Cerebrovascular accidents in patients treated for choroidal neovascularization with ranibizumab in randomized controlled trials.
ABSTRACT : To analyze cerebrovascular accidents (CVAs) pooled from large, randomized, controlled clinical trials of ranibizumab treatment for neovascular age-related macular degeneration.
: Events in five trials (FOCUS, MARINA, ANCHOR, PIER, and SAILOR) were analyzed using a standard safety monitoring process. Exact methods, stratified by study, were used to test for treatment differences based on odds ratios. A stepwise logistic regression model was fit to classify subjects' risk for CVA based on medical history. Treatment differences in CVA rates at 1 year or 2 years were evaluated within risk groups using stratified exact methods.
: Pooled 2-year CVA rates were <3%; odds ratios (95% confidence intervals) for CVA risk were 1.2 (0.4-4.4) for ranibizumab 0.3-mg versus control, 2.2 (0.8-7.1) for 0.5 mg versus control, and 1.5 (0.8-3.0) for 0.5-mg versus 0.3-mg ranibizumab. No substantial increased risk of CVA for 0.5 mg versus 0.3 mg was identified in pooled analyses or any of the individual trials. In pooled analyses, the difference between 0.5-mg ranibizumab and control was larger (7.7 [1.2-177]) among high-risk CVA patients.
: This analysis provided some evidence, although not definitive, of a potential increased risk of CVA with ranibizumab versus control or with 0.5-mg versus 0.3-mg ranibizumab. Continued monitoring for CVA within clinical trials seems warrented.
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ABSTRACT: Ranibizumab (Lucentis®), an inhibitor of multiple vascular endothelial growth factor A isoforms, is approved for the intravitreal treatment of neovascular (wet) age-related macular degeneration (AMD). In clinical trials in patients with neovascular AMD, monthly or less frequent injections of ranibizumab were effective in the treatment of predominantly classic choroidal neovascularization (CNV) and minimally classic or occult CNV lesions. Ranibizumab has a well-established safety profile, and is associated with low rates of ocular and systemic serious adverse events. In head-to-head comparisons, the efficacy of monthly bevacizumab was equivalent to monthly ranibizumab at 1 and 2 years, individualized treatment with bevacizumab was equivalent to individualized treatment with ranibizumab at 1 and 2 years, and bimonthly aflibercept was noninferior to monthly ranibizumab at 1 year. These trials were not powered to detect between-treatment differences in safety.Drugs & Therapy Perspectives 09/2013; DOI:10.1007/s40267-013-0062-8
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ABSTRACT: Abstract BACKGROUND: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Although grid or focal laser photocoagulation has been shown to reduce the risk of visual loss in DMO or clinically significant macular oedema (CSMO), vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities has recently been proposed for improving vision in people with DMO. OBJECTIVES: To assess the effectiveness, safety and cost-effectiveness of anti-VEGF therapy for preserving or improving vision in people with DMO. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 6), MEDLINE (January 1946 to June 2012), EMBASE (January 1980 to June 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2012. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any antiangiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment, or no treatment in patients with DMO. We also included economic evaluations to assess cost-effectiveness. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data. The risk ratio (RR) of visual loss and visual gain of three or more lines was estimated at least six months after treatment. Each economic analysis was described narratively using a structured format. MAIN RESULTS: Eleven studies provided data on three comparisons of interest in this review. We based our conclusions on the RR of gain or loss of three or more lines of vision at about one year, which was more consistently reported as follow-up.Compared with sham treatment, there was evidence of moderate quality in three studies (497 participants, follow-up 8 to 12 months) that antiangiogenic therapy (pegaptanib: two studies, 246 participants; ranibizumab: one study, 151 participants) doubled and, respectively, halved, the chance of gaining or losing three or more lines of vision (RR: 2.19, 95% confidence interval (CI) 1.36 to 3.53; RR: 0.28, 95% CI: 0.13 to 0.59). In meta-analyses, the benefit was larger for ranibizumab compared to pegaptanib, but no significant subgroup difference could be demonstrated regarding our primary outcome.Compared with grid laser photocoagulation, there was evidence of moderate quality that antiangiogenic therapy (bevacizumab: two studies, 167 participants; ranibizumab: two studies, 300 participants; aflibercept: one study, 221 participants, 89 used for data extraction) more than doubled and, respectively, reduced by at least two thirds, the chance of gaining or losing three or more lines of vision (RR: 3.20, 95% CI 2.07 to 4.95 and RR: 0.13, 95% CI: 0.05 to 0.34, respectively). In meta-analyses, no significant subgroup difference could be demonstrated between bevacizumab, ranibizumab and aflibercept regarding our primary outcome, but, again, there was little power to detect a difference.Compared with grid laser photocoagulation alone, there was high quality evidence that ranibizumab plus photocoagulation (three studies, 783 participants) doubled and, respectively, at least halved, the chance of gaining or losing three or more lines of vision (RR: 2.11, 95% CI 1.67 to 2.67; RR: 0.29, 95% CI: 0.15 to 0.55).Systemic and ocular adverse events were rare in the included studies. Meta-analyses conducted for all antiangiogenic drugs compared with either sham or photocoagulation (nine studies, 104 events in 2159 participants) did not show a significant difference regarding arterial thromboembolic events (RR: 0.85 (0.56 to 1.28). Similarly, no difference was suggested regarding overall mortality (53 events, RR: 0.95 (0.52 to 1.74), but clinically significant differences could not be ruled out. AUTHORS' CONCLUSIONS: There is moderate quality evidence that antiangiogenic drugs provide a definite, but small, benefit compared to current therapeutic options for DMO, i.e. grid laser photocoagulation, or no treatment when laser is not an option. The quality and quantity of the evidence was larger for ranibizumab, but there was little power to investigate drug differences. Most data were obtained at one year, and a long-term confirmation is needed, since DMO is a chronic condition. Safety of both drug and the intravitreal injection procedure were good in the trials, but further long-term data are needed to exclude small, but clinically important differences regarding systemic adverse events.Cochrane database of systematic reviews (Online) 12/2012; DOI:10.1002/14651858.CD007419.pub3 · 5.70 Impact Factor
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ABSTRACT: Decades of research into the pathophysiology and management of diabetic retinopathy have revolutionized our understanding of the disease process. Diabetic retinopathy is now more accurately defined as a neurovascular rather than a microvascular disease as neurodegenerative disease precedes and coexists with microvascular changes. However, the complexities of the pathways involved in different stages of disease severity continue to remain a challenging issue for drug discovery. Currently, laser photocoagulation is the mainstay of treatment for proliferative diabetic retinopathy, but is gradually being superseded for diabetic macular oedema. However, it is destructive and at best results in a gradual but modest improvement in vision in the long term. So, diabetic retinopathy remains the most prevalent cause of visual impairment in the working-age population despite established screening programmes, early diagnosis and treatment of the condition. The recent discovery of inhibitors of vascular endothelial growth factors is revolutionizing the management of diabetic retinopathy, particularly diabetic macular oedema. However, not all patients respond to anti-vascular endothelial growth factors agents, reinforcing the fact that diabetic retinopathy is a multifactorial disease. Studies are still required to improve our understanding of how retinal structure correlates with visual function. It is hoped that these will lead to better characterization of the disease phenotype based on treatment responses to different agents and allow an algorithm to be developed that will guide the management of diabetic retinopathy and diabetic macular oedema at different stages of severity. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.Diabetic Medicine 12/2012; 30(6). DOI:10.1111/dme.12089 · 3.06 Impact Factor