Different lasers and techniques for proliferative diabetic retinopathy

Tanya Moutray; Jennifer R Evans; Noemi Lois; David J Armstrong; Tunde Peto; Augusto Azuara‐Blanco

doi:10.1002/14651858.CD012314.pub2

. 2018 Mar 15;2018(3):CD012314. doi: 10.1002/14651858.CD012314.pub2

Different lasers and techniques for proliferative diabetic retinopathy

Tanya Moutray ^1,^✉, Jennifer R Evans ², Noemi Lois ³, David J Armstrong ¹, Tunde Peto ⁴, Augusto Azuara‐Blanco ⁴

Editor: Cochrane Eyes and Vision Group

PMCID: PMC6494342 PMID: 29543992

Abstract

Background

Diabetic retinopathy (DR) is a chronic progressive disease of the retinal microvasculature associated with prolonged hyperglycaemia. Proliferative DR (PDR) is a sight‐threatening complication of DR and is characterised by the development of abnormal new vessels in the retina, optic nerve head or anterior segment of the eye. Argon laser photocoagulation has been the gold standard for the treatment of PDR for many years, using regimens evaluated by the Early Treatment of Diabetic Retinopathy Study (ETDRS). Over the years, there have been modifications of the technique and introduction of new laser technologies.

Objectives

To assess the effects of different types of laser, other than argon laser, and different laser protocols, other than those established by the ETDRS, for the treatment of PDR. We compared different wavelengths; power and pulse duration; pattern, number and location of burns versus standard argon laser undertaken as specified by the ETDRS.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 5); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 8 June 2017.

Selection criteria

We included randomised controlled trials (RCTs) of pan‐retinal photocoagulation (PRP) using standard argon laser for treatment of PDR compared with any other laser modality. We excluded studies of lasers that are not in common use, such as the xenon arc, ruby or Krypton laser.

Data collection and analysis

We followed Cochrane guidelines and graded the certainty of evidence using the GRADE approach.

Main results

We identified 11 studies from Europe (6), the USA (2), the Middle East (1) and Asia (2). Five studies compared different types of laser to argon: Nd:YAG (2 studies) or diode (3 studies). Other studies compared modifications to the standard argon laser PRP technique. The studies were poorly reported and we judged all to be at high risk of bias in at least one domain. The sample size varied from 20 to 270 eyes but the majority included 50 participants or fewer.

Nd:YAG versus argon laser (2 studies): very low‐certainty evidence on vision loss, vision gain, progression and regression of PDR, pain during laser treatment and adverse effects.

Diode versus argon laser (3 studies): very‐low certainty evidence on vision loss, vision gain, progression and regression of PDR and adverse effects; moderate‐certainty evidence that diode laser was more painful (risk ratio (RR) troublesome pain during laser treatment (RR 3.12, 95% CI 2.16 to 4.51; eyes = 202; studies = 3; I² = 0%).

0.5 second versus 0.1 second exposure (1 study): low‐certainty evidence of lower chance of vision loss with 0.5 second compared with 0.1 second exposure but estimates were imprecise and compatible with no difference or an increased chance of vision loss (RR 0.42, 95% CI 0.08 to 2.04, 44 eyes, 1 RCT); low‐certainty evidence that people treated with 0.5 second exposure were more likely to gain vision (RR 2.22, 95% CI 0.68 to 7.28, 44 eyes, 1 RCT) but again the estimates were imprecise . People given 0.5 second exposure were more likely to have regression of PDR compared with 0.1 second laser PRP again with imprecise estimate (RR 1.17, 95% CI 0.92 to 1.48, 32 eyes, 1 RCT). There was very low‐certainty evidence on progression of PDR and adverse effects.

'Light intensity' PRP versus classic PRP (1 study): vision loss or gain was not reported but the mean difference in logMAR acuity at 1 year was −0.09 logMAR (95% CI −0.22 to 0.04, 65 eyes, 1 RCT); and low‐certainty evidence that fewer patients had pain during light PRP compared with classic PRP with an imprecise estimate compatible with increased or decreased pain (RR 0.23, 95% CI 0.03 to 1.93, 65 eyes, 1 RCT).

'Mild scatter' (laser pattern limited to 400 to 600 laser burns in one sitting) PRP versus standard 'full' scatter PRP (1 study): very low‐certainty evidence on vision and visual field loss. No information on adverse effects.

'Central' (a more central PRP in addition to mid‐peripheral PRP) versus 'peripheral' standard PRP (1 study): low‐certainty evidence that people treated with central PRP were more likely to lose 15 or more letters of BCVA compared with peripheral laser PRP (RR 3.00, 95% CI 0.67 to 13.46, 50 eyes, 1 RCT); and less likely to gain 15 or more letters (RR 0.25, 95% CI 0.03 to 2.08) with imprecise estimates compatible with increased or decreased risk.

'Centre sparing' PRP (argon laser distribution limited to 3 disc diameters from the upper temporal and lower margin of the fovea) versus standard 'full scatter' PRP (1 study): low‐certainty evidence that people treated with 'centre sparing' PRP were less likely to lose 15 or more ETDRS letters of BCVA compared with 'full scatter' PRP (RR 0.67, 95% CI 0.30 to 1.50, 53 eyes). Low‐certainty evidence of similar risk of regression of PDR between groups (RR 0.96, 95% CI 0.73 to 1.27, 53 eyes). Adverse events were not reported.

'Extended targeted' PRP (to include the equator and any capillary non‐perfusion areas between the vascular arcades) versus standard PRP (1 study): low‐certainty evidence that people in the extended group had similar or slightly reduced chance of loss of 15 or more letters of BCVA compared with the standard PRP group (RR 0.94, 95% CI 0.70 to 1.28, 270 eyes). Low‐certainty evidence that people in the extended group had a similar or slightly increased chance of regression of PDR compared with the standard PRP group (RR 1.11, 95% CI 0.95 to 1.31, 270 eyes). Very low‐certainty information on adverse effects.

Authors' conclusions

Modern laser techniques and modalities have been developed to treat PDR. However there is limited evidence available with respect to the efficacy and safety of alternative laser systems or strategies compared with the standard argon laser as described in ETDRS

Plain language summary

Do newer laser treatments work better than standard laser treatments for proliferative diabetic retinopathy?

What was the aim of this review?  The aim of this Cochrane Review was to find out if new ways of doing laser treatment for proliferative diabetic retinopathy (explained under 'What was studied in the review?' below) work better than standard treatment. Cochrane researchers collected and analysed all relevant studies to answer this question and found 11 studies.

Key messages  There is limited evidence on the benefits and harms of different laser systems or strategies compared with the standard treatment.

What was studied in the review?  People with diabetes can have problems in the back of their eyes that may affect their sight. One of these problems is the growth of harmful new blood vessels in the retina (the layer that covers the back of the eye that allows people to see); this is called proliferative diabetic retinopathy, referred to as ‘PDR’. Sight loss can occur as a result of PDR. Argon laser has been used to treat PDR for many years. New types of laser and new ways of doing laser treatment have been developed to treat PDR. The aim of this review was to assess the evidence for the benefits and harms of these new treatments.

What are the main results of the review?  The Cochrane researchers found 11 relevant studies. Four studies were done in Italy, two studies were done in the US, one in South Korea, one in Iran, one in Slovenia, one in Greece and one in India. All the people included in these studies had PDR due to type 1 or type 2 diabetes. Most of these studies were small and provide limited evidence on which to base treatment decisions.

How up to date is this review?  Cochrane researchers searched for studies that had been published up to 8 June 2017.

Summary of findings

Background

Description of the condition

Diabetic retinopathy (DR) is a chronic, progressive, potentially sight‐threatening disease of the retinal microvasculature associated with prolonged hyperglycaemia. As the leading cause of blindness among working‐aged adults around the world, DR is a major public health problem (Klein 2007). Its incidence is rising dramatically along with the incidence of type 2 diabetes, driven by greater longevity combined with sedentary lifestyles and increasing levels of obesity (Geiss 2011). Globally, there are approximately 93 million people with DR, including 17 million with proliferative DR, 21 million with diabetic macular oedema (DMO), and 28 million with vision‐threatening diabetic retinopathy (VTDR) (Yau 2012). A pooled analysis from diabetic population‐based studies around the world found overall prevalence rates of 34.6% for any DR, 6.96% for PDR, 6.81% for DMO and 10.2% for VTDR. All DR prevalence endpoints increased with diabetes duration, haemoglobin A(1c), and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes (Yau 2012).    These data highlight the substantial worldwide public health burden of DR and the importance of tackling modifiable risk factors to reduce its occurrence. The Diabetes Control and Complications Trial (DCCT) showed that intensive glycaemic control was effective in delaying the onset, as well as slowing the progression, of DR in patients with type 1 diabetes (DCCT Research Group 1993). The UK Prospective Diabetes Study (UKPDS) showed the risk of complications in type 2 diabetics was independently and additively correlated with hyperglycaemia and hypertension, with risk reductions of 21% per 1% decrease in HbA1c and 11% per 10 mmHg decrease in systolic blood pressure (Stratton 2006; UKPDS Group 1998). There are various classifications of DR, but all recognise the two basic mechanisms leading to loss of vision: retinopathy (risk of developing new vessels); and maculopathy (risk of damage to the central fovea). The differences between classifications relate mainly to levels of retinopathy and to terminology used. Severity is ranked into a stepwise scale from no retinopathy through various stages of non‐proliferative or pre‐proliferative disease to advanced proliferative disease (ETDRS Research Group 1991). This review is concerned with Vision Threatening Diabetic Retinopathy (VTDR) related to the development of PDR.

PDR is characterised by the development of new vessels and can be further defined by their location and severity. With regards to location, there may be: new vessels on the disc or within 1 disc diameter (DD) of the margin of the disc (NVD); elsewhere in the retina (NVE); on the iris (NVI); or anterior chamber angle (NVA). Classification of PDR severity includes: early PDR (NVD < 1/4 DD, NVE without haemorrhage); PDR with high risk characteristics such as NVD equal to or greater than 1/4 DD, any NVD‐ or NVE‐associated vitreous haemorrhage; florid (aggressive presentation) PDR; and gliotic (with the development of fibrotic tissue) PDR. 'Involutionary' PDR refers to new vessels that have regressed, usually in response to treatment but (rarely) spontaneously.

Description of the intervention

Laser photocoagulation reduces the oxygen demand of the outer layers of the retina and helps divert adequate oxygen and nutrients to the retina, favourably altering the haemodynamics (Stefánsson 2001). Laser photocoagulation appears also to act by reducing the expression of vasoactive factors such as vascular endothelial growth factor (VEGF) and protein kinase C (PKC) in the retina (Ghosh 2005). Indeed, different landmark studies have supported the efficacy of laser PRP in preventing vision loss. The Diabetic Retinopathy Study (DRS) demonstrated that laser photocoagulation of the retina reduced severe visual loss (defined as visual acuity of 5/200 or less on two consecutive visits at least four months apart) (DRS Research Group 1978); and the Early Treatment Diabetic Retinopathy Study (ETDRS) addressed the question of the appropriate time for performing laser photocoagulation, showing that PRP was beneficial only in cases where proliferative changes were present and specifically when high‐risk characteristics PDR were present (ETDRS Research Group 1985). It also showed that focal or grid photocoagulation was beneficial in reducing visual loss due to macular oedema (ETDRS Research Group 1985). As PRP may be associated with morbidity, the risk‒benefit ratio of PRP in people at higher risk would favour the performance of PRP. The visual loss due to PRP is much less debilitating at this stage compared with the high risk of severe vision loss in the near future if the retinopathy were to remain untreated (Feman 2004). The ETDRS also showed that focal or grid photocoagulation was beneficial in reducing the risk of visual loss due to DMO (ETDRS Research Group 1985).

How the intervention might work

It is believed that in the majority of cases, PDR represents an angiogenic response of the retina to extensive capillary closure. New vessels grow at the interface of perfused and non‐perfused retina. Peripheral retinal ischaemia, in the absence of surrogate markers or capillary drop‐out (blot haemorrhage, venous beading, intraretinal microvascular anomalies), may not always be readily discernible clinically, and hence fluorescein angiography — especially wide field fluorescein angiography — is especially useful in detecting ischaemic changes.

The aim of laser PRP treatment is to destroy the areas where there is capillary non‐perfusion and retinal ischaemia as it is in these ischaemic areas where VEGF, a permeability and angiogenic factor, is produced. Lasers act by inducing thermal damage after absorption of energy by tissue pigments. If there is an inadequate response after a standard PRP is undertaken and full regression of new vessels is not achieved, clinicians often supplement the treatment by undertaking further laser in untreated areas.

Following the guidelines published by the DRS and ETDRS, argon laser photocoagulation has been the gold standard for the treatment of PDR. Level 1 evidence from the DRS recommended multisession scatter PRP laser (800 to 1600 spots in one or two sittings, and follow‐up treatment applied as needed at 4‐month intervals) extending to or beyond the vortex vein ampullae (midperipheral retina) (DRS Research Group 1981). Practitioners still widely follow this guideline as a frame of reference. In general, ophthalmologists administer laser covering 360° of the midperipheral retina, with adequate spacing between laser burns (˜ 1 burn apart) to avoid compromising peripheral vision. In clinical practice, the power of the laser selected is set for each individual patient to achieve an adequate burn in the retina and is dependent on variables such as media clarity, fundus pigmentation, and method of delivery. Avoiding very intense white spots is advised to reduce possible complications such as haemorrhage and breaks through Bruch’s membrane which could lead to choroidal neovascularisation.

It has been suggested also that laser strategies other than single pulse argon laser peripheral PRP used by the ETDRS may help reduce ocular side effects, such as laser burn scarring and visual field loss (Muqit 2010). The newer 'yellow' wavelength lasers have the highest combined absorption in the melanin‐oxyhaemoglobin layers of the RPE/choriocapillaris complex and are thought to induce less scatter with increased efficiency compared to green laser photocoagulators (Castillejos‐Rios 1992). Diode laser may produce energy in the 532 nm (green) band, the 577 nm (yellow) band, or in the invisible infrared band (810 nm). These laser treatment strategies can target threshold level, or subthreshold level depending on the power used. MicroPulse mode is available for the 810 nm infrared band wavelength.

Laser PRP can be delivered as a single spot but now multispot laser delivery systems allow a reduced pulse duration compared with conventional argon laser (100 ms to 200 ms) with the aim of a quicker and less painful experience. Additionally, the procedure can be semiautomated by delivering multiple laser burns to the retina with a single depression of the foot pedal.

Why it is important to do this review

Current guidelines for the management of PDR recommend that an ophthalmologist promptly perform PRP until regression of neovascularisation is achieved (Ghanchi 2013). However, most of the evidence relies on the previously described landmark trials, which used older lasers from the 1980s. It does not provide enough evidence to recommend newer laser protocols which may be equally effective but safer and less uncomfortable for patients. Thus a high‐quality review, comparing the standard ETDRS laser treatment for PDR with alternative laser strategies and including modern lasers, was necessary. This systematic review was designed to examine efficacy and safety of alternative types of laser in people with PDR when compared with standard argon laser. It assessed the evidence base for alternative laser treatment strategies such as ischaemia‐targeted laser to the peripheral retina as seen on fluorescein angiography compared with standard argon laser. This review followed on from the preliminary work carried out by Evans 2014 in a recent Cochrane Review assessing the effects of laser photocoagulation for DR compared to no treatment or deferred treatment. PRP has been the mainstay of treatment of PDR for many years, but reviews on variations in the laser treatment protocol were recommended. A NIHR‐HTA project (12/71/01) addressed a similar question but in different populations, with earlier disease than in our review (Royle 2015).

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included only randomised controlled trials (RCTs) in this review.

Types of participants

We included people with type 1 or 2 diabetes mellitus of all ages and both sexes with PDR as defined in the included studies. We included a subgroup of trials where participants have received previous pharmacological treatments for diabetic eye disease. We did not exclude studies that enrolled participants with other associated retinal diseases such as retinal vein occlusion as long as the diabetic subgroup with PDR is clearly identified and the reason for laser is PDR.

Types of interventions

We included RCTs that consider laser pan‐retinal photocoagulation (PRP) for PDR but only those with a comparator group of standard argon laser PRP.

Interventions

We compared variations of the following parameters to the standard argon laser single spot treatment (comparator). We excluded studies that considered lasers that are not in common use, such as the xenon arc photocoagulation, ruby or Krypton laser.

Wavelength

Any ophthalmic laser type (wavelength) including but not limited to:

810 nm
577 nm
532 nm

Laser burn application

Any laser burn application method including but not limited to:

variations in total number of burns required to induce regression of neovascularisation, including number of laser sessions required;
use of multispot pattern laser delivery;
use of conventional slit lamp or the fundus camera‐navigated laser system.

Location of laser burns

Any laser burn target location including but not limited to ischaemia‐targeted retinal location.

Laser combined with other treatments

We included studies in which participants may have also received non‐laser based therapies for other indications such as diabetic macular oedema (DMO), for example anti‐VEGF, intraocular steroid implants or traditional Chinese medicine; however, we considered these as a separate subset.

We excluded studies that compare laser versus laser plus another non‐laser intervention for PDR, as this is covered in another Cochrane Review (Martinez‐Zapata 2014)

Comparator

The comparator was standard argon laser single spot treatment according to ETDRS guidelines. Specifically, the recommendations in the ETDRS are an initial treatment of midperipheral scatter laser consisting of 1200 to 1600 burns of moderate intensity, 200 μm to 500 μm spot size, with one‐half spot to one‐spot diameter spacing. Argon pulse duration is 100 ms to 200 ms with power titrated to produce moderate‐intensity burns but with full treatment divided over at least two sessions according to different clinical scenarios (ETDRS Research Group 1987).

Types of outcome measures

Primary outcomes

The primary outcome was best‐corrected visual acuity (BCVA). Specifically we used the proportion of people who lost or gained at least 15 ETDRS letters (equivalent to 3 ETDRS lines) as measured on a LogMAR chart at the one‐ and five‐year time point.

Secondary outcomes

We considered the following secondary outcomes.

Change in mean BCVA (LogMAR) from baseline to 12 months and five years.
Change in mean best‐corrected near visual acuity (NVA) from baseline to 12 months and five years.
Progression of diabetic retinopathy and/or maculopathy from baseline to 12 months and five years as defined by trial investigators, including optical coherence tomography (OCT) mean central subfield thickness (CMT) where measured.
Visual field (VF) loss from baseline to 12 months and five years compared to baseline including mean deviation (MD).
Patient‐reported outcome measure (PROM) for pain associated with the treatment, vision‐related quality of life (QoL) measured using any validated questionnaire, or loss of driving licence at 12 months and five years.
Resource use and costs.

We recorded two additional outcomes (not planned at the protocol stage).

Regression of diabetic retinopathy.
Need for further laser treatment after 3 months.

The reason we recorded these additional two outcomes is because progression and regression of diabetic retinopathy, and also need for further laser PRP treatment, all represent the same domain, i.e. disease control. This is an important clinical outcome so we wanted to capture all possible data, and several trials do not report progression but report regression or need for further treatment.

Adverse events

Adverse events reported in the studies at any time including but not limited to: macular oedema, retinal detachment, vitreous haemorrhage, need for vitrectomy surgery, severe visual loss (BCVA < 6/60).

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist conducted systematic searches in the following databases for randomised controlled trials and controlled clinical trials. There were no language or publication year restrictions. The date of the search was 8 June 2017.

Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 5) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 8 June 2017) (Appendix 1);
MEDLINE Ovid (1946 to 8 June 2017) (Appendix 2);
Embase Ovid (1980 to 8 June 2017) (Appendix 3);
ISRCTN registry (www.isrctn.com/editAdvancedSearch; searched 8 June 2017) (Appendix 4);
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 8 June 2017) (Appendix 5);
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 8 June 2017) (Appendix 6).

Searching other resources

We searched the reference lists of potentially includable studies to identify any additional trials. We did not handsearch conference proceedings for this review.

Data collection and analysis

Selection of studies

Two authors independently reviewed the titles and abstracts identified from the electronic and manual searches against the inclusion criteria using web‐based review management software (Covidence 2015). We obtained full‐text copies of all potentially or definitely relevant articles. We contacted trial investigators for further information if required. We resolved discrepancies between authors as to whether or not studies met inclusion criteria by discussion. We documented the excluded studies and the reasons for exclusion.

Data extraction and management

We extracted the following participant and trial characteristics and report them in a table format (Appendix 7).

Participant characteristics (age, sex, glycated haemoglobin (HbA1c), cholesterol, blood pressure, diagnostic criteria used for PDR, baseline visual acuity, OCT‐determined CMT, and areas of ischaemic retinal tissue according to fluorescein angiography).
Intervention (laser agent, laser settings, number of spots delivered, treatment interval and number, retinal target location).
Methodology (group size, randomisation, masking (blinding)).
Outcomes data as specified above.

We contacted trial investigators for key unpublished information that is missing from reports of included studies. Two review authors independently extracted the data, entering data into web‐based review management software (Covidence 2015), and using pre‐piloted data extraction templates. Covidence enabled us to compare discrepancies, which we resolved by discussion. We directly imported data from Covidence into Review Manager 5 (RevMan 5) (Review Manager 2014).

Assessment of risk of bias in included studies

Two review authors independently assessed the risk of bias of the included trials according to Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We considered the following main criteria.

Selection bias: random sequence generation, allocation concealment.
Performance bias: masking of participants, researchers and outcome assessors.
Attrition bias: loss to follow‐up, rates of adherence.
Reporting bias: selective outcome reporting. We reported each parameter as being at high, low, or unclear risk of bias, resolving any discrepancies between the authors by discussion. We contacted study authors to clarify study details relating to any unclear risk of bias. When there was no response from the authors, we classified the trial based on available information.

See Table 9 for additional information on assessment of risk of bias.

1. Risk of bias.

Item	Low	Unclear	High
Sequence generation	Computer generated list, random table, other method of generating random list	Not reported how list was generated. Trial may be described as 'randomised' but with no further details	Alternate allocation, date of birth, records (review authors should exclude these RCTs)
Allocation concealment	Central centre (web/telephone access), sealed opaque envelopes	Not reported how allocation administered. Trial may be described as 'randomised' but with no further details	Investigator involved in treatment allocation or treatment allocation clearly not masked
Blinding (masking) of participants and personnel	Clearly stated that participants and personnel (apart from doctor) not aware of which lens received	Described as 'double‐masked' with no information on who was masked	No information on masking. As lenses different we will assume that in absence of reporting on this, participants and personnel were not masked
Blinding (masking) of outcome assessors	Clearly stated that outcome assessors were masked	Described as 'double‐masked' with no information on who was masked	No information on masking. As lenses different we will assume that in absence of reporting on this, outcome assessors were not masked
Incomplete outcome data*	Missing data less than 20% (i.e. more than 80% follow‐up) and equal follow‐up in both groups and no obvious reason why loss to follow‐up should be related to outcome	Follow‐up not reported or missing data > 20% (i.e. follow‐up < 80%) but follow‐up equal in both groups	Follow‐up different in each group and related to outcome
Selective outcome reporting	All outcomes in protocol, trials registry entry or both are reported	No access to protocol or trials registry entry	Outcomes in protocol or trials registry entry selectively reported

Nd:YAG laser compared to argon‐green laser for proliferative diabetic retinopathy
Patient or population: people with proliferative diabetic retinopathy  Setting: eye hospital  Intervention: Nd:YAG laser  Comparison: argon‐green laser
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with argon‐green laser	Risk with Nd:YAG laser
BCVA: loss of 15 or more ETDRS letters  follow‐up: 1 year	Study population		RR 0.80  (0.30 to 2.13)	20  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
	500 per 1000	400 per 1000  (150 to 1000)
BCVA: gain of 15 or more ETDRS letters	Study population		RR 0.33 (0.02 to 7.32)	20  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
	100 per 1000	33 per 1000  (2 to 732)
Progression of PDR  follow‐up: 1 year	Study population		RR 1.00  (0.07 to 14.95)	42  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 2 4}
	48 per 1000	48 per 1000  (3 to 712)
Regression of PDR  follow‐up: 1 year	Study population		RR 1.00  (0.87 to 1.14)	42  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 2 5}
	952 per 1000	952 per 1000  (829 to 1000)
Pain during laser treatment	Study population		RR 1.00 (0.36 to 2.76)	62 (2 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 6}
	190 per 1000	190 per 1000  (69 to 524)
Vision‐related QoL ‐ not reported	‐	‐	‐	‐	‐
Adverse events	Vitreous haemorrhage, 13% of argon group, RR 1.22 (0.38 to 3.94); choroidal detachment, 19% of argon group, RR 0.23 (0.04 to 1.27); neurotrophic keratopathy, 10% of argon group, RR 1.29 (0.35 to 4.75).			62 (2 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 2 7}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Diode laser compared to argon laser for proliferative diabetic retinopathy
Patient or population: people with proliferative diabetic retinopathy  Setting: eye hospital  Intervention: diode laser  Comparison: argon laser
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with argon	Risk with Diode
BCVA: loss of 15 or more ETDRS letters  follow‐up: 1 year	Study population		RR 0.95 (0.66 to 1.36)	134  (2 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
	345 per 1000	379 per 1000  (231 to 628)
BCVA: gain of 15 or more ETDRS letters  follow‐up: 1 year	Study population		RR 0.60 (0.25 to 1.45)	134  (2 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
	190 per 1000	119 per 1000  (47 to 302)
Progression of PDR follow‐up: 1 year	Study population		RR 0.90 (0.41 to 2.00)	66 (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 3 4}
	286 per 1000	257 per 1000  (117 to 571)
Regression of PDR  follow‐up: 1 year	Study population		RR 0.75  (0.35 to 1.60)	66  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 3 4}
	343 per 1000	257 per 1000  (120 to 549)
Pain during laser treatment	211 per 1000	688 per 1000 (428 to 1000)	RR 3.07 (2.15 to 4.39)	228 (4 RCTs)	⊕⊕⊕⊝  MODERATE ¹
Vision‐related QoL ‐ not reported	‐	‐	‐	‐	‐
Adverse events	Vitreous haemorrhage, 15% of argon group. inconsistent results between two studies, RR 0.50 (0.05, 4.86) and RR 1.82 (0.76, 4.35); choroidal detachment, 8% of argon group RR 4.00 (0.51, 31.13; neurotrophic keratopathy, 0% of argon group, RR 3.00 (0.13, 67.51), maculopathy, 14% of argon group, RR 1.30 (0.54, 3.13), cataract, 16% of argon group, RR 0.52 (0.17, 1.57), pre‐retinal membrane, 5% of argon group, RR 1.16 (0.24, 5.49).			134 (2 studies)	⊕⊝⊝⊝  VERY LOW ^{1 5}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

0.5 compared to 0.1 second exposure for proliferative diabetic retinopathy
Patient or population: proliferative diabetic retinopathy  Setting: eye hospital  Intervention: 0.5 second exposure  Comparison: 0.1 second exposure
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with 0.1 second exposure	Risk with 0.5 second exposure
BCVA: loss of 15 or more EDTRS letters ‐ 1 year	Study population		RR 0.42 (0.08 to 2.04	44  (1 RCT)	⊕⊕⊝⊝  LOW ^{1 2}
	200 per 1000	84 per 1000  (16 to 408)
BCVA: gain of 15 or more EDTRS letters ‐ 1 year	Study population		RR 2.22 (0.68 to 7.28)	44  (1 RCT)	⊕⊕⊝⊝  LOW ^{1 2}
	150 per 1000	333 per 1000  (102 to 1000)
Progression of PDR ‐ 1 year	Study population		RR 0.33 (0.02 to 7.14)	16 (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 3}
	125 per 1000	41 per 1000  (3 to 893)
Regression of PDR ‐ 1 year	Study population		RR 1.17  (0.92 to 1.48)	32  (1 RCT)	⊕⊕⊝⊝  LOW ^{1 2}
	857 per 1000	1000 per 1000  (789 to 1000)
Pain during laser treatment ‐ not reported	‐	‐	‐	‐	‐
Adverse events	Pre‐retinal or vitreous haemorrhage, 30% of 0.1 sec group, (RR 0.56 (0.18 to 1.70)); macular thickening, 2 cases in 0.1 sec group; combined rhegmatous and traction retinal detachment, 1 case in 0.5 sec group.		‐	44 (1 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 3}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Light PRP compared to classic PRP for proliferative diabetic retinopathy
Patient or population: proliferative diabetic retinopathy  Setting: eye hospital  Intervention: light PRP  Comparison: classic PRP
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with classic	Risk with Light
BCVA: loss of 15 letters or more ‐ not reported	‐	‐	‐	‐	‐	Mean difference in logMAR acuity at 1 year was −0.09, 95% CI −0.22 to 0.04; participants = 65; studies = 1.
BCVA: gain of 15 letters or more ‐ not reported
Progression of DR ‐ not reported	‐	‐	‐	‐	‐
Regression of PDR ‐ not reported	‐	‐	‐	‐	‐
Pain during laser treatment	Study population		RR 0.23  (0.03 to 1.93)	65  (1 RCT)	⊕⊕⊝⊝  LOW ^{1 2}
	129 per 1000	30 per 1000  (4 to 249)
Adverse events	Vitreous haemorrhage, 19% in classic group, RR 0.07 (0.00 to 1.20); choroidal detachment 3 cases in classic group; neurotrophic keratopathy, 2 cases in classic group; clinically significant macular oedema, 23% of classic group, RR 0.13 (0.02 to 1.00).		‐	65 (1 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 3}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Mild scatter PRP compared to full scatter PRP for proliferative diabetic retinopathy
Patient or population: proliferative diabetic retinopathy  Setting: eye hospital  Intervention: mild scatter PRP  Comparison: full scatter PRP
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with Full scatter PRP	Risk with Mild scatter PRP	Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
BCVA: loss of 15 or more ETDRS letters ‐ not reported	‐	‐	‐	‐	‐	Mean Snellen decimal acuity was similar in the two groups at 3 months. Mild scatter 0.93 (SD 0.11), full scatter 0.89 (SD 0.19).
BCVA: gain of 15 or more ETDRS letters ‐ not reported	‐	‐	‐	‐	‐
Progression if PDR ‐ not reported	‐	‐	‐	‐	‐
Regression of PDR ‐ not reported	‐	‐	‐	‐	‐
Pain during laser treatment ‐ not reported	‐	‐	‐	‐	‐
Vision‐related QoL ‐ not reported	‐	‐	‐	‐	‐
Adverse events ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Central compared to peripheral for proliferative diabetic retinopathy
Patient or population: proliferative diabetic retinopathy  Setting: eye hospital  Intervention: central  Comparison: peripheral
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with peripheral	Risk with Central
BCVA: loss of 15 or more ETDRS letters ‐ 1 year	Study population		RR 3.00  (0.67 to 13.46)	50  (1 RCT)	⊕⊕⊝⊝  LOW ^{1 2}
	80 per 1000	240 per 1000  (54 to 1000)
BCVA: gain of 15 or more ETDRS letters ‐ 1 year	Study population		RR 0.25 (0.03 to 2.08)	50  (1 RCT)	⊕⊕⊝⊝  LOW ^{1 2}
	160 per 1000	40 per 1000  (5 to 333)
Progression of DR ‐ not reported					‐
Regression of PDR ‐ not reported	‐	‐	‐	‐	‐
Pain during laser treatment ‐ not reported	‐	‐	‐	‐	‐
Vision‐related QoL ‐ not reported	‐	‐	‐	‐	‐
Adverse events	Vitreous haemorrhage requiring additional PRP, 1 case in each group; macular traction detachment requiring pars plana vitrectomy, 3 cases in central group, 1 case in peripheral group; macular thickening associated with loss of 2 or more lines of visual acuity, 2 cases in each group.		‐	50 (1 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 3}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Centre sparing PRP compared to full scatter PRP for proliferative diabetic retinopathy
Patient or population: proliferative diabetic retinopathy  Setting: eye hospital  Intervention: centre sparing PRP  Comparison: full scatter PRP
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with full scatter PRP	Risk with Centre sparing
BCVA: loss of 15 or more ETDRS letters  follow‐up: 1 year	Study population		RR 0.67  (0.30 to 1.50)	53  (1 RCT)	⊕⊕⊝⊝  LOW ^{1 2}
	385 per 1000	258 per 1000  (115 to 577)
BCVA: gain of 15 or more ETDRS letters follow‐up: 1 year ‐ not reported	‐	‐	‐	‐	‐
Progression of DR ‐ not reported	‐	‐	‐	‐	‐
Regression of PDR  follow up: 1 year	Study population		RR 0.96  (0.73 to 1.27)	53  (1 RCT)	⊕⊕⊝⊝  LOW ^{1 2}
	808 per 1000	775 per 1000  (590 to 1000)
Pain during laser treatment ‐ not reported	‐	‐	‐	‐	‐
Vision‐related QoL ‐ not reported	‐	‐	‐	‐	‐
Adverse events ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence  High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Extended targeted PRP compared with standard PRP for proliferative diabetic retinopathy
Patient or population: people with diabetic retinopathy Settings: eye hospital Intervention: extended targeted PRP Comparison: standard PRP
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	standard PRP	extended targeted PRP
BCVA: loss of 15 or more ETDRS letters: follow‐up 1 year	Study population		RR 0.94 (0.70 to 1.28)	270 (1 RCT)	⊕⊕⊝⊝  LOW^{1 2}	Mean difference in BCVA at 1 year was: 0.00 logMAR, (−0.05 to 0.05)
	393 per 1000	369 per 1000  (275 to 503)
BCVA: gain of 15 or more ETDRS letters: follow‐up 1 year, not reported	‐	‐	‐	‐	‐	‐
Progression of DR ‐ not reported	‐	‐	‐	‐	‐	‐
Regression of PDR follow‐up 1 year	Study population		RR 1.11 (0.95 to 1.31)	270 (1 RCT)	⊕⊕⊝⊝  LOW^{1 2}
	644 per 1000	715 per 1000  (612 to 844)
Pain during laser treatment ‐ not reported	‐	‐	‐	‐	‐	‐
Vision‐related QoL ‐ not reported	‐	‐	‐	‐	‐	‐
Adverse events	Quote: "None of the eyes developed tractional retinal detachment during the study. Additionally, no ocular or non‐ocular AEs related to the study intervention were detected by the investigators or reported by patients"				⊕⊝⊝⊝  VERY LOW ³
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk Ratio; AE: adverse events
GRADE Working Group grades of evidence  High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Change in BCVA
Study	Nd: YAG: mean decimal Snellen acuity at follow‐up (SD)	N	Argon: mean decimal Snellen acuity at follow‐up (SD)	N
Bandello 1996	0.5 (0.25)	21	0.45 (0.27)	21
Brancato 1991	0.5 (0.25)	10	0.5 (0.25)	10

Adverse event	Study	Nd:YAG n/N (%)	Argon n/N (%)	RR (95% CI)	Pooled RR (95% CI)
Vitreous haemorrhage	Bandello 1996	5/21 (24%)	2/21 (10%)	2.50 (0.54, 11.48)	1.22 (0.38 to 3.94) I² = 57%)
Vitreous haemorrhage	Brancato 1991	0/10 (0%)	2/10 (20%)	0.20 (0.01, 3.70)	1.22 (0.38 to 3.94) I² = 57%)
Choroidal detachment	Bandello 1996	1/21 (5%)	5/21(24%)	0.20 (0.03, 1.57)	0.23 (0.04 to 1.27) I² = 0%)
Choroidal detachment	Brancato 1991	0/10 (0%)	1/10 (10%)	0.33 (0.02, 7.32)	0.23 (0.04 to 1.27) I² = 0%)
Neurotrophic keratopathy	Bandello 1996	3/21 (14%)	3/21 (14%)	1.00 (0.23, 4.40)	1.29 (0.35 to 4.75) I² = 0%)
Neurotrophic keratopathy	Brancato 1991	1/10 (10%)	0/10 (0%)	3.00 (0.14, 65.90)	1.29 (0.35 to 4.75) I² = 0%)

Adverse event	Study	Diode n/N (%)	Argon n/N (%)	RR (95% CI)	Pooled RR (95% CI)
Vitreous haemorrhage	Bandello 1993	7/22 (32%)	4/22 (18%)	1.75 [0.60, 5.14]	1.80 (0.91 to 3.53)
	Han 1995	11/50 (22%)	7/58 (12%)	1.82 (0.76, 4.35)
	Tewari 2000	NR	NR
Choroidal detachment	Bandello 1993	4/22 (18%)	1/22 (5%)	4.00 [0.48, 33.00]	NA
	Han 1995	NR	NR
	Tewari 2000	NR	NR
Neurotrophic keratopathy	Bandello 1993	1/22 (5%)	0/22 (0%)	3.00 [0.13, 69.87]	NA
	Han 1995	NR	NR
	Tewari 2000	NR	NR
Maculopathy	Bandello 1993	NR	NR		NA
	Brancato 1990	NR	NR
	Han 1995	9/50 (18%)	8/58 (14%)	1.30 (0.54, 3.13)
	Tewari 2000	NR	NR
Cataract	Bandello 1993	NR	NR		NA
	Brancato 1990	NR	NR
	Han 1995	4/50 (8%)	9/58 (16%)	0.52 (0.17, 1.57)
	Tewari 2000	NR	NR
Pre‐retinal membrane	Bandello 1993	NR	NR		NA
	Brancato 1990	NR	NR
	Han 1995	3/50 (6%)	3/58 (5%)	1.16 (0.24, 5.49)
	Tewari 2000	NR	NR

Mandatory items		Optional items
Methods
Study design	Parallel group RCT(i.e. people randomised to treatment) Within‐person RCT (i.e. eyes randomised to treatment) Cluster RCT (i.e. communities randomised to treatment) Cross‐over RCT Other, specify	Exclusions after randomisation Losses to follow‐up Number randomised/analysed How were missing data handled? (e.g. available case analysis, imputation methods) Reported power calculation (Y/N), if yes, sample size and power Unusual study design/issues
Eyes or Unit of randomisation/unit of analysis	One eye included in study, specify how eye selected Two eyes included in study, both eyes received same treatment, briefly specify how analysed (best/worst/average/both and adjusted for within person correlation/both and not adjusted for within person correlation) and specify if mixture one eye and two eye Two eyes included in study, eyes received different treatments,specify if correct pair‐matched analysis done
Participants
Country		Setting Ethnic group Equivalence of baseline characteristics (Y/N)
Total number of participants	This information should be collected for total study population recruited into the study. If these data are only reported for the people who were followed up only, please indicate.
Number (%) of men and women
Average age and age range
Inclusion criteria
Exclusion criteria
Interventions
Intervention (n = ) Comparator (n = ) See MECIR 65 and 70	Number of people randomised to this group Drug (or intervention) name Dose Frequency Route of administration
Outcomes
Primary and secondary outcomes as defined in study reports See MECIR R70	List outcomes Adverse events reported (Y/N) Length of follow‐up and intervals at which outcomes assessed	Planned/actual length of follow‐up
Notes
Date conducted	Specify dates of recruitment of participants mm/yr to mm/yr	Full study name: (if applicable) Reported subgroup analyses (Y/N) Were trial investigators contacted?
Sources of funding
Declaration of interest See MECIR 69

Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Baseline characteristics Diode laser Number of people (eyes) randomised: 17 (22) Number (%) of people followed up: 17 (100%) Average age in years: 54 Age range in years: NR Percentage women: 29% Ethnic group: NR Percentage type I diabetes: 66% Percentage type II diabetes: 34% Mean baseline visual acuity (SD): 0.7 (0.3) Argon‐green laser Number of people (eyes) randomised: 17 (22) Number (%) of people followed up: 17 (100%) Average age in years: 44 Age range in years: NR Percentage women: 41% Ethnic group: NR Percentage type I diabetes: 41% Percentage type II diabetes: 59% Mean baseline visual acuity (SD): 0.7 (0.2) Overall Number of people (eyes) randomised: 34 (44) Number (%) of people followed up: 34 (100%) Average age in years: 49 Age range in years: NR Percentage women: 35% Ethnic group: Percentage type I diabetes: Percentage type II diabetes: Mean baseline visual acuity (SD): Inclusion criteria: age at least 18 years; visual acuity (VA) of 0.3 or more;  PDR with clinically obvious disc new vessels or neovascularisations elsewhere along the vascular arcades (equal to or more than one‐half the disc area or associated with hemorrhage). Exclusion criteria: vitreous hemorrhage obscuring more than 25 % of the fundus, maculopathy reducing the VA to below 0.3, tractional retinal detachment, Pretreatment: Possible differences in demographics, type of diabetes and duration of disease (Table 1). No statistical analysis on differences Eyes: 44 eyes of 34 people with 10 people having a within‐person design. No adjustment made in the analysis.
Interventions	Intervention characteristics Diode laser Type of laser: diode laser (810nm) Total number of burns: 2335 (SD 703) Number of laser sessions: 10 Laser application (single/multispot): single Laser route (slit lamp/fundus camera): slit lamp Laser target location (panretinal/ischaemia targeted): ablation of nonperfused peripheral and midperipheral retinal areas Any additional therapy (non‐PDR related): Mean laser power and size: 752 (SD 113) mW, 500 microns. Power decreased to 670 (SD 90) mW after the first 13 cases. Argon‐green laser Type of laser: argon laser Total number of burns: 2041 (SD 305) Number of laser sessions: 5 Laser application (single/multispot): single Laser route (slit lamp/fundus camera): slit lamp Laser target location (panretinal/ischaemia targeted): Any additional therapy (non‐PDR related): ablation of nonperfused peripheral and midperipheral retinal areas Mean laser power and size: 432 (SD 116) mW, 500 microns
Outcomes	Visual acuity, PDR regression, vitreous haemorrhage, choroidal detachment, pain, complications Follow‐up: mean follow‐up 24 (SD 4) months in the diode laser group and 25 (SD 5) months in argon laser group
Notes	Funding: NR Declaration: NR Country: Italy Setting: eye hospital Date of study: November 1989 to July 1990 Contacting of study investigator: not contacted Trial registration number: NR
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote "Randomization assigned consecutively one eye to ALT and the next to DLT. Of the ten patients in which both eyes were included in the study, the right eye was assigned to DLT and the left to DLT" Judgement comment: Assignment appears to be by alternation.
Allocation concealment (selection bias)	High risk	Judgement comment: Allocation was not concealed
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Judgement comment: no information on masking. We assume that in absence of reporting on this, participants and personnel were not masked.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Judgement comment: no information on masking. We assume that in absence of reporting on this, outcome assessors were not masked.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Judgement comment: no apparent loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no access to protocol or trials registry entry.

Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Baseline Characteristics Intervention Number of people (eyes) randomised: 24 (25 eyes) Number (%) of people followed up: 25 eyes (100%) Average age in years: 40 Age range in years: 19 to 65 Percentage women: 58% Ethnic group: NR Percentage type I diabetes: 92% maintained with insulin Percentage type II diabetes: NR Mean baseline visual acuity (SD): NR Comparator Number of people (eyes) randomised: 24 (25 eyes) Number (%) of people followed up: 25 eyes(100%) Average age in years: 46 Age range in years: 23 to 69 Percentage women: 50% Ethnic group: NR Percentage type I diabetes: 80% maintained with insulin Percentage type II diabetes: NR Mean baseline visual acuity (SD): NR Overall Number of people (eyes) randomised: 40 (50 eyes) Number (%) of people followed up: 100% Average age in years: 43 Age range in years: 19 to 69 Percentage women: 54 Ethnic group: NR Percentage type I diabetes: 85% maintained with insulin Percentage type II diabetes: NR Mean baseline visual acuity (SD): NR Inclusion criteria: diabetes mellitus; available for follow‐up; 6/30 or better BCVA; 3 or 4 diabetic retinopathy risk factors; media clarity to permit argon laser PRP within a single session. Exclusion criteria: prior photocoagulation; substantial lens opacities or vitreous haemorrhages sufficient to prevent complete argon laser PRP. Pretreatment: groups were similar. Eyes: Both eyes were enrolled in 10 people (50 eyes of 40 people); both eyes reported but not adjusted for within‐person correlation. In comparator group 1 eye not randomised to make both arms equal.
Interventions	Intervention characteristics Intervention Type of laser: central argon PRP laser Total number of burns: 452 midperiphery + 437 posteriorly (mean n) Number of laser sessions: 1 Laser application (single/multispot): single Laser route (slit lamp/fundus camera): slit lamp Laser target location (panretinal/ischaemia targeted): panretinal Any additional therapy (non‐PDR related): no post‐treatment medications Spot size (μm): 500 Laser burn intensity (light/moderate/heavy): moderate blanching Laser burn spacing: NR Any additional information on intervention/comparator: retrobulbar anaesthesia used for all cases as per protocol. Comparator Type of laser: peripheral argon PRP laser Total number of burns: 446 midperiphery + 441 more peripherally (mean n) Number of laser sessions: 1 Laser application (single/multispot): single Laser route (slit lamp/fundus camera): slit lamp Laser target location (panretinal/ischaemia targeted): panretinal Any additional therapy (non‐PDR related): no post treatment medications Spot size (μm): 500 Laser burn intensity (light/moderate/heavy): moderate blanching Laser burn spacing: NR Any additional information on intervention/comparator: retrobulbar anaesthesia
Outcomes	Best corrected visual acuity (Snellen lines) visual fields scores; macular thickening; neovascularisation of the disc and retina; intraocular pressure; vitreous haemorrhage. Follow‐up: 6 months
Notes	Funding: "Supported in part by patients and contributors of the Bascom Palmer Eye Institute, Research to Prevent Blindness. Inc, New York, the Florida Lions Eye Bank, and the Brenn Green Diabetic Retinopathy Fund, Miami, Florida." Declaration of interest: NR Country: USA Setting: eye hospital Date study conducted: NR Trial registration number: not reported Contacting study investigators: not contacted
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "After the patient had been informed and had consented to participate, a coin was flipped which determined whether the eye was to receive central or peripheral PRP argon laser treatment. The last two eyes were not Randomised but received central PRP treatment to make an equal number of 25 eyes in each group."
Allocation concealment (selection bias)	Low risk	Quote: "a coin was flipped which determined whether the eye was to receive central or peripheral PRP argon laser treatment. The last two eyes were not Randomised but received central PRP treatment to make an equal number of 25 eyes in each group." Judgement comment: allocation decided after informed and agreed to participate.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Judgement comment: no information on masking. We assume that in the absence of reporting on this, participants and personnel were not masked.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Judgement comment: no information on masking. We assume that in the absence of reporting on this, participants and personnel were not masked.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "All of the patients returned for follow‐up evaluations 6 months after treatment." Judgement comment: 1‐ and 6‐month follow‐up available for all participants
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no access to protocol or trial register entry.

Change in BCVA
Study	Follow‐up	Diode: mean Snellen decimal acuity at follow‐up (SD)	N	Argon: mean Snellen decimal acuity at follow‐up (SD)	N
Bandello 1993	Average of approximately 2 years (24 months)	0.4 (0.3)	22	0.4 (0.3)	22
Tewari 2000	6 months	3,62 (2.12) reciprocal of Snellen decimal acuity	25	4.76 (2.83) reciprocal of Snellen decimal acuity	25

Adverse event	0.5 sec n/N (%)	0.1 sec n/N (%)	RR (95% CI)
Pre‐retinal or vitreous haemorrhage	4/24 (17%)	6/20 (30%)	0.56 (0.18 to 1.70)
Macular thickening	0/24 (0%)	2/20 (10%)	0.17 (0.01 to 3.31)
Combined rhegmatous and traction retinal detachment requiring pars plana vitrectomy	1/24 (4%)	0/20 (0%)	2.52 (0.11 to 58.67)

Adverse event	Light n/N (%)	Classic n/N (%)	RR (95% CI)
Vitreous haemorrhage	0/34 (0%)	6/31 (19%)	0.07 (0.00 to 1.20)
Choroidal detachment	0/34 (0%)	3/31 (10%)	0.13, (0.01 to 2.43)
Neurotrophic keratopathy	0/34 (0%)	2/31 (6%)	0.18 (0.01 to 3.67)
Clinically significant macular oedema	1/34 (3%)	7/31 ( 23%)	0.13 (0.02 to 1.00)

Change in BCVA
Study	Mild scatter: mean Snellen decimal acuity (SD)	N	Full scatter: mean Snellen decimal acuity (SD)	N
Pahor 1998	0.93 (0.11)	19	0.89 (0.19)	21

Adverse event	Central n/N (%)	Peripheral n/N (%)	RR (95% CI)
Vitreous haemorrhage (requiring additional PRP)	1/25 (4%)	1/25 (4%)	RR 1.00 (0.07 to 15.12)
Macular traction detachment (requiring pars plana vitrectomy)	3/25 (12%)	1/25 (4%)	RR 3.00 (0.33 to 26.92)
Macular thickening (associated with loss of 2 or more lines of visual acuity)	2/25 (8%)	2/25 (8%)	RR 1.00 (0.15 to 6.55)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 BCVA: loss of 15 or more ETDRS letters	1		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
2 BCVA: gain of 15 or more ETDRS letters	1		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
3 Change in BCVA			Other data	No numeric data
4 Progression of PDR	1		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
5 Regression of PDR	1		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
6 Pain during laser treatment	2	62	Risk Ratio (IV, Fixed, 95% CI)	1.0 [0.36, 2.76]
7 Adverse effects	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.1 Vitreous haemorrhage	2	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.38, 3.94]
7.2 Choroidal detachment	2	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.04, 1.27]
7.3 Troublesome pain	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.17, 5.77]
7.4 Neurotrophic keratopathy	2	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.35, 4.75]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 BCVA: loss of 15 or more EDTRS letters	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 BCVA: gain of 15 or more EDTRS letters	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Progression of PDR	1	Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
4 Regression of PDR	1	Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
5 Adverse effects	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.1 Pre‐retinal or vitreous haemorrhage	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Macular thickening	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Combined rhegmatous and traction retinal detachment requiring pars plana vitrectomy	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Change in BCVA	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2 Pain during laser treatment	1	Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
3 Adverse effects	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.1 Vitreous haemorrhage	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Choroidal detachment	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Neurotrophic keratopathy	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Clinically significant macular oedema	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 BCVA: loss of 15 or more letters	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Change in BCVA	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3 Regression of PDR	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Change in central macular thickness	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Study	Reason for exclusion
Al Hussainy 2008	No standard comparator group ‐ Nd:YAG laser only
Alvarez Verduzco 2010	Not a randomised controlled trial
Beetham 1969	Ruby laser no longer in common use
Belucio‐Neto 2015	No standard (argon laser) comparator group
Blankenship 1986	Krypton laser not in common use
Blankenship 1991	No standard comparator group ‐ argon laser compared with xenon laser and untreated comparator group.
Canning 1991	Relevant outcomes not reported and may not have been measured as study focuses on macular function. Study too old (<25 years) to obtain data from investigators.
Capoferri 1990	Krypton laser not in common use
Chen 2004	Krypton laser not in common use
Chen 2013	No standard (argon laser) comparator group
Chew 1991	Krypton laser no longer in common use
Chhablani 2014	No standard (argon laser) comparator group
Crick 1978	Xenon laser no longer in common use
Doft 1982	Compared single versus multiple treatment sessions which was not one of our pre‐defined comparisons
Dong 2008	Not a randomised controlled trial
Fankhauser 1972	Not a randomised controlled trial
Francois 1971	Xenon laser no longer in common use
Francois 1977	Not a randomised controlled trial
Geltzer 1972	Not a randomised controlled trial
Ghassemi 2013	Measured nerve fibre layer thickness only
Guo 2013	Compared one versus two sittings which was not one of our pre‐defined comparisons
Hamilton 1981	Xenon laser no longer in common use
Inan 2016	No standard comparator group
KARNS 1994	Krypton laser no longer in common use
Khosla 1994	Compared one versus two sittings which was not one of our pre‐defined comparisons
Kovacic 2012	Not a randomised controlled trial
Li 1986	Only measured electroretinographic changes
Liang 1983	Xenon arc laser not in use any more
Lopez 2008	Not a randomised controlled trial
Ludwig 1994	Not a randomised controlled trial
MAPASS 2010	No standard (argon) comparator group ‐ pascal laser only (532nm)
McLean 1976	Xenon laser no longer in common use
Menchini 1990	Krypton laser no longer in common use
Menchini 1995	Krypton laser no longer in common use
Mirshahi 2013	No standard (argon) comparator group ‐ Nd:YAG (532nm) laser only
Muraly 2011	No standard (argon) comparator group ‐ Nd:YAG (532nm) laser only
Nagpal 2008	No standard (argon) comparator group (conference abstract only).
Nagpal 2010	No standard (argon) comparator group (conference abstract only).
Peng 2013	No standard (argon) comparator group
PETER PAN 2011	No standard (argon) comparator group ‐ PASCAL laser only
Plumb 1982	Xenon arc laser no longer in common use.
Roohipoor 2016	Intervention not in common use (red laser)
Sato 2012	Participants had pre‐proliferative diabetic retinopathy
Schulenburg 1979	Krypton laser not in common use
Seiberth 1987	Participants in this study had pre‐proliferative diabetic retinopathy
Seiberth 1993	Participants had pre‐proliferative diabetic retinopathy
Seymenoglu 2013	Not a randomised controlled trial
Shiraya 2014	Not a randomised controlled trial
Ulbig 1994	Not a randomised controlled trial
Yassur 1980	No standard (argon) comparator group ‐ comparator group was untreated.
Yilmaz 2016	Not a randomised controlled trial
Zhang 2017	No standard (argon) comparator group ‐ pattern scan (577nm) only

PERMALINK

Different lasers and techniques for proliferative diabetic retinopathy

Tanya Moutray

Jennifer R Evans

Noemi Lois

David J Armstrong

Tunde Peto

Augusto Azuara‐Blanco

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Interventions

Wavelength

Laser burn application

Location of laser burns

Laser combined with other treatments

Comparator

Types of outcome measures

Primary outcomes

Secondary outcomes

Adverse events

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

1. Risk of bias.

Measures of treatment effect

Dichotomous data

Continuous data

Qualitative data

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup and sensitivity analyses

'Summary of findings' table

Results

Description of studies

Results of the search

1.

Included studies

Types of study

Participants

Interventions

Outcomes

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Effects of interventions

Summary of findings for the main comparison. Nd:YAG laser compared to argon‐green laser for proliferative diabetic retinopathy.

Summary of findings 2. Diode laser compared to argon laser for proliferative diabetic retinopathy.

Summary of findings 3. 0.5 compared to 0.1 second exposure for proliferative diabetic retinopathy.

Summary of findings 4. Light PRP compared to classic PRP for proliferative diabetic retinopathy.

Methods	Prospective study
Participants	People with proliferative diabetic retinopathy
Interventions	Panretinal photocoagulation
Outcomes	Not known
Notes	We were unable to find either an abstract or a full text copy of this citation

Methods	Within‐person study
Participants	146 eyes of 73 participants with proliferative diabetic retinopathy
Interventions	Single spot laser photocoagulation Pattern scan laser photocoagulation Unclear what laser was used
Outcomes	Changes in retinal ischemia Regression of neovascularisation Follow‐up: 6 months Quote "Findings: There was no significant difference in the retinal neovascularization regression of disc and elsewhere in eyes treated with pattern scan (P = 0.26) or single spot laser (P = 0.31). While the areas of the retinal ischemia progression was significantly higher (9 cases) in group treated with pattern scan in comparison to other group (2 cases) (P = 0.02)."
Notes	We were unable to source a copy of this and did not receive a response from the author.

Methods	Parallel group study
Participants	60 people with PDR
Interventions	Pascal versus conventional laser
Outcomes	Successful outcome
Notes	Investigator contacted but no reply.

Methods	Prospective study, possibly randomised
Participants	Quote "30 eyes with PDR and presenting visual acuity of 20/100 or better. Eyes with vitreous hemorrhage or prior laser treatment were excluded."
Interventions	Central PRP (n=16 eyes) versus peripheral PRP (n=14 eyes) Quote "A Mainster panfunduscopic lens was used to deliver 1600 spots in 500 micron size in each group."
Outcomes	Macular oedema, visual acuity, retinal detachment, decrease in vision. Follow‐up: 6 weeks and 5 months
Notes	Quote "There was no significant difference in either group in. macular edema on IVFA. Three eyes (20%) have lost two lines of Snellen acuity at their six week follow up in the central group, but no significant difference in the final visual accuity was noted at the five month follow up. One eye in the central group and two in the peripheral group also developed fractional macular retinal detachment. Central PRP in PDR may carry a higher incidence of transient decrease in vision compared to peripheral PRP. An analysis of the risk factors in these 30 eyes is presented." Reported as abstract only. We contacted author for further clarification as to whether this was a randomised controlled trial but did not receive any reply.

Methods	Randomised controlled trial
Participants	People with diabetic retinopathy
Interventions	Patterned panretinal photocoagulation with short laser exposure time (0.02 seconds) Conventional panretinal photocoagulation with long laser exposure time (0.2 seconds)
Outcomes	Progression of diabetic retinopathy Best‐corrected visual acuity Central macular thickness Pain during treatment Follow‐up: 1, 2, 4, 8 weeks and 1 year Quote "The progression of diabetic retinopathy was not different in both groups at the 1‐year follow‐up visit. The best‐corrected visual acuities at 1, 2, 4, and 8 weeks after PRP were decreased in both groups and, in the conventional PRP group, the decrements of visual acuity were greater than in the patterned PRP group. The increments of central macular thickness were also greater in the conventional PRP group than the patterned PRP group."
Notes	Awaiting translation