Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration : a Patient-Level Pooled Analysis

Topic: This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham \ub1 verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Clinical Relevance: Intravitreal anti\u2013vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Methods: Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists\u2019 Collaboration (APTC). Results: The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72\u20131.88) for ATE, 1.33 (0.59\u20132.97) for MI, 1.43 (0.54\u20133.77) for stroke excluding TIA, 1.25 (0.61\u20132.55) for stroke or TIA, 0.57 (0.18\u20131.78) for vascular death, and 1.12 (0.64\u20131.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. Conclusions: The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit\u2013risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses

A randomised controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation (IBS-C).

none9BACKGROUND: It has been proposed that treatments for irritable bowel syndrome with constipation (IBS-C) should provide rapid symptomatic relief, be intermittent and effective upon repeated use. AIMS: To evaluate the efficacy and safety of tegaserod on IBS symptoms, and its impact on quality of life and health-economic measures. PATIENTS: Women (>/=18 years of age) with IBS-C according to the Rome II criteria. METHODS: Prospective, double-blind, placebo- controlled, randomised trial. Women with IBS-C either received tegaserod 6 mg b.i.d. or placebo for 1 month. Patients with at least a partial response entered a treatment-free interval. Upon symptom recurrence, tegaserod-treated patients were re-randomised to tegaserod or placebo for an additional month. Primary efficacy variables were response (overall IBS symptoms and abdominal discomfort/pain) to first and repeated treatment. Analysis was by intention-to-treat. RESULTS: 2,660 patients and 1,191 patients were randomised for first and repeated treatment respectively. Tegaserod was superior to placebo for each primary efficacy variable (first treatment: 33.7% vs 24.2% responders respectively for relief of IBS symptoms and 31.3% vs 22.1% for relief of abdominal discomfort/pain; repeated treatment: 44.9% vs 28.7%, and 42.4% vs 27.1%, all p<0.0001). Tegaserod was superior to placebo for every secondary efficacy variable (relief of abdominal discomfort/pain, bloating and constipation; stool frequency and consistency). A response to tegaserod was observed within the first treatment week. Tegaserod produced greater satisfaction, work productivity and improved quality of life than placebo (p<0.05). CONCLUSION: Tegaserod provides rapid and sustained relief of IBS-C symptoms both during first and repeated treatment.noneTack J; Muller-Lissner S; Bytzer P; Corinaldesi R; Chang L; Viegas A; Schnekenbuehl S; Dunger-Baldauf C; Rueegg P.Tack J; Muller-Lissner S; Bytzer P; Corinaldesi R; Chang L; Viegas A; Schnekenbuehl S; Dunger-Baldauf C; Rueegg P

Vascular safety of ranibizumab in patients with diabetic macular edema : a pooled analysis of patient-level data from randomized clinical trials

Importance: Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events. Objective: To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME. Data Sources: Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials. Study Selection: Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013. Data Extraction and Synthesis: Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015. Main Outcomes and Measures: Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Results: Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96). Conclusions and Relevance: This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials

Real-world outcomes with ranibizumab in branch retinal vein occlusion: The prospective, global, LUMINOUS study

Objective To evaluate the effectiveness, safety, and treatment patterns of ranibizumab 0.5 mg in treatment-na\uefve patients with branch retinal vein occlusion (BRVO) enrolled in the LUMINOUS\u2122 study. Study design A 5-year, global, prospective, multicenter, observational, open-label study conducted in a clinical practice (real-world) setting at outpatient ophthalmology clinics that recruited 30,138 consenting adult patients from all approved indications for ranibizumab across 42 countries. Patients with BRVO were treated according to the local ranibizumab label of the participating countries. Mean change in visual acuity (VA) in Early Treatment Diabetic Retinopathy Study letters from baseline to Year 1, treatment exposure during Year 1, and adverse events (AEs) over 5 years were assessed. Results Of the 1366 recruited BRVO patients, 405 were treatment-na\uefve at baseline with a mean (standard deviation [SD]) age of 67.9 (12.5) years, 57.5% were female, and 71.8% were White. At Year 1 (n = 189), the mean (SD) VA gain was 11.9 (17.66) letters from a baseline of 49.2 (\ub120.32) letters with a mean (SD) of 5.0 (2.34) injections. VA gains were higher in patients (n = 83) who received 6-9 injections (13.6 [20.16] letters) than in those who received 2-5 injections (n = 92, 11.7 [15.43] letters), or 1 injection (n = 14, 3.6 [13.72] letters). Patients with baseline VA <23 letters had numerically highest VA gains (n = 20, 31.1 [24.48] letters). Over 5 years, the rate of ocular/non-ocular AEs was 7.4%/9.1% and serious AEs was 0.3%/4.4% in treatment-na\uefve BRVO patients (n = 405). Conclusions One year results from the LUMINOUS real-world study showed a clinically meaningful VA improvement with ranibizumab in treatment-na\uefve patients with BRVO; numerically higher VA gains were achieved in patients who received more injections and those with poor baseline VA. No new safety signals were observed