Design

All included studies were parallel RCTs, except for Figueira 2009, which randomised one eye to standard macular photocoagulation and the fellow eye to subthreshold micropulse photocoagulation.

Sample size

Twenty of the included studies did not report any details relating to sample size calculation. Sample sizes ranged from 23 eyes (Laursen 2004) to 2244 eyes (ETDRS 1985).

Setting

The trials took place in a variety of settings:

• nine in Europe (Bandello 2005; Casswell 1990; Figueira 2009; Freyler 1990; Ladas 1993; Laursen 2004; Rutllan Civit 1994; Vujosevic 2010; Vujosevic 2015);

• seven trials took place in the USA (Akduman 1997; Blankenship 1979; DRCRNET 2007; ETDRS 1985; Olk 1986; Olk 1990; Striph 1988);

• four in Asia: two in China (Pei‐Pei 2015; Xie 2013), and two in India (Tewari 1998; Venkatesh 2011);

• one in Europe‐Asian (Turkey) (Karacorlu 1993);

• one in Latin America (Lavinsky 2011);

• one in Africa (Khairallah 1996);

• one in Oceania (Casson 2012).

Participants and duration of trials

Fifteen studies followed participants for 12 months or less (Akduman 1997; Bandello 2005; Casson 2012; DRCRNET 2007; Figueira 2009; Karacorlu 1993; Khairallah 1996; Laursen 2004; Lavinsky 2011; Pei‐Pei 2015; Rutllan Civit 1994; Tewari 1998; Venkatesh 2011; Vujosevic 2010; Xie 2013). Six studies followed participants for more than 12 months (Blankenship 1979; Casswell 1990; ETDRS 1985; Ladas 1993; Olk 1986; Olk 1990). One study did not report the follow‐up (Striph 1988), and one study presented a follow‐up of six to 24 months (Freyler 1990).

Types of intervention

Four studies randomised participants to macular grid/focal argon laser or no intervention (Blankenship 1979; ETDRS 1985; Ladas 1993; Olk 1986).

Nine studies randomised participants to either argon or other types of laser (Akduman 1997; Casswell 1990; Freyler 1990; Karacorlu 1993; Khairallah 1996; Olk 1990; Rutllan Civit 1994; Striph 1988; Tewari 1998). Two studies compared argon versus diode laser (Akduman 1997; Tewari 1998); four studies compared argon versus krypton laser (Casswell 1990; Khairallah 1996; Olk 1990; Striph 1988); and three studies compared argon versus dye laser (Freyler 1990; Karacorlu 1993; Rutllan Civit 1994).

One study compared standard modified ETDRS grid technique with a mild macular grid (MMG) technique (DRCRNET 2007). The standard modified ETDRS grid technique consisted of treating leaking microaneurysms with mild‐grey laser burns and a grid laser with barely visible spots applied to all areas with diffuse leakage or non‐perfusion within the area considered for grid treatment. The MMG technique consisted of barely visible spots applied to the entire area considered for grid treatment (including unthickened retina). Because laser spots of similar intensity were applied in both treatment arms, and the difference was either in treating microaneurysms (standard) or in the area to be treated (larger in MMG), we did not include this study when different intensities of the visible versus invisible laser spots were compared.

Nine studies compared treatment strategies that adopted laser spots of different intensity to explore whether barely visible or invisible laser spots (subthreshold photocoagulation), obtained with either standard laser or with micropulse laser, were similarly effective to standard argon macular laser with visible, usually mild‐grey, laser spot on the retina. Two studies used a standard macular, continuous‐wave laser to achieve subthreshold photocoagulation (Bandello 2005; Pei‐Pei 2015). Six studies obtained subthreshold macular laser treatment with a micropulse photocoagulator, in which a series of very short duration impulses are delivered consecutively (typically with 5% to 15% laser duty‐cycle) and no visible spot can be seen on the retina, with the aim of causing minimal or no retinal tissue destruction (Figueira 2009; Laursen 2004; Lavinsky 2011; Venkatesh 2011; Vujosevic 2010; Xie 2013). Among studies using micropulse photocoagulation, Lavinsky 2011 evaluated three groups: both normal and high‐density micropulse diode, and standard macular photocoagulation. Based on the reports, effects on the visual acuity and the interpretation of other studies as well as personal communication (Chen 2016a; ISRCTN17742985; Luttrull 2012), we decided to select the high‐density group compared to standard macular photocoagulation. One study, Casson 2012 compared 3‐ms nanopulse retina treatment (2RT) with standard photocoagulation, both delivered with an Integre 532 nm laser (Ellex Medical Lasers Ltd, Adelaide, Australia). 2RT applications were delivered with a spot size of 400 mm at an energy setting that produced nil reaction or a barely discernible retinal reaction (approximately 0.3 mJ), and slightly lower energy was then selected for treatment. The applications were advanced to thickened retinal regions, and applied in a grid pattern, one ‘burn' width apart to thickened areas of retina at least 500 mm from the foveal centre.

One study compared subthreshold micropulse yellow laser versus subthreshold micropulse infrared laser (Vujosevic 2015).

Conflict of interest

Conflict of interest was an issue in two studies (Akduman 1997; Casson 2012).

Types of outcome measures

Eleven studies measured improvement/remained the same on change in visual acuity (Akduman 1997; Bandello 2005; Blankenship 1979; Casswell 1990; DRCRNET 2007; Ladas 1993; Karacorlu 1993; Khairallah 1996; Olk 1986; Olk 1990; Tewari 1998). Eight studies reported on mean BCVA (Casson 2012; DRCRNET 2007; Figueira 2009; Lavinsky 2011; Pei‐Pei 2015; Venkatesh 2011; Vujosevic 2010; Vujosevic 2015). The proportion of participants with improvement/remained the same on change in visual acuity was used as the primary outcome data were not available.

Twelve studies measured worse or change in visual acuity (Akduman 1997; Bandello 2005; Blankenship 1979; Casson 2012; Casswell 1990; ETDRS 1985; Karacorlu 1993; Khairallah 1996; Ladas 1993; Olk 1986; Olk 1990; Tewari 1998).

Nine studies reported continuous BCVA (Bandello 2005; Casson 2012; DRCRNET 2007; Figueira 2009; Lavinsky 2011;Pei‐Pei 2015; Venkatesh 2011;Vujosevic 2010; Vujosevic 2015).

Sixteen studies reported on anatomic measures (Akduman 1997; Bandello 2005; Casson 2012; Casswell 1990; DRCRNET 2007; ETDRS 1985;Figueira 2009; Karacorlu 1993; Khairallah 1996; Lavinsky 2011; Olk 1990; Pei‐Pei 2015; Tewari 1998; Venkatesh 2011; Vujosevic 2010; Vujosevic 2015).

Two studies assessed local complications (Casswell 1990; Khairallah 1996), and four studies measured sensitivity contrast (Bandello 2005; Figueira 2009; Venkatesh 2011; Vujosevic 2015).

Studies awaiting classification

One study requires translation and is currently awaiting classification (Ludwig 1991).

Ongoing studies

Eight studies are currently ongoing and will be added to the review when they are published (CTRI/2015/03/005628; ISRCTN17742985; ISRCTN66877546; NCT01045239; NCT01928654; NCT02309476; NCT03641144; NCT03519581). See Characteristics of ongoing studies table for further information.

Outcome: functional outcomes ‐ improvement or worsening of best‐corrected visual acuity (BCVA)

There were no data regarding visual improvement. Macular photocoagulation with argon laser prevented the worsening of BCVA at 12 months' follow‐up compared to no intervention (RR 0.42, 95% CI 0.20 to 0.90; 3703 eyes; 4 studies; I² = 71%; Analysis 1.1; moderate‐certainty evidence). Although the studies were heterogeneous, all were in the direction of benefit with laser and were pooled.

Compared to no intervention, macular argon laser prevented visual impairment at 24 months' follow‐up (RR 0.63, 95% CI 0.53 to 0.74; 3421 eyes; 3 studies; I² = 60%; Analysis 1.2) and at 36 months' follow‐up (RR 0.68, 95% CI 0.58 to 0.79; 3194 eyes; 2 studies; I² = 0%; Analysis 1.3).

Outcome: functional outcomes ‐ continuous BCVA on the logMAR scale

None of the included studies reported on this outcome.

Outcome: anatomic measures

Macular laser improved the chances of partial or complete resolution of macular thickening at 36 months' follow‐up compared to no intervention in eyes with CSMO (RR 1.55, 95% CI 1.30 to 1.86; 350 eyes; 1 study; Analysis 1.4; moderate‐certainty of evidence). However, we were uncertain on whether laser reduced the occurrence of retinal thickening with the centre of the macula in eyes without CSMO, in which thickening did not affect the central retina (RR 1.12, 95% CI 0.98 to 1.27; 254 eyes; 1 study; Analysis 1.4; low‐certainty evidence due to imprecision and high risk of bias related to incomplete outcome data).

Outcome: contrast sensitivity

None of the included studies reported on this outcome.

Outcome: quality of life

None of the included studies reported on this outcome.

Outcome: local or systemic adverse effects or both

ETDRS 1985 wrote that "very few adverse effects of focal photocoagulation have been observed to date" with "only minor adverse effects (not statistically significant) on central visual fields and no adverse effects on colour vision." Olk 1986 reported one case or premacular fibrosis possibly due to "too heavy" laser burns in the macula.

None of the included studies reported on systemic adverse effects.

Outcome: economic data

None of the included studies reported on this outcome.

Outcome: functional measures ‐ improvement or worsening of best‐corrected visual acuity (BCVA)

Only Bandello 2005, a small study on 29 eyes, reported our dichotomous functional primary outcomes comparing standard macular photocoagulation with subthreshold photocoagulation obtained by halving the laser power with a standard macular photocoagulation. Estimates of effects were very imprecise, which made it difficult to assess any benefit regarding both BCVA improvement and BCVA worsening (improvement: RR 0.31, 95% CI 0.01 to 7.09; worsening: RR 0.93, 95% CI 0.15 to 5.76; very low‐certainty evidence; Analysis 2.1; Analysis 2.2).

Outcome: functional outcomes ‐ continuous BCVA on the logMAR scale

Seven studies (385 eyes) reported on final (or change of) logMAR BCVA. There was low‐certainty evidence of no important difference between subthreshold photocoagulation and standard photocoagulation (MD –0.02, 95% CI –0.07 to 0.03; 385 eyes; 7 studies; I² = 42%; Analysis 2.3). There was subgroup heterogeneity among standard, micropulse and nanopulse subthreshold lasers (P = 0.07 and I² = 61.5% for subgroup heterogeneity). Four studies using micropulse laser found a benefit compared to standard photocoagulation, but estimates were very imprecise (MD –0.08, 95% CI –0.16 to 0.00; 276 eyes; 4 studies; I² = 22%). This evidence was of low‐certainty because of unclear risk of bias in most studies and subgroup heterogeneity.

Two studies (130 eyes) comparing micropulse with standard photocoagulation reported contrast sensitivity at 12 months, but yielded inconsistent results, with Figueira 2009 showing no difference and Venkatesh 2011 favouring micropulse laser, but not to a statistically significant extent (Analysis 2.4).

Outcome: anatomic measures

Seven studies reported central macular thickness at 12 months. Pooled estimates suggested moderate‐certainty evidence of no large difference between subthreshold and standard macular photocoagulation (MD –9.1 μm, 95% CI –26.2 to 8.0; 385 eyes; 7 studies; I² = 0%; Analysis 2.6). In this analysis, there was no subgroup inconsistency between micropulse, nanopulse and non‐visible conventional photocoagulation (P = 0.81; I² = 0%). One study reported a partial or complete regression of CSMO (Bandello 2005). There was low‐certainty evidence of some benefit with standard photocoagulation but estimates of effect were imprecise (RR 0.47, 95% CI 0.21 to 1.03; 29 eyes; 1 study) (Analysis 2.5).

Outcome: contrast sensitivity

Macular photocoagulation can cause focal scotoma and the aim of subthreshold laser is to avoid this potential complication, especially using micropulse laser.

Bandello 2005 found little change in central retinal sensitivity, as Humphrey perimeter Mean Deviation, from baseline to 12 months for standard and conventional subthreshold ("light") macular laser photocoagulation (–0.04 dB (SD 1.39) with standard versus 0.03 dB (SD 1.84) with conventional subthreshold; P = 0.99).

Regarding micropulse versus standard macular laser, Figueira 2009 found the masked grader detected laser scars in 6/43 (13.9%) eyes from the micropulse group compared with 23/39 (59.0%) eyes from standard laser group (P = 0.001) in participants with good‐quality colour photographs at 12 months. Lavinsky 2011 reported similar favourable outcomes with micropulse laser anecdotally. Venkatesh 2011 used multifocal electroretinography and reported a surrogate measure such as implicit time, which slightly improved for both micropulse and standard laser. Vujosevic 2010 used microperimetry and found mean central retinal sensitivity significantly increased at 12‐month follow‐up in the micropulse group (mean increase 0.87 dB (SD 1.89); Student's t‐test; P = 0.0075), whereas it significantly decreased in the standard macular photocoagulation group (mean decrease 21.69 dB (SD 2.45); Student's t‐test; P = 0.0026).

Outcome: quality of life

None of the included studies reported on this outcome.

Outcome: local or systemic adverse effects or both

None of the included studies reported on this outcome.

Outcome: economic data

None of the included studies reported on this outcome.

Outcome: functional outcomes ‐ improvement or worsening of best‐corrected visual acuity (BCVA)

Six studies (490 participants, 773 eyes) reported data for this comparison. We found no difference in the effect of macular argon laser as compared to other types of lasers both regarding improvement (RR 0.87, 95% CI 0.62 to 1.22; 773 eyes; 6 studies; I² = 0%; Analysis 3.1) and worsening (RR 0.83, 95% CI 0.57 to 1.21; 773 eyes; 6 studies; I² = 0%; Analysis 3.2). This evidence was of moderate‐certainty since most studies were at unclear risk of bias. There was no suggestion of subgroup differences for subgroups of argon versus diode, dye or krypton laser both for improvement and worsening of BCVA (test for subgroup differences: improvement: P = 0.85, I² = 0%; worsening: P = 0.39, I² = 0%).

Outcome: functional outcomes ‐ continuous BCVA on the logMAR scale

None of the included studies reported on this outcome.

Outcome: anatomic measures

Data on partial or complete resolution of DMO were consistent with the primary outcomes at six and 12 months (6 months: RR 1.36, 95% CI 0.98 to 1.90; 80 eyes; 1 study; Analysis 3.3; 12 months: RR 1.01, 95% CI 0.98 to 1.05; 773 eyes; 6 studies; I² = 0%; Analysis 3.4).

Outcome: contrast sensitivity

None of the included studies reported on this outcome.

Outcome: quality of life

None of the included studies reported on this outcome.

Outcome: local or systemic adverse effects or both

Regarding adverse events of grid laser that caused visual loss, Casswell 1990 reported that two participants developed subretinal neovascularisation at a laser burn in the argon group and Khairallah 1996 found a similar complication, subretinal fibrosis, in the argon group, with both studies finding no such cases in the krypton group. Olk 1990 reported one case of subretinal fibrosis in the krypton groups and one of subretinal neovascularization in the argon group.

Outcome: economic data

None of the included studies reported on this outcome.

Outcome: functional outcomes ‐ improvement or worsening of best‐corrected visual acuity (BCVA)

One study (263 participants, 323 eyes) compared the MMG with the modified ETDRS (mETDRS) grid technique (see Types of interventions section) (DRCRNET 2007). The MMG was no better than the mETDRS technique for visual outcomes at one year: visual improvement: RR 1.43 (95% CI 0.56 to 3.65, Analysis 4.1); and visual worsening RR 1.40 (95% CI 0.64 to 3.05, Analysis 4.2). The evidence for the primary outcomes was of low‐certainty since the study was at unclear risk of bias and effect estimates were imprecise.

Outcome: functional outcomes ‐ continuous BCVA on the logMAR scale

The MMG was no better than the mETDRS technique for visual outcomes at one year: visual improvement: change of logMAR visual acuity: –0.04 logMAR in the mETDRS group and MD worse by 0.04 logMAR (95% CI –0.01 to 0.09, Analysis 4.3) in the MMG group, which are both consistent with little change of vision from baseline at one year.

Outcome: anatomic measures

There was a greater reduction of central macular thickness with the mETDRS compared to the MMG technique, since final retinal thickness in the mETDRS group was 290 µm and it was 34.0 µm worse (95% CI 8.3 to 59.8; Analysis 4.4) in the MMG group. This evidence was of low quality due to unclear risk of bias and imprecision.

Outcome: contrast sensitivity

The included study do not reported on this outcome.

Outcome: quality of life

The included study do not reported on this outcome.

Outcome: local or systemic adverse effects or both

The authors of DRCRNET 2007 did not report significant adverse effects and found no difference between treatments, in relation to the damage caused by retinal photocoagulation.

Outcome: economic data

The included study do not reported on this outcome.

The study authors recommended no further research on MMG as an alternative technique.

Outcome: functional outcomes ‐ improvement or worsening of best‐corrected visual acuity (BCVA)

The included study do not reported on this outcome.

Outcome: functional outcomes ‐ continuous BCVA on the logMAR scale

Vujosevic 2015 (53 participants, 53 eyes) compared yellow (26 eyes) and diode (27 eyes) micropulse laser to treat DMO. At 12 months, they found no statistically significant difference regarding continuous final BCVA (Analysis 5.1).

Outcome: anatomic measures

At 12 months, they found no statistically significant difference regarding central macular thickness (Analysis 5.3), but estimates were too imprecise to draw any conclusion and the evidence was of very low‐certainty.

Outcome: contrast sensitivity

At 12 months, they found no statistically significant difference regarding contrast sensitivity (Analysis 5.2), but estimates were too imprecise to draw any conclusion and the evidence was of very low‐certainty.

Outcome: quality of life

The included study do not reported on this outcome.

Outcome: economic data

The included study do not reported on this outcome.