The current standard therapy for patients with diabetic macular oedema (DME)—focal/grid laser photocoagulation—usually does not improve impaired vision, and many patients lose vision despite laser therapy. Recent approval of ranibizumab by the European Medicines Agency to treat visual impairment due to DME fulfils the previously unmet medical need for a treatment that can improve visual acuity (VA) in these patients. We reviewed 1- and 2-year clinical trial findings for ranibizumab used as treatment for DME to formulate evidence-based treatment recommendations in the context of this new therapy. DME with or without visual impairment should be considered for treatment when it fulfils the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria for clinically significant oedema. For DME with centre involvement and associated vision loss due to DME, monthly ranibizumab monotherapy with treatment interruption and re-initiation based on VA stability is recommended. Laser therapy based on ETDRS guidelines is recommended for other forms of clinically significant DME without centre involvement or when no vision loss has occurred, despite centre involvement. Because these recommendations are based on randomised controlled trials of 1–2 years duration, guidance may need updating as long-term ranibizumab data become available and as additional therapeutic agents are assessed in clinical trials.
diabetic retinopathy; expert recommendations; vascular endothelial growth factor inhibitors
Describe the underlying principles used to develop a web-based algorithm that incorporated intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) in a Diabetic Retinopathy Clinical Research Network (DRCR.net) randomized clinical trial.
Discussion of treatment protocol for DME.
Subjects with vision loss from DME involving the center of the macula.
The DRCR.net created an algorithm incorporating anti-VEGF injections in a comparative effectiveness randomized clinical trial evaluating intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser in eyes with vision loss from center-involved DME. Results confirmed that intravitreal ranibizumab with prompt or deferred laser provides superior visual acuity outcomes, compared with prompt laser alone through at least 2 years. Duplication of this algorithm may not be practical for clinical practice. In order to share their opinion on how ophthalmologists might emulate the study protocol, participating DRCR.net investigators developed guidelines based on the algorithm's underlying rationale.
Main Outcome Measures
Clinical guidelines based on a DRCR.net protocol.
The treatment protocol required real time feedback from a web-based data entry system for intravitreal injections, focal/grid laser, and follow-up intervals. Guidance from this system indicated whether treatment was required or given at investigator discretion and when follow-up should be scheduled. Clinical treatment guidelines, based on the underlying clinical rationale of the DRCR.net protocol, include repeating treatment monthly as long as there is improvement in edema compared with the previous month, or until the retina is no longer thickened. If thickening recurs or worsens after discontinuing treatment, treatment is resumed.
Duplication of the approach used in the DRCR.net randomized clinical trial to treat DME involving the center of the macula with intravitreal ranibizumab may not be practical in clinical practice, but likely can be emulated based on an understanding of the underlying rationale for the study protocol. Inherent differences between a web-based treatment algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. The closer the clinical approach is to the algorithm used in the study, the more likely the outcomes will be similar to those published.
Perform a cost-effectiveness analysis of the treatment of Diabetic macular edema (DME) with ranibizumab plus prompt or deferred laser versus triamcinolone plus prompt laser. Data for the analysis was drawn from reports of the Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocol I.
Computer simulation based on Protocol I data. Analyses were conducted from the payor perspective.
Simulated participants assigned characteristics reflecting those seen in Protocol I.
Markov models were constructed to replicate Protocol I’s 104 week outcomes using a microsimulation approach to estimation. Baseline characteristics, visual acuity (VA), treatments, and complications were based on Protocol I data. Costs were identified by literature search. One-way sensitivity analysis was performed and the results were validated against Protocol I data.
Main Outcome Measures
Direct cost of care for two years, change in VA from baseline, and incremental cost-effectiveness ratio (ICER) measured as cost per additional letter gained from baseline (ETDRS).
For sham plus laser (S+L), ranibizumab plus prompt laser (R+pL), ranibizumab plus deferred laser (R+dL), and triamcinolone plus laser (T+L), effectiveness through 104 weeks was predicted to be 3.46, 7.07, 8.63, and 2.40 letters correct, respectively. ICER values in terms of dollars per VA letter were $393 (S+L vs. T+L), $5,943 (R+pL vs. S+L), and $20 (R+dL vs. R+pL). For pseudophakics, the ICER value for comparison triamcinolone with laser versus ranibizumab with deferred laser was $14,690 per letter gained. No clinically relevant changes in model variables altered outcomes. Internal validation demonstrated good similarity to Protocol I treatment patterns.
In treatment of phakic patients with DME, ranibizumab with deferred laser provided an additional 6 letters correct compared to triamcinolone with laser at an additional cost of $19,216 over two years. That would indicate that if the gain in visual acuity seen at two years is maintained in subsequent years, then the treatment of phakic patients with DME using ranibizumab may meet accepted standards of cost-effectiveness. For pseudophakic patients, first line treatment with triamcinolone appears to be the most cost-effective option.
Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
Multicenter, randomized clinical trial.
A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea.
Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (≥24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.
Main Outcome Measures
Best-corrected visual acuity and safety at 1 year.
The 1-year mean change (±standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9±11, P<0.001) and ranibizumab + deferred laser group (+9±12, P<0.001) but not in the triamcinolone + prompt laser group (+4±13, P=0.31) compared with the sham + prompt laser group (+3±13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.
Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.
Diabetic macular edema (DME) is the main cause of visual impairment in diabetic patients. Macular edema within 1 disk diameter of the fovea is present in 9% of the diabetic population. The management of DME is complex and often multiple treatment approaches are needed. This review demonstrates the benefits of intravitreal triamcinolone, bevacizumab and ranibizumab as adjunctive therapy to macular laser treatment in DME. The published results indicate that intravitreal injections of these agents may have a beneficial effect on macular thickness and visual acuity, independent of the type of macular edema that is present. Therefore, pharmacotherapy could complement focal/grid laser photocoagulation in the management of DME. For this review, we performed a literature search and summarized recent findings regarding combined therapy for DME.
Anti-vascular Endothelial Growth Factor; Diabetic Macular Edema; Macular Laser Photocoagulation
Diabetic retinopathy is the leading cause of blindness among individuals of working age in industrialized nations, with most of the vision loss resulting from diabetic macular edema (DME). The formation of DME depends on the action of several growth factors and inflammatory mediators, but vascular endothelial growth factor (VEGF) appears to be critical for breaking down the blood-retinal barrier and promoting the accumulation of macular edema. Laser photocoagulation has been the standard-of-care for three decades, and although it stabilizes vision, significant gains in visual acuity after treatment are unusual. Several VEGF inhibitors (pegaptanib, aflibercept, and ranibizumab) have been initially developed and tested for the treatment of age-related macular degeneration and subsequently for DME. In Phase I, II, and III trials for DME, ranibizumab has been shown to be superior to macular laser photocoagulation and intraocular triamcinolone acetonide injections for improving visual acuity and drying the macula. As a result, ranibizumab is the only anti-VEGF drug that has been approved by the United States Food and Drug Administration for the treatment of DME. Most experts now consider intravitreal anti-VEGF therapy to be standard-of-care for DME involving the fovea.
aflibercept; bevacizumab; diabetic macular edema; diabetic retinopathy; ranibizumab; vascular endothelial growth factor
Neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME) are major causes of visual impairment in the elderly population worldwide. With the aging population, the prevalence of neovascular AMD and DME has increased substantially over the recent years. Vascular endothelial growth factor (VEGF) has been implicated as playing an important role in the pathogenesis of both neovascular AMD and DME. Since its introduction in 2006, ranibizumab, a recombinant, humanized, monoclonal antibody fragment against all isoforms of VEGF-A, has revolutionized the treatment of neovascular AMD and DME. The efficacy and safety of ranibizumab in neovascular AMD has been demonstrated in the ANCHOR and MARINA trials. Further studies including the PIER, PrONTO, and SUSTAIN trials have also evaluated the optimal dosing regimen of ranibizumab in neovascular AMD. The CATT and IVAN trials compared the safety and efficacy of ranibizumab with off-label use of bevacizumab. Studies such as SUSTAIN and HORIZON have shown that ranibizumab has a good safety profile and is well tolerated for over 4 years with very few serious ocular and systemic adverse events. For DME, Phase II RESOLVE study and Phase III RISE and RIDE studies have demonstrated superiority of ranibizumab treatment in improving vision over placebo controls. Phase II READ and Phase III RESOLVE and REVEAL studies have shown that ranibizumab is more effective both as monotherapy and in combination with laser compared with laser monotherapy. The 3-year results from the DRCRnet protocol I study found that ranibizumab with deferred laser resulted in better long-term visual outcome compared with ranibizumab with prompt laser. This review summarizes various important clinical trials on the long-term efficacy and safety of ranibizumab in the treatment of neovascular AMD and DME. The pharmacological properties of ranibizumab, its cost effectiveness, and impact on quality of life will also be discussed.
ranibizumab; anti-VEGF therapy; age-related macular degeneration; diabetic macular edema; safety; diabetic retinopathy; cost-effectiveness
The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center.
RESEARCH DESIGN AND METHODS
This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age >18 years, type 1 or 2 diabetes, central retinal thickness [CRT] ≥300 μm, and best corrected visual acuity [BCVA] of 73–39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n = 51 each) or sham (n = 49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n = 151, patients receiving ≥1 injection).
At month 12, mean ± SD BCVA improved from baseline by 10.3 ± 9.1 letters with ranibizumab and declined by 1.4 ± 14.2 letters with sham (P < 0.0001). Mean CRT reduction was 194.2 ± 135.1 μm with ranibizumab and 48.4 ± 153.4 μm with sham (P < 0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P < 0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab.
Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.
Diabetic macular edema (DME) is the leading cause of blindness in the diabetic population. However, there is limited understanding of the epidemiology of DME with visual impairment (VI) and treatment in patients with diabetes in Canada. This observational, retrospective study used records from the Southwestern Ontario database to observe the demographics, prevalence, and treatment characteristics of VI due to DME compared to a healthy population in a real-world Canadian setting. Data was compared between a cohort of 8,368 diabetic (type 1 or 2) patients, who were ≥18 years old and had a diagnosis of DME with VI (visual acuity <20/40 in Snellen equivalent), and 76,077 age- and gender-matched subjects representing a healthy population. Among diabetic patients, prevalence of DME was 15.7%, and prevalence of VI due to DME was 2.56%. Laser monotherapy was the most frequently used treatment. Public funding covered costs for 85% of persons with DME while 18% were paid for with private funds. This study provides insight into the demographics, prevalence, and treatment of VI due to DME in a representative Canadian cohort. This data can help to inform evaluation of current DME treatment patterns and of proposed new treatment on drug plan budgets in Canada.
To determine the most cost-effective treatment for patients with newly diagnosed neovascular macular degeneration: monthly or as-needed bevacizumab injections, or monthly or as-needed ranibizumab injections.
Using a Markov model with a 20-year time horizon, we compared the incremental cost-effectiveness of treating a hypothetical cohort of 80-year-old patients with newly diagnosed neovascular macular degeneration using monthly bevacizumab, as-needed bevacizumab, monthly ranibizumab, or as-needed ranibizumab. Data came from the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT), the Medicare Fee Schedules, and the medical literature.
Compared with as-needed bevacizumab, the incremental cost-effectiveness ratio of monthly bevacizumab is $242,357 per quality-adjusted life year (QALY). Monthly ranibizumab gains an additional 0.02 QALYs vs monthly bevacizumab at an incremental cost-effectiveness ratio of more than $10 million per QALY. As-needed ranibizumab was dominated by monthly bevacizumab. In sensitivity analyses assuming a willingness to pay of $100,000 per QALY, the annual risk of serious vascular events would have to be at least 2.5 times higher with bevacizumab than that observed in the CATT trial for as-needed ranibizumab to have an incremental cost-effectiveness ratio of <$100,000 per QALY. In another sensitivity analysis, even if every patient receiving bevacizumab experienced declining vision by one category (eg, from 20/25–20/40 to 20/50–20/80) after 2 years but all patients receiving ranibizumab retained their vision level, as-needed ranibizumab would have an incremental cost-effectiveness ratio of $97,340 per QALY.
Even after considering the potential for differences in risks of serious adverse events and therapeutic effectiveness, bevacizumab confers considerably greater value than ranibizumab for the treatment of neovascular macular degeneration.
Intravitreal ranibizumab prevents vision loss and improves visual acuity in patients with neovascular age-related macular degeneration, but it is expensive, and efficacy beyond 2 years is uncertain.
We assessed the cost-effectiveness of ranibizumab compared with no ranibizumab over 10 years, using randomized trial efficacy data for the first 2 years, post-trial efficacy assumptions, and ranibizumab acquisition costs ranging from the wholesale price ($1,950 per dose) to the price of bevazicumab ($50), a similar molecule which may be equally efficacious. We used a computer simulation model to estimate the probability of blindness, the number of quality-adjusted life-years (QALYs), direct costs (in 2004 U.S. dollars), and cost-effectiveness ratios for a 67-year old woman. Costs and QALYs were discounted at 3% per year.
The probability of blindness over 10 years was reduced from 56% to 34% if ranibizumab was efficacious for only 2 years, 27% if efficacy was maintained for a further 2 years only (base-case scenario), and 17% if visual acuity at 4 years was then sustained. It was cost-saving under all price assumptions, when caregiver costs were included. When caregiver costs were excluded, the cost per QALY for the base-case ranged from $5,600, assuming the bevazicumab price, to $91,900 assuming the wholesale ranibizumab price. The cost per QALY was < $50,000 when the cost of ranibizumab was less than $1000.
From a societal perspective, ranibizumab was cost-saving. From a health care funder's perspective, ranibizumab was an efficient treatment when it cost less than $1000 per dose.
To identify factors that predict treatment success or failure in patients treated with intravitreal ranibizumab for diabetic macular edema (DME).
Thirty-seven baseline demographic, systemic, ocular, optical coherence tomography (OCT), and fundus photographic variables were assessed for association with change in visual acuity (VA) or OCT between baseline and 1 year in 361 eyes thatwere assigned randomly to intravitreal ranibizumab with prompt or deferred laser within a trial of ranibizumab, triamcinolone, and laser for center involved DME. A categorical variable describing follow-up anatomic responses to therapy was added to the vision outcome model.
After adjusting for baseline VA, a larger VA treatment benefit was associated with younger age (P < 0.001), less severe diabetic retinopathy on clinical exam (P = 0.003), and absence of surface wrinkling retinopathy (P<0.001). Central subfield (CSF) thickness evolution during the first treatment year also predicted better vision outcomes (P<0.001). After adjusting for baseline CSF thickness, lipid was associated with more favorable OCT improvement (P = 0.004). As only11 eyes experienced vision loss and 6 eyes experienced CSF worsening, factors for poor outcomes could not be evaluated.
A review of baseline factors and anatomic responses during the first year of ranibizumab therapy for association with vision outcome did not identify any features that would preclude ranibizumab treatment. However, baseline thickness is the strongest predictor of anatomic outcome and reduction in thickness during the first treatment year is associated with better vision outcomes.
To relate costs and treatment benefits for macular edema due to diabetes (DME) and branch and central retinal vein occlusion (BRVO, CRVO).
A model of resource utilization, outcomes, and cost effectiveness and utility.
Results from published clinical trials (index studies) of laser, intravitreal corticosteroids, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and vitrectomy trials were used to ascertain visual benefit and clinical protocols. Calculations followed from the costs of one year of treatment for each treatment modality and the visual benefits as ascertained.
Main Outcome measures
Visual acuity (VA) saved, cost of therapy, cost per line saved, cost per line-year saved, and costs per quality adjusted life years (QALYs).
The lines saved for DME (0.26 to 2.02), BRVO (0.74 to 4.92), and CRVO (1.2 to 3.75) yielded calculations of costs/line of saved VA for DME ($1329 to 11609), BRVO ($494 to 13039), and CRVO ($704 to 7611), costs/line-year for DME ($60 to 561), BRVO ($25 to 754), and CRVO ($45 to 473), and costs/QALY of $824 to $25566.
Relative costs and benefits should be considered in perspective when applying and developing treatment strategies.
Macular edema; anti-VEGF therapy; laser photocoagulation; medical costs
To report 3-year follow-up within a previously reported randomized trial evaluating prompt versus deferred (for ≥24 weeks) focal/grid laser treatment in eyes treated with intravitreal 0.5-mg ranibizumab for diabetic macular edema (DME).
Multicenter randomized clinical trial.
Three hundred and sixty one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea.
Ranibizumab every four weeks until no longer improving (with resumption if worsening) and random assignment to focal/grid laser treatment promptly or deferred (≥24 weeks).
Main Outcome Measures
Best-corrected visual acuity and safety at the 156-week (“3-year”) visit.
The estimated mean change in visual acuity letter score from baseline through the 3-year visit was 2.9 letters greater (9.7 versus 6.8, mean difference = 2.9, 95% confidence interval 0.4 to 5.4, P = 0.02) in the deferral group compared with the prompt laser treatment group. In the prompt laser treatment group and deferral group, respectively, the percentage of eyes with a ≥10 letter gain was 42% and 56% (P = 0.02), while the percentage of eyes with a ≥10 letter loss was 10% and 5% (P = 0.12). Up to the 3-year visit, the median numbers of injections were 12 and 15 in the prompt and deferral groups, respectively (P = 0.007), including 1 and 2, respectively, from the 2- up to the 3-year visit. At the 3-year visit, the percentages of eyes with central subfield thickness ≥250 μm on time domain optical coherence tomography were 36% in both groups (P = 0.90). In the deferral group, 54% did not receive laser treatment during the trial. Systemic adverse events appeared similar in the two groups.
These 3-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse for vision outcomes, than deferring laser treatment for ≥ 24 weeks in eyes with DME involving the fovea and with vision impairment. Some of the observed difference in visual acuity at three years may be related to fewer cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through five years continues.
Diabetic retinopathy (DR) is a leading cause of vision loss in the working-age population and is relatedto 1%-5% of cases of blindness worldwide. Diabetic macular edema (DME) is the most frequent cause of DR vision loss and is an important public health problem. Recent studies have implicated vascular endothelial growth factor (VEGF) in DR and DME pathogenesis, as well as provided evidence of the benefits of anti-VEGF agents for the management of such conditions. Despite the benefits of intravitreal ranibizumab injection for the management of DME, the cost-effectiveness of intravitreal bevacizumab therapy has gained increasing interest in the scientific community. This review summarizes the studies examining bevacizumab for the management of DME, focusing on the efficacy and duration of the clinical benefits of decreasing DME and the improvement of best-corrected visual acuity (BCVA). There is strong evidence that intravitreal bevacizumab injection therapy has a good cost-effective profile in the management of DME and may be associated with laser photocoagulation; however, its clinical superiority in terms of the duration of DME regression and the improvement of BCVA compared with intravitreal ranibizumab and other intravitreal anti-VEGF therapies remains unclear and deserves further investigation.
Diabetic macular edema; Bevacizumab; Anti-vascular endothelial growth factor; Diabetic retinopathy
To evaluate 14-week effects of intravitreal ranibizumab or triamcinolone in eyes receiving focal/grid laser for diabetic macular edema (DME) and panretinal photocoagulation (PRP).
Three hundred and forty-five eyes with a visual acuity of 20/320 or better, center-involved DME receiving focal/grid laser, and diabetic retinopathy receiving prompt PRP were randomly assigned to sham (n=123), 0.5-mg ranibizumab (n=113) at baseline and 4 weeks, or 4-mg triamcinolone at baseline and sham at 4 weeks (n=109). Treatment was at investigator discretion from 14 to 56 weeks.
Mean changes (±standard deviation) in visual acuity letter score from baseline were significantly better in the ranibizumab (+1±11, P<0.001) and triamcinolone (+2±11, P<0.001) groups compared with the sham group (-4±14) at the 14-week visit, mirroring retinal thickening results. These differences were not maintained when study participants were followed for 56 weeks for safety outcomes. One eye (0.9%, 95% CI: 0.02% to 4.7%) developed endophthalmitis after receiving ranibizumab. Cerebrovascular/cardiovascular events occurred in 4%, 7%, and 3% of the sham, ranibizumab, and triamcinolone groups, respectively.
The addition of 1 intravitreal triamcinolone or 2 ranibizumab injections in eyes receiving focal/grid laser for DME and PRP is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial cannot be determined from this study.
proliferative diabetic retinopathy; diabetic macular edema; panretinal photocoagulation; ranibizumab; triamcinolone; randomized clinical trial; Diabetic Retinopathy Clinical Research Network
There is increasing impetus to use pharmaceutical interventions, ie, ranibizumab or bevacizumab, for the treatment of particular macular diseases. This paper describes the evidence and decision-making of the National List of Essential Medicines Committee that recently announced the inclusion of bevacizumab for the treatment of macular diseases in its pharmaceutical benefit package. The findings of a systematic review and meta-analysis in this paper indicate that the intravitreal administration of bevacizumab is superior to nonpharmaceutical treatments for age-related macular degeneration (AMD) and diabetic macular edema (DME), but inconclusive for retinal vein occlusion, given the limited evidence. The study also failed to distinguish among the differences in terms of visual acuity improvement, reduction of central macular thickness, and response to treatment between AMD and DME patients treated with bevacizumab and those treated with ranibizumab. Although bevacizumab was not licensed for AMD and DME, the committee decided to include bevacizumab in the National List of Essential Medicines. It is expected that many patients who are in need of treatment but who are unable to afford the expensive alternative drug, ranibizumab, will be able to receive this effective treatment instead and be prevented from suffering irreversible loss of vision. At the same time, this policy will help generate evidence about the real-life effectiveness and safety profiles of the drug for future policy development in Thailand and other settings.
bevacizumab; macular degeneration; diabetic macular edema; retinal vein occlusion; comparative effectiveness research
To report expanded 2-year follow up of a previously reported randomized trial evaluating intravitreal 0.5-mg ranibizumab or 4-mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
Multicenter, randomized clinical trial.
Eight hundred and fifty four study eyes of 691 participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea.
Continuation of procedures previously reported for the randomized trial.
Main Outcome Measures
Best-corrected visual acuity and safety at the 2-year visit.
At the 2-year visit, compared with the sham plus prompt laser group, the mean change in the visual acuity letter score from baseline was 3.7 letters greater in the ranibizumab plus prompt laser group (95% confidence interval adjusted for multiple comparisons [aCI]: -0.4 to +7.7) l, 5.8 letters greater in the ranibizumab plus deferred laser group (95% aCI: +1.9 to +9.8) and 1.5 letters worse in the triamcinolone plus prompt laser group (95% aCI : -5.5 to +2.4). After the 1- through the 2-year visit in the ranibizumab with prompt or deferred laser groups, the median numbers of injections were 2 and 3 (potential maximum of 13), respectively. At the 2-year visit, the percentages of eyes with central subfield thickness ≥250 μm were 59% in the sham + prompt laser group, 43% in the ranibizumab + prompt laser group, 42% in the ranibizumab + deferred laser group, and 52% in the triamcinolone + prompt laser group. No systemic events attributable to study treatment were apparent. Three eyes in 3 (0.8%) of 375 participants had injection-related endophthalmitis in the ranibizumab groups while elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone+prompt laser group.
The expanded 2-year results reported herein are similar to results published previously and reinforce the conclusions originally reported, that ranibizumab should be considered for patients with DME and characteristics similar to the cohort in this clinical trial, including vision impairment with DME involving the center of the macula.
Diabetic macular oedema is the leading causes of blindness. Laser photocoagulation reduces the risk of visual loss. However recurrences are common and despite laser treatment, patients with diabetic macular oedema experienced progressive loss of vision. Stabilization of the blood retinal barrier introduces a rationale for intravitreal triamcinolone treatment in diabetic macular oedema. This study is intended to compare the best corrected visual acuity (BCVA) and the macular oedema index (MEI) at 3 month of primary treatment for diabetic macular oedema between intravitreal triamcinolone acetonide (IVTA) and laser photocoagulation.
This comparative pilot study consists of 40 diabetic patients with diabetic macular oedema. The patients were randomized into two groups using envelope technique sampling procedure. Treatment for diabetic macular oedema was based on the printed envelope technique selected for every patient. Twenty patients were assigned for IVTA group (one injection of IVTA) and another 20 patients for LASER group (one laser session). Main outcome measures were mean BCVA and mean MEI at three months post treatment. The MEI was quantified using Heidelberg Retinal Tomography II.
The mean difference for BCVA at baseline [IVTA: 0.935 (0.223), LASER: 0.795 (0.315)] and at three months post treatment [IVTA: 0.405 (0.224), LASER: 0.525 (0.289)] between IVTA and LASER group was not statistically significant (p = 0.113 and p = 0.151 respectively). The mean difference for MEI at baseline [IVTA: 2.539 (0.914), LASER: 2.139 (0.577)] and at three months post treatment [IVTA: 1.753 (0.614), LASER: 1.711 (0.472)] between IVTA and LASER group was also not statistically significant (p = 0.106 and p = 0.811 respectively).
IVTA demonstrates good outcome comparable to laser photocoagulation as a primary treatment for diabetic macular oedema at three months post treatment.
Diabetes is a serious chronic condition, which increase the risk of cardiovascular diseases, kidney failure and nerve damage leading to amputation. Furthermore the ocular complications include diabetic macular edema, is the leading cause of blindness among adults in the industrialized countries. Today, blindness from diabetic macular edema is largely preventable with timely detection and appropriate interventional therapy. The treatment should include an optimized control of glycemia, arterial tension, lipids and renal status. The photocoagulation laser is currently restricted to focal macular edema in some countries, but due the high cost of intravitreal drugs, the use of laser treatment for focal and diffuse diabetic macular edema (DME), can be valid as gold standard in many countries. The intravitreal anti vascular endothelial growth factor drugs (ranibizumab and bevacizumab), are indicated in the treatment of all types of DME, but the correct protocol for administration should be defined for the different Retina Scientific Societies. The corticosteroids for diffuse DME, has a place in pseudophakic patients, but its complications restricted the use of these drugs for some patients. Finally the intravitreal interface plays an important role and its exploration is mandatory in all DME patients.
Diabetic macular edema; Diabetic retinopathy; Laser, Anti-vascular endothelial growth factor drugs; Intravitreal dexamethasone; Triamcinolone; Vitrectomy
To evaluate the efficacy of vitrectomy combined with intravitreal injection of triamcinolone acetonide (IVTA) and macular laser photocoagulation for the treatment of nontractional diabetic macular edema (DME) refractory to anti-vascular endothelial growth factor (VEGF) therapy.
Twenty-eight eyes from 28 subjects who were diagnosed with nontractional DME refractory to three or more sequential anti-VEGF injections underwent sequential vitrectomy, IVTA, and macular laser photocoagulation. Changes in best-corrected visual acuity (BCVA) and central subfield thickness (CST) during the six months following vitrectomy were evaluated. Additionally, the CST and BCVA outcomes were compared with those of 26 eyes treated with the same triple therapy for nontractional DME refractory to conventional treatment, such as IVTA or macular laser photocoagulation, or both.
The mean logarithm of the minimum angle of resolution BCVAs before and one, three, and six months after vitrectomy were 0.44 ± 0.15, 0.36 ± 0.18, 0.31 ± 0.14, and 0.34 ± 0.22, respectively. The mean CSTs were 433.3 ± 77.9, 329.9 ± 59.4, 307.2 ± 60.2, and 310.1 ± 80.1 microns, respectively. The values of both BCVA and CST at one, three, and six months were significantly improved from baseline (p < 0.05). The extent of CST reduction during the first month after triple therapy was greater in eyes refractory to conventional treatment than in eyes refractory to anti-VEGF (p = 0.012).
Vitrectomy combined with IVTA and macular laser photocoagulation had a beneficial effect on both anatomical and functional outcomes in eyes with nontractional DME refractory to anti-VEGF therapy.
Anti-vascular endothelial growth factor; Diabetic macular edema; Triple therapy; Vitrectomy
Purpose: To assess the natural course of the mild diabetic macular edema(DME) and to compare the visual outcomes with the patients with receiving either macular laser photocoagulation or intravitreal injection of triamcinolone acetonide(IVTA).
Methods: 28 eyes with central macular thickness (CMT) of between 250 to 300µm were followed without treatment and 48 eyes with CMT between 300 to 500µm had been divided into 3 subgroups according to treatment. We evaluated the best corrected visual acuity (BCVA) and CMT of natural course group and compared the BCVA and CMT of the patients who had been treated with IVTA or macular laser treatment.
Results: The eyes with DME between 250 to 300µm showed no significant change in BCVA and CMT at 6 month. Among the eyes with DME between 300 to 500µm, all 3 subgroups showed no statistically significant change of BCVA at any follow up period and no significant difference was revealed among the subgroups. All subgroups showed significant reduction of CMT after 1 month and maintained until final follow-up and there was no significant difference among subgroups.
Conclusions: Mild DME between 250 to 500µm did not show significant worsening of BCVA or macular edema without any specific treatment.
Diabetic Macular Edema; Intravitreal triamcinolone; Macular laser photocoagulation.
Diabetic Macular Edema (DME) is one of the major causes of visual loss and increase in central macular thickness (CMT). The aim of this study was to determine the efficacy of a single intravitreal injection of bevacizumab (IVB) alone or in combination with intravitreal triamcinolone acetonide (IVB/IVT) versus macular laser photocoagulation (MPC) as primary treatment for DME when confounders were considered.
Skew-symmetric bivariate mixed modeling according to best corrected visual acuity (BCVA) and CMT was done on the data of 103 diabetic patients from ophthalmic research center of Labbafinejad medical center (Tehran, Iran) to determine the best DME treatment by adjusting the effect of confounders.
Although there was no significant difference between IVB/IVT (p > 0.05), these two treatments increased BCVA and decreased CMT better than MPC (p < 0.05). The following three groups showed better treatment responses: 1) women, 2) patients with more diabetes duration, 3) patients whose CMT were higher and VA were lower at the beginning of the clinical trial.
Using skew-symmetric mixed effect model as updated statistical method in presence of asymmetric or outlier data, we received different results compared to the same investigation on this study by analyzing BCVA and CMT simultaneously. This research demonstrated the effect of IVB alone or in combination with intravitreal IVB/IVT on visual power and decreasing CMT during follow up.
Best-Corrected Visual Acuity; Central Macular Thickness; Diabetic Macular Edema; Skew-symmetric Mixed Models
To compare the efficacy between macular laser grid (MLG) photocoagulation and MLG plus intravitreal triamcinolone acetonide (IVTA; MLG+IVTA) therapy in diabetic macular edema (DME) patients.
A prospective, randomized, clinical trial was conducted of DME patients. A total of 60 eyes (54 patients) affected by DME were observed for a minimum of 6 months. Thirty eyes of 28 patients who received MLG treatment and 30 eyes of 26 patients who received the combined MLG+IVTA treatment were included in the study. Main outcome measures were BCVA and central macular thickness (CMT) as measured by optical coherence tomography (OCT) at 1, 3, and 6 months after treatment. Additionally, the authors examined retrospectively 20 eyes of 20 patients who were treated with only IVTA and compared with the 2 groups (MLG group and MLG+IVTA group).
Baseline BCVA was 0.53±0.32 and CMT was 513.9±55.1 µm in the MLG group. At 1 and 3 months after treatment, the MLG group showed no significant improvement of BCVA and CMT, although there was significant improvement after 6 months. In the MLG+IVTA group, the baseline BCVA was 0.59±0.29 and CMT was 498.2±19.8 µm. After treatment, significant improvement of BCVA and CMT was observed at all follow-up time periods. When comparing the MLG group with the MLG+IVTA group, the latter had better results after 1 and 3 months, although at 6 months, there was no significant difference of BCVA and CMT between the 2 groups. Additionally, the IVTA group showed more improvement than the MLG group at 1 and 3 months but showed no significant difference at 6 months. In addition, the IVTA group showed no significant difference with the MLG+IVTA group at all follow-up time periods.
For DME patients, the combined MLG+IVTA treatment had a better therapeutic effect than the MLG treatment for improving BCVA and CMT at the early follow-up time periods. IVTA treatment alone could be an additional alternative therapeutic option to combined therapy.
Central macular thickness; Diabetic macular edema; Diabetic retinopathy; Intravitreal triamcinolone acetonide injection; Macular laser grid photocoagulation
Purpose. To report the outcomes after primary intravitreal pegaptanib sodium in patients with diabetic macular edema (DME).
Methods. We conduced a retrospective analysis of eyes with DME treated with primary intravitreal pegaptanib sodium (Macugen) (intravitreal pegaptanib group). The results were compared with the ones of eyes treated with intravitreal pegaptanib sodium associated with macular laser photocoagulation (combined treatment group), and the ones of eyes treated with primary macular laser photocoagulation (macular laser photocoagulation group).
Results. For the intravitreal pegaptanib group (13 eyes), we found significant changes in mean best-corrected visual acuity (BCVA) and reductions in mean central macular thickness (CMT) at the last follow-up visit (P = .0014
and P = .0001). For the macular laser photocoagulation group (15 eyes), we found no statistically significant changes in mean BCVA and CMT at the last follow-up visit (P > .05). For the combined treatment group (12 eyes), we found no significant changes in mean BCVA at the last follow-up visit (P > .05) despite significant reductions in mean CMT (P = .0188).
Conclusion. Intravitreal pegaptanib treatment alone may be superior to macular laser photocoagulation alone and to combined intravitreal pegaptanib treatment associated with macular laser photocoagulation in patients with DME.