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.
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.
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.
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 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 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.
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
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.
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
Diabetic macular edema is the major cause of visual acuity impairment in diabetic patients. The exact etiopathogenesis is unknown and, currently, grid/focal retinal laser photocoagulation represents the recommended treatment. It has been demonstrated that vascular endothelial growth factor (VEGF) plays a key role in the pathogenesis of diabetic macular edema by mediating vascular permeability and accumulation of intracellular and extracellular fluid, and thereby represents an appealing candidate as a therapeutic target for the treatment of diabetic macular edema. The advent of intravitreal anti-VEGF drugs has opened up a new era for the management of diabetic macular edema. At present, three anti-VEGF substances are available for routine clinical use, ie, pegaptanib, ranibizumab, and bevacizumab. The aim of this review is to summarize the evidence supporting the use of ranibizumab in clinical practice. Most of the studies analyzed in this review are prospective, controlled clinical trials that have focused on documenting the therapeutic effect of ranibizumab and its safety, providing encouraging results.
ranibizumab; diabetic macular edema; anti-VEGF; diabetic macular edema
Two new drugs provide startling benefits in the treatment of age‐related macular degeneration (AMD). The clinical and cost effectiveness of ranibizumab (Lucentis) was compared to that of bevacizumab (Avastin), which costs up to 100 times less. A cost effectiveness model was developed to assess the cost per quality adjusted life year (QALY) over 10 years. For predominantly classic AMD, the efficacy of bevacizumab relative to ranibizumab would have to be around 40% for the latter to achieve £30k per QALY, a NICE threshold. Similar but worse results applied to the other main forms of AMD, minimally occult and occult with no classic lesions. The price of ranibizumab would have to be drastically reduced for it to be cost effective. Continued unlicensed use of bevacizumab raises ethical, legal and policy questions. Public pressure may be the most potent weapon in persuading Genentech to license bevacizumab for AMD.
To compare same-day combined therapy of photodynamic therapy with verteporfin (PDT-V) and intravitreal ranibizumab versus monotherapy with ranibizumab for the treatment of choroidal neovascularization.
In this prospective study, the total number of eyes was randomized into two groups: in the first, treatment consisted of a combined therapy of PDT-V and ranibizumab 0.5 mg on the same day; in the second, ranibizumab 0.5 mg in 3 monthly injections. Best-corrected visual acuity (BCVA) and central macular thickness (CMT) on optical coherence tomography (OCT) were recorded before and 6 months after treatment.
A total of 47 eyes of 47 subjects were enrolled in the study. In the combined-therapy group (group 1), the mean baseline BCVA ± standard deviation (SD) was 32.65 ± 11.09 letters (Snellen equivalent, 20/59); in the ranibizumab-alone group (group 2), 29.13 ± 9.03 letters (20/70). At 6 months’ follow-up, in group 1 the mean baseline BCVA was 39.06 ± 10.12 letters (20/42); in group 2, 33.87 ± 12.06 letters (20/57). Improvement was significant in both group 1 (P = 0.03) and group 2 (P = 0.002). In group 1, the mean CMT at baseline ± SD was 315 ± 95.49 μm; in group 2, 306.33 ± 71.61 μm. At 6 months’ follow-up, in group 1 it was 202 ± 52.02 μm; in group 2, 226 ± 65.58 μm. Reduction was significant in both group 1 (P = 0.0007) and group 2 (P = 0.00001). After 6-months, the rate of retreated eyes was 29.4% in group 1 and 43.3% in group 2. The need for retreatment did not depend on the treatment protocol (P = 0.34).
From a functional and anatomic point of view, the two treatments showed equivalent efficacy, with fewer retreatments in group 1. No serious adverse events, such as retinal detachment, endophthalmitis, or ocular hypertension occurred in either group.
Inflammation contributes significantly to the pathogenesis of diabetic macular edema (DME). In particular, retinal microglia demonstrate increased activation and aggregation in areas of DME. Study authors investigated the safety and potential efficacy of oral minocycline, a drug capable of inhibiting microglial activation, in the treatment of DME.
A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with fovea-involving DME who received oral minocycline 100 mg twice daily for 6 months. Main outcome measurements included best-corrected visual acuity (BCVA), central retinal subfield thickness (CST), and central macular volume using spectral domain optical coherence tomography (SD-OCT) and late leakage on fluorescein angiography (FA).
Findings indicated that the study drug was well tolerated and not associated with significant safety issues. In study eyes, mean BCVA improved continuously from baseline at 1, 2, 4, and 6 months by +1.0, +4.0, +4.0, and +5.8 letters, respectively, while mean retinal thickness (CST) on OCT decreased by −2.9%, −5.7%, −13.9, and −8.1% for the same time points. At month 6, mean area of late leakage on FA decreased by −34.4% in study eyes. Mean changes in contralateral fellow eyes also demonstrated similar trends. Improvements in outcome measures were not correlated with concurrent changes in systemic factors.
In this pilot proof-of-concept study of DME, minocycline as primary treatment was associated with improved visual function, central macular edema, and vascular leakage, comparing favorably with historical controls from previous studies. Microglial inhibition with oral minocycline may be a promising therapeutic strategy targeting the inflammatory etiology of DME. (ClinicalTrials.gov number, NCT01120899.)
A pilot phase I/II, proof-of-concept clinical trial investigating the effect of oral minocycline, a microglial inhibitor, for the treatment of DME demonstrates good tolerability and potential efficacy for this clinical indication. (ClinicalTrials.gov number, NCT01120899.)
To determine whether the extensiveness of diabetic macular edema (DME) using a ten step scale based on optical coherence tomography (OCT) explains pretreatment variation in visual acuity and predicts change in macular thickness or visual acuity after laser photocoagulation.
323 eyes from a randomized clinical trial of two methods of laser photocoagulation for DME were studied. Baseline number of thickened OCT subfields was used to characterize DME on a ten step scale from 0 – 9. Associations were explored between baseline number of thickened subfields and baseline fundus photographic variables, visual acuity (VA), central subfield mean thickness (CSMT), and total macular volume (TMV). Associations were also examined between baseline number of thickened subfields and changes in VA, CSMT, and TMV at 3.5 and 12 months after laser photocoagulation.
For baseline visual acuity, the number of thickened subfields explained no more variation than did CSMT, age and fluorescein leakage. A greater number of thickened subfields was associated with a greater baseline CSMT, TMV, area of retinal thickening, and degree of thickening at the center of the macula (r=0.64, 0.77, 0.61–0.63, and 0.45, respectively) and with a lower baseline visual acuity (r=0.38). Baseline number of thickened subfields showed no association with change in visual acuity (r≤0.01–0.08) and weak associations with change in CSMT and TMV (r from 0.11–0.35).
This OCT based assessment of the extensiveness of DME did not explain additional variation in baseline visual acuity above that explained by other known important variables nor predict changes in macular thickness or visual acuity after laser photocoagulation.
Objective: To estimate the cost utility of treatment with combination therapy (ribavirin and interferon α) for hepatitis C compared with no treatment or monotherapy (interferon α) based on UK costs and clinical management.
Design: Decision analysis model using a Markov approach to simulate disease progression.
Setting: UK secondary care.
Participants: Hypothetical cohort of patients with hepatitis C.
Main outcome measures: Cost per quality adjusted life year (QALY) gained.
Results: Discounted cost per QALY for combination therapy over no treatment was £3791. Cost per QALY varied between £1646 and £9170 according to subgroup, with the lowest ratios being for genotype 2 or 3, women, those aged less than 40 years, and those with moderate hepatitis. The discounted cost per QALY of the combination over monotherapy was £3485. Similar findings were shown for subgroups as for the comparison with no treatment. One way sensitivity analysis showed that while drug costs were more important in the analysis than assumptions about disease progression or costs of treating hepatitis C disease, the results were robust to large changes in underlying assumptions.
Conclusions: Combination therapy for hepatitis C is a cost effective treatment option and is superior to monotherapy. Considerable uncertainties remain over the appropriate management strategies in the populations excluded from randomised controlled trials and in whom treatment is currently being considered in the UK.
hepatitis C virus; cost effectiveness; interferon α; ribavirin
Objective To indirectly compare the effectiveness of ranibizumab and bevacizumab in the treatment of diabetic macular oedema.
Design Systematic review and indirect comparison.
Data sources Medline (1996–September 2011), Embase (1996–September 2011), and the Cochrane Central Register of Controlled Trials (Issue 4, 2011).
Selection criteria for studies Randomised trials evaluating ranibizumab or bevacizumab in diabetic macular oedema with a common comparator and sufficient methodological similarity to be included within an indirect comparison were eligible for inclusion.
Main outcome measures The primary outcome was the proportion of patients with an improvement in best corrected visual acuity of more than two lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Secondary outcomes included mean changes in best corrected visual acuity and in central macular thickness, and adverse events. Best corrected visual acuity was converted to logMAR units, a linear scale of visual acuity with positive values representing increasing visual loss. Indirect comparisons were done using Bayesian methods to estimate relative treatment effects of bevacizumab and ranibizumab.
Results Five randomised controlled trials with follow-up of 6–12 months and a common comparator (multiple laser treatment) were sufficiently similar to be included in the indirect comparison. Generally studies were small, resulting in wide credible intervals. The proportions of patients with an improvement in best corrected visual acuity of >2 lines were 21/77 participants (27%) for bevacizumab and 60/152 participants (39%) for ranibizumab (odds ratio 0.95 (95% credible interval 0.23 to 4.32)). The wide credible intervals cannot exclude a greater improvement, or worse outcome, for either drug. The mean change in best corrected visual acuity non-significantly favoured bevacizumab (treatment effect −0.08 logMAR units (−0.19 to 0.04)). The difference in mean change in central macular thickness was not statistically significant between ranibizumab and bevacizumab (treatment effect −6.9 μm (−88.5 to 65.4)).
Conclusions Results suggest no difference in effectiveness between bevacizumab and ranibizumab, but the wide credible intervals cannot exclude the possibility that either drug might be superior. Sufficiently powered, direct head to head trials are needed.
The purpose of this study was to evaluate and compare clinical outcomes and retreatment rates using navigated macular laser versus conventional laser for the treatment of diabetic macular edema (DME).
In this prospective, interventional pilot study, 46 eyes from 46 consecutive patients with DME were allocated to receive macular laser photocoagulation using navigated laser. Best corrected visual acuity and retreatment rate were evaluated for up to 12 months after treatment. The control group was drawn based on chart review of 119 patients treated by conventional laser at the same institutions during the same time period. Propensity score matching was performed with Stata, based on the nearest-neighbor method.
Propensity score matching for age, gender, baseline visual acuity, and number of laser spots yielded 28 matched patients for the control group. Visual acuity after navigated macular laser improved from a mean 0.48 ± 0.37 logMAR by a mean +2.9 letters after 3 months, while the control group showed a mean −4.0 letters (P = 0.03). After 6 months, navigated laser maintained a mean visual gain of +3.3 letters, and the conventional laser group showed a slower mean increase to +1.9 letters versus baseline. Using Kaplan-Meier analysis, the laser retreatment rate showed separation of the survival curves after 2 months, with fewer retreatments in the navigated group than in the conventional laser group during the first 8 months (18% versus 31%, respectively, P = 0.02).
The short-term results of this pilot study suggest that navigated macular photocoagulation is an effective technique and could be considered as a valid alternative to conventional slit-lamp laser for DME when focal laser photocoagulation is indicated. The observed lower retreatment rates with navigated retinal laser therapy in the first 8 months suggest a more durable treatment effect.
navigated focal laser; macular laser; Navilas®; diabetic macular edema; diabetes mellitus; diabetic retinopathy
In spite of laser being the gold standard treatment for Diabetic Macular edema (DME), some patients do not respond to laser. Various treatment modalities are being tried in the management of refractory diffuse DME (DDME).
To compare the efficacy of intravitreal bevacizumab (IVB), intravitreal triamcinolone acetonide (IVTA), and macular grid augmentation in the management of refractory DDME.
Settings and Design:
Prospective randomized study in a tertiary eye care center.
Materials and Methods:
Sixty patients with refractory DDME were randomly assigned to three groups: Group 1 received IVB (1.25 mg/0.05 ml), Group 2 received IVTA (4 mg/0.1ml), and Group 3 underwent laser augmentation. Primary outcome measures were best corrected visual acuity (BCVA) and central macular thickness (CMT) at the end of 6 months.
Analysis was performed using SPSS 14.0
Group 1 and 2 showed significant improvement in mean BCVA from 20/160 at baseline to 20/80 and from 20/125 to 20/63, respectively, at 6 months (P < 0.05). These groups also showed a significant reduction in the mean CMT from 457 ± 151 μ at baseline to 316 ± 136 μ and from 394 ± 61 μ to 261 ± 85 μ, respectively, at 6 months (P < 0.05). Group 3 showed only small improvement in mean BCVA from 20/100 to 20/80 (P = 1.0) while mean CMT increased from 358 ± 89 μ at baseline to 395 ± 127 μ at 6 months (P = 0.191). Eight (40%) eyes in Group 2 had intraocular pressure (IOP) rise and 10 (50%) eyes developed cataract.
Both IVB and IVTA may be effective in the treatment of refractory DDME compared with macular grid augmentation. IVTA may be associated with side effects such as IOP rise and cataract formation.
Diabetic macular edema; Intravitreal bevacizumab; Intravitreal triamcinolone; laser photocoagulation
This prospective multi-center pilot study compares the use of half-fluence photodynamic therapy combined with ranibizumab with ranibizumab monotherapy for the treatment of neovascular age-related macular degeneration.
All patients presenting with untreated subfoveal neovascular age-related macular degeneration were considered for inclusion. Patients were randomized to receive either ranibizumab with half-fluence photodynamic therapy or ranibizumab alone. Patients in the ranibizumab alone group were given three consecutive monthly ranibizumab injections and were followed monthly. They were treated with ranibizumab as needed, based on clinical discretion, using vision and optical coherence tomography. Patients in the combined group were given one same-day combined ranibizumab and half-fluence (25 j/cm2) photodynamic therapy treatment and were treated monthly as needed. Outcomes included changes in standardized visual acuity, optical coherence tomography foveal thickness, and percentage of as-needed injections to maintenance examinations.
Fifty-six out of 60 enrolled patients completed the twelve month primary outcome visit; this consisted of 27 patients receiving ranibizumab alone and 29 receiving combined treatment. The average age was 79.1 for the ranibizumab alone group and 79.3 for the combined group. The mean visual acuity in the ranibizumab alone group improved from 52.9 Early Treatment of Diabetic Retinopathy letters initially to 62.8 letters at twelve months. The mean visual acuity in the combined group improved from 49.2 letters to 51.8 letters at twelve months. The differences in visual acuity improvements were not statistically significant based on a two-tailed t-test (P = 0.2). Due to the presence of outliers in each group, a Mann–Whitney U test was performed to confirm the results (U = 325; P = 0.28). The mean optical coherence tomography foveal thickness improved 92.5 microns and 106.7 microns in the ranibizumab alone and the combined group, respectively. The difference was not significant based on a two-tailed t-test (P = 0.6). The ranibizumab alone group received an average of 6.8 injections, while the combined group received an average of three injections. This difference was not significant based on a chi-square test (P = 0.11).
The groups appeared similar based on statistical analysis, but larger studies are needed to determine possible small differences between combination therapy and monotherapy.
ranibizumab; macular degeneration; photodynamic therapy; verteporfin; choroidal neovascularization; anti-vegf
Diabetic Macular Edema (DME) is a common cause of impaired vision and blindness amongst diabetics. If not detected and treated early, the resulting vision loss can lead to considerable health costs and decreased health-related quality of life (HRQoL). The aim of this study was to provide evidence of the psychometric properties of the National Eye Institute - Visual Functioning Questionnaire (VFQ-25) for use in a cohort of DME patients who participated in a clinical efficacy and safety trial of pegaptinib sodium (Macugen).
A phase 2/3 randomised, double masked trial evaluated pegaptanib injection versus sham injection in patients with DME. The analysis was conducted using baseline HRQoL data of the VFQ-25 and the EQ-5D, on a modified intent-to-treat sample of 235 patients. These measures were administered by a trained interviewer by telephone in all but one of the study countries, where face-to-face interviews were conducted in the clinic. The measures were completed in the week prior to baseline, and after 54 weeks of treatment. Distance visual acuity, measured according to the Early Treatment Diabetic Retinopathy Study (ETDRS), was assessed at all time points. Psychometric properties of the VFQ-25 assessed included domain structure, reliability, concurrent and construct validity, responsiveness.
The VFQ-25 was found to consist of 11 domains slightly different than those proposed. Nevertheless, none of the eight established multi-item scales met the criterion for further splitting and the VFQ-25 was scored as in the developers’ instructions. Internal consistency reliability was demonstrated for six out of the eight original multi-item scales, with Cronbach's alpha ranging from 0.58 (Distance Activities) to 0.85 (Vision Specific: Dependency). The VFQ-25 domains generally showed a low to moderate correlation with EQ-5D visual analogue scale (range 0.16-0.43) and with the visual acuity score (range 0.10-0.41). Construct validity was upheld with higher VFQ-25 scores for patients who saw more letters according to the ETDRS. Almost all scales were shown to be responsive with Guyatt's statistic ranging from 0.10 to 0.56 at 54 weeks.
The VFQ-25 has evidence to support its validity and reliability for measuring HRQoL in DME. However, some operating characteristics of the instrument need further consideration and discussion in the case of DME patients. Further research is therefore warranted in this indication.
Diabetic macular edema; Visual functioning questionnaire; Psychometric analyses