Laser photocoagulation for proliferative diabetic retinopathy
Abstract
Background
Diabetic retinopathy is a complication of diabetes in which high blood sugar levels damage the blood vessels in the retina. Sometimes new blood vessels grow in the retina, and these can have harmful effects; this is known as proliferative diabetic retinopathy. Laser photocoagulation is an intervention that is commonly used to treat diabetic retinopathy, in which light energy is applied to the retina with the aim of stopping the growth and development of new blood vessels, and thereby preserving vision.
Objectives
To assess the effects of laser photocoagulation for diabetic retinopathy compared to no treatment or deferred treatment.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 5), Ovid MEDLINE, Ovid MEDLINE In‐Process and Other Non‐Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2014), EMBASE (January 1980 to June 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 June 2014.
Selection criteria
We included randomised controlled trials (RCTs) where people (or eyes) with diabetic retinopathy were randomly allocated to laser photocoagulation or no treatment or deferred treatment. We excluded trials of lasers that are no longer in routine use. Our primary outcome was the proportion of people who lost 15 or more letters (3 lines) of best‐corrected visual acuity (BCVA) as measured on a logMAR chart at 12 months. We also looked at longer‐term follow‐up of the primary outcome at two to five years. Secondary outcomes included mean best corrected distance visual acuity, severe visual loss, mean near visual acuity, progression of diabetic retinopathy, quality of life, pain, loss of driving licence, vitreous haemorrhage and retinal detachment.
Data collection and analysis
We used standard methods as expected by the Cochrane Collaboration. Two review authors selected studies and extracted data.
Main results
We identified a large number of trials of laser photocoagulation of diabetic retinopathy (n = 83) but only five of these studies were eligible for inclusion in the review, i.e. they compared laser photocoagulation with currently available lasers to no (or deferred) treatment. Three studies were conducted in the USA, one study in the UK and one study in Japan. A total of 4786 people (9503 eyes) were included in these studies. The majority of participants in four of these trials were people with proliferative diabetic retinopathy; one trial recruited mainly people with non‐proliferative retinopathy. Four of the studies evaluated panretinal photocoagulation with argon laser and one study investigated selective photocoagulation of non‐perfusion areas. Three studies compared laser treatment to no treatment and two studies compared laser treatment to deferred laser treatment. All studies were at risk of performance bias because the treatment and control were different and no study attempted to produce a sham treatment. Three studies were considered to be at risk of attrition bias.
At 12 months there was little difference between eyes that received laser photocoagulation and those allocated to no treatment (or deferred treatment), in terms of loss of 15 or more letters of visual acuity (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.89 to 1.11; 8926 eyes; 2 RCTs, low quality evidence). Longer term follow‐up did not show a consistent pattern, but one study found a 20% reduction in risk of loss of 15 or more letters of visual acuity at five years with laser treatment. Treatment with laser reduced the risk of severe visual loss by over 50% at 12 months (RR 0.46, 95% CI 0.24 to 0.86; 9276 eyes; 4 RCTs, moderate quality evidence). There was a beneficial effect on progression of diabetic retinopathy with treated eyes experiencing a 50% reduction in risk of progression of diabetic retinopathy (RR 0.49, 95% CI 0.37 to 0.64; 8331 eyes; 4 RCTs, low quality evidence) and a similar reduction in risk of vitreous haemorrhage (RR 0.56, 95% CI 0.37 to 0.85; 224 eyes; 2 RCTs, low quality evidence).
None of the studies reported near visual acuity or patient‐relevant outcomes such as quality of life, pain, loss of driving licence or adverse effects such as retinal detachment.
We did not plan any subgroup analyses, but there was a difference in baseline risk in participants with non‐proliferative retinopathy compared to those with proliferative retinopathy. With the small number of included studies we could not do a formal subgroup analysis comparing effect in proliferative and non‐proliferative retinopathy.
Authors' conclusions
This review provides evidence that laser photocoagulation is beneficial in treating proliferative diabetic retinopathy. We judged the evidence to be moderate or low, depending on the outcome. This is partly related to reporting of trials conducted many years ago, after which panretinal photocoagulation has become the mainstay of treatment of proliferative diabetic retinopathy.
Future Cochrane Reviews on variations in the laser treatment protocol are planned. Future research on laser photocoagulation should investigate the combination of laser photocoagulation with newer treatments such as anti‐vascular endothelial growth factors (anti‐VEGFs).
PICOs
Plain language summary
Laser photocoagulation for proliferative diabetic retinopathy
Review question
Is laser photocoagulation an effective treatment for diabetic retinopathy?
Background
Diabetic retinopathy (DR) is a common problem for people with diabetes and can lead to loss of vision. The back of the eye (retina) can develop problems because of diabetes, including the growth of harmful new blood vessels (proliferative DR, referred to here as 'PDR'). Laser photocoagulation is a commonly used treatment for DR in which the eye doctor uses a laser on the back of the eye to stop some of the harmful changes.
Study characteristics
We found five studies. The searches were done in April 2014. Three studies were done in the USA, one study in the UK and one study in Japan. A total of 4786 people (9503 eyes) were included in these studies. Most participants had PDR.
Key results
We found that moderate vision loss at 12 months was similar in eyes treated with laser and eyes that were not treated, but similar assessments made at a later date showed that eyes treated with laser were less likely to have suffered moderate vision loss. Treatment with laser reduced the risk of severe visual loss by over 50% at 12 months. There was a similar effect on the progression of DR. None of the studies reported patient‐relevant outcomes such as pain or loss of driving licence.
Quality of the evidence
We did not find very many studies and those we found were done quite a long time ago when standards of trial conduct and reporting were lower. We judged the quality of the evidence to be low, with the exception of the results for severe visual loss, which we judged to be moderate quality evidence.
Authors' conclusions
Summary of findings
| Laser photocoagulation compared to no treatment (or deferred treatment) for diabetic retinopathy | ||||||
| Patient or population: people with diabetic retinopathy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk* | Corresponding risk | |||||
| No treatment or deferred treatment | Laser photocoagulation | |||||
| Loss of 15 or more letters BCVA Follow‐up: 12 months | Low risk (non‐proliferative DR) | RR 0.99 | 8926 | ⊕⊕⊝⊝ | The pooled RR 0.99 (0.89 to 1.11) is derived from one study with mainly low risk population RR 1.07 (0.92 to 1.23) and one study with mainly high risk population 0.86 (0.71 to 1.04) | |
| 100 per 1000 | 99 per 1000 | |||||
| High risk (proliferative DR) | ||||||
| 250 per 1000 | 248 per 1000 | |||||
| BCVA measured using logMAR acuity (0 = 6/6 visual acuity, higher score is worse visual acuity) Follow‐up: 12 months | The mean BCVA at 12 months in the control group was 0.12 logMAR | The mean BCVA at 12 months in the intervention group was 0.02 logMAR units higher (worse; 0.23 lower to 0.27 higher) | 36 | ⊕⊕⊝⊝ | ||
| Severe visual loss (BCVA < 6/60) Follow‐up: 12 months | Low risk (non‐proliferative DR) | RR 0.46 | 9276 | ⊕⊕⊕⊝ | ||
| 10 per 1000 | 5 per 1000 | |||||
| High risk (proliferative DR) | ||||||
| 50 per 1000 | 23 per 1000 | |||||
| Progression of diabetic retinopathy Follow‐up: 12 months | Low risk (non‐proliferative DR) | RR 0.49 | 8331 | ⊕⊕⊝⊝ | ||
| 100 per 1000 | 49 per 1000 | |||||
| High risk (proliferative DR) | ||||||
| 400 per 1000 | 196 per 1000 (148 to 256) | |||||
| Quality of life Follow‐up: 12 months | See comment | See comment | No studies reported this outcome | |||
| Pain Follow‐up: at time of treatment | See comment | See comment | No studies reported this outcome | |||
| Loss of driving licence Follow‐up: within three months of treatment | See comment | See comment | No studies reported this outcome | |||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| *Estimates of assumed risk are indicative only, as estimates at 12 months were not available in all studies. For the low risk populations they were estimated from ETDRS (but acknowledging that the control group received deferred laser) and for the high risk populations they were estimated from DRS and Hercules 1977. 1Downgraded for risk of bias (‐1): studies were not masked and treatment groups different 2Downgraded for inconsistency (‐1): I2 = 69% and effect estimates were in different directions. See comments for details 3Downgraded for imprecision (‐1): wide confidence intervals 4 There was heterogeneity (I2 = 70%) but all effect estimates favoured laser photocoagulation so we did not downgrade for inconsistency 5Downgraded for indirectness (‐1): study results were reported at 1, 3, 4 and 5 years | ||||||
Background
Description of the condition
Diabetic retinopathy (DR) is a microvascular complication of diabetes in which high blood sugar levels damage the blood vessels in the retina (Davidson 2007). These blood vessels may become blocked, which leads to a reduction or cessation of blood supply to the retina (non‐proliferative diabetic retinopathy). Sometimes the vessels swell up and leak fluid (macular oedema) and sometimes new vessels grow (neovascularisation) on the retina and vitreous (also called the vitreous humour); this is known as proliferative diabetic retinopathy (PDR).
In general, the early stages of the disease are not associated with any symptoms. Disease progression is associated with visual loss and blindness, if left untreated. DR is an important cause of visual impairment worldwide. An estimated 285 million people are visually impaired and of these approximately 39 million people are blind (Pascolini 2012). DR is believed to account for approximately 1% of visual impairment and blindness, meaning nearly three million people worldwide are visually impaired due to this condition. The total number of people with diabetes is projected to increase from 171 million people in 2000 to 366 million in 2030 (Wild 2004).
This Cochrane Review is concerned with the treatment of DR, both proliferative and non‐proliferative, but not macular oedema which is addressed in another review (Jorge 2013).
Description of the intervention
Laser photocoagulation involves applying light energy to the retina. This is absorbed by the retinal pigments, which heat up and cause thermal damage to the retinal tissues. There are several types of laser: gas (argon, krypton), diode, dye and YAG (RCOphth 2012).
| Type of laser | Wavelength in nm (colour) | Comments |
| Argon | 488 (blue) 514 (green) | ‐ |
| Krypton | 568 (yellow) 647 (red) | ‐ |
| Dye laser | 570 to 630, 577 (yellow) often used | ‐ |
| Diode laser | 810 (infrared) | Micropulse mode available |
| Frequency‐doubled yttrium aluminium garnet (YAG) laser | 532 (green) often used | Pattern scan laser (PASCAL) often used |
Laser application may focus on microaneurysms or be delivered in a grid‐pattern around the centre of the macula in people with diabetic macular oedema (DMO). When delivered to the peripheral retina, it may be focal, directed to neovascular tufts, or more commonly scattered, which is also known as panretinal photocoagulation (PRP) and in which 1200 to 2000 burns are applied to the peripheral retina. Laser photocoagulation may be applied in one session or may be delivered over several sessions to reduce the risk of adverse effects.
Peripheral or panretinal laser treatment is commonly delivered to ischaemic areas (i.e. those with low oxygen levels) in the retinal periphery, with the aims of causing regression of retinal neovascularisation and prevention of visual loss due to vitreous haemorrhage, tractional retinal detachment, or neovascular glaucoma, which are the main causes of visual loss in patients with end‐stage PDR. Panretinal peripheral laser treatment was also initially proposed as a treatment that might prevent the occurrence of PDR.
How the intervention might work
The aim of laser photocoagulation is to slow down the growth of new blood vessels in the retina and thereby prevent the progression of visual loss (Ockrim 2010). Focal laser photocoagulation uses the heat of light to seal or destroy abnormal blood vessels in the retina. Individual vessels are treated with a small number of laser burns.
PRP aims to slow down the growth of new blood vessels in a wider area of the retina. Many hundreds of laser burns are placed on the peripheral parts of the retina to stop blood vessels from growing (RCOphth 2012). It is thought that the anatomic and functional changes that result from photocoagulation may improve the oxygen supply to the retina, and so reduce the stimulus for neovascularisation (Stefansson 2001). Again the exact mechanisms are unclear, but it is possible that the decreased area of retinal tissue leads to improved oxygenation and a reduction in the levels of anti‐vascular endothelial growth factor. A reduction in levels of anti‐vascular endothelial growth factor may be important in reducing the risk of harmful new vessels forming.
Why it is important to do this review
Laser photocoagulation is a well‐established common treatment for DR and there are many different potential strategies for delivery of laser treatment that are likely to have different effects. A systematic review of the evidence for laser photocoagulation will provide important information on benefits and harms to guide treatment choices. With the advent of new treatments, especially the anti‐vascular endothelial growth factor (anti‐VEGF) agents, laser photocoagulation may become less commonly used in higher income countries, but may still have relevance as a potentially cost‐effective treatment in other parts of the world. This review should be read in conjunction with related Cochrane Reviews of treatment of DR, including laser photocoagulation for diabetic macular oedema (Jorge 2013), anti‐VEGF for proliferative retinopathy (Martinez‐Zapata 2014), anti‐VEGF for diabetic macular oedema (Virgili 2012), and steroids for diabetic macular oedema (Grover 2008).
This is the first in a series of planned reviews on laser photocoagulation. Future reviews will compare different photocoagulation techniques.
Objectives
To assess the effects of laser photocoagulation for diabetic retinopathy compared to no treatment or deferred treatment.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs) irrespective of the language in which they were published, or publication status (published or unpublished).
Types of participants
People with pre‐proliferative (DR) or proliferative diabetic retinopathy (PDR). We excluded trials where the primary aim was to treat diabetic macular oedema as this is covered in a separate Cochrane Review (Jorge 2013).
Types of interventions
We considered trials of peripheral laser photocoagulation with any ophthalmic laser at any wavelength, either focal or panretinal. We compared this to no treatment, sham treatment or deferred treatment.
We included studies using any type of laser, but not studies using xenon arc photocoagulation or ruby laser, since these lasers have not been used for decades because of an observed increase in the risk of side‐effects, such as peripheral field damage and macular traction (DRS 1981).
We excluded trials that compared different types (wavelength) of laser, laser application at different powers or for different exposure times, and trials that compared different regimens for the application of the laser (e.g. compared the number, pattern or location of burns, or compared different numbers of treatment sessions) as these will be considered in future Cochrane Reviews.
This review should be read in conjunction with related Cochrane Reviews that address the comparison between laser photocoagulation and other treatments such as anti‐VEGF (Martinez‐Zapata 2014; Virgili 2012), and steroids (Grover 2008).
Types of outcome measures
Primary outcomes
-
Proportion of people who lose 15 or more letters (3 lines) of best‐corrected visual acuity (BCVA) as measured on a logMAR chart.
Secondary outcomes
-
Mean distance visual acuity (BCVA).
-
Mean near visual acuity (NVA).
-
Severe visual loss (BCVA < 6/60).
-
Progression of diabetic retinopathy, as defined by trial investigators.
-
Quality of life measured using any validated questionnaire.
-
Adverse events: pain, loss of driving licence, vitreous haemorrhage, retinal detachment.
With the exception of adverse events, we aimed to collect data on these outcomes at one year after initiation of treatment, which we defined as the period between six and 18 months. We considered adverse events at any time point, but these are most likely to occur within three months of treatment. We also planned to report the primary outcome at longer time periods ‐ two to five years ‐ in order to comment on whether any effects observed are sustained in the long term.
We made some amendments to the outcomes from the protocol. See Differences between protocol and review.
Search methods for identification of studies
Electronic searches
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 5), Ovid MEDLINE, Ovid MEDLINE In‐Process and Other Non‐Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2014), EMBASE (January 1980 to June 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 June 2014.
See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), mRCT (Appendix 4), ClinicalTrials.gov (Appendix 5) and the ICTRP (Appendix 6).
Searching other resources
We searched the reference lists of included studies and other reviews identified by the searches.
Data collection and analysis
Selection of studies
Two review authors (JE, MM) independently screened the search results and selected trials for inclusion. We resolved disagreements through discussion.
We screened the list of citations and abstracts and classified records into 'possibly relevant' and 'definitely not relevant'. For the records we identified as 'possibly relevant' we obtained the full‐text articles. Following the Criteria for considering studies for this review we classified trials into 'to be included' or 'to be excluded'. We documented excluded trials in the category in the Characteristics of excluded studies section.
Data extraction and management
Two authors (JE, MM) independently extracted data from trial reports and entered the data into Review Manager (RevMan 2014). We resolved any differences in opinion through discussion. We used a data collection spreadsheet. We obtained English translations of any trial reported in a language other than English before extracting data.
We collected data on trial characteristics as detailed in Appendix 7.
We obtained the following data on outcomes specified in Types of outcome measures: for dichotomous outcomes, we collected data on the number of events and total participants followed up in each trial arm; for continuous outcomes, we collected data on the mean and standard deviation in each trial arm.
We did not attempt to obtain further information from trialists.
Assessment of risk of bias in included studies
We assessed risk of bias using the Cochrane Collaboration's tool for assessing the risk of bias as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Measures of treatment effect
We calculated the risk ratio (RR) for all dichotomous variables. This was a variation on the protocol ‐ see Differences between protocol and review.
For continuous variables (only data on distance visual acuity were available) we calculated the mean difference.
All measures of effect were reported with 95% confidence intervals (CIs).
Unit of analysis issues
Four of the five studies were within‐person studies but were reported as unmatched. We have used these data as reported, which is a conservative analysis. One trial considered one eye per person only, but it was not clear how that eye was selected for inclusion in the trial.
Dealing with missing data
We documented follow‐up by intervention group. We aimed to collect data on reasons for loss to follow‐up, but this information was not usually available. We documented when loss to follow‐up was high (over 20%), or unbalanced between treatment groups, as a potential source of attrition bias. We planned to conduct an intention‐to‐treat (ITT) analysis if this was reported by the trialists, but we have conducted an available case analysis because the majority of trials did not report an ITT and the one small trial that did only reported one outcome as an ITT analysis (Sato 2012). An available case analysis makes the assumption that the treatment effect in people lost to follow‐up was the same as that in people who were observed (assessed).
Assessment of heterogeneity
We assessed heterogeneity by visual inspection of the forest plots and by calculating the I2 value (Higgins 2002). We also considered the Chi2 test for heterogeneity, but this may have low power as few trials met the inclusion criteria.
Assessment of reporting biases
We were unable to look at small trial effects as we had planned because there were only five included trials.
We considered selective outcome reporting bias as part of the assessment of risk of bias in the individual studies (see Assessment of risk of bias in included studies section).
Data synthesis
We pooled data using a random‐effects model, unless there were three or fewer trials, in which case we used a fixed‐effect model.
There was considerable heterogeneity, and for many analyses the I2 statistic was over 50%. In most analyses all effect estimates were in the same direction and we report a pooled value. The exception was Analysis 1.1, but as the effect estimates were relatively close to 1 we have reported a pooled estimate. This is a variation from our protocol ‐ see Differences between protocol and review.
Subgroup analysis and investigation of heterogeneity
We did not plan any subgroup analysis at the protocol stage, but there was considerable heterogeneity in terms of baseline risk in participants with non‐proliferative retinopathy and those with proliferative retinopathy.
There was not enough evidence to do subgroup analysis based on these groups, and new trials in future are unlikely.
Sensitivity analysis
We planned to repeat the analyses excluding studies at high risk of selection, or detection bias, or both. In most analyses trials were similar with respect to these risk of bias domains and so a sensitivity analysis was not possible. We did one sensitivity analysis for the outcome progression of DR.
Summary of findings
We report absolute risks and measures of effect in a 'Summary of findings' table, providing an overall assessment of the quality of the evidence for each outcome using the GRADE system (Guyatt 2011). Two review authors (JE, GV) independently performed the GRADE assessment.
Our pre‐specified outcome measures were:
-
proportion of people who lose 15 or more letters (3 lines) of BCVA as measured on a logMAR chart;
-
mean logMAR visual acuity;
-
averse event: loss of driving licence;
-
adverse event: severe visual loss (BCVA < 6/60);
-
adverse event: pain;
-
quality of life measured using a validated questionnaire.
We planned to report outcomes 1, 2 and 6 at one year, outcomes 3 and 4 within three months of treatment and outcome 5 at time of treatment.
We modified the protocol to include severe visual loss as an effectiveness outcome measured at one year. See Differences between protocol and review.
Results
Description of studies
Results of the search
The electronic searches yielded a total of 3517 references (Figure 1). The Trials Search Co‐ordinator removed 545 duplicate records, screened the remaining 2972 records and removed 2660 references that were not relevant to the scope of the review. We screened a total of 312 references and discarded 173 reports as these were not relevant to the scope of the review. We reviewed 139 full‐text reports and included 30 reports of five studies that were eligible for inclusion in the review. We were unable to assess 13 reports, either because the full‐text copy was unavailable or because a translation was needed. These reports are listed in the Studies awaiting classification section, but are unlikely to be eligible trials. We also excluded 96 reports that referred to 78 trials, see Characteristics of excluded studies for details.
Results from searching for studies for inclusion in the review
Included studies
We identified five studies that compared laser photocoagulation to a control. Three studies were conducted in the USA (DRS 1978; ETDRS 1991; Yassur 1980), one study in the UK (Hercules 1977), and one study in Japan (Sato 2012).
Four studies were within‐person RCTs i.e. one eye was randomly allocated to laser photocoagulation and the other eye to the control (DRS 1978; ETDRS 1991; Hercules 1977; Yassur 1980). Sato 2012 randomly allocated people to treatment and only one eye was included in the study; it was unclear how the eye was selected.
The number of participants enrolled ranged from 45 in Yassur 1980 to 3711 in ETDRS 1991. The average age of participants ranged from 41 years in Hercules 1977 to 60 years in Sato 2012. Most studies recruited participants aged approximately 18 to 70 years with an average age of around 45 years. The percentage of women enrolled ranged from 25% in Sato 2012 to 48% in Yassur 1980, but on average between 40% and 45% of the participants in each trial were women.
Two studies enrolled people with PDR only (Hercules 1977; Yassur 1980); two studies enrolled people either with moderate or severe non‐proliferative DR or PDR (DRS 1978; ETDRS 1991); and one study enrolled participants with pre‐proliferative DR (Sato 2012). In the DRS 1978 study approximately 80% of participants had PDR; in the ETDRS 1991 study approximately 20% of participants had PDR.
Most studies used PRP with argon laser (Table 1). The exception was Sato 2012, which evaluated selective photocoagulation of non‐perfusion areas. Three studies compared laser to no treatment (DRS 1978; Hercules 1977; Yassur 1980); two studies compared laser to deferred laser treatment (ETDRS 1991; Sato 2012; i.e. control participants received laser when severe non‐proliferative (ETDRS 1991) or PDR (ETDRS 1991; Sato 2012) developed).
| Study | Type of laser | Type of photocoagulation | Number (size) of burns | Intensity | Exposure time (seconds) | Number of sessions |
| Argon | Panretinal Focal treatment of new vessels | 800‐1600 (500 µm) or 500‐1000 (1000 µm) | Not reported | 0.1 | 1 (usually) | |
| Argon | Panretinal | Full: 1200‐1600 (500 µm) Mild: 400‐650 (500 µm) | Moderate | 0.1 | Full: 2 or more Mild: 1 | |
| Argon | Panretinal | 800 to 3000 (200 µm and 500 µm) | Minimal retinal blanching | Not reported | Up to 6 | |
| Not reported | Selective photocoagulation of non‐perfusion areas | (400 µm‐500 µm) | Not reported | Not reported | ||
| Argon | Panretinal | As for DRS 1978 | As for DRS 1978 | As for DRS 1978 | As for DRS 1978 |
Excluded studies
Risk of bias in included studies
See Figure 2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Generation of the allocation sequence was considered adequate in two trials (DRS 1978; Sato 2012) and was not clearly described in the rest. As most of the studies were within‐person studies, allocation concealment was not judged to be a problem (as all participants received both intervention and control). In the one parallel group study the allocation was clearly described and judged to be at low risk of bias (Sato 2012).
Blinding
We judged the studies that measured and reported visual acuity to be at a high risk of bias because the treatment and control groups were obviously different and patient knowledge of intervention could affect the measurement of visual acuity. However, the extent of the bias is difficult to judge, and some studies had specific protocols to improve the accuracy of the measurement of vision, such as encouraging patients to read as far down the chart as possible (DRS 1978). In general, we judged that patient and carer knowledge of assignment would not affect the progression of DR.
Incomplete outcome data
We judged within‐person studies to be at low risk of attrition bias by definition because, although there may be attrition in patient follow‐up, the follow‐up between intervention and control groups, i.e. between eyes, will always be equal. However, two studies selectively removed participants who received treatment in the control eye (Hercules 1977; Yassur 1980), which we considered to be a potential source of bias for the effect estimate. The one parallel group study had considerable loss to follow‐up (Sato 2012).
Selective reporting
In general reporting bias was difficult to judge with the information available. None of the studies reported all our review outcomes.
Other potential sources of bias
The Sato 2012 study was stopped early.
Effects of interventions
1.1 Loss of 15 or more letters BCVA at 12 months
For this outcome we found two relevant trials (DRS 1978; ETDRS 1991: n = 8926; Figure 3; Analysis 1.1). One of these studies reported loss of 10 or more letters rather than loss of 15 or more letters (DRS 1978). There was considerable heterogeneity of effect (I2 = 69%; P value = 0.07). In the DRS 1978 study fewer eyes given laser photocoagulation lost 10 or more letters compared to untreated eyes, but there was uncertainty and the confidence intervals included 1 (RR 0.86, 95% CI 0.71 to 1.04). In the ETDRS 1991 study more eyes treated with laser photocoagulation lost 15 or more letters over 12 months compared to eyes given deferred treatment, but again there was uncertainty and the confidence intervals included 1 (RR 1.07, 95% CI 0.92 to 1.23).
Forest plot of comparison: 1 Laser photocoagulation versus control, outcome: 1.1 Loss of 15 or more letters BCVA at 12 months
1.2 Loss of 15 or more letters BCVA at longer follow‐up times
Two trials reported this outcome at two years (DRS 1978; ETDRS 1991: n = 8306; Analysis 1.2). Fewer eyes given laser photocoagulation lost 15 (or 10) or more lines of visual acuity at two years compared to untreated (DRS 1978), or deferred treatment eyes (ETDRS 1991; RR 0.88, 95% CI 0.80 to 0.97). There was considerable heterogeneity I2 = 73%, P value = 0.06). However, as both effect estimates were in the same direction (0.74 and 0.92) we have reported a pooled estimate.
Two trials reported this outcome at three years (ETDRS 1991; Sato 2012: n = 7458; Analysis 1.3). More eyes receiving laser photocoagulation lost 15 or more letters BCVA at three years compared to eyes with deferred treatment, but there was uncertainty in the result and the confidence intervals included 1 (RR 1.07, 95% CI 0.93 to 1.23). The results of the two trials were reasonably consistent I2 = 14%.
No trials reported this outcome at four years.
One study reported this outcome at five years (ETDRS 1991; n = 7422). Eyes receiving laser photocoagulation were less likely to lose 15 or more letters compared to eyes receiving deferred treatment (RR 0.79, 95% CI 0.72 to 0.85).
1.3 Mean BCVA at 12 months
One study reported mean logMAR BCVA at three years (Sato 2012). The difference between the groups was small and uncertain (MD 0.02, 95% CI ‐0.23 to 0.27; n = 36).
2 Mean NVA at 12 months
None of the studies reported near visual acuity.
3 Severe visual loss (BCVA < 6/60)
For the outcome of severe visual loss (BCVA < 6/60) we found four relevant trials (DRS 1978; ETDRS 1991; Hercules 1977; Sato 2012: n = 9276; Figure 4; Analysis 1.4). Eyes receiving laser photocoagulation were less likely to experience severe visual loss compared to untreated eyes or eyes that received deferred treatment (RR 0.46, 95% CI 0.24 to 0.86). This outcome had high levels of heterogeneity (I2 = 70%, P value = 0.02), but as all the effect estimates were in the same direction we report a pooled estimate. Such heterogeneity seemed due to Hercules 1977, a small study including only patients with proliferative retinopathy, which recorded the largest benefit with laser.
Forest plot of comparison: 1 Laser photocoagulation versus control, outcome: 1.4 Severe visual loss (BCVA < 6/60)
4 Progression of diabetic retinopathy
For the outcome of progression of DR we found four relevant trials (DRS 1978; ETDRS 1991; Sato 2012; Yassur 1980: n = 8331; Figure 5; Analysis 1.5).
Forest plot of comparison: 1 Laser photocoagulation versus control, outcome: 1.5 Progression of diabetic retinopathy
In the DRS 1978 study progression was based on grading of fundus photographs. Eyes were graded for new vessels and severity was graded by comparison with standard images. The following categories were used and progression was defined as change of one or more grades from no new vessels to moderate or severe NVD (NVD means new vessels on or within 1 disc diameter of the optic disc; NVE means new vessels elsewhere):
-
no new vessels;
-
mild NVE, no NVD;
-
moderate or severe NVE, no NVD;
-
mild NVD;
-
moderate or severe NVD.
In the ETDRS 1991 study progression was defined as the development of 'high risk proliferative diabetic retinopathy'. This was defined as PDR with high risk characteristics as defined by DRS 1978. These were new vessels on or within 1 disc diameter of the optic disc worse than a standard photograph, with or without vitreous or preretinal haemorrhage; or vitreous or preretinal haemorrhage accompanied by new vessels, either NVD (less than standard photograph) or NVE greater than or equal to a quarter of the disc area.
In Sato 2012 progression was defined as the development of PDR, i.e. the growth of new vessels (detected by ophthalmoscopy or fluorescein angiography), or preretinal/vitreous haemorrhage.
Yassur 1980 considered only new vessels on or near the optic disc. These were graded into five grades of severity based on the number of involved disc quadrants, calibre of the new vessels, density of neovascularisation (NVD) or fibrous proliferation at the disc (FPD), total area of NVD or FPD proliferation, plane of NVD or FPD proliferation, and fluorescein leakage from NVD. Progression was defined as increase in severity of one or more grades.
The time frames at which these outcomes were reported were different ‐ ranging from 12 months to five years, and these are indicated on the figure.
DR was less likely to progress in eyes that received laser photocoagulation (RR 0.49, 95% CI 0.37 to 0.64). There was considerable heterogeneity I2 = 63%, P value = 0.05) but all effect estimates were in the same direction, so we report a pooled estimate.
5 Quality of life
None of the included studies reported quality of life.
6.1 Adverse events: pain
None of the included studies reported pain.
6.2 Adverse events: loss of driving licence
None of the included studies reported patient outcomes such as loss of driving licence.
6.3 Adverse events: vitreous haemorrhage
For this outcome of vitreous haemorrhage we found two relevant trials (Hercules 1977; Sato 2012: n = 224; Analysis 1.6). People receiving laser photocoagulation were less likely to develop vitreous haemorrhage (RR 0.56, 95% CI 0.37 to 0.85; I2 = 0%).
6.4 Adverse events: retinal detachment
None of the studies reported retinal detachment by intervention group.
Sensitivity analysis
For Analysis 1.5 progression of diabetic retinopathy, exclusion of two trials at high risk of selection or detection bias resulted in a RR of 0.55 (95% CI 0.48 to 0.64; participants = 8183; studies = 2; I2 = 41%; Sato 2012; Yassur 1980). This is not dissimilar to the analysis of all four trials (RR 0.49, 95% CI 0.37 to 0.64; participants = 8331; studies = 4; I2 = 63%).
Discussion
Summary of main results
See summary of findings Table for the main comparison.
We identified five trials. In the majority of these studies (4 trials, 99% of all participants) the intervention was panretinal photocoagulation (PRP) using an argon laser. There were differences in the patient population included in these studies. Two trials included 94% of the participants in this review (DRS 1978; ETDRS 1991). These two studies were conducted in the US population and were complementary: DRS 1978 assessed whether PRP is effective compared to no treatment in people mostly affected by proliferative diabetic retinopathy (PDR); ETDRS 1991 assessed whether earlier peripheral laser treatment of diabetic retinopathy (DR) in its non‐proliferative or early proliferative stage is beneficial, compared to a strategy in which laser is used at a later stage, in high‐risk PDR. Thus, any benefit in ETDRS 1991 should have been less than that seen in DRS 1978 as laser is also part of the control strategy in the former. In most of the analyses the effects observed in ETDRS 1991 were indeed lower than DRS 1978 but not significantly so. Even though there was evidence for statistical heterogeneity, effects were generally in the same direction, so we pooled the results to obtain (approximate) overall estimates of effect.
At 12 months there was little difference between eyes receiving laser photocoagulation and those allocated to no treatment (or deferred treatment), in terms of loss of 15 or more letters of visual acuity. Longer term follow‐up did not show a consistent pattern, but ETDRS 1991 reported a 20% reduction in risk of loss of 15 or more letters of visual acuity at five years.
Treatment with laser reduced the risk of severe visual loss by over 50% at 12 months.
There was a beneficial effect on progression of DR with treated eyes experiencing a 50% reduction in risk of progression and a similar reduction in risk of vitreous haemorrhage.
None of the studies reported near visual acuity, quality of life, pain, or patient relevant outcomes such as loss of driving licence or adverse effects such as retinal detachment.
Overall completeness and applicability of evidence
Overall there is not a large amount of evidence from randomised controlled trials (RCTs) on laser photocoagulation compared to no treatment or deferred treatment. The evidence is dominated by two large studies conducted in the US population (DRS 1978; ETDRS 1991).
Reflecting the fact that the studies were conducted some time ago, there was a lack of data reported for many of our current pre‐specified review outcomes, in particular patient‐relevant outcomes such as quality of life.
We did not consider lasers that are not commonly used today but the treatment parameters used in the included trials were different to those in current use, in particular, smaller size and shorter duration burns are now used (RCOphth 2012).
Overall the evidence is applicable to people presenting with moderate to severe pre‐proliferative and PDR, however, the fact that relatively few trials were identified, and that these were all conducted some time ago in high‐income countries leaves a lack of evidence for lower‐ and middle‐income countries and different parts of the world. However, we have no reason to suppose that the effectiveness of these treatments would be different in lower‐income countries.
The introduction of anti‐vascular endothelial growth factor (anti‐VEGF) therapy for treating several chorioretinal vascular diseases has made it possible to achieve a rapid, but transient, regression of new vessels in PDR, especially to try to clear vitreous haemorrhage, but also to limit side effects of PRP regarding the occurrence of diabetic macular oedema in patients at risk. Moreover, anti‐VEGF therapy is sometimes used in preparation of vitrectomy ‐ which includes use of an endolaser ‐ in advanced PDR. However, use of anti‐VEGF in PDR may have adverse effects and requires multiple treatments. Other Cochrane Reviews compare the effectiveness of anti‐VEGF and laser treatment for PDR (Martinez‐Zapata 2014), and diabetic macular oedema (Virgili 2012).
Quality of the evidence
Overall there is not a large amount of evidence from RCTs on the effects of laser photocoagulation compared to no treatment or deferred treatment. The evidence is dominated by two large studies conducted in the US population (DRS 1978; ETDRS 1991). These two studies were generally judged to be at low or unclear risk of bias, with the exception of inevitable unmasking of patients due to differences between intervention and control.
Four of the studies were within‐person (i.e. pair‐matched), but none of the studies reported the results taking into account the matching. This means that the results will be conservative (confidence intervals wider than if matching had been taken into account). One study reported that they had repeated the analyses taking into account the pair‐matching and that ignoring the pair‐matching was indeed a conservative approach (ETDRS 1991).
Overall we judged the quality of the evidence to be moderate or low (summary of findings Table for the main comparison), reflecting the fact that the studies contributing to the review were conducted some time ago, when standards of trial conduct and reporting were lower; heterogeneity was also present.
Potential biases in the review process
We followed standard methods expected by the Cochrane Collaboration. All changes from protocol are documented in Differences between protocol and review.
Agreements and disagreements with other studies or reviews
In current clinical guidelines, e.g. RCOphth 2012, PRP is recommended in high‐risk PDR. The recommendation is that "as retinopathy approaches the proliferative stage, laser scatter treatment (PRP) should be increasingly considered to prevent progression to high risk PDR" based on other factors such as patients' compliance or planned cataract surgery.
These recommendations need to be interpreted while considering the risk of visual loss associated with different levels of severity of DR, as well as the risk of progression. Since PRP reduces the risk of severe visual loss, but not moderate visual loss that is more related to diabetic maculopathy, most ophthalmologists judge that there is little benefit in treating non‐proliferative DR at low risk of severe visual damage, as patients would incur the known adverse effects of PRP, which, although mild, include pain and peripheral visual field loss and transient DMO. The results of this review would confirm this approach.
Results from searching for studies for inclusion in the review
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Laser photocoagulation versus control, outcome: 1.1 Loss of 15 or more letters BCVA at 12 months
Forest plot of comparison: 1 Laser photocoagulation versus control, outcome: 1.4 Severe visual loss (BCVA < 6/60)
Forest plot of comparison: 1 Laser photocoagulation versus control, outcome: 1.5 Progression of diabetic retinopathy
Comparison 1 Laser photocoagulation versus control, Outcome 1 Loss of 15 or more letters BCVA at 12 months.
Comparison 1 Laser photocoagulation versus control, Outcome 2 Loss of 15 or more letters BCVA at 2 years.
Comparison 1 Laser photocoagulation versus control, Outcome 3 Loss of 15 or more letters BCVA at 3 years.
Comparison 1 Laser photocoagulation versus control, Outcome 4 Severe visual loss (BCVA < 6/60).
Comparison 1 Laser photocoagulation versus control, Outcome 5 Progression of diabetic retinopathy.
Comparison 1 Laser photocoagulation versus control, Outcome 6 Vitreous haemorrhage.
| Laser photocoagulation compared to no treatment (or deferred treatment) for diabetic retinopathy | ||||||
| Patient or population: people with diabetic retinopathy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk* | Corresponding risk | |||||
| No treatment or deferred treatment | Laser photocoagulation | |||||
| Loss of 15 or more letters BCVA Follow‐up: 12 months | Low risk (non‐proliferative DR) | RR 0.99 | 8926 | ⊕⊕⊝⊝ | The pooled RR 0.99 (0.89 to 1.11) is derived from one study with mainly low risk population RR 1.07 (0.92 to 1.23) and one study with mainly high risk population 0.86 (0.71 to 1.04) | |
| 100 per 1000 | 99 per 1000 | |||||
| High risk (proliferative DR) | ||||||
| 250 per 1000 | 248 per 1000 | |||||
| BCVA measured using logMAR acuity (0 = 6/6 visual acuity, higher score is worse visual acuity) Follow‐up: 12 months | The mean BCVA at 12 months in the control group was 0.12 logMAR | The mean BCVA at 12 months in the intervention group was 0.02 logMAR units higher (worse; 0.23 lower to 0.27 higher) | 36 | ⊕⊕⊝⊝ | ||
| Severe visual loss (BCVA < 6/60) Follow‐up: 12 months | Low risk (non‐proliferative DR) | RR 0.46 | 9276 | ⊕⊕⊕⊝ | ||
| 10 per 1000 | 5 per 1000 | |||||
| High risk (proliferative DR) | ||||||
| 50 per 1000 | 23 per 1000 | |||||
| Progression of diabetic retinopathy Follow‐up: 12 months | Low risk (non‐proliferative DR) | RR 0.49 | 8331 | ⊕⊕⊝⊝ | ||
| 100 per 1000 | 49 per 1000 | |||||
| High risk (proliferative DR) | ||||||
| 400 per 1000 | 196 per 1000 (148 to 256) | |||||
| Quality of life Follow‐up: 12 months | See comment | See comment | No studies reported this outcome | |||
| Pain Follow‐up: at time of treatment | See comment | See comment | No studies reported this outcome | |||
| Loss of driving licence Follow‐up: within three months of treatment | See comment | See comment | No studies reported this outcome | |||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| *Estimates of assumed risk are indicative only, as estimates at 12 months were not available in all studies. For the low risk populations they were estimated from ETDRS (but acknowledging that the control group received deferred laser) and for the high risk populations they were estimated from DRS and Hercules 1977. 1Downgraded for risk of bias (‐1): studies were not masked and treatment groups different 2Downgraded for inconsistency (‐1): I2 = 69% and effect estimates were in different directions. See comments for details 3Downgraded for imprecision (‐1): wide confidence intervals 4 There was heterogeneity (I2 = 70%) but all effect estimates favoured laser photocoagulation so we did not downgrade for inconsistency 5Downgraded for indirectness (‐1): study results were reported at 1, 3, 4 and 5 years | ||||||
| Study | Type of laser | Type of photocoagulation | Number (size) of burns | Intensity | Exposure time (seconds) | Number of sessions |
| Argon | Panretinal Focal treatment of new vessels | 800‐1600 (500 µm) or 500‐1000 (1000 µm) | Not reported | 0.1 | 1 (usually) | |
| Argon | Panretinal | Full: 1200‐1600 (500 µm) Mild: 400‐650 (500 µm) | Moderate | 0.1 | Full: 2 or more Mild: 1 | |
| Argon | Panretinal | 800 to 3000 (200 µm and 500 µm) | Minimal retinal blanching | Not reported | Up to 6 | |
| Not reported | Selective photocoagulation of non‐perfusion areas | (400 µm‐500 µm) | Not reported | Not reported | ||
| Argon | Panretinal | As for DRS 1978 | As for DRS 1978 | As for DRS 1978 | As for DRS 1978 |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Loss of 15 or more letters BCVA at 12 months Show forest plot | 2 | 8926 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.89, 1.11] |
| 2 Loss of 15 or more letters BCVA at 2 years Show forest plot | 2 | 8306 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.80, 0.97] |
| 3 Loss of 15 or more letters BCVA at 3 years Show forest plot | 2 | 7458 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.93, 1.23] |
| 4 Severe visual loss (BCVA < 6/60) Show forest plot | 4 | 9276 | Risk Ratio (M‐H, Random, 95% CI) | 0.46 [0.24, 0.86] |
| 5 Progression of diabetic retinopathy Show forest plot | 4 | 8331 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.37, 0.64] |
| 6 Vitreous haemorrhage Show forest plot | 2 | 224 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.37, 0.85] |
