was determined in a masked fashion at the 24-month follow-up visit by masked readers at the Central Administrative Research Facility (CARF) at Queen’s University Belfast. Images sent to CARF were anonymised. The Heidelberg Spectralis SD-OCT (Heidelberg Engineering GmbH, Heidelberg, Germany) was used to obtain the CRT measurements for each participant at baseline and at each follow-up visit, unless for any reason, this was not possible.

Two vision-related quality of life tools, the National Eye Institute Visual Function Questionnaire – 25 (NEI-VFQ-25) and the Vision and Quality of Life Index (VisQol), were used in the DIAMONDS trial, in addition to a generic preference-based health-related quality of life measure to generate utility data [the EuroQol-5 Dimensions, five-level version (EQ-5D-5L)]. Questionnaires were self-completed by patients at baseline and at 12 and 24 months. Baseline questionnaires were completed before the first session of laser treatment.

Participants were followed up at 4-month intervals following laser treatment for a total of seven visits. Additional visits (interim visits) took place, if required. To maximise retention, the DIAMONDS trial was designed as a pragmatic trial, with the 4-monthly visits being akin to those in usual, routine care. In most visits, with the exception of those at baseline and at 12 and 24 months, the tests were the same as those done in routine care (i.e. a measure of visual acuity and SD-OCT scans). Consent was also obtained from the participants to allow for an evaluation of longer-term patient outcomes (at 5 years), which would be subject to a future funding application.

Outcomes

The primary outcome was the difference between treatment groups in the mean change in BCVA in the study eye from baseline to month 24.

The secondary outcomes comprised the following:

• mean change in binocular BCVA from baseline to month 24

• mean change in CRT in the study eye, as determined by SD-OCT, from baseline to month 24

• mean change in the MD of the Humphrey 10–2 visual field in the study eye from baseline to month 24

• change in the percentage of people meeting driving standards from baseline to month 24

• mean change in EQ-5D-5L, NEI-VFQ-25 and VisQoL scores from baseline to month 24

• cost per quality-adjusted life-year (QALY) gained

• adverse effects

• number of laser treatments carried out

• additional treatments required (other than laser).

Data collection and management

Case report forms were used to collect data for each participant in the DIAMONDS trial. On-site monitoring visits during the trial checked the accuracy of entries on CRFs against the source documents and adherence to the protocol and procedures, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use – Good Clinical Practice (ICH-GCP) guidelines, and regulatory requirements. Monitoring visits were undertaken by a monitor from the Northern Ireland Clinical Trials Unit (NICTU). To ensure accurate, complete and reliable data were collected, the chief investigator and the NICTU provided training to site staff through investigator meetings and site initiation visits.

Adverse events

The safety of the treatment was assessed at each visit by noting any complications during or after laser treatment, including self-reported visual disturbances, and an ETDRS visual acuity loss of ≥ 10 letters and ≥ 15 letters occurring from visit to visit. Patients were asked specifically about reduced colour vision, presence of paracentral scotomas or distortion (‘waviness’ of straight lines) at each visit and responses were recorded in the appropriate CRF. Although serious adverse events (SAEs) related to the study procedures were unlikely to occur as a result of any of the study procedures (see below), all SAEs were recorded on the patient’s CRF and the sponsor and the Research Ethics Committee were informed of these. The DMEC was also provided with information on all SAEs on a routine basis.

As the DIAMONDS trial did not investigate medicinal products, adverse event reporting followed the Health Research Authority guidelines on safety reporting in non-Clinical Trials of Investigational Medicinal Products (non-CTIMP) studies. Adverse events (AEs) and SAEs were recorded on the patient’s CRF and the information was updated with the date and time of resolution or confirmation that the event was due to the participant’s illness when this information became available.

An AE was defined as any untoward medical occurrence in a participant in a research study, including occurrences which were not necessarily caused by or related to the study. AEs relating to pre-existing underlying diseases were not recorded in the DIAMONDS trial.

A SAE was defined as an untoward occurrence that met one or more of the following criteria:

• resulted in death

• was life-threatening

• required hospitalisation or prolongation of existing hospitalisation

• resulted in persistent or significant disability or incapacity

• consisted of a congenital anomaly or birth defect

• was otherwise considered medically significant by the investigator.

Hospitalisation was defined as an inpatient admission regardless of length of stay, even if the hospitalisation was a precautionary measure for continued observation. Hospitalisations for a pre-existing condition, including elective procedures, did not constitute a SAE.

Statistical methods for effectiveness analyses

Health economics methods

Trial management

The chief investigator had overall responsibility for the conduct of the DIAMONDS trial. The chief investigator and NICTU undertook trial management including clinical trial applications (Ethics and Research Governance), site initiation and training, monitoring, analysis and reporting. The trial co-ordinator was responsible on a day-to-day basis for overseeing and co-ordinating the work of the multi-disciplinary trial team and was the main contact between the trial team and other parties. Before the DIAMONDS trial started, site training ensured that all relevant essential documents and trial supplies were in place and that site staff were fully aware of the study protocol and procedures. The following trial committees were established.

Sponsor

The Belfast Health and Social Care Trust (BHSCT) was the sponsor for the DIAMONDS trial.

Reporting

The reporting of the DIAMONDS trial follows the Consolidated Standards of Reporting Trials (CONSORT) guidelines45 and guidelines on reporting for equivalence and non-inferiority trials. 46

Changes in trial methodology since trial conception

There were no changes made in the design, outcomes or conductance of the DIAMONDS trial after trial commencement.

Participating sites and characteristics of DIAMONDS trial participants

Table 2 lists the 16 participating sites, the date when they were opened to recruitment and the total number of participants screened and recruited at each site.

Participants

Participant flow

The CONSORT flow diagram in Figure 2 details the flow of patients through the DIAMONDS trial.

FIGURE 2.

Participant flow in the DIAMONDS trial. a, Total number of reasons can be greater than number of patients excluded as patients can have multiple exclusion reasons; b, n = 1 patient withdrew permission for their data to be used and will not be included in any analysis going forward. Reproduced with permission from Lois et al. 47 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The figure above includes minor additions and formatting changes to the original figure.

Reproduced with permission from Lois et al. 47 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The figure above includes minor additions and formatting changes to the original figure.

Patient recruitment took place between 18 January 2017 and 20 November 2018. A total of 336 participants were assessed for eligibility and 266 (79%) of those assessed as eligible agreed to join the trial and were randomised (intervention, n = 133; control, n = 133). One participant withdrew consent for their data to be used and was excluded from all analyses. The first month 24 follow-up visit was conducted on 25 January 2019 and the final month 24 follow-up visit was conducted on 22 December 2020. Recruitment was initially due to be completed by April 2018 but, at that time, the recruitment of participants had not been completed. An extension was subsequently approved to extend this timeline until December 2018; recruitment was then completed. The cumulative patient recruitment against the anticipated pre-trial sample size is shown in Figure 3.

FIGURE 3.

Patient recruitment.

Primary outcome: mean change in best-corrected visual acuity in the study eye at 24 months after treatment

The primary analysis was PP and included all participants who satisfied the PP criteria and had BCVA data at baseline and month 24. Of the 265 participants randomised (excluding the single patient that fully withdrew consent for their data to be used), primary outcome data were available for 87% (n = 231; SML, n = 116 and SL, n = 115).

The primary outcome was the mean change in BCVA in the study eye from baseline to month 24. The difference between lasers in change in BCVA (with a 95% CI) from baseline to month 24 (primary endpoint) was compared with the permitted maximum difference of 5 ETDRS letters (0.1 log-MAR) in the non-inferiority analysis. The mean change in BCVA in the study eye from baseline to month 24 was –2.43 ETDRS letters (SD 8.2 ETDRS letters) in the SML group and –0.45 ETDRS letters (SD 6.72 ETDRS letters) in the SL group. The difference in the mean change in BCVA in the study eye from baseline to month 24 was –1.98 ETDRS letters (95% CI –3.9 to –0.0 ETDRS letters; p = 0.046), which although statistically significant was not clinically relevant. Therefore, SML was deemed to be non-inferior to SL because the lower limit of the 95% confidence interval of the treatment difference (–3.9 ETDRS letters) was above the non-inferiority margin (–5.0 ETDRS letters). Furthermore, SML was also deemed equivalent to SL as the 95% CI (–3.9 to –0.0 ETDRS letters) was wholly within both the upper and lower margins of the permitted maximum difference (–5.0 to 5.0 ETDRS letters). An ITT analysis was also undertaken, which supported the findings from the PP analysis. Table 6 displays the analysis results for the primary outcome for both the PP and ITT analyses.

TABLE 6 - Primary outcome (observed values)

Number of patients with BCVA data available at baseline and month 24.

p-value from independent two-sample t-test.

Note

Reproduced with permission from Lois et al. 47 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The table above includes minor additions and formatting changes to the original table.

Analysis	Mean change in BCVA in the study eye from baseline to month 24 (ETDRS letters), mean (SD)		Difference in ETDRS letters (95% CI)	p-valueb
	SML group (n = 116a)	SL group (n = 115a)
PP analysis	–2.43 (8.20) [n = 115]	–0.45 (6.72)	–1.98 (–3.9 to –0.0)	0.046
ITT analysis	–2.41 (8.16)	–0.45 (6.72)	–1.96 (–3.9 to –0.0)	0.047

Figure 4 shows graphically the non-inferiority margin of –5 ETDRS letters; the shaded area represents the equivalence zone. It illustrates that the 95% CIs from both the PP and ITT analyses lay wholly within the equivalence zone and were also above the non-inferiority margin of –5 ETDRS letters.

FIGURE 4.

Primary outcome (observed values). Dashed line represents the non-inferiority margin and shaded area represents the equivalence zone. PP difference is –1.98 ETDRS letters (95% CI –3.93 to –0.035 ETDRS letters); ITT difference is –1.96 ETDRS letters (95% CI –3.90 to –0.022 ETDRS letters).

In accordance with the statistical analysis plan, the primary outcome was also adjusted for baseline BCVA score, baseline CRT, and previous cataract surgery in the study eye prior to enrolment in the trial as well as the minimisation factors on both the PP and the ITT populations. These results support the findings from the unadjusted analyses in Table 6. The adjusted mean change in BCVA in the study eye from baseline to month 24 was –2.36 ETDRS letters (SE 0.67 ETDRS letters) in the SML group and –0.53 ETDRS letters (SE 0.67 ETDRS letters) in the SL group. The difference of –1.84 ETDRS letters (95% CI –3.72 to 0.047 ETDRS letters; p = 0.056) was found to be neither statistically significant nor clinically important.

Table 7 displays the analysis results for the primary outcome, for both PP and ITT analyses, after adjusting for baseline BCVA score, baseline CRT, cataract surgery in the study eye prior to enrolment in the trial, and the following minimisation factors/covariates: centre, distance BCVA at baseline, previous use of anti-VEGF therapies and previous use of macular laser in the study eye.

TABLE 7 - Primary outcome adjusted analyses

Number of patients with BCVA data available at baseline and month 24.

ANCOVA adjusted for baseline BCVA score, baseline CRT and the following minimisation factors/covariates: centre; a distance BCVA at baseline of ≥ 69 ETDRS letters (Snellen equivalent of ≥ 20/40; log-MAR ≥ 0.3) or 24–68 ETDRS letters (Snellen equivalent ≤ 20/50; log-MAR 0.4–1.2); previous use of anti-VEGF therapies in the study eye; and previous use of macular laser in the study eye. Change in BCVA from baseline to month 24 was also adjusted for the occurrence of cataract surgery in the study eye and sensitivity analyses (see Sensitivity analyses) examined the impact of visits outside the scheduled time window.

Note

Reproduced with permission from Lois et al. 47 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The table above includes minor additions and formatting changes to the original table.

Adjusted analysis	Mean change in BCVA in the study eye from baseline to month 24 (ETDRS letters), mean (SE)		Difference in ETDRS letters (95% CI)b	p-value
	SML group (n = 116a)	SL group (n = 115a)
PP analysis	–2.36 (0.67) [n = 115]	–0.53 (0.67)	–1.84 (–3.7 to 0.0)	0.056
ITT analysis	–2.34 (0.66)	–0.53 (0.66)	–1.81 (–3.7 to 0.1)	0.058

A secondary analysis was performed on the subset of participants with both eyes included in the trial (Table 8), including study eye as a random effect within the mixed model. The mean change in BCVA in both eyes from baseline to month 24 was –2.34 ETDRS letters (SE 8.10 ETDRS letters) in the SML group and –0.52 ETDRS letters (SE 6.81 ETDRS letters) in the SL group. The difference of –1.82 ETDRS letters (95% CI –2.42to –1.23 ETDRS letters; p = < 0.001) was statistically significant but is not considered clinically important.

TABLE 8 - Primary outcome secondary analysis (PP population)

Results from study eye and fellow eye included in this analysis. Eye (study eye/fellow eye) included as a random effect within the mixed model.

n value is the number of eyes rather than number of patients.

Note

Reproduced with permission from Lois et al. 47 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The table above includes minor additions and formatting changes to the original table.

Primary outcome	Mean change in BCVA in both eyesa from baseline to month 24 (ETDRS letters), mean (SD)		Difference in ETDRS letters (95% CI)	p-value
	SML group (n = 119b)	SL group (n = 123b)
PP analysis	–2.34 (8.10)	–0.52 (6.81)	–1.82 (–2.42 to –1.23)	< 0.001

Overview of the health economics analysis

The protocol for the DIAMONDS trial22 envisaged that economic modelling might be required if visual outcomes differed between treatment groups. However, the protocol was designed to minimise any visual loss. As per standard clinical practice, laser treatment was repeated following the initial session at the discretion of the treating ophthalmologists if it was felt to be required. Similarly, as per standard clinical care, rescue treatment with anti-VEGF therapy was allowed if rescue criteria were met. Intravitreal steroid injections could also be used if needed, at the discretion of the treating ophthalmologist.

Subthreshold micropulse laser was found to be not only non-inferior but indeed equivalent to SL. Thus, modelling was not required. This chapter provides the results from the within-trial cost-effectiveness analysis comparing SML with SL. The chapter presents (1) missing data by treatment group, (2) resource use and economic costs for different health resource categories, (3) health outcomes (EQ-5D-5L utility, NEI-VFQ-25 and VisQoL scores) and (4) cost-effectiveness results of the base-case and sensitivity analyses.

Results of the health economics analysis

National Eye Institute Visual Functioning Questionnaire – 25 and Vision and Quality of Life Index outcomes

The VisQoL analysis showed no statistically significant differences in utility scores between the two treatment groups for any of the VisQoL dimensions at any follow-up time point (see Appendix 1, Table 28). Similar results were observed for the NEI-VFQ-25 subscales (Figures 5 and 6, and Appendix 1, Table 29). Overall baseline (pre laser treatment) utility scores from analysis of all six VisQoL dimensions and NEI-VFQ-25 subscales are detailed in Appendix 1, Tables 28 and 29 and in Report Supplementary Materials 3 and 4. The tables show that there are no statistically significant differences in utility scores for the VisQoL or the NEI-VFQ-25 subscales between baseline and 24 months.

FIGURE 5.

The baseline NEI-VFQ-25 subscale and composite scores in participants treated with SML vs. SL.

FIGURE 6.

The NEI-VFQ-25 subscale and composite scores in participants treated with SML vs. SL at 24 months.

Cost-effectiveness analysis

The cost-effectiveness results are presented in Table 19 with the SL group as the referent and the SML group as the comparator (i.e. SML minus SL) for the estimation of ICER values. The time horizon is the 24-month follow-up period of the trial. The joint distributions of costs and outcomes for the base-case analysis are represented in Figures 7 and 8.

TABLE 19 - Cost-effectiveness analysis: cost (£, 2020) per QALY for SML compared with SL

Adjusted for baseline EQ-5D-5L utility, BMI and minimisation variables at baseline (BCVA and previous use of laser treatment).

Scenario	SML vs. SL		ICER	Probability of cost-effectiveness			NMB (£)
	Incremental cost (£), mean (95% CI)	Incremental QALYs, mean (95% CI)		At £15,000/QALY	At £20,000/QALY	At £30,000/QALY	At £15,000/QALY	At £20,000/QALY	At £30,000/QALY
Base-case analysis
ITT approach: imputed attributable costs and QALYs, covariate adjusteda	–365 (–822 to 93)	0.008 (–0.059 to 0.075)	SML dominant	0.80	0.763	0.716	479 (–652 to 1610)	520 (–925 to 1965)	600 (–1495 to 2695)
Sensitivity analyses
PP approach: imputed attributable costs and QALYs, covariate adjusteda	–374 (–830 to 83)	0.0077 (–0.056 to 0.072)	SML dominant	0.811	0.773	0.724	483 (–606 to 1572)	521 (–868 to 1910)	598 (–1413 to 2609)
25% reduction in anti-VEGF costs	–327 (–729 to 75)	0.008 (–0.059 to 0.075)	SML dominant	0.789	0.751	0.706	422 (–676 to 1520)	463 (–954 to 1880)	543 (–1529 to 2615)
25% increase in anti-VEGF costs	–402 (–922 to 118)	0.008 (–0.059 to 0.075)	SML dominant	0.811	0.774	0.726	536 (–634 to 1706)	577 (–902 to 2056)	657 (–1464 to 2778)

FIGURE 7.

Cost-effectiveness scatterplot with 95% confidence ellipses at 24 months for the base case. Imputed, additionally controlled for baseline utilities and minimisation variables (previous use of anti-VEGF therapy and previous laser treatment).

FIGURE 8.

Cost-effectiveness acceptability curves at 24 months for base case. Imputed, additionally controlled for baseline utilities and baseline minimisation variables.

Discussion

Total costs were higher in the SL group, but the difference seemed to be driven by a higher number of anti-VEGF rescue injections, largely owing to five patients in the SL group having 10 or more injections. The CI around total costs were wide and overlapped, so findings should be interpreted with caution. There was no statistically significant difference in EQ-5D-5L scores and no clinically relevant difference on visual outcomes; SML and SL were found to be clinically equivalent.

Statement of principal findings

The DIAMONDS trial was a pragmatic, allocation-concealed, multicentre, randomised, non-inferiority clinical trial (but powered to detect equivalence and superiority, if it were to exist) in which outcome assessors and participants were masked to treatment allocation. The DIAMONDS trial recruited in full, for a total of 266 participants with 133 participants allocated to each laser group; one participant in the SL group withdrew consent for their data to be used and thus 265 participants were included in the analysis. Despite the COVID-19 pandemic, which occurred during the second year of follow-up for most participants, primary outcome data (measured at 24 months from trial initiation) was available in the majority of participants: 116 (87%) and 115 (86%) in the SML group and SL group, respectively. Participants were predominantly white males with uncontrolled (mean HbA_1c of 8.5%) type 2 diabetes and were mostly overweight, obese, or morbidly obese. Participants had a mean age of 62 years, a mean duration of DMO diagnosis of 2.5 years, a mean BCVA of 80 letters (6/7.5 Snellen Equivalent) and a mean CRT of 329.2 µm on SD-OCT.

Best-corrected visual acuity was selected as the primary outcome in the DIAMONDS trial. Central vision is very important to people with diabetes as it is used in many tasks including recognising faces and reading (many people with diabetes need to read medication labels and instructions specifying, for example, the amount of insulin needed for their treatment). The non-inferiority margin of 5 ETDRS letters (equivalence margin of± 5 ETDRS letters) was chosen as changes within this range are not considered to be clinically relevant and could be the result of test/re-test variability. The DIAMONDS trial found SML to be equivalent to SL, with an adjusted mean change in BCVA in the study eye from baseline to month 24 of –2.36 ETDRS letters (SE 0.67 ETDRS letters) in the SML group compared with –0.53 ETDRS letters (SE 0.67 ETDRS letters) in the SL group (mean difference –1.84 ETDRS letters, 95% CI –3.72 to 0.05 ETDRS letters; p = 0.056).

There were no statistically significant differences in the pre-defined secondary outcomes with the exception of the number of laser treatments performed, which was slightly higher (less than one further session) in the SML group. This finding appeared to be driven, however, by a small number of participants (n = 13) that required a larger number of laser treatments in the SML group. Most participants (approximately 80% and 90% of participants in SML group and SL group, respectively) required 1–3 laser sessions throughout the 2-year period (see Appendix 1, Table 30).

A similar number of participants in each laser treatment group (approximately one-third) met eligibility criteria to receive rescue treatment at any time during the 2-year period of the study. Fewer participants, however, actually received rescue treatment [24 (18%) in the SML group and 28 (21%) in the SL group; odds ratio 0.78, 95% CI 0.42 to 1.45; p = 0.44 and percentage point difference –2.8, 95% CI –13.1 to 7.5; p = 0.59]; all received anti-VEGF therapy and one, in the SL group, received intravitreal steroids in addition. Most participants maintained good vision throughout the trial, with only a small proportion [25 (9%) participants: 17 (13%) in the SML group and 8 (6%) in the SL group] experienced a drop of 10 ETDRS letters (which would be considered a clinically relevant change) from baseline to month 24 (see Appendix 1, Tables 31–33). Similarly, most participants (over 95% for each type of laser) met driving standards at the 24-month trial visit. Meeting driving standards was identified at the time of trial conception by the DIAMONDS PPI group and in consultation with patients with diabetic retinopathy and DMO to be very important to people with diabetes; as a result this was one of the secondary outcomes investigated. The DIAMONDS PPI group contributed not only to the design of the trial, elaboration of participant-related materials and planning of recruitment strategies, but also to the interpretation and dissemination of findings.

Most participants maintained good HRQoL and vision-related quality of life throughout the trial period. The total cost of the treatment, including the laser (first session and subsequent laser sessions), any additional treatments required and follow-up for the 2 years was £897.83 and £1125.66 for the SML group and SL group, respectively.

The DIAMONDS trial was designed as a pragmatic trial. 49 On its conception, we followed the PRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary 2) tool50 to ensure as much as possible that trial results would be generalisable and reproducible in clinical practice if implemented in the NHS.

Published randomised trials and systematic reviews comparing subthreshold micropulse laser with standard laser

We carried out a literature review at the time the DIAMONDS trial was designed. In addition, we ran auto-alerts during the duration of the trial, up to January 2021, to identify studies that could be pertinent to the DIAMONDS trial. We then extended the searches up to December 2021. We found six systematic reviews comparing SML with SL published since 2016: Chen et al. ,16 Qiao et al. ,17 Wu et al. ,18 Jorge et al. ,19 Scholz et al. 51 and Blindbaek et al. 2018. 52 These were quality assessed using the National Institutes of Health (NIH) checklist (see Appendix 1, Table 34). 53 Based on this, four of these reviews (Chen et al. ,16 Jorge et al. ,19 Qiao et al. 17 and Wu et al. 18) were judged to be of good or high quality.

Chen et al. 16 found statistically significantly better visual acuity (0.1 log-MAR) with SML laser treatment at 12 months follow-up only,16 but this was due to one trial by Lavinsky et al. 9 and the high-density arm of that trial. The review concluded that SML laser is an effective therapy for treating DMO, but that compared with SL, the changes were of limited clinical significance.

Qiao et al. 17 included seven RCTs; six of these seven trials were included in the review by Chen et al. 16 mentioned above. Meta-analysis found no statistically significant differences in BCVA or central macular thickness at any time point. The results of meta-analyses for contrast sensitivity were mixed, with some trials favouring SL and others favouring SML.

The results in the Qiao et al. 17 review differ somewhat from those of Chen et al. 16 Qiao et al. 17 reported mean BCVA at 12 months with three trials, Figueira et al. ,11 Lavinsky et al. 9 and Vujosevic et al. ,10 whereas Chen et al. reported change from baseline in only two trials, Lavinsky et al. 9 and Vujosevic et al. 10 The Chen et al. review16 used only the high-density arm of Lavinsky et al.,9 whereas Qiao et al. 17 used only the normal density arm of this trial. Their different conclusions between these two reviews appear to be due to the results of Lavinsky et al. ,9 deemed to give a significant result in Chen et al. 16 (based on change in BCVA from baseline) but not in Qiao et al. 17 (based on mean BCVA at 12 months).

The review by Wu et al. 18 included a Bayesian network meta-analysis of RCTs and quasi-randomised trials comparing any two treatments of interest, including SML or SL photocoagulation as monotherapy or SL combined with anti-VEGF therapy. The review included 18 studies: 15 reported BCVA and 16 reported CRT and were included in the network meta-analysis, and 11 studies compared SL alone with laser plus ranibizumab. Of seven trials comparing SL with SML, four (Casson et al. ,54 Laursen et al. ,14 Venkatesh et al. 12 and Xie et al. 15) had only six months’ follow-up. The remaining three were those by Figueira et al. ,11 Lavinsky et al. 9 and Vujosevic et al. 10 Wu et al. 18 found no statistically significant difference in visual acuity improvement between monotherapy laser photocoagulation with SL and SML. 18

Scholz et al. 51 reviewed the effects of SML for the treatment of macular disorders including central serous chorioretinopathy, DMO and retinal vein occlusion. Although a comprehensive search was undertaken, the review did not specify eligibility criteria or any other review methods and, thus, was subsequently rated as being of low quality. Eleven prospective studies in DMO were included, although the review stated that a larger number of studies were identified. The review calculated change scores for CRT and BCVA but the methods of these calculations were not reported. The conclusions made by the authors, who stated that included studies demonstrated efficacy of SML, should, therefore, be taken with caution.

A review by Blindbaek et al. 52 of the potential role of focal/grid laser photocoagulation in DMO treatment was not rated as high quality. They noted that few high-quality studies have compared SML with SL therapy and that results were mixed. Quality of life was not discussed.

One of the problems with all available meta-analyses was that only three trials were analysed, each with a follow-up period of 12 months; none had a longer follow-up period. The mean CRTs in the trials by Lavinsky et al. 9 and Vujosevic et al. 10 were approximately 370 µm, so many patients would have had a CRT of > 400 µm, unlike those participants included in the DIAMONDS trial. None of the reviews reported effects on quality of life or costs.

Fazel et al. 20 conducted a single centre trial that randomised 68 eyes of 68 patients to SML or SL. Inclusion criteria included a CRT of 300–449 µm. With SL there was no statistically significant change in BCVA whereas a significant change was observed with SML, with an improvement of 0.07 Log-MAR by 4 months. CRT was reduced by 13 µm following SML and by 5 µm following SL. The small number of patients included in each treatment group and the short follow-up period (maximum 4 months) limits greatly the usefulness of the results presented. There was no power calculation for the trial shown. Owing to its year of publication, this trial was not included in the reviews by Chen et al. ,16 Qiao et al. 17 and Wu et al. 18

A review by Cooper et al. 55 aimed to synthesise the evidence on the psychological, social and everyday visual impact of diabetic retinopathy and DMO from the patient perspective. Eighty-five studies with a range of study designs were included; 23 of these studies assessed quality of life. However, the studies appeared to focus on diabetic retinopathy; quality of life in DMO was not discussed. Visual functioning and psychological wellbeing measures were reported in other studies, including some in DMO; however, limited numerical data were reported and no data on DMO were summarised.

Adverse events

If SML has a similar effectiveness to SL, as most trials including the DIAMONDS trial suggest, the next question is whether or not it has significantly fewer adverse effects, and whether or not these are clinically meaningful.

In the DIAMONDS trial both lasers proved to be very safe, with only a very small number of participants (the highest proportion of participants for any of the following events being ≈ 2%) experiencing AEs potentially related to the laser treatment, including central/paracentral scotomas, epiretinal membrane, choroidal neovascularisation, and self-reported reduced colour vision and metamorphopsia. No statistically significant differences in the occurrence of AEs were found between laser groups. These potential AEs owing to laser treatment were identified a priori before the trial commenced; patients were questioned at each of the follow-up visits about their occurrence and ophthalmologists also evaluated participants to determine whether or not any of these had happened. None of these reported AEs, however, was regarded by the investigators as being definitively caused by the laser treatment.

In the RCT by Vujosevic et al. ,10 it was found that contrast sensitivity measured by microperimetry increased after SML, but decreased after SL. Qiao et al. 17 included in their meta-analysis three trials (Kumar et al. 13 and Venkatesh et al. 12 at 6 months, and Figueira et al. 11 at 3 months) that had included contrast sensitivity and found no difference overall between SML and SL. There was considerable heterogeneity among trials.

Chhablani et al. 60 randomised 30 eyes from 20 patients with non-centre-involving DMO to two SML strategies (5% and 15% duty cycle) or to SL. Patients had microperimetry, CRT and BCVA measured at baseline and at 6 and 12 weeks post treatment. Retinal sensitivity increased in the SML group but decreased in the SL group.

The majority of previously published studies9,10,13 reported a lack of visible retinal changes after SML, whereas laser scars are most often present after SL. Figueira et al. 11 reported scars in 59% of eyes after SL versus 14% after SML after a follow-up of 12 months.

None of the above studies assessed patient-reported outcomes, with the exception of the DIAMONDS trial. The DIAMONDS trial showed no differences in health-related or vision-related quality of life, suggesting that differences in retinal sensitivity and the presence of retinal scars may not be perceived by and be relevant to patients or, alternatively, that the quality of life tools used are unable to detect them, if they were to exist.

Clinical implications

For many years, macular laser was the mainstay therapy to treat DMO, with the ETDRS demonstrating in 1985 that it reduced the risk of visual loss (loss of ≥ 3 ETDRS lines = loss of 15 ETDRS letters) by 50% at 3 years in people with CSMO. 5 As only a small (≈ 3%) proportion of participants in the ETDRS experienced an improvement in vision of 15 ETDRS letters, it has been usually stated that macular laser does not improve vision. The great majority of eyes in the ETDRS (1903/2243; 85%) had excellent vision, of 20/40 or better at baseline,5 which may explain the limited improvement in vision observed in this large trial. Indeed, a Diabetic Retinopathy Clinical Research Network trial showed that 32% and 44% of patients with centre-involving DMO experienced a 10-letter visual acuity improvement at 2 and 3 years, respectively, following macular laser. 6,7 Thus, macular laser can improve vision in people with centre-involving DMO. However, with the advent of anti-VEGF therapies the benefits of macular laser have been ignored by many, as shown in the published European Society of Retina Specialists (EURETINA) guidelines. 61 The DIAMONDS trial shows that for patients with DMO fulfilling the DIAMONDS inclusion criteria, and as advised by NICE based on best available evidence, macular laser has still an important place in the management of people with centre-involving DMO. 2,3 In addition, as highlighted by Bakri et al. in the American Society of Retinal Specialists guidelines,62 macular laser also remains the treatment of choice in patients with non-centre-involving DMO. Furthermore, it has been shown in a publicly funded RCT that 41–64% of people receiving anti-VEGF therapies (bevacizumab, ranibizumab or aflibercept) required macular laser to control DMO during the 2-year period following initiation of therapy. 8 Thus, macular laser is still needed even in people treated with anti-VEGF therapy.

A retrospective study by Lai et al. 63 which included 164 eyes from 164 patients with centre-involving DMO and a CRT of > 300 µm treated with either SML (86 eyes) or intravitreal aflibercept monotherapy (78 eyes) found that although at the 6-month follow-up a higher percentage of eyes in the aflibercept group experienced at least a 5-letter visual acuity improvement when compared with those in the SML group (56% vs. 38%; p = 0.044), this was no longer the case at 12 months (45% vs. 49%; p = 0.584) or at 24 months (49% vs. 57%; p = 0.227). Similarly, although at the 6-month visit the aflibercept group had a higher percentage of eyes with an improvement of at least 10% in CRT than the SML group (73% vs. 49%; p = 0.005), this was no longer the case at the 12-month (73% vs. 70%; p = 0.995) or 24-month visits (85% vs. 84%; p = 0.872).

A publicly funded RCT by the Diabetic Retinopathy Clinical Research Network compared observation, standard macular laser and anti-VEGF therapy (aflibercept) in patients with centre-involving DMO with good vision, with the primary outcome being a loss of ≥ 5 ETDRS letters from baseline to 2 years. 64 A total of 625 of the 702 participants (89%) completed the 2-year visit. Participants had normal vision [mean ETDRS letter score 85 ETDRS letters (6/6)], and had better glycaemic control (median HbA_1c 7.6) and less severe DMO [mean CRT ≈ 300 µm (306  µm, 314  µm and 314 µm in aflibercept, laser and observation groups, respectively)] than those included in DIAMONDS. The percentage of eyes with a loss of ≥ 5-ETDRS letters at 2 years was 16% in the aflibercept arm, 17% in the macular laser arm and 19% in the observation arm, with no statistically significant differences among groups. Similarly, there were no statistically significant differences in change in CRT from baseline to 2 years among treatment groups. The median number of aflibercept injections over 2 years in the aflibercept group was eight (interquartile range 6–11) and macular laser was additionally required in 6% of eyes in this group. A small proportion of participants (9%, 7% and 7% in the aflibercept, macular laser and observation arms, respectively) experienced a loss of 10 or more ETDRS letters from baseline to month 24. The authors concluded that observation without treatment, unless visual acuity worsens, was a reasonable strategy for eyes with centre-involving DMO. Given that DIAMONDS trial participants had poor diabetes control (mean HbA_1c 8.5%), reduced vision [mean ETDRS score of 80 letters (6/7.5 Snellen equivalent)] and more severe DMO (mean CRT 329.2 µm), observation is unlikely to have been the right approach for the management of their DMO.

The DIAMONDS trial showed that SML had comparable efficacy and cost to SL, suggesting that either treatment could be equally offered to patients with centre-involving DMO with a CRT of < 400 µm that was suitable for macular laser. Given that SML has been shown to preserve photoreceptor cells (visual cells),21,56,65 RPE and neurosensory retina,10,21 and produce no burn or objective damage, it should be easier and safer to teach to, for example, junior ophthalmologists and non-medical staff, as a foveal burn would be avoided. The possibility of having trained non-medical staff contributing to the management of people living with complications of diabetic retinopathy could help the NHS to cope with the high and ever-increasing demand for care in HES. Specialist nurses and trained hospital optometrists are already providing intravitreal injections for people with DMO in the NHS. 66 A new pathway involving allied health care professionals has been recently shown to have good sensitivity and acceptable specificity, as well as to be cost saving, for the surveillance of people with previously treated complications of diabetic retinopathy, including DMO. 47,67–69 Thus, the possibility of expanding the role of allied non-medical staff to deliver macular laser treatment using SML seems to be reasonable and worth pursuing.

Strengths and limitations

The DIAMONDS trial was a robustly designed and appropriately powered multicentre RCT. It was powered to detect not only non-inferiority of SML when compared with SL, but also equivalence and superiority if these were to exist. It was powered to detect differences not only in the primary outcome but also in important secondary outcomes (CRT and vision-related quality of life). It was estimated at the trial conception that 113 participants in each laser arm were required to have completed primary outcome data at month 24 for the trial to answer the research questions formulated; at trial completion (24-month follow-up) a higher number of participants (116 and 115 in the SML and SL groups, respectively) were available. The trial was designed as a pragmatic trial so that its results could be reproduced in routine clinical practice. Unlike many RCTs evaluating treatments for DMO, in which the primary outcome was measured at 1 year, the DIAMONDS trial set the primary outcome at 2 years, as it is possible that benefits of treatments may wane overtime or, as shown in some laser trials, improve over time. Similarly, unlike many RCTs evaluating treatments for DMO, the DIAMONDS trial included patient-reported outcomes and, importantly, incorporated a clinical outcome that was suggested by people with diabetes and DMO, namely meeting driving standards. This highlights the importance of PPI in the design of research studies, including RCTs. Furthermore, and unlike most trials on treatments for DMO, it incorporated a prospective within-trial health economic evaluation to compare the cost-effectiveness of the alternative treatments investigated. Limitations include the fact that the great majority of participants enrolled had poorly controlled diabetes and, thus, it is possible that better outcomes in both treatment groups could be achieved in people with adequately controlled diabetes.

Implications for health care

The results of the DIAMONDS trial show that ≈ 80% of patients with centre-involving DMO and a CRT of < 400 µm can be managed successfully with macular laser alone and that either SML or SL can be used given that both laser treatments are equivalent. Only ≈ 20% of people in the DIAMONDS trial required additional anti-VEGF treatment. Despite this, one European group61 has recommended anti-VEGF therapy over laser treatment for people with DMO. However, because of the cost of these drugs and the frequency of patient visits required when anti-VEGF therapies are used, implementation of this anti-VEGF strategy for all patients with DMO would be much more expensive for, and would increase demand for care within, health-care systems. Moreover, it is likely that macular laser may be more convenient for patients, given that it requires fewer visits to the clinic for monitoring/repeating treatment when needed and is less painful.

Recommendations for research

The DIAMONDS trial showed that laser treatment remains an effective treatment strategy for patients with centre-involving DMO with a CRT of < 400 µm as determined by SD-OCT. A study determining which patient’s baseline characteristics, besides CRT, are associated with a higher likelihood of an adequate functional (visual acuity) and anatomical (clearance of DMO) treatment response to macular laser would be recommended, so that a more individualised treatment strategy could be offered to patients (i.e. those less likely to respond to macular laser could be offered alternative therapies).

A RCT comparing anti-VEGF monotherapy with anti-VEGF plus laser therapy once the CRT has decreased to less than 400 µm following anti-VEGF treatment would be of interest, as it may reduce the number of anti-VEGF injections required and may improve functional and anatomical outcomes more effectively than either treatment alone. Such a study has not been undertaken. In RCTs in which macular laser was combined with anti-VEGF therapy, it was not stipulated in the protocol that macular laser should be performed only once CRT had decreased to < 400 µm following anti-VEGF injections.

A study evaluating the feasibility of allied non-medical staff delivering SML to patients with DMO would be of benefit as this strategy, if safe and acceptable to patients, could increase capacity in the NHS.

Patient and public involvement

The DIAMONDS PPI group had a substantial input in the trial. As stated in Chapter 2, DIAMONDS patient and public involvement group, the PPI group contributed to the trial design, including the selection of outcomes, preparation of patient related materials for the trial and recruitment strategies. One outcome (meeting driving standards) came directly from this group (i.e. it had not been anticipated by the trial investigators) as it was identified as being a very important outcome for people living with diabetes and DMO. The PPI group participated in the interpretation of trial results and voiced the importance of the overall finding of the trial (i.e. the fact that SML, which does not cause any detectable damage in the retina, is as effective as SL in the treatment of people with centre-involving DMO suitable for macular laser and with a CRT of < 400 µm) and the subsequent importance of future implementation of trial data into clinical practice. The PPI group is currently taking part in the dissemination of the trial results.

Conclusions

Subthreshold micropulse laser was found to be equivalent to SL in clinical benefits, safety and associated costs and, thus, either laser can be used for the treatment of people with centre-involving DMO suitable for macular laser and with a CRT of < 400 µm.

Patient and public involvement

We would like to thank the DIAMONDS PPI Group and especially Martin Adams for providing a patient and public perspective on the design, findings and interpretation of the results of this trial. We thank the members of the ‘Diabetes Family’ Facebook (Meta Platforms, Inc., Menlo Park, CA, USA) group, who provided very important feedback at the time of trial conception. This included the suggestion of adding ‘meeting driving standards’ as an outcome in the trial, after having recognised this to be a very important outcome for people living with diabetes.

DIAMONDS study group

Noemi Lois, Queen’s University and Royal Victoria Hospital, BHSCT; Evie Gardner, NICTU; Norman Waugh, Warwick University; Augusto Azuara-Blanco, Queen’s University and Royal Victoria Hospital, BHSCT; Hema Mistry, Warwick University; Danny McAuley, Queen’s University and Royal Victoria Hospital, BHSCT; Mike Clarke, Queens University; Tariq M Aslam, Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust; Clare Bailey, Bristol Eye Hospital, University Hospitals Bristol NHS Foundation Trust; Victor Chong, Royal Free Hospital NHS Foundation Trust, London; Sobha Sivaprasad, Moorfields Eye Hospital NHS Foundation Trust; David H Steel, Sunderland Eye Infirmary, City Hospitals Sunderland NHS Foundation Trust; James Stephen Talks, Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust; Catherine Adams, NICTU; Christina Campbell, NICTU; Matthew Mills, NICTU; Paul Doherty, NICTU; Aby Joseph, NICTU; Nachiketa Acharya, Sheffield Teaching Hospitals NHS Foundation Trust; Louise Downey, Hull and East Yorkshire Hospital, Hull and East Yorkshire NHS Trust; Haralabos Eleftheriadis, King’s College Hospital NHS Foundation Trust; Samia Fatum, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust; Sheena George, Hillingdon Hospitals NHS Foundation Trust; Faruque Ghanchi, Bradford Teaching Hospitals NHS Trust; Markus Groppe, Stoke Mandeville Hospital, Buckinghamshire NHS Trust; Robin Hamilton, Moorfields Eye Hospital NHS Foundation Trust; Geeta Menon, Frimley Park Hospital NHS Foundation Trust; Ahmed Saad, James Cook University Hospital, South Tees Hospitals NHS Foundation Trust; and Marianne Shiew; Hinchingbrooke Hospital North West Anglia NHS Trust.

Research teams at participating sites

The DIAMONDS trial was a collaborative effort across many sites. We thank all staff at the participating sites for making a valuable contribution to the trial, both in delivering the intervention and in measuring patient outcomes. We are also grateful to those staff at the NICTU who worked on the early phases of the trial, including Catherine Adams, Fiona McCourt, Evie Gardner, Mairead North and Matthew Mills.

Trial Management Group

The following were members of the TMG for some or all of the duration of the study: Professor Noemi Lois (chief investigator, chair); Professor Augusto Azuara-Blanco, Professor Mike Clarke, Professor Danny McAuley, Mr Paul Doherty, Ms Catherine Adams and Ms Fiona McCourt (trial managers); Mr Matthew Mills and Ms Pauline McElhill (clinical trial co-ordinators); Mr Aby Joseph and Ms Omowumi Odusina (data managers); Mr Mark Wilson (database developer); Ms Christina Campbell, Ms Evie Gardner and Ms Mairead North (statisticians); Professor Norman Waugh (health economist), Dr Hema Mistry and Dr Mandy Maredza (health economists); Ms Nicola Duff and Ms Lesley-Anne Dougan (clinical trial administrators); and Ms Emma McAuley and Mr Ryan Craig (clinical research monitors).

Trial Steering Committee

Mr Alistair Laidlaw (clinician, chair), Mr Andrew Elders (statistician), Mr Ian Pearce (clinician) and Mr Tom Rush (PPI representative).

Data Monitoring and Ethics Committee

Mr Graeme MacLennan (statistician, chair), Professor Baljean Dhillon (clinician) and Professor Tom Williamson (clinician).

Sponsor

BHSCT.

Contributions of authors

Noemi Lois (https://orcid.org/0000-0003-2666-2937) (Clinical Professor of Ophthalmology) is the Chief Investigator for the DIAMONDS trial; led the team of co-applicants, researchers and trial supporting staff; conceived and designed the trial with input from co-applicants; and contributed to the identification, recruitment, examination and treatment of all participants enrolled at the Belfast site, as well as to data collection, analysis and interpretation of the trial findings. She led the drafting of this report, revised it critically for important intellectual content and approved its final draft for submission.

Christina Campbell (https://orcid.org/0000-0002-8446-523X) (Trial Statistician) performed the statistical analyses, assisted with the interpretation of data, contributed to the drafting of the report and critically reviewed it.

Norman Waugh (https://orcid.org/0000-0003-0934-4961) (Professor of Public Health and Health Technology Assessment) and Hema Mistry (https://orcid.org/0000-0002-5023-1160) (Health Economist) contributed to the design of the health economics plan and provided oversight for all aspects of the economic evaluation including its design, conduct, analysis and reporting.

Augusto Azuara-Blanco (https://orcid.org/0000-0002-4805-9322) (Clinical Professor of Ophthalmology) contributed to the design of this trial, to the interpretation of the data and to the critical review of this report.

Mandy Maredza (https://orcid.org/0000-0002-2030-3338) (Health Economist) undertook the economic evaluation, supported by Norman Waugh and Hema Mistry.

Danny McAuley (https://orcid.org/0000-0002-3283-1947) (Clinical Professor and Consultant in Intensive Care Medicine and former Director of the Northern Ireland Clinical Trials Unit) contributed to the design of this trial, the interpretation of the data and the critical review of this report.

Nachiketa Acharya (https://orcid.org/0000-0002-0794-689X) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Tariq M Aslam (https://orcid.org/0000-0002-9739-7280) (Consultant Ophthalmologist) contributed to the design of this trial, the interpretation of the data and the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Clare Bailey (https://orcid.org/0000-0003-2141-4512) (Consultant Ophthalmologist) contributed to the design of this trial, the interpretation of the data and the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Victor Chong (https://orcid.org/0000-0002-7693-522X) (Consultant Ophthalmologist) contributed to the design of this trial, the interpretation of the data and the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Louise Downey (https://orcid.org/0000-0001-5944-3437) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Haralabos Eleftheriadis (https://orcid.org/0000-0002-9980-4070) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Samia Fatum (https://orcid.org/0000-0002-5760-4038) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Sheena George (https://orcid.org/0000-0002-9953-1834) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Faruque Ghanchi (https://orcid.org/0000-0002-4448-8162) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Markus Groppe (https://orcid.org/0000-0003-1963-3484) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Robin Hamilton (https://orcid.org/0000-0003-2861-8761) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Geeta Menon (https://orcid.org/0000-0001-7532-6564) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Ahmed Saad (https://orcid.org/0000-0002-5159-8001) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Sobha Sivaprasad (https://orcid.org/0000-0001-8952-0659) (Consultant Ophthalmologist) contributed to the design of this trial, the interpretation of the data and the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Marianne Shiew (https://orcid.org/0000-0003-4774-3576) (Consultant Ophthalmologist) contributed to the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

David H Steel (https://orcid.org/0000-0001-8734-3089) (Consultant Ophthalmologist) contributed to the design of this trial, the interpretation of the data and the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

James Stephen Talks (https://orcid.org/0000-0001-6126-6476) (Consultant Ophthalmologist) contributed to the design of this trial, the interpretation of the data and the critical review of this report, as well as to the recruitment and evaluation of participants enrolled and followed up in this trial.

Paul Doherty (https://orcid.org/0000-0002-3263-7052) (Trial Manager) provided training and support to sites, co-ordinated and managed the trial, was involved in the management of the study and critically reviewed the manuscript.

Clíona McDowell (https://orcid.org/0000-0002-7644-7197) (Trial Statistician) contributed to the statistical analyses, assisted with the interpretation of data, contributed to the drafting of the statistical sections of the report and critically reviewed it.

Mike Clarke (https://orcid.org/0000-0002-2926-7257) (Professor of Research Methodology at the MRC Methodology Hub and Director of the Northern Ireland Clinical Trials Unit) was involved in the conception and design of this trial, contributed to the interpretation of data and drafting of this report, and revised it critically for important intellectual content.

Publications

Lois N, Gardner E, Waugh N, Azuara-Blanco A, Mistry H, McAuley D, et al. Diabetic macular oedema and diode subthreshold micropulse laser (DIAMONDS): study protocol for a randomised controlled trial. Trials 2019;20:122.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to available anonymised data or trial materials may be granted following review.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research funded by the National Institute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care.