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1.  Cost-Effectiveness of Treatment of Diabetic Macular Edema 
Annals of internal medicine  2014;160(1):18-29.
Background
Macular edema is the most common cause of visual loss among patients with diabetes.
Objective
To determine the cost-effectiveness of different treatments of diabetic macular edema (DME).
Design
Markov model.
Data Sources
Published literature and expert opinion.
Target Population
Patients with clinically significant DME.
Time Horizon
Lifetime.
Perspective
Societal.
Intervention
Laser treatment, intraocular injections of triamcinolone or a vascular endothelial growth factor (VEGF) inhibitor, or a combination of both.
Outcome Measures
Discounted costs, gains in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).
Results of Base-Case Analysis
All treatments except laser monotherapy substantially reduced costs, and all treatments except triamcinolone monotherapy increased QALYs. Laser treatment plus a VEGF inhibitor achieved the greatest benefit, gaining 0.56 QALYs at a cost of $6975 for an ICER of $12 410 per QALY compared with laser treatment plus triamcinolone. Monotherapy with a VEGF inhibitor achieved similar outcomes to combination therapy with laser treatment plus a VEGF inhibitor. Laser monotherapy and triamcinolone monotherapy were less effective and more costly than combination therapy.
Results of Sensitivity Analysis
VEGF inhibitor monotherapy was sometimes preferred over laser treatment plus a VEGF inhibitor, depending on the reduction in quality of life with loss of visual acuity. When the VEGF inhibitor bevacizumab was as effective as ranibizumab, it was preferable to because of its lower cost.
Limitation
Long-term outcome data for treated and untreated diseases are limited.
Conclusion
The most effective treatment of DME is VEGF inhibitor injections with or without laser treatment. This therapy compares favorably with cost-effective interventions for other conditions.
Primary Funding Source
Agency for Healthcare Research and Quality.
doi:10.7326/M13-0768
PMCID: PMC4020006  PMID: 24573663
2.  Cost-Effectiveness Analysis of Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema 
Ophthalmology  2012;119(8):1679-1684.
Objective
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.
Design
Computer simulation based on Protocol I data. Analyses were conducted from the payor perspective.
Participants
Simulated participants assigned characteristics reflecting those seen in Protocol I.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.ophtha.2012.01.049
PMCID: PMC3612959  PMID: 22503301
3.  Long-term effectiveness of ranibizumab for age-related macular degeneration and diabetic macular edema 
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.
doi:10.2147/CIA.S36811
PMCID: PMC3677930  PMID: 23766636
ranibizumab; anti-VEGF therapy; age-related macular degeneration; diabetic macular edema; safety; diabetic retinopathy; cost-effectiveness
4.  Comparative Evaluation of Combined Navigated Laser Photocoagulation and Intravitreal Ranibizumab in the Treatment of Diabetic Macular Edema 
PLoS ONE  2014;9(12):e113981.
Objective
To evaluate if a standardized combination therapy regimen, utilizing 3 monthly ranibizumab injections followed by navigated laser photocoagulation, reduces the number of total ranibizumab injections required for treatment of diabetic macular edema (DME).
Research Design and Methods
A 12-month, prospective comparison of 66 patients with center-involving DME: 34 patients with combination therapy were compared to 32 patients treated with ranibizumab monotherapy. All patients initially received 3 monthly ranibizumab injections (loading phase) and additional injections pro re nata (PRN). Combination therapy patients additionally received navigated laser photocoagulation after the loading phase. Main outcome measures were mean number of injections after the loading phase and change in BCVA from baseline to month 12.
Results
Navigated laser combination therapy and ranibizumab monotherapy similarly improved mean BCVA letter score (+8.41 vs. +6.31 letters, p = 0.258). In the combination group significantly less injections were required after the 3 injection loading phase (0.88±1.23 vs. 3.88±2.32, p< = 0.001). By month 12, 84% of patients in the monotherapy group had required additional ranibizumab injections as compared to 35% in the combination group (p< = 0.001).
Conclusions
Navigated laser combination therapy demonstrated significant visual gains in most patients. Retreatment rate and number of injections were significantly lower compared to ranibizumab monotherapy and compared to the results of conventional laser combination therapy previously reported in pivotal anti-VEGF studies.
doi:10.1371/journal.pone.0113981
PMCID: PMC4277267  PMID: 25541960
5.  Efficacy of Anti-VEGF and Laser Photocoagulation in the Treatment of Visual Impairment due to Diabetic Macular Edema: A Systematic Review and Network Meta-Analysis 
PLoS ONE  2014;9(7):e102309.
Objective
Compare the efficacy of ranibizumab, aflibercept, laser, and sham in the first-line treatment of diabetic macular edema (DME) to inform technology assessments such as those conducted by the UK National Institute for Health and Care Excellence (NICE).
Data sources
MEDLINE, Embase, Cochrane Library, congress abstracts, ClinicalTrials.gov registry and Novartis data on file.
Inclusion criteria
Studies reporting 6- or 12-month results of randomized controlled trials (RCTs) evaluating at least two of ranibizumab 0.5 mg pro re nata, aflibercept 2.0 mg bi-monthly, laser photocoagulation or sham. Study quality was assessed based on likelihood of bias in selection, attrition, detection and performance.
Outcome measure
Improvement in best-corrected visual acuity (BCVA) measured as the proportion of patients gaining ≥10 letters on the Early Treatment Diabetic Retinopathy Study scale. The outcome was chosen following acceptance by NICE of a Markov model with 10-letter health states in the assessment of ranibizumab for DME.
Meta-analysis
Bayesian network meta-analyses with fixed and random effects adjusted for differences in baseline BCVA or central retinal thickness.
Results
The analysis included 1,978 patients from eight RCTs. The random effects model adjusting for baseline BCVA was the best model based on total residual. The efficacy of ranibizumab was numerically, but not statistically, superior to aflibercept (odds ratio [OR] 1.59; 95% credible interval [CrI], 0.61–5.37). Ranibizumab and aflibercept were statistically superior to laser monotherapy with ORs of 5.50 (2.73–13.16) and 3.45 (1.62–6.84) respectively. The probability that ranibizumab is the most efficacious treatment was 73% compared with 14% for aflibercept, 12% for ranibizumab plus laser, and 0% for laser.
Limitations
Three of the eight RCTs included are not yet published. The models did not adjust for all potential effect modifiers.
Conclusion
Ranibizumab was non-significantly superior to aflibercept and both anti-VEGF therapies had statistically superior efficacy to laser.
doi:10.1371/journal.pone.0102309
PMCID: PMC4100770  PMID: 25029255
6.  Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis 
PLoS Medicine  2012;9(9):e1001316.
David Boulware and colleagues assess the cost effectiveness of different treatment strategies in low- and middle-income countries for cryptococcal meningitis, one of the most common opportunistic infections of people with HIV.
Background
Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.
Methods and Findings:
We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.
Conclusions
Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is “very cost effective” per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Cryptococcal meningitis, a fungal infection of the membranes around the brain and spinal cord, affects about a million people every year (most of them living in sub-Saharan Africa and Southeast Asia) and kills about 640,000 people annually. People become infected with Cryptococcus neoformans, the fungus that causes cryptococcal meningitis and which is found in soil and dirt, by breathing it in. In healthy individuals, infection rarely causes disease. But in people living with AIDS, whose immune system has been damaged by HIV infection, and in people whose immune system is compromised for other reasons, the fungus can invade and damage many organs, including the brain. Cryptococcal meningitis, the symptoms of which include fever, stiff neck, headache, and vomiting, is diagnosed by looking for the fungus in fluid taken from the spinal cord in a procedure called a lumbar puncture. Cryptococcal meningitis is treated with antifungal drugs such as amphotericin, fluconazole, and flucytosine (induction therapy); recurrence of the infection is prevented by taking fluconazole daily for life or until the immune system recovers.
Why Was This Study Done?
The World Health Organization (WHO) recommends a 14-day regimen of intravenous (injected) amphotericin and oral flucytosine or fluconazole for induction therapy of cryptococcal meningitis. Unfortunately, this regimen is impractical in many resource-limited settings because of the cost of the drugs and hospital care and the need for intensive monitoring—amphotericin is extremely toxic. Consequently, high-dose fluconazole monotherapy is the usual treatment for cryptococcal meningitis in resource-limited countries, although this regimen is much less effective. Another regimen that has improved survival in trials is flucytosine with fluconazole for two weeks. However, flucytosine is very expensive and is not licensed in most sub-Saharan African countries. Stakeholders in developing countries badly need guidance, therefore, on which induction treatment for cryptococcal meningitis they should recommend to optimize outcomes in their particular countries. In this cost-effectiveness analysis (a study that compares the costs and health effects of different interventions), the researchers use costs in Uganda to estimate the survival, cost, and cost per benefit associated with various induction treatments for cryptococcal meningitis in HIV-infected patients.
What Did the Researchers Do and Find?
The researchers calculated the overall cost of six induction treatments using 2012 healthcare costs in Uganda for medications, supplies, and hospital care, and average laboratory costs for monitoring treatment from three African countries. They used data from published trials of cryptococcal meningitis treatment in resource-limited areas to estimate ten-week and one-year survival, life expectancy, and quality-adjusted life years (QALYs, the number of years of life added by an intervention, adjusted for the quality of life) for each intervention. Finally, they calculated the cost-effectiveness ratio (cost per QALY gained) and the incremental cost effectiveness ratio (ICER, the additional cost of a treatment strategy compared to fluconazole monotherapy divided by the incremental improvement in QALYs) for each intervention. The estimated costs per person for each induction treatment strategy ranged from US$154 for 14 days of fluconazole monotherapy to US$467 for 14 days of amphotericin plus flucytosine. Estimated average one-year survival was lowest for fluconazole (40%) and highest for short-course (seven days) amphotericin plus 14 days of fluconazole (66%), similar to other amphotericin-based treatments. Cost-effectiveness ratios ranged from US$20 per QALY for short-course amphotericin plus fluconazole to US$44 per QALY for 14 days of amphotericin plus flucytosine. Short-course amphotericin plus fluconazole had the lowest ICER (US$15.11 per additional QALY over fluconazole monotherapy).
What Do These Findings Mean?
These findings suggest that, among the treatments investigated, a seven-day course of amphotericin with high-dose fluconazole for at least two weeks is the most cost-effective induction treatment for cryptococcal meningitis in Uganda. Although this result should be generalizable to other African countries, it needs to be treated with caution because very few trials have actually looked at the clinical effectiveness of this particular regimen. While short short-course amphotericin appears to be substantially more effective than fluconazole monotherapy, large-scale trials comparing short-course amphotericin regimens with more traditional 14-day regimens in resource-limited countries must be undertaken before short-course amphotericin-based treatments are adopted. Notably, however, if these trials confirm that survival with short-course amphotericin with fluconazole is about 30% better than with fluconazole alone, the researchers calculate that moving to short-course amphotericin could save about 150,000 lives every year in sub-Saharan Africa at a cost of US$220 per life saved.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001316.
This study is further discussed in a PLOS Medicine Perspective by Andrew Farlow
Preventcrypto.org provides a clearinghouse for updated guidelines for cryptococcal diagnosis and treatment.
The US Centers for Disease Control and Prevention provides information on Cryptococcus neoformans and a training manual called the Cryptococcal Screening Program Training Manual for Healthcare Providers
NAM/aidsmap provides information about all aspects of infection with Cryptococcus neoformans, including a personal story about cryptococcal meningitis
AIDS InfoNet has a fact sheet on cryptococcal meningitis (in several languages)
The not-for-profit organization Project Inform, which provides information, inspiration, and advocacy for people with HIV/AIDS and hepatitis C (in English and Spanish), has a fact sheet on cryptococcal meningitis
The MedlinePlus encyclopedia has a page on cryptococcal meningitis (in English and Spanish)
doi:10.1371/journal.pmed.1001316
PMCID: PMC3463510  PMID: 23055838
7.  Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(12):e115797.
Objective
To evaluate the relative efficacy of ranibizumab (RBZ) monotherapy or combined with laser (RBZ + Laser) versus laser monotherapy for the treatment of diabetic macular edema (DME).
Methods
A comprehensive literature search using PUBMED, ClinicalTrials.gov, and the Cochrane Library to identify randomized controlled trials (RCTs) comparing RBZ or RBZ + Laser to laser monotherapy in patients with DME. Efficacy estimates were determined by comparing weighted mean differences (WMD) in the change of best corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline, and the risk ratios (RR) for the proportions of patients with at least 15 letters change from baseline. Safety analysis estimated the RR of cardiac disorders at 6 to 12 months in RBZ therapy vs. laser monotherapy. Statistical analysis was performed using the RevMan 5.1 software.
Results
Seven RCTs were selected for this meta-analysis, including 1749 patients (394 patients in the RBZ group, 642 patients in the RBZ + Laser group, and 713 patients in the laser group). RBZ and RBZ + Laser were superior to laser monotherapy in the mean change of BCVA and CMT from baseline (WMD = 5.65, 95% confidence interval (CI), 4.44–6.87, P<0.00001; WMD  = 5.02, 95% CI, 3.83–6.20, P<0.00001, and WMD  = −57.91, 95% CI, −77.62 to −38.20, P<0.00001; WMD  = −56.63, 95% CI, −104.81 to −8.44, P = 0.02, respectively). The pooled RR comparing the proportions of patients with at least 15 letters improvement or deterioration were also in favor of RBZ and RBZ + Laser (RR = 2.94, 95% CI, 1.82–4.77, P<0.00001; RR = 2.04, 95% CI, 1.50–2.78, P<0.00001, and RR = 0.21, 95% CI, 0.06–0.71, P = 0.01; RR = 0.52, 95% CI, 0.29–0.95, P = 0.03, respectively). There were no significant differences between RBZ and RBZ + Laser for any of the parameters. There were no difference in the safety profile between RBZ and laser.
Conclusion
RBZ and RBZ + Laser had better visual and anatomic outcomes than laser monotherapy in the treatment of DME. RBZ + Laser seemed to be equivalent to RBZ.
doi:10.1371/journal.pone.0115797
PMCID: PMC4277392  PMID: 25541937
8.  Cost-Effectiveness of Various Interventions for Newly Diagnosed Diabetic Macular Edema 
Ophthalmology  2013;120(9):1835-1842.
Objective
Anti-vascular endothelial growth factor therapies have revolutionized the treatment of clinically significant diabetic macular (CSDME); yet these agents are expensive, and whether they are cost-effective is unclear. The purpose of this study is to determine the most cost-effective treatment option for patients with newly diagnosed CSDME: focal laser photocoagulation alone (L), focal laser plus intravitreal ranibizumab (L+R), focal laser plus intravitreal bevacizumab (L+B), or focal laser plus intravitreal triamcinolone (L+T) injections.
Design
Cost effectiveness analysis
Participants
Hypothetical cohort of 57 year old patients with newly-diagnosed CSDME.
Methods
Using a Markov model with a 25-year time horizon, we compared the incremental cost-effectiveness of treating patients with newly-diagnosed CSDME using L, L+R, L+B, or L+T. Data came from the DRCRnet randomized controlled trial, the Medicare Fee Schedule, and the medical literature.
Main Outcome Measures
Costs, quality-adjusted life years (QALYs), and incremental costs per QALY gained.
Results
Compared with L, the incremental cost-effectiveness of L+R and L+B were $89,903/QALY and $11,138/QALY, respectively. L+T was dominated by L. A probabilistic sensitivity analysis demonstrated, at a willingness-to-pay (WTP) of $50,000/QALY, that L was approximately 70% likely to be the preferred therapy over L+R and L+T. However, at a WTP of $100,000/QALY, more than 90% of the time, L+R therapy was the preferred therapy, compared with L and L+T. In the probabilistic sensitivity analysis, L+B was found to be the preferred therapy over L and L+T for any WTP value above $10,000/QALY. Sensitivity analyses revealed that the annual risk of cerebrovascular accident would have to be at least 1.5% higher with L+B than with L+R for L+R to be the preferred treatment. In another sensitivity analysis, if patients require < 8 injections per year over the remainder of the 25-year time horizon, L+B would cost less than $100,000/QALY, whereas L+R would be cost-effective at a WTP of $100,000/QALY if patients require fewer than 0.45 injections per year after year 2.
Conclusion
With bevacizumab and ranibizumab assumed to have equivalent effectiveness and similar safety profiles when used in the management of CSDME, bevacizumab therapy confers the greatest value among the different treatment options for CSDME.
doi:10.1016/j.ophtha.2013.02.002
PMCID: PMC3737388  PMID: 23642372
9.  New approaches for the treatment of diabetic macular oedema: recommendations by an expert panel 
Eye  2012;26(4):485-493.
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.
doi:10.1038/eye.2011.337
PMCID: PMC3325561  PMID: 22241014
diabetic retinopathy; expert recommendations; vascular endothelial growth factor inhibitors
10.  Ranibizumab, Verteporfin Photodynamic Therapy or Observation for the Treatment of Myopic Choroidal Neovascularization: Cost Effectiveness in the UK 
Drugs & Aging  2014;31(11):837-848.
Purpose
The aim of this study was to evaluate the cost effectiveness of ranibizumab compared with verteporfin photodynamic therapy (vPDT) or no treatment (observation) in patients with visual impairment due to myopic choroidal neovascularization (CNV).
Methods
A Markov model with health states defined by best-corrected visual acuity and a 3-month cycle length was developed. It had a healthcare provider (UK National Health Service and personal social services) perspective, a lifetime time horizon, and was based on 2011 prices; future costs and health outcomes were discounted at 3.5 % per annum. Baseline characteristics were based on the phase III RADIANCE (Ranibizumab and vPDT Evaluation in Myopic CNV) study, and year 1 health-state transitions were based on this and the VIP (Verteporfin in Photodynamic Therapy) study. Extensive sensitivity analyses tested the robustness of the model.
Results
The lifetime cost of treating myopic CNV with ranibizumab was £12,866, whereas vPDT and observation were associated with total costs of £14,421 and £8,163, respectively. Ranibizumab treatment produced higher cumulative quality-adjusted life-years (QALYs; 12.99) than vPDT (12.60) or observation (12.45). Ranibizumab treatment was therefore dominant, with greater health gains and lower overall costs than vPDT. Ranibizumab was cost effective compared with observation, with an incremental cost-effectiveness ratio of £8,778/QALY. In the probabilistic sensitivity analysis, ranibizumab had a 100 % and 88 % probability of being cost effective compared with vPDT and observation, respectively, at a willingness-to-pay threshold of £20,000/QALY.
Conclusion
This study indicates that ranibizumab therapy is dominant over vPDT for the treatment of visual impairment due to CNV secondary to pathologic myopia in the UK healthcare setting and cost effective compared with observation.
Electronic supplementary material
The online version of this article (doi:10.1007/s40266-014-0216-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s40266-014-0216-y
PMCID: PMC4210643  PMID: 25300507
11.  Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration 
Background
Age-related macular degeneration (AMD) is a common cause of severe vision loss in people 55 years and older.
Objectives
The objective of this review was to investigate the effects of anti-VEGF (vascular endothelial growth factor) modalities for treating neovascular AMD.
Search strategy
We searched CENTRAL, MEDLINE, EMBASE and LILACS. We handsearched ARVO abstracts for 2006, 2007 for ongoing trials.
Selection criteria
We included randomized controlled trials (RCTs).
Data collection and analysis
Two review authors independently extracted data. We contacted trial authors for additional data. We summarized outcomes as relative risks (RR), number needed to treat (NNT) and weighted mean differences.
Main results
We included five RCTs of good methodological quality. All five trials were conducted by pharmaceutical companies. An intention-to-treat analysis using the last observation carried forward method was done in most trials.
Two trials compared pegaptanib versus sham. One trial compared ranibizumab versus sham, another compared ranibizumab/sham verteporfin PDT versus verteporfin PDT/sham ranibizumab, and the final trial compared ranibizumab plus verteporfin PDT versus verteporfin PDT alone.
Fewer patients treated with pegaptanib lost 15 or more letters of visual acuity at one year follow-up compared to sham (pooled relative risk (RR) 0.71; 95% confidence interval (CI) 0.61 to 0.84). The NNT was 6.67 (95% CI 4.35 to 14.28) for 0.3 mg pegaptanib, 6.25 (95% CI 4.17 to 12.5) for 1 mg pegaptanib and 14.28 (95% CI 6.67 to 100) for 3 mg pegaptanib. In a trial of ranibizumab versus sham, RR for loss of 15 or more letters visual acuity at one year was 0.14 (95% CI 0.1 to 0.22) in favour of ranibizumab. The NNT was 3.13 (95% CI 2.56 to 3.84) for 0.3 mg ranibizumab and 3.13 (95% CI 2.56 to 3.84) for 0.5 mg ranibizumab. In a trial of ranibizumab versus verteporfin PDT, RR for loss of 15 or more letters at one year was 0.13 (95% CI 0.07 to 0.23) favouring ranibizumab. The NNT was 3.33 (95% CI 2.56 to 4.76) for 0.3 mg ranibizumab and 3.12 (95% CI 2.43 to 4.17) for 0.5 mg ranibizumab. In another trial of combined ranibizumab plus verteporfin PDT versus verteporfin PDT, RR for loss of 15 or more letters at one year favoured combined therapy (RR 0.3 (95% CI 0.15 to 0.60). The NNT was 4.35 (95% CI 2.78 to 11.11).
Pooled RR for gain of 15 or more letters visual acuity at one year was 5.81 (95% CI 3.29 to 10.26) for ranibizumab versus sham, 6.79 (95% CI 3.41 to 13.54) for ranibizumab/sham verteporfin PDT versus verteporfin PDT/sham ranibizumab, and 4.44 (95% CI 1.40 to 14.08) for ranibizumab plus verteporfin PDT versus verteporfin PDT.
Frequency of endophthalmitis in included studies was between 0.7% to 4.7% with ranibizumab and 1.3% with pegaptanib. Improvement in vision-specific quality of life was reported for both treatments.
Authors' conclusions
Pegaptanib and ranibizumab reduce the risk of visual acuity loss in patients with neovascular AMD. Ranibizumab causes gains in visual acuity in many eyes. Quality of life and cost will be important for treatment decisions. Other agents blocking VEGF are being tested in ongoing trials.
doi:10.1002/14651858.CD005139.pub2
PMCID: PMC4267250  PMID: 18425911
Angiogenesis Inhibitors [*therapeutic use]; Antibodies; Monoclonal [therapeutic use]; Aptamers; Nucleotide [therapeutic use]; Choroidal Neovascularization; Macular Degeneration [*drug therapy]; Porphyrins [therapeutic use]; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A [*antagonists & inhibitors]; Aged; Humans; Middle Aged
12.  Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema 
Ophthalmology  2010;117(6):1064-1077.e35.
Objective
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).
Design
Multicenter, randomized clinical trial.
Participants
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ophtha.2010.02.031
PMCID: PMC2937272  PMID: 20427088
13.  Cost-Effectiveness of Bevacizumab and Ranibizumab for Newly Diagnosed Neovascular Macular Degeneration (An American Ophthalmological Society Thesis) 
Purpose:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
PMCID: PMC3797829  PMID: 24167325
14.  Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE Study*) 
Diabetes Care  2010;33(11):2399-2405.
OBJECTIVE
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).
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc10-0493
PMCID: PMC2963502  PMID: 20980427
15.  Cost Effectiveness of Guanfacine Extended Release as an Adjunctive Therapy to a Stimulant Compared with Stimulant Monotherapy for the Treatment of Attention-Deficit Hyperactivity Disorder in Children and Adolescents 
Pharmacoeconomics  2012;30(8):e1-e15.
Background
Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in childhood, affecting 3–7% of school-age children in the US and imposing substantial economic burden. Stimulants are considered first-line pharmacological treatment and are the most prescribed treatment for ADHD. However, approximately 30% of children with ADHD do not have an optimal response to a single stimulant and may require adjunctive therapy.
Objective
Our objective was to conduct a cost-effectiveness analysis (CEA) of adding a non-stimulant, guanfacine extended release (GXR), to stimulants versus maintaining existing stimulant monotherapy in the treatment of ADHD in children and adolescents with suboptimal response to stimulant monotherapy.
Methods
A 1-year Markov model was developed to estimate costs and effectiveness from a US third-party payer perspective. Effectiveness was measured by the QALY. The model assumed that patients transitioned among four health states (normal, mild, moderate and severe), defined by the Clinical Global Impression-Severity (CGI-S) scale. Transition probabilities were estimated in an ordered logit model using patient-level data from a multicentre, 9-week, double-blind, placebo-controlled, dose-optimization study, where subjects (n=461) continued their stable morning stimulant and were randomized to GXR administered in the morning, GXR administered in the evening, or placebo. The model assumed that patients in moderate/severe health states after week 8 would discontinue ADHD treatment and remain in that state for the rest of the study period. Direct costs included drug wholesale acquisition costs and health state costs, all in $US, year 2010 values. Utility associated with each health state was obtained from the literature and disutilities associated with adverse events were applied for the first 4 weeks. Oneway sensitivity analyses and probabilistic sensitivity analysis (PSA) were conducted by varying costs, utilities, adverse-event duration, and transition probabilities.
Results
Compared with maintaining existing stimulant monotherapy, adding GXR to existing stimulant monotherapy was associated with an incremental drug cost of $US1016 but a lower medical cost of $US124, resulting in a total incremental cost of $US892 at 1 year. The addition of GXR to stimulants led to an incremental QALY of 0.03 and an incremental cost-effectiveness ratio (ICER) of $US31 660/QALY. In one-way sensitivity analysis, ICER values ranged from $US19 723, when 100% of patients were assumed to be severe in their initial health state, to $US46631, when the last observed states from the clinical trial were carried forward to the end of the 1-year analysis period. PSA demonstrated a 94.6% likelihood that the ICER falls below $US50 000/QALY.
Conclusions
The impairment associated with residual ADHD symptoms after stimulant therapy is becoming increasingly recognized. This is the first analysis of the cost effectiveness of stimulants combined with an adjunctive medication. This study suggests that the adjunctive therapy of GXR with stimulants is a cost-effective treatment based on a willingness-to-pay threshold of $US50 000/QALY. This may address an unmet need among patients with suboptimal response to stimulant monotherapy.
doi:10.2165/11632920-000000000-00000
PMCID: PMC3576910  PMID: 22788263
16.  Combination of ranibizumab with photodynamic therapy vs ranibizumab monotherapy in the treatment of age-related macular degeneration: a systematic review and meta-analysis of randomized controlled trials 
AIM
To compare the efficacy and safety of combination of ranibizumab with photodynamic therapy (PDT) vs ranibizumab monotherapy in the treatment of age-related macular degeneration (AMD).
METHODS
The Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Pubmed, and Embase were searched. There were no language or data restrictions in the search for trials. Only randomized controlled trials (RCTs) were included. Methodological quality of the literatures was evaluated according to the Jadad Score. RevMan 5.2.6 software was used to do the meta-analysis.
RESULTS
Seven studies were included in our systematic review, among which four of them were included in quantitative analysis. The result shows that the ranibizumab monotherapy group had a better mean best corrected visual acuity (BCVA) change vs baseline at month 12 compared with that of the combination treatment group, and the statistical difference was significant (WMD, -2.61; 95% CI, -5.08 to -0.13; P=0.04). However, after the removal of one study, the difference between the two groups showed no significant difference (WMD, -2.29; 95% CI, -4.81 to 0.23; P=0.07). Meanwhile, no significant central retinal thickness (CRT) reduction was found in the combination treatment group and the ranibizumab monotherapy group at 12 months follow-up. Nevertheless, the combination group tended to have a greater reduction in CRT (WMD, -4.13µm; 95%CI, -25.88 to 17.63, P=0.71). The proportion of patients gaining more than 3 lines at month 12 in the ranibizumab group was higher than in the combination group and there was a significant difference (RR, 0.72; 95% CI, 0.54 to 0.95; P=0.02). Whereas there was no significant difference for the proportion of patients gaining more than 0 line at month 12 between the two groups (RR, 0.93; 95% CI, 0.76 to 1.15; P=0.52). The general tendency shows a reduction in ranibizumab retreatment number in the combination treatment group compared with the ranibizumab monotherapy group. As major adverse events, the differences in the number of eye pain, endophthalmitis, hypertension and arterial thromboembolic events were not significant between the two groups, and the incidence of serious adverse events in the two groups was very low.
CONCLUSION
For the maintenance of vision, the comparison of the combination of ranibizumab with PDT vs ranibizumab monotherapy shows no apparent difference. Compared with the combination of ranibizumab and PDT, patients treated with ranibizumab monothearpy may gain more visual acuity (VA) improvement. The combination treatment group had a tendency to reduce the number of ranibizumab retreatment. Both the two treatment strategies were well tolerated.
doi:10.3980/j.issn.2222-3959.2014.03.28
PMCID: PMC4067674  PMID: 24967206
ranibizumab; photodynamic therapy; age-related macular degeneration; meta-analysis
17.  Expanded 2-year Follow-up of Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema 
Ophthalmology  2011;118(4):609-614.
Objective
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).
Design
Multicenter, randomized clinical trial.
Participants
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.
Methods
Continuation of procedures previously reported for the randomized trial.
Main Outcome Measures
Best-corrected visual acuity and safety at the 2-year visit.
Results
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.
Conclusions
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.
doi:10.1016/j.ophtha.2010.12.033
PMCID: PMC3096445  PMID: 21459214
18.  Cost-effectiveness of ranibizumab for neovascular age-related macular degeneration 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1478-7547-6-12
PMCID: PMC2443361  PMID: 18573218
19.  Cost-effectiveness of ranibizumab and bevacizumab for age-related macular degeneration: 2-year findings from the IVAN randomised trial 
BMJ Open  2014;4(7):e005094.
Objective
To assess the incremental cost and cost-effectiveness of continuous and discontinuous regimens of bevacizumab (Avastin) and ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) from a UK National Health Service (NHS) perspective.
Design
A within-trial cost-utility analysis with a 2-year time horizon, based on a multicentre factorial, non-inferiority randomised controlled trial.
Setting
23 hospital ophthalmology clinics.
Participants
610 patients aged ≥50 years with untreated nAMD in the study eye.
Interventions
0.5 mg ranibizumab or 1.25 mg bevacizumab given continuously (monthly) or discontinuously (as-needed) for 2 years.
Main outcome measures
Quality-adjusted life-years (QALYs).
Results
Total 2-year costs ranged from £3002/patient ($4700; 95% CI £2601 to £3403) for discontinuous bevacizumab to £18 590/patient ($29 106; 95% CI £18 258 to £18 922) for continuous ranibizumab. Ranibizumab was significantly more costly than bevacizumab for both continuous (+£14 989/patient ($23 468); 95% CI £14 522 to £15 456; p<0.001) and discontinuous treatment (+£8498 ($13 305); 95% CI £7700 to £9295; p<0.001), with negligible difference in QALYs. Continuous ranibizumab would only be cost-effective compared with continuous bevacizumab if the NHS were willing to pay £3.5 million ($5.5 million) per additional QALY gained. Patients receiving continuous bevacizumab accrued higher total costs (+£599 ($938); 95% CI £91 to £1107; p=0.021) than those receiving discontinuous bevacizumab, but also accrued non-significantly more QALYs (+0.020; 95% CI −0.032 to 0.071; p=0.452). Continuous bevacizumab therefore cost £30 220 ($47 316) per QALY gained versus discontinuous bevacizumab. However, bootstrapping demonstrated that if the NHS is willing to pay £20 000/QALY gained, there is a 37% chance that continuous bevacizumab is cost-effective versus discontinuous bevacizumab.
Conclusions
Ranibizumab is not cost-effective compared with bevacizumab, being substantially more costly and producing little or no QALY gain. Discontinuous bevacizumab is likely to be the most cost-effective of the four treatment strategies evaluated in this UK trial, although there is a 37% chance that continuous bevacizumab is cost-effective.
Trial registration number
ISRCTN92166560.
doi:10.1136/bmjopen-2014-005094
PMCID: PMC4120317  PMID: 25079928
Neovascular age-related macular degeneration (AMD); vascular endothelial growth factor (VEGF) inhibitors; trial-based economic evaluation; cost-utility analysis; cost-minimisation analysis; cost-effectiveness
20.  Bevacizumab for the management of diabetic macular edema 
World Journal of Diabetes  2013;4(2):19-26.
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.
doi:10.4239/wjd.v4.i2.19
PMCID: PMC3627413  PMID: 23593532
Diabetic macular edema; Bevacizumab; Anti-vascular endothelial growth factor; Diabetic retinopathy
21.  Exploratory Analysis of Effect of Intravitreal Ranibizumab or Triamcinolone on Worsening of Diabetic Retinopathy in a Randomized Clinical Trial 
JAMA ophthalmology  2013;131(8):1033-1040.
Importance
The standard care for proliferative diabetic retinopathy (PDR) usually is panretinal photocoagulation (PRP), an inherently destructive treatment which can cause iatrogenic vision loss. Therefore, evaluating effects of therapies for diabetic macular edema (DME) on development or worsening of PDR might lead to new therapies for PDR.
Objective
To evaluate effects of intravitreal ranibizumab or triamcinolone acetonide, administered to treat DME, on worsening of diabetic retinopathy.
Design
Exploratory analysis was performed on worsening of retinopathy, defined as one or more of the following: (1) worsening from no PDR to PDR, (2) worsening of 2 or more severity levels on reading center assessment of fundus photographs in eyes without PDR at baseline, (3) having PRP, (4) vitreous hemorrhage, or (5) vitrectomy for treatment of PDR.
Setting
Community- and university-based ophthalmology practices.
Participants
Subjects with central-involved diabetic macular edema causing visual acuity impairment.
Interventions
Eyes were assigned randomly to sham+prompt focal/grid laser, 0.5-mg intravitreal ranibizumab+prompt or deferred (≥24 weeks) laser, or 4-mg intravitreal triamcinolone+prompt laser.
Main Outcome Measure
3-year cumulative probabilities for retinopathy worsening.
Results
For eyes without PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening (P value comparison with sham+prompt laser) were 23% using sham+prompt laser, 18% with ranibizumab+prompt laser (P = 0.25), 7% with ranibizumab+deferred laser (P = 0.001), and 37% with triamcinolone+prompt laser (P = 0.10). For eyes with PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening were 40%, 21% (P = 0.05), 18% (P = 0.02), and 12% (P<0.001), respectively.
Conclusions and Relevance
Intravitreal ranibizumab appears to be associated with a reduced risk of diabetic retinopathy worsening in eyes with or without PDR. Intravitreal triamcinolone also appears to be associated with a reduced risk of PDR worsening. These findings suggest that use of these drugs to prevent worsening of diabetic retinopathy may be feasible. Given the exploratory nature of these analyses, the risk of endophthalmitis following intravitreal injections, and that intravitreal triamcinolone can cause cataract or glaucoma, use of these treatments to reduce the rates of worsening of retinopathy, with or without PDR, does not seem warranted at this time.
doi:10.1001/jamaophthalmol.2013.4154
PMCID: PMC4162127  PMID: 23807371
22.  THE GOAL OF VALUE-BASED MEDICINE ANALYSES: COMPARABILITY. THE CASE FOR NEOVASCULAR MACULAR DEGENERATION 
Purpose
To evaluate the comparability of articles in the peer-reviewed literature assessing the (1) patient value and (2) cost-utility (cost-effectiveness) associated with interventions for neovascular age-related macular degeneration (ARMD).
Methods
A search was performed in the National Library of Medicine database of 16 million peer-reviewed articles using the key words cost-utility, cost-effectiveness, value, verteporfin, pegaptanib, laser photocoagulation, ranibizumab, and therapy. All articles that used an outcome of quality-adjusted life-years (QALYs) were studied in regard to (1) percent improvement in quality of life, (2) utility methodology, (3) utility respondents, (4) types of costs included (eg, direct healthcare, direct nonhealthcare, indirect), (5) cost bases (eg, Medicare, National Health Service in the United Kingdom), and (6) study cost perspective (eg, government, societal, third-party insurer).
To qualify as a value-based medicine analysis, the patient value had to be measured using the outcome of the QALYs conferred by respective interventions. As with value-based medicine analyses, patient-based time tradeoff utility analysis had to be utilized, patient utility respondents were necessary, and direct medical costs were used.
Results
Among 21 cost-utility analyses performed on interventions for neovascular macular degeneration, 15 (71%) met value-based medicine criteria. The 6 others (29%) were not comparable owing to (1) varying utility methodology, (2) varying utility respondents, (3) differing costs utilized, (4) differing cost bases, and (5) varying study perspectives.
Among value-based medicine studies, laser photocoagulation confers a 4.4% value gain (improvement in quality of life) for the treatment of classic subfoveal choroidal neovascularization. Intravitreal pegaptanib confers a 5.9% value gain (improvement in quality of life) for classic, minimally classic, and occult subfoveal choroidal neovascularization, and photodynamic therapy with verteporfin confers a 7.8% to 10.7% value gain for the treatment of classic subfoveal choroidal neovascularization. Intravitreal ranibizumab therapy confers greater than a 15% value gain for the treatment of subfoveal occult and minimally classic subfoveal choroidal neovascularization.
Conclusions
The majority of cost-utility studies performed on interventions for neovascular macular degeneration are value-based medicine studies and thus are comparable. Value-based analyses of neovascular ARMD monotherapies demonstrate the power of value-based medicine to improve quality of care and concurrently maximize the efficacy of healthcare resource use in public policy. The comparability of value-based medicine cost-utility analyses has important implications for overall practice standards and public policy. The adoption of value-based medicine standards can greatly facilitate the goal of higher-quality care and maximize the best use of healthcare funds.
PMCID: PMC2258104  PMID: 18427606
23.  Anti-vascular endothelial growth factor for neovascular age-related macular degeneration 
Background
Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to neovascular AMD accounts for most AMD-related severe vision loss. Anti-vascular endothelial growth factor (anti-VEGF) agents, injected intravitreally, aim to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, improve vision.
Objectives
To investigate: (1) the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.
Search methods
We searched Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2014), EMBASE (January 1980 to March 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2014), the metaRegister of Controlled Trials (mRCT) (www.controlledtrials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 27 March 2014.
Selection criteria
We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or a control treatment (e.g., sham treatment or photodynamic therapy). All trials followed participants for at least one year.
Data collection and analysis
Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We analyzed outcomes as risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by The Cochrane Collaboration.
Main results
We included 12 RCTs including a total of 5496 participants with neovascular AMD (the number of participants per trial ranged from 28 to 1208). One trial compared pegaptanib, three trials ranibizumab, and two trials bevacizumab versus controls; six trials compared bevacizumab with ranibizumab. Four trials were conducted by pharmaceutical companies; none of the eight studies which evaluated bevacizumab were funded by pharmaceutical companies. The trials were conducted at various centers across five continents (North and South America, Europe, Asia and Australia). The overall quality of the evidence was very good, with most trials having an overall low risk of bias.
When compared with control treatments, participants who received any of the three anti-VEGF agents were more likely to have gained 15 letters or more of visual acuity, lost fewer than 15 letters of visual acuity, and had vision 20/200 or better after one year of follow up. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same regimens were compared in the same RCTs, despite the substantially lower cost for bevacizumab compared with ranibizumab. No trial directly compared pegaptanib with other anti-VEGF agents; however, when compared with controls, ranibizumab or bevacizumab yielded larger improvements in visual acuity outcomes than pegaptanib.
Participants treated with anti-VEGFs showed improvements in morphologic outcomes (e.g., size of CNV or central retinal thickness) compared with participants not treated with anti-VEGF agents. There was less reduction in central retinal thickness among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD −13.97 μm; 95% confidence interval (CI) −26.52 to −1.41); however, this difference is within the range of measurement error and we did not interpret it as being clinically meaningful.
Ocular inflammation and increased intraocular pressure after intravitreal injection were the most frequently reported serious ocular adverse events. Endophthalmitis was reported in fewer than 1% of anti-VEGF treated participants; no cases were reported in control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to detect a meaningful difference between groups. Data for visual function, quality of life, and economic outcomes were sparsely measured and reported.
Authors’ conclusions
The results of this review indicate the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; ranibizumab and bevacizumab were also shown to improve visual acuity. The information available on the adverse effects of each medication do not suggest a higher incidence of potentially vision-threatening complications with intravitreal injection compared with control interventions; however, clinical trial sample sizes may not have been sufficient to detect rare safety outcomes. Research evaluating variable dosing regimens with anti-VEGF agents, effects of long-term use, combination therapies (e.g., anti-VEGF treatment plus photodynamic therapy), and other methods of delivering the agents should be incorporated into future Cochrane reviews.
doi:10.1002/14651858.CD005139.pub3
PMCID: PMC4270425  PMID: 25170575
Angiogenesis Inhibitors [*therapeutic use]; Antibodies, Monoclonal [therapeutic use]; Antibodies, Monoclonal, Humanized, Aptamers, Nucleotide [therapeutic use]; Choroidal Neovascularization; Macular Degeneration [*drug therapy]; Porphyrins [therapeutic use]; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A [*antagonists & inhibitors]; Aged; Humans; Middle Aged
24.  A prospective pilot study comparing combined intravitreal ranibizumab and half-fluence photodynamic therapy with ranibizumab monotherapy in the treatment of neovascular age-related macular degeneration 
Purpose
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.
Methods
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.
Results
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).
Conclusion
The groups appeared similar based on statistical analysis, but larger studies are needed to determine possible small differences between combination therapy and monotherapy.
doi:10.2147/OPTH.S31010
PMCID: PMC3460704  PMID: 23055673
ranibizumab; macular degeneration; photodynamic therapy; verteporfin; choroidal neovascularization; anti-vegf
25.  Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt vs Deferred Laser Treatment: 3-year Randomized Trial Results 
Ophthalmology  2012;119(11):2312-2318.
Objective
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).
Design
Multicenter randomized clinical trial.
Participants
Three hundred and sixty one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ophtha.2012.08.022
PMCID: PMC3490003  PMID: 22999634

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