diabetic retinopathy and maculopathy management

- EXECUTIVE SUMMARY

In PDR and severe NPDR

Severe non proliferative DR

·  compliant patient without diabetic maculopathy: regular follow up

Recommendation: conditional

·    non-compliant patient without diabetic maculopathy: laser PRP

Recommendation: Strong

 PDR and high risk PDR without diabetic maculopathy and no abundant fibrosis

·   Non-compliant patient: laser PRP

Recommendation: strong

·  Compliant patient: Laser PRP or antiVEGF injection within 4 weeks;

Recommendation: strong

PDR and high risk PDR with diabetic maculopathy

·  Compliant patient: antiVEGF before PRP

Recommendation: moderate

Non compliant patient: laser PRP with focal/grid laser for the macula

Recommendation: moderate

NCI-DME:

·  Vision 6/12 or better in compliant patients: observe with control of risk factors.

 Recommendation: strong

·  Vision 6/12 or better in non-compliant patients: laser treatment based on angiography and OCT

Recommendation:  strong

· Vision less than 6/12: no treatment and investigate to exclude ischemic maculopathy, if present, IVI of anti VEGF or steroids

Recommendation: consensous

CI-DME

·   Vision better than 6/12 compliant patient: observe with control of risk factors

Recommendation: Conditional

·   Vision better than 6/12 non compliant patient: laser treatment

Recommendation: strong

·  Vision less than 6/12 in compliant patient: AntiVEGF

Recommendation: strong

·  Vision less than 6/12 in non compliant patient: laser

Recommendation: strong

·  Vision less than 6/12 with signs of vitreo-retinal traction: Vitrectomy +/-AntiVEGF

Recommendation: strong

·  Refractory DME: received a minimum of three monthly injections of AntiVEGF with poor anatomical and functional response in compliant patient: intra vitreal steroids/vitrectomy

only in places with subspecialty retinal service.

Recommendation: strong

Introduction:

Diabetes mellitus (DM) is an alarming public health issue globally and its prevalence is increasing heavily in developing countries [1-4]. The number of diabetics between 20 and 79 years of age is estimated to be 415 million people in the world and is expected to rise to 642 million in 2040.[5] In Egypt, DM is a dilemma and a fast-expanding concern. According to the International Diabetes Federation (IDF), the prevalence of DM among Egyptian adults is 15.2%, which may be an underestimation [6]. Diabetic retinopathy (DR) is one of the major complications of diabetes and leading cause of visual impairment or blindness. One of the most devastating complications of diabetes is diabetic retinopathy, which can be potentially blinding [7-14]. Evidence through the years reveals that almost all type I and around 60% of type II diabetic patients develop some degree of retinopathy within 20 years after diagnosis [15]. Given the increasing number of diabetics worldwide, developing countries are expected to receive the greatest toll [14].  

- Recommendations

 Severe non proliferative DR

·   compliant patient without diabetic maculopathy: regular follow up

Recommendation: conditional

Evidence level: high [19-21]

·   non-compliant patient without diabetic maculopathy: laser PRP

Recommendation: Strong

Evidence level: high [19-21]

 PDR and high risk PDR without diabetic maculopathy and no abundant fibrosis

·   Non-compliant patient: laser PRP

Recommendation: strong

Evidence level: high [22-27]

· Compliant patient: Laser PRP or antiVEGF injection within 4 weeks;

Recommendation: strong

Evidence level: high [28-121]

PDR and high risk PDR with diabetic maculopathy

· Compliant patient: antiVEGF before PRP

Recommendation: moderate

Evidence level: moderate

Non compliant patient: laser PRP with focal/grid laser for the macula

Recommendation: moderate

Evidence level: high [22-121]

NCI-DME:

· Vision 6/12 or better in compliant patients: observe with control of risk factors.

 Recommendation: conditional

Evidence level: high [22-121]

· Vision 6/12 or better in non-compliant patients: laser treatment based on angiography and OCT

Recommendation:  strong

Evidence level: high [22-121]

·   Vision less than 6/12: no treatment and investigate to exclude ischemic maculopathy, if present, IVI of anti VEGF or steroids

Recommendation: consensous

Evidence level: low         [22-121]

CI-DME

·  Vision better than 6/12 compliant patient: observe with control of risk factors

Recommendation: Conditional

Evidence level: low [28-121]

· Vision better than 6/12 non compliant patient: laser treatment

Recommendation: strong

Evidence level: high [28-121]

·  Vision less than 6/12 in compliant patient: AntiVEGF

Recommendation: strong

Evidence: high [28-121]

·   Vision less than 6/12 in non compliant patient: laser

Recommendation: strong

Evidence: low [28-121]

·   Vision less than 6/12 with signs of vitreo-retinal traction: Vitrectomy +/-AntiVEGF

Recommendation: strong

Evidence: very low [22-118]

Refractory DME: received a minimum of three monthly injections of AntiVEGF with poor anatomical and functional response in compliant patient: intra vitreal steroids/vitrectomy only in places with subspecialty retinal service.

Recommendation: strong

Evidence level: low [22-118]

Remarks on treatment

1.  Laser PRP :

•   Laser for mild PDR (neovessels less than 1/3 DD) should be between 1200-1800 shot 500um size, moderate PDR (NVD: greater than third of disc diameter, and forward NVD extending beyond the disc margin or NVE: complexes in all quadrants, forward NVE in any quadrant) 2000-2500 shot, severe PDR (Large, NVE complexes in any quadrant, NVE with tractional retinal detachment, large, forward NVD covering whole optic disc surface, NVD with tractional retinal detachment.These cases are high risk of continued traction and haemorrhagic complications following PRP) full PRP 3000 sots

Evidence level: high [22-118]

•  If possible, PRP should be delivered on the same day of the diagnosis of high‑risk PDR and if not, within 2 weeks from the time of diagnosis.

Evidence level moderate [22-118]

•  PRP should be postponed until clinically significant macular edema (CSME) is treated.

Evidence level moderate [22-118]

•  Coexisting high-risk PDR and CSME should be treated with combined PRP plus intravitreal antivascular endothelial growth factor (VEGF) injection or macular laser photocoagulation (MPC).

Evidence level: very low [22-118]

• In cases with fresh vitreous hemorrhage, PRP is usually applied after intravitreal injection of anti‑VEGF when the ocular media is clear.

Evidence level: very low [22-118]

•  In patients with florid type DR, PRP may be applied with shorter intervals (3‑5 days between PRP sessions instead of 1‑4 weeks).

Evidence level: very low [22-118]

Recommendations for follow up laser therapy:

•  First follow up should be at three to four months – ideally at two months

Evidence level: high [22-118]

•  PDR: Retreatment is required if vessels have not regressed, or further new vessels develop [22-121]

2.   AntiVEGF monotherapy for PDR

•  Frequent, regular, follow up i.e., every two to three months for at least a year is an essential prerequisite for the treatment of PDR with AntiVEGF agents.

•  Repeat injections, if required. [119-120]

3. Vitrectomy

Recommendations for treatment

•  Early vitrectomy (within three months) is indicated for people with Type 1 DM who develop severe vitreous haemorrhage in whom severe PDR is suspected

Evidence level: high [123-127]

•  Consider early vitrectomy in eyes where PDR does not respond to extensive and aggressive laser PRP

Evidence level: moderate [123-127]

•  Consider vitreoretinal surgery to relieve vitreoretinal traction if the macular is detached or threatening to detach, to salvage some vision

Evidence level: very low [123-127]

•  Consider combined cataract surgery / vitrectomy in eyes with DR and/or DME with lens opacities, to enable subsequent management of PDR and/or DME.

Evidence: moderate [123-127]

Recommendations for practice

•  Counselling patients before treatment, regarding improving the control of their diabetes and comorbidities is essential.

The procedure should be explained, including the likely outcome as well as the need for and timing and frequency of follow up, the likelihood of repeat treatment and the need for lifelong care. [123-127]

Intravitreal injection before vitrectomy

•      Patients with PDR and active neovascularization who have been planned for vitrectomy may receive intravitreal anti‑VEGF injection within one week before surgery to minimize intraoperative and early

postoperative bleeding.

Evidence level: high [123-127]

• Patients with advanced DR and active fibrovascular tissue who are vitrectomy candidates may receive intravitreal anti‑VEGF injection within one week before the surgery to minimize the risk of bleeding during and after the surgical procedure.

Evidence level: high[123-127]

•  Extensive fibrovascular tissue increases the risk of traction retinal detachment following intravitreal injection of anti‑VEGF drugs; the time interval between the injection and vitrectomy should be not more than 2‑3 days in such cases.

Evidence level: moderate [123-127]

➡️Updates:

To keep these recommendations up to date and ensure its validity it will be periodically updated. This will be done whenever new strong evidence is available and necessitates updating.

- ACKNOWLEDGEMENTS

The Ophthalmology Committee of National Egyptian Guidelines, Ministry of Health and

Ophthalmology 

Chair of the committee: Prof. Hany S. Nasr.

Committee members professors: A. Farag, A. Alghoneimy, E. El-Toukhy, K. Rizk, M. Maher, M. Zaatar, M. Mourad, R. Zaki, W. Ahmad

- ABBREVIATIONS

Anti-VEGF: See Anti-vascular endothelial growth factor.

BCVA: best corrected visual acuity

CI-DME: center-involving macular edema

CSME: clinically significant macular edema

DME: diabetic macular edema

DR: diabetic retinopathy

ERM: epiretinal membrane

ETDRS: Early Treatment for Diabetic Retinopathy Study

FFA: fundus fluorescein angiography   

IRMA: Intraretinal microvascular abnormalities.

IVI: intravitreal injections

NCI-DME: non center-involving macular edema

NPDR: non proliferative diabetic retinopathy

OCT: optical coherence tomography

PDR: proliferative diabetic retinopathy

PRP: pan retinal photocoagulation

VEGF: vascular endothelial growth factor

- GLOSSARY

Anti-vascular endothelial growth factor (anti-VEGF): Substances that inhibit the action of vascular endothelial growth factor protein.

Clinically significant macular edema (CSME): Retinal thickening at or within 500 µm of the center of the macula; and/or hard exudates at or within 500 µm of the center of the macula, if associated with thickening of the adjacent retina; and/or a zone or zones of retinal thickening 1 disc area in size, any part of which is within 1 disc diameter of the center of the macula.

Diabetes mellitus: According to the American Diabetes Association Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, the criteria for the diagnosis of diabetes mellitus are as follows.

·        Fasting plasma glucose equal to or exceeding 126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours.

or

·        Symptoms of hyperglycemia and a casual plasma glucose concentration equal to or exceeding 200 mg/dL (11.1 mmol/L). “Casual” is defined as any time of day without regard to time since last meal. The classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss. or

·        A plasma glucose measurement at 2 hours postload equal to or exceeding 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. However, the expert committee has recommended against oral glucose tolerance testing for routine clinical use. (Source: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2008;31 (suppl):55-60.)

Diabetic macular edema: The accumulation of fluid in the macula due to leaky blood vessels.

Early proliferative diabetic retinopathy (i.e., proliferative retinopathy without DRS high-risk characteristics): New vessels that do not meet the criteria of high-risk proliferative retinopathy.

Focal photocoagulation: A laser technique directed to abnormal blood vessels with specific areas of focal leakage (i.e., microaneurysms) to reduce chronic fluid leakage in patients with macular edema.

Grid photocoagulation: A laser technique in which a grid pattern of scatter burns is applied in areas of diffuse macular edema and nonperfusion. Typically, fluorescein angiograms of these areas show a diffuse pattern rather than focal leakage.

High-risk proliferative diabetic retinopathy: New vessels on or within 1 disc diameter of the optic disc about one-quarter to one-third disc area, with or without vitreous or preretinal hemorrhage; or vitreous and/or preretinal hemorrhage accompanied by new vessels either on the optic disc less than ¼ disc area, or new vessels elsewhere equaling or exceeding one-quarter disc area.  

Intraretinal microvascular abnormalities: Tortuous intraretinal vascular segments, varying in caliber from barely visible to 31 µm in diameter (one-quarter the width of a major vein at the disc margin); they occasionally can be larger. Intraretinal microvascular abnormalities may be difficult to distinguish from neovascularization.

Macular edema: Thickening of the retina within 1 or 2 disc diameters of the center of the macula. (See Clinically significant macular edema.) Any other thickening of the macula not within this area is non-CSME.

Mild nonproliferative diabetic retinopathy: At least 1 microaneurysm and less than moderate nonproliferative diabetic retinopathy.

Moderate nonproliferative diabetic retinopathy: Hemorrhages and/or microaneurysms greater than standard photograph 2A, and/or soft exudates, venous beading, or IRMA present but less than severe nonproliferative retinopathy.

Moderate visual loss: The loss of 15 or more letters on the ETDRS visual acuity chart, or doubling of the visual angle (e.g., 6/6 to 6/12 etc.).

New vessels at the optic disc: New vessels at the optic disc; neovascularization on or within 1 disc diameter of the optic disc.

New vessels elsewhere in the retina: New vessels elsewhere in the retina; neovascularization elsewhere in the retina and greater than 1 disc diameter from the optic disc margin.

New vessels on the iris: New vessels on the iris; neovascularization of the iris.

Nonproliferative diabetic retinopathy: The phases of diabetic retinopathy with no evidence of retinal neovascularization.

Optical coherence tomography: A diagnostic test using low energy lasers that takes a cross-section image of the retina, Used mostly to determine if there are membranes on the surface of the macula or fluid within or beneath it. 

Panretinal photocoagulation: A type of laser surgery used for patients with PDR. The surgery is delivered in a scatter pattern throughout the peripheral fundus and is intended to lead to a regression of neovascularization.

Proliferative diabetic retinopathy: Advanced disease characterized by NVD and/or new vessels elsewhere in the retina.

Retinal hard exudate: Protein and lipid accumulation within the retina.

Refractory DME: in which the patient received 3 monthly doses of antiVEGF with poor anatomical and functional response.

Scatter photocoagulation: See Panretinal photocoagulation.

Severe nonproliferative diabetic retinopathy: Using the 4-2-1 rule, the presence of at least one of the following features: (1) severe intraretinal hemorrhages and microaneurysms, in 4 quadrants; (2) venous beading in 2 or more quadrants; or (3) moderate IRMA in 1 or more quadrants.

Severe visual loss: Occurrence of visual acuity worse than 5/200 at any two consecutive visits scheduled at 4-month intervals.

- Purpose

Identifying the stages of diabetic retinopathy and maculopathy

Initiate an appropriate management plan for all stages of diabetic retinopathy and maculopathy

- Scope

Methodology for treating diabetic retinopathy and maculopathy

- Target audience

Ophthalmologists - Pediatricians – Family doctors - High nurses.

- Methods

A comprehensive search for guidelines was undertaken to identify the most relevant guidelines to consider for adaptation. 

The inclusion/exclusion criteria followed in the search and retrieval of guidelines to be adapted:  

•  Selecting only evidence-based guidelines (guideline must include a report on systematic literature searches and explicit links between individual recommendations and their supporting evidence)  

•  Selecting peer reviewed publications only  

•   Selecting guidelines written in English language  

•  Excluding guidelines written by a single author not on behalf of an organization in order to be valid and comprehensive, a guideline ideally requires multidisciplinary input  

•  Excluding guidelines published without references as the panel needs to know whether a thorough literature review was conducted and whether current evidence was used in the preparation of the recommendations  

The following characteristics of the retrieved guidelines were summarized in a table:  

•  Developing organization/authors  

•    Date of publication, posting, and release  

•   Country/language of publication  

•   Date of posting and/or release  

•   Dates of the search used by the source guideline developers

- Evidence assessment

According to WHO handbook for Guidelines (5) we used the GRADE (Grading of

Recommendations, Assessment, Development and Evaluation) approach to assess the quality of a body of evidence, develop and report recommendations. GRADE methods are used by WHO

because they represent internationally agreed standards for making transparent recommendations. Detailed information on GRADE is available on the following sites:  

■ GRADE working group: http://www.gradeworkinggroup.org

■ GRADE online training modules:http://cebgrade.mcmaster.ca/

Table 1 Quality of evidence in GRADE  

WHO guideline reporting tool - V1.5, December 2021  

Table 2 Significance of the four levels of evidence  

Table 3 Factors that determine how to upgrade or downgrade the quality of evidence  

WHO guideline reporting tool - V1.5, December 2021  

The strength of the recommendation  

The strength of a recommendation communicates the importance of adherence to this recommendation.

Strong recommendations

With strong recommendations, the guideline communicates the message that the desirable effects of adherence to the recommendation outweigh the undesirable effects. This means that in most situations the recommendation can be adopted as policy. 

Conditional recommendations

These are made when there is greater uncertainty about the four factors mentioned in table 3 or if local adaptation has to account for a greater variety in values and preferences, or when resource use makes the intervention suitable for some, but not for other locations. This means that there is a need for substantial debate and involvement of stakeholders before this recommendation can be adopted as policy.

When not to make recommendations

When there is lack of evidence on the effectiveness of an intervention, it may be appropriate not to make a recommendation.  

- Research Gaps

It is recommended to have high quality randomised controlled studies from combining different types of antiVEGF and concomitant use of laser.

- Clinical indications for monitoring

1.      History of vascular occlusions, and associated conditions.

2.      Blood sugar level.

3.      Corrected visual acuity in all visits.

4.      Detailed fundus biomicroscopy.

5.      Prior to treatment, fundus fluorescein angiography or OCTA and OCT macula.

6.      OCT macula after one month at the end of initial loading doses.

7.      According to retreatment protocol OCT in each visit has to be presented with measurement of visual acuity.

- Appendix 1

Major study results

The Diabetic Retinopathy Study (DRS) was designed to investigate the value of laser photocoagulation surgery for patients with severe nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). The results are shown in Table A4-1.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) began in 1979. It was initially funded by the National Eye Institute, which is part of the National Institutes of Health. The purpose of the WESDR is to describe the frequency and incidence of complications associated with diabetes (eye complications such as diabetic retinopathy and visual loss, kidney complications such as diabetic nephropathy, and amputations), and to identify risk factors (such as poor glycemic control, smoking, and high blood pressure) that may contribute to the development of these complications.

The Early Treatment Diabetic Retinopathy Study (ETDRS) investigated the value of photocoagulation surgery for patients with NPDR or PDR without high-risk characteristics. The results for eyes with macular edema are shown in Table A4-2. Visual loss was defined as at least doubling of the visual angle (e.g., 20/20 to 20/40, or 20/50 to 20/100). In eyes with NPDR or non-high-risk PDR, early panretinal photocoagulation (PRP) was compared with deferral of photocoagulation, and although there was a beneficial treatment effect, the outlook for maintaining vision was good in both groups. The 5-year rates of severe visual loss or vitrectomy ranged from 2% to 6% in eyes assigned to early photocoagulation and from 4% to 10% in eyes assigned to deferral. Early PRP was associated with side effects (small decreases in visual acuity and visual field) in some eyes, and the ETDRS concluded that deferral of photocoagulation was preferable at least until retinopathy was approaching the highrisk stage. Eyes approaching that stage had a 50% risk of reaching it within 12 to 18 months. Eyes in this category had very severe NPDR or non-high-risk PDR characterized by NVD less than one-quarter to one-third disc area and/or NVE, without vitreous or preretinal hemorrhage.

Recent additional analyses of visual outcome in ETDRS patients with severe NPDR to nonhigh-risk PDR suggest that the recommendation to consider PRP before the development of high-risk PDR is particularly appropriate for patients with type 2 diabetes. The risk of severe vision loss or vitrectomy was reduced by 50% in patients who were treated early compared with those who deferred treatment until high-risk PDR developed.

For patients with type 1 diabetes, the timing of the PRP will depend on the compliance with follow-up, status and response to treatment of the fellow eye, impending cataract surgery, and/or pregnancy status.

The Diabetic Retinopathy Vitrectomy Study (DRVS) investigated the role of vitrectomy in managing eyes with very severe PDR. The benefit of early vitrectomy for severe vitreous hemorrhage (defined as hemorrhage obscuring the macula or major retinal vessels for 3 disc diameters from the macular center) was seen in type 1 patients, but no such advantage was found in type 2 patients, who did not benefit from earlier surgery. Early vitrectomy was beneficial among patients with visual acuity of 5/200 or worse and severe vitreous hemorrhage with reduced vision for at least 1 month and without previous treatment or complications such as retinal detachment or neovascularization of the iris. Overall, at 2 years after surgery, 25% of the early vitrectomy group and 15% of the deferral group had visual acuity of 20/40 or better. The advantage was most pronounced in patients with type 1 diabetes (36% vs. 12% for early vitrectomy versus deferral of vitrectomy, respectively) and was not statistically significant for patients with type 2 diabetes.

The DRVS showed that early vitrectomy was beneficial for patients with visual acuity of 20/400 or better plus 1 of the following: (1) severe neovascularization and fibrous proliferation; (2) fibrous proliferation and moderate vitreous hemorrhage; or (3) moderate neovascularization, severe fibrous proliferation, and moderate vitreous hemorrhage. Among such patients, 44% with early vitrectomy and 28% in the observation group had visual acuity of 20/40 or better at 4 years of follow-up.

The results of the DRVS should be interpreted in light of subsequent advances in vitreoretinal surgery, such as the introduction of small-gauge vitrectomy technology, endoscopic and indirect ophthalmoscopic laser photocoagulation surgery, and advanced instrumentation. The use of longacting intraocular gases such as sulfur hexafluoride (SF6) and perfluoropropane (C3F8), the use of viscodissection, and the use of heavier-than-water liquids such as perfluoro-octane are advances in vitreoretinal surgery that developed after the DRVS. Thus, the results may actually be better than those reported in the DRVS. Early vitrectomy should be considered for selected patients with type 2 diabetes, particularly those in whom severe vitreous hemorrhage prohibits laser therapy photocoagulation of active neovascularization.

The FIELD study was a randomized controlled trial that evaluated long-term fenofibrate therapy for the reduction of cardiovascular events in 9795 patients with type 2 diabetes mellitus. Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer nonfatal myocardial infarctions and revascularizations. The higher rate of starting statin therapy in patients allocated to receive placebo might have masked a moderately larger treatment benefit.

The Diabetic Retinopathy Clinical Research Network (DRCR.net) is a collaborative network dedicated to facilitating multicenter clinical research of diabetic retinopathy, diabetic macular edema

(DME), and associated conditions. The DRCR.net supports the identification, design, and implementation of multicenter clinical research initiatives focused on diabetes-induced retinal disorders. Principal emphasis is placed on clinical trials, but epidemiologic outcomes and other research may be supported as well.  The DRCR.net was formed in 2002 and currently includes over 115 participating sites (offices) with over 400 physicians throughout the United States. The DRCR.net is funded by the National Eye Institute (NEI), which is a part of the National Institutes of Health, the branch of government that funds medical research. The DRCR.net has completed multiple clinical trials evaluating the role of anti-vascular endothelial growth factor (anti-VEGF), laser treatment, and corticosteroids in DME, anti-VEGF efficacy in PDR and vitreous hemorrhage, and even diabetes education effectiveness on DME (See Table A3-3). Most importantly, DRCR.net Protocol T (Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema) compared the effectiveness of ranibizumab, aflibercept, and bevacizumab in the treatment of DME.⁹⁶ This study found that all three drugs resulted in improvement in visual acuity at 1 year with similar safety profiles. However, the mean visual acuity using aflibercept was better for eyes with visual acuity of 20/50 or worse at 1 year. At 2 years, the mean visual acuity in the aflibercept was no longer superior to ranibizumab, although it remained superior to bevacizumab.  Another important treatment comparison was done in Protocol I: Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt vs. Deferred Laser Treatment. Three-year results were reported in 2012. The study utilized ranibizumab monthly until improvement no longer occurred (with resumption if the condition worsened) and random assignment to focal/grid laser treatment promptly or deferred (≥24 weeks). The 3-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and  worse for vision outcomes, than deferring laser treatment for ≥24 weeks in eyes with DME involving the fovea and with vision impairment.⁹⁴

A previous publication from Protocol I results confirmed the 1-year results that intravitreal ranibizumab with prompt or deferred laser was more effective through 2 years compared with prompt laser alone for the treatment of DME involving the central macula. Laser was not associated with endophthalmitis, the rare but potentially devastating complication of injecting ranibizumab. In pseudophakic eyes, results with intravitreal triamcinolone plus prompt laser appeared similar to results in the ranibizumab arms and were more effective than laser alone, but the triamcinolone plus prompt laser arm had an increased risk of IOP elevation.¹⁸⁹

Most recently, the DRCR.net Protocol S evaluated the effects of anti-VEGF versus PRP.²⁹¹ In a randomized, multicenter, noninferiority trial, 394 eyes of 305 adults with PDR were randomized to receive either PRP or anti-VEGF therapy. Ranibizumab 0.5 mg was given at baseline and as frequently as every 4 weeks based on a structured retreatment design. Eyes in both groups were allowed ranibizumab if DME was present. In eyes with PDR, ranibizumab was not inferior to PRP in terms of visual acuity outcomes at 2 years. Mean visual acuity improvement was +2.8 letters for ranibizumab and +0.2 letters for PRP-treated eyes (P<0.001). When the totality of the visual acuity data was included (area under the curve analysis), eyes given ranibizumab had overall better visual acuity outcomes than eyes treated with PRP. There was less mean reduction in peripheral visual field (-23 dB vs. -422 dB; P<0.001) with ranibizumab than with PRP treatment. The rates for vitrectomy were more frequent (15% vs. 4%; P<0.001), and DME development was more frequent (28% vs. 9%; P<0.001) in the PRP group than in the ranibizumab group. Moreover, rates of active neovascularization or rates of regression of neovascularization were similar between the two groups.

The RISE and RIDE trials were parallel phase III multicenter double-masked sham injection– controlled randomized studies conducted at private and university-based retina specialty clinics in the

United States and South America. (See Glossary.)

The phase III results for both studies were published in 2012. The studies utilized monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections, with macular laser available if needed. The study concluded that ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular side effects.

READ-2 was a phase II multicenter randomized controlled trial that compared 0.5 mg injections of ranibizumab versus focal laser treatment over 2 years in patients with type 1 or type 2 diabetes mellitus and DME. Patients randomized to one arm of the trial received ranibizumab at baseline, and at 1, 3 and 5 months after baseline; a second arm received laser treatment at baseline and at 3 months (if needed); the third arm received both ranibizumab and laser treatment at baseline and 3 months. From month 5, all subjects received ranibizumab every 2 months and/or maintenance laser treatment every 3 months.

At 24 months, differences between the groups were not statistically significant, and all groups experienced improved visual acuity. Patients receiving combined ranibizumab and laser treatment required fewer injections than patients receiving ranibizumab alone.

BOLT was a phase II 2-year randomized controlled trial that compared intravitreal 1.25 mg bevacizumab injections and focal laser treatment in patients with persistent DME and visual impairment. Bevacizumab patients received an injection every 6 weeks, whereas laser patients were treated every 4 weeks.

At 2 years, visual acuity results were substantially better in the bevacizumab group compared with the laser group, with significant differences in the proportions of patients gaining 10 letters and 15 letters. No patients lost 10 or more letters in the bevacizumab group, compared with 14% of patients treated

with laser.

These studies compared the efficacy and safety of intravitreal aflibercept injection (IAI) with macular laser photocoagulation surgery for DME. Visual improvement were observed in the IAI treatment regimens over laser control at 52, 100 and 148 weeks. Incidence of adverse events was consistent with the known safety profile of IAI. 

The DRCR.net compared the efficacy and safety of bevacizumab, ranibizumab, and aflibercept in a multicentered, randomized clinical trial. At the primary endpoint at 1 year, the mean change in vision was greater for aflibercept than for either of the other two drugs. However, the mean visual acuity changes were dependent on the baseline visual acuity. For eyes with milder visual acuity loss, the drugs resulted in similar visual outcomes (8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab; P>0.50 for each pairwise comparison). However, for eyes with 20/50 or worse vision, the mean visual acuity in eyes treated with aflibercept had greater improvements in vision (18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab; P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs.

bevacizumab). There were no significant differences in rates of adverse events. However, at 2 years, the mean visual acuity results were similar for ranibizumab and aflibercept, although aflibercept results remained significantly better than bevacizumab results. There was a slightly higher rate of Antiplatelet Trialists' Collaboration (APTC) events with ranibizumab compared with the other two drugs at the 2-year endpoint. All three drugs improved visual acuity at 2 years, and the number of injections decreased in year 2 compared to year 1.

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