Antiplatelet Trialists Research Articles

Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema

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. 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. Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials. Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013. 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. 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). 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). 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.

Cardiovascular effects of urate-lowering therapies in patients with chronic gout: a systematic review and meta-analysis

To determine if urate-lowering treatment (ULT) in gout can reduce cardiovascular (CV) outcomes. Randomized trials were searched for treatment with ULT in gout. Eligible trials had to report CV safety of a ULT. Potential medications included allopurinol, febuxostat, pegloticase, rasburicase, probenecid, benzbromarone, sulphinpyrazone, losartan, fenofibrate and sodium-glucose linked transporter 2 inhibitors. A total of 3084 citations were found, with 642 duplicates. After the primary screen, 35 studies were selected for review. Several trials did not report CV events. Six were not randomized controlled trials (RCTs). Four studies reported no events in either intervention arm while the other four had 40 events in the febuxostat group ( n = 3631) and 5 in allopurinol group ( n = 1154). Overall, the pooled analysis did not show a significant difference between the two [febuxostat vs allopurinol: relative risk (RR) 1.69 (95% CI 0.54, 5.34), P = 0.37]. CV events did not decrease over time. Comparing shorter studies (<52 weeks) to longer ones did not reveal any statistical differences. However, in long-term studies with febuxostat vs allopurinol, results were nearly significant, with more CVE occurring with febuxostat treatment. Comparing any ULT to placebo (eight studies, n = 2221 patients) did not demonstrate a significant difference in non-Anti-Platelet Trialists' Collaboration events [any ULT vs placebo: RR 1.47 (95% CI 0.49, 4.40), P = 0.49] or all-cause mortality [any ULT vs placebo: RR 1.45 (95% CI 0.35, 5.77), P = 0.60]. RCT data do not suggest differences in CV events among ULTs in gout. Trials had few events despite high-risk patients being enrolled and may have been too short to show CV reduction by controlling inflammatory attacks and lowering uric acid.

Long-term Safety and Visual Outcome of Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: VIEW 1 Extension Study

To assess the long-term safety and vision change in patients who received intravitreal aflibercept injection (IAI) for neovascular age-related macular degeneration in an extension study after completing VIEW 1 trial. Prospective, open-label, multicenter, extension study. Three hundred twenty-three patients. In VIEW 1, 1217 patients were randomized to receive fixed dosing of 0.5 mg IAI every 4 weeks (0.5q4), 2 mg IAI every 4 weeks (2q4), 2 mg IAI every 8 weeks after 3 initial monthly dosing (2q8), or 0.5 mg ranibizumab every 4 weeks (Rq4) from baseline through week 52, followed by modified quarterly injections of the same dose of anti-vascular endothelial growth factor agent from weeks 52 to 96. After completing VIEW 1 at week 96, patients (n= 323) enrolled in an extension study and received 2 mg IAI on a modified quarterly injection schedule followed by at least an every 8-week dosing through week212. Long-term safety and vision change in patients followed for a median duration of 116 weeks in the extension study (total follow-up time of 212 weeks from the VIEW 1 baseline). Patients enrolled in the extension study gained a mean of 10.2 letters from the VIEW 1 baseline at week 96. These patients largely maintained vision over the extension study with a mean gain of 7.1 letters from the VIEW 1 baseline to week 212. The proportion of patients who lost ≥15 letters from the VIEW 1 extension baseline was 8.2% at week 212. Mean number of injections was 12.9 (range, 1-41) in the extension study. The most common serious ocular adverse event was endophthalmitis (0.9%). The overall incidence of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events was 6.2%. Vision gains achieved with anti-vascular endothelial growth factor therapy in VIEW 1 were largely maintained by continued treatment with IAI 2 mg in the extension study. Anti-vascular endothelial growth factor injections (including 4 years of IAI 2 mg) were well-tolerated with no new safety signals compared with the known profile of IAI.

Perioperative Aspirin for Prevention of Venous Thromboembolism: The PeriOperative ISchemia Evaluation-2 Trial and a Pooled Analysis of the Randomized Trials.

The PeriOperative ISchemia Evaluation-2 (POISE-2) trial compared aspirin with placebo after noncardiac surgery. The authors randomly assigned 10,010 patients undergoing noncardiac surgery to receive 200 mg aspirin or placebo 2 to 4 h before surgery and then 100 mg aspirin daily or placebo daily for up to 30 days after surgery. Herein, the authors report the effect of aspirin on venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, as well as an updated pooled analysis of randomized trials of antiplatelet therapy for VTE prevention in noncardiac surgery patients. Six thousand five hundred forty-eight patients (65.4%) received anticoagulant prophylaxis. VTE occurred in 53 patients (1.1%) allocated to aspirin and in 60 patients (1.2%) allocated to placebo (hazard ratio, 0.89; 95% CI, 0.61 to 1.28). Major or life-threatening bleeding occurred in 312 patients (6.3%) allocated to aspirin and in 256 patients (5.1%) allocated to placebo (hazard ratio, 1.22; 95% CI, 1.04 to 1.44). Concomitant use of anticoagulant prophylaxis did not modify the effect of aspirin on VTE or bleeding. Pooled analysis of the POISE-2 and Pulmonary Embolism Prevention trials demonstrated that symptomatic VTE occurred in 173 (1.3%) of 13,724 patients allocated to aspirin and in 246 (1.8%) of 13,730 patients allocated to placebo (odds ratio, 0.71; 95% CI, 0.56 to 0.89; heterogeneity P = 0.27; I = 17%); the impact of aspirin was very similar in those who did and did not receive pharmacologic prophylaxis. Pooled estimates for symptomatic VTE were similar to the pooled estimates for any deep vein thrombosis and pulmonary embolism from the POISE-2 trial, Pulmonary Embolism Prevention trial, and the Antiplatelet Trialists' Collaboration meta-analysis. Aspirin in the POISE-2 trial did not reduce VTE, but two thirds of patients received anticoagulant prophylaxis, there were few VTE events, and results were consistent with a wide range of aspirin effects. A pooled analysis of the randomized trials demonstrates evidence for the efficacy of aspirin for VTE prevention in hospitalized surgical patients.

Randomized Trial of Treat and Extend Ranibizumab with and without Navigated Laser for Diabetic Macular Edema: TREX-DME 1 Year Outcomes

To compare monthly dosing with a treat and extend algorithm using ranibizumab 0.3 mg with and without angiography-guided macular laser photocoagulation for center-involving diabetic macular edema (DME). Multicenter, prospective, randomized clinical trial. A total of 150 eyes from 116 subjects were randomized into 3 cohorts: Monthly (n= 30), TReat and EXtend without macular laser photocoagulation (TREX; n= 60), and treat and extend with angiography-GuIded macular LAser photocoagulation (GILA; n= 60). Monthly cohort eyes received ranibizumab 0.3 mg every 4 weeks. Eyes in the TREX and GILA cohorts received 4 monthly injections of ranibizumab 0.3 mg followed by a treat and extend algorithm based on disease activity. Eyes in the GILA cohort also received angiography-guided macular laser photocoagulation at month 1 and again every 3 months for microaneurysm leakage. Change in mean best-corrected visual acuity (BCVA), mean central retinal thickness (CRT), number of injections from baseline to 1 year, and percentage gaining/losing 2 and 3 lines of vision. Baseline demographics were well balanced among the cohorts. A total of 137 eyes (91%) completed the 1-year end point visit. At 1 year, the mean BCVA improved by 8.6, 9.6, and 9.5 letters in the Monthly, TREX, and GILA cohorts, respectively (P= 0.8). There was no significant difference between the cohorts in the percentage gaining/losing 2 and 3 lines of vision. The CRT improved by 123 μm, 146 μm, and 166 μm in theMonthly, TREX, and GILA cohorts, respectively (P= 0.47). The mean number of macular laser treatments in theGILA cohort at 1 year was 2.9 (range, 1-4). The number of injections was significantly reduced in both the TREX (10.7) and GILA (10.1) cohorts compared with the Monthly cohort (13.1, P < 0.001). There were no cases of endophthalmitis, and the total incidence of Anti-Platelet Trialists' Collaboration events was 4.7%. This prospective, randomized trial found that treat and extend dosing of ranibizumab 0.3 mg with and without angiography-guided macular laser photocoagulation significantly decreased the number of injections given while providing similar visual and anatomic outcomes compared with monthly dosing at 1 year. Adding angiography-guided laser photocoagulation to this dosing algorithm did not significantly improve outcomes at 1 year.

Comprehensive Review of Ocular and Systemic Safety Events with Intravitreal Aflibercept Injection in Randomized Controlled Trials

To assess the ocular and systemic safety of intravitreal aflibercept injection (IAI) compared with controls in IAI trials in neovascular age-related macular degeneration (nAMD), macular edema following central retinal vein occlusion (MEfCRVO), macular edema following branch retinal vein occlusion (MEfBRVO), and diabetic macular edema (DME). Comprehensive review of 10 phase II and III trials of IAI in retinal diseases. Patients were included from IAI trials in nAMD (CLEAR-IT 2 [52 weeks], VIEW 1 [96 weeks], VIEW 2 [96 weeks], VIEW 1 extension [208 weeks]); MEfCRVO (COPERNICUS [100 weeks], GALILEO [76 weeks]); MEfBRVO (VIBRANT [52 weeks]); and DME (DA VINCI [52 weeks], VIVID [100 weeks], VISTA [100 weeks]). Rates were calculated as events/100 person-years at risk (PYR). When applicable, rate ratios (RRs) and 95% confidence intervals (CIs) were provided. Outcomes included rates for intraocular inflammation, endophthalmitis, serious adverse events (SAEs), wound-healing complications, hypertension (HTN), adjudicated Anti-Platelet Trialists' Collaboration (APTC)-defined arterial thromboembolic events (ATEs) (nonfatal myocardial infarction, nonfatal stroke, and vascular death), and death from all causes. More than 4000 patients contributed >7000 PYR. For all outcomes, there were no meaningful differences between evaluated adverse event rates for IAI and controls. Overall intraocular inflammation rates were 2.37 (control) and 2.06 (IAI); overall RR was 0.87 (95% CI, 0.61-1.27). Overall endophthalmitis rates were 0.52 (control) and 0.22 (IAI); overall RR was 0.42 (95% CI, 0.18-1.03). Overall SAE rates were 23.09 (control) and 20.80 (IAI); overall RR was 0.90 (95% CI, 0.80-1.02). Overall rates of wound-healing complications were 0.17 (control) and 0.15 (IAI); overall RR was 0.85 (95% CI, 0.24-3.86). Overall HTN rates were 14.87 (control) and 11.27 (IAI), with an overall RR of 0.76 (95% CI, 0.65-0.89); HTN rates were highest in MEfBRVO and lowest in nAMD. For adjudicated APTC-defined ATEs, rates were 2.04 (control) and 2.19 (IAI), with an RR of 1.07 (95% CI, 0.73-1.61). Overall death rates were 1.16 (control) and 1.49 (IAI); overall RR was 1.28 (95% CI, 0.80-2.15). Rates of selected ocular and systemic adverse events with IAI were similar to those of controls and similar across disease states in evaluated IAI trials. Intravitreal aflibercept injection was generally well tolerated in the patients evaluated.

Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial

To provide 2-year results comparing anti-vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen. Randomized clinical trial. Six hundred sixty participants with visual acuity (VA) impairment from DME. Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up andretreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable. Change in VA, adverse events, and retreatment frequency. Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P= 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P < 0.001; aflibercept vs. ranibizumab, P= 0.04; bevacizumab vs. ranibizumab, P= 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA (P= 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P= 0.02; aflibercept vs. ranibizumab, P= 0.18; ranibizumab vs. bevacizumab, P= 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P= 0.047; aflibercept vs. bevacizumab, P= 0.34; aflibercept vs. ranibizumab, P= 0.047; ranibizumab vs. bevacizumab, P= 0.20; global P= 0.09 adjusted for potential confounders). All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials.

Effect of Allopurinol on Cardiovascular Outcomes in Hyperuricemic Patients: A Cohort Study

BackgroundHyperuricemia and gout have been associated with increased cardiovascular risk. Allopurinol is an effective urate-lowering drug. Whether lowering of urate by allopurinol improves the cardiovascular risk in hyperuricemic patients remains to be established. ObjectiveOur objective was to investigate the effect of allopurinol on cardiovascular outcomes in hyperuricemic patients in an observational setting. MethodsWe had access to a study population consisting of all patients from Funen County, Denmark with high urate levels (≥6 mg/dL) from 1992 to 2010. We linked 4 registries; all blood samples, all in- and outpatient contacts in hospitals, all reimbursed prescriptions and causes of death. We identified all incident allopurinol users and matched them 1:1 to nonusers of urate-lowering therapy, with similar urate levels, by using propensity scores. Hazard ratios were calculated using competing risk regression model, with respect to Antiplatelet Trialists' Collaboration composite outcome (myocardial infarction, stroke, or cardiovascular death) and all-cause mortality. ResultsAmong 65,971 patients with hyperuricemia, we found 7127 patients on allopurinol treatment. In the propensity score-matched cohort we found a hazard ratio of 0.89 (95% confidence interval, 0.81-0.97) for the main outcome among allopurinol treated compared with nonusers of allopurinol. The corresponding hazard ratio for all-cause mortality was 0.68 (95% confidence interval, 0.62-0.74). ConclusionAllopurinol treatment is associated with a decreased cardiovascular risk among hyperuricemic patients.

Scheduled versus Pro Re Nata Dosing in the VIEW Trials

To analyze visual acuity (VA) outcomes before and after preplanned treatment regimen change in the VIEW studies at week 52 (W52). Multiple post hoc analyses for retrospectively defined subgroups in 2 multicenter, multinational, double-masked trials. Two thousand four hundred fifty-seven neovascular age-related macular degeneration (AMD) patients. Patients were randomized to treatment with 0.5 mg ranibizumab given monthly, a 0.5-mg or 2-mg intravitreal aflibercept injection given monthly, or 2 mg intravitreal aflibercept given every other month, after 3 initial monthly doses, up to W52. From W52 through W96, patients received their original dosing assignment using a capped pro re nata (PRN) regimen, with defined retreatment criteria based on VA and morphologic signs of disease activity and mandatory dosing at least every 12 weeks. Best-corrected VA (BCVA) and optical coherence tomography assessments were mandatory at all visits from baseline to W96. Outcomes were changes in BCVA and central retinal thickness. Outcomes were evaluated in all patients who completed 2 years of the VIEW studies using the last observation carried forward method for missing data at interim visits. After W52, approximately 20% of patients lost 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more across all treatment arms with PRN treatment. Patients who met the retreatment criterion of loss of 5 ETDRS letters or more in the first quarter of the PRN dosing phase did not recover; mean final VA loss across the 4 study arms was -4.4 to -5.8 letters. Outcomes of these patients up to W52 were indistinguishable from those of the overall population. There were no differences between groups in serious ocular adverse events or Anti-Platelet Trialists' Collaboration arterial thromboembolic events through W96. These analyses suggest that there are subgroups of patients for whom VA outcomes in the second year of the VIEW studies were less stable than in the first year and for whom W52 seems to be an important inflection point. Although alternate reasons specific to the nature of the underlying AMD cannot be fully excluded, the switch in treatment regimen at W52 is a plausible explanation.

Intravitreal Aflibercept (IVT‐AFL) for Diabetic Macular Edema (DME): 3 Year Data from VIVID‐DME and VISTA‐DME

PurposeTo evaluate long‐term outcomes with IVT‐AFL injection in the treatment of DME.Methods406 patients (VIVID‐DME) and 466 patients (VISTA‐DME) were randomized to IVT‐AFL 2 mg every 4 weeks + sham laser (2q4), IVT‐AFL 2 mg every 8 weeks (after 5 initial monthly doses) + sham laser (2q8), or laser + sham injections. From week (W)100 to W148, laser patients could receive IVT‐AFL if retreatment criteria were met. Primary efficacy endpoint was the mean change from baseline (BL) in best corrected visual acuity (BCVA) at W52. Outcomes at W100 and W148 are described.ResultsAt W100, mean BCVA gains from BL in the IVT‐AFL 2q4, 2q8 and laser groups were +11.4, +9.4 and +0.7 letters (VIVID‐DME; P &lt; 0.0001), and +11.5, +11.1 and +0.9 letters (VISTA‐DME; P &lt; 0.0001). In VISTA‐DME, improvements in BCVA were maintained to W148 in the IVT‐AFL 2q4 (+10.4 letters) and 2q8 (+10.5 letters) groups. Cataract was the most frequent ocular serious AE in both studies through 100 weeks (VIVID‐DME: 2.2%; VISTA‐DME: 1.3%); incidence of Antiplatelet Trialists’ Collaboration‐defined arterial thromboembolic events with IVT‐AFL was similar across the studies (VIVID‐DME: 4.8%; VISTA‐DME: 7.8%). Safety outcomes at W148 in VISTA‐DME were consistent with W100 data with no new safety signals observed. The third year of VIVID‐DME is ongoing.ConclusionsIn both studies, IVT‐AFL demonstrated superior outcomes compared with laser through W100, with similar efficacy in the 2q4 and 2q8 groups. In VISTA‐DME, BCVA gains from BL with both IVT‐AFL regimens were sustained through W148. Through 100 weeks the incidence of AEs was consistent with the known safety profile of IVT‐AFL.

Individual patient data meta-analysis of antiplatelet regimens after noncardioembolic stroke or TIA: rationale and design.

The Cerebrovascular Antiplatelet Trialists' Collaborative Group was formed to obtain and analyze individual patient data from the major randomized trials of common antiplatelet regimens after cerebral ischemia. Although the risk of stroke can be reduced by antiplatelet drugs, there continues to be uncertainty about the balance of risk and benefits of different antiplatelet regimens for an individual patient. Our aim is to provide clinicians with a thorough evidence-based answer on these therapeutic alternatives. We have identified six large randomized trials and plan to meta-analyze the data on an individual patient level. In total, these trials have enrolled 46 948 patients with cerebral ischemia. Uniquely, the Cerebrovascular Antiplatelet Trialists' Collaborative Group has secured access to the individual data of all of these trials, with the participation of key investigators and pharmaceutical companies. Our principal objective includes deriving a reliable estimate of the efficacy of different antiplatelet regimens on key outcomes including serious vascular events, major ischemic events, major bleeding, and intracranial hemorrhage. We propose to redefine composite outcome events, if necessary, to achieve comparability. Further, we aim to build and validate prognostic models for the risk of major bleeding and intracranial hemorrhage and to build a decision model that may support evidence-based decision making about which antiplatelet regimen would be most effective in different risk groups of patients. This paper outlines inclusion criteria, outcome measures, baseline characteristics, and planned statistical analysis.

Intravitreal Aflibercept for Macular Edema Following Branch Retinal Vein Occlusion: The 24-Week Results of the VIBRANT Study

To compare the efficacy and safety of intravitreal aflibercept injection (IAI) with macular grid laser photocoagulation for the treatment of macular edema after branch retinal vein occlusion (BRVO). The VIBRANT study was a double-masked, active-controlled, randomized, phase III trial. Treatment-naïve eyes with macular edema after BRVO were included in the study if the occlusion occurred within 12 months and best-corrected visual acuity (BCVA) was between ≤73 and ≥24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (20/40-20/320 Snellen equivalent). Eyes (1 eye per patient) received either IAI 2 mg every 4 weeks (n=91) from baseline to week 20 or grid laser (n=92) at baseline with a single grid laser rescue treatment, if needed, from weeks 12 through 20. The primary outcome measure was the proportion of eyes that gained ≥15 ETDRS letters from baseline BCVA at week 24. Secondary end points included mean change from baseline BCVA and central retinal thickness (CRT) at week 24. The proportion of eyes that gained ≥15 ETDRS letters from baseline at week 24 was 52.7% in the IAI group compared with 26.7% in the laser group (P=0.0003). The mean improvement from baseline BCVA at week 24 was 17.0 ETDRS letters in the IAI group and 6.9 ETDRS letters in the laser group (P<0.0001). The mean reduction in CRT from baseline at week 24 was 280.5 μm in the IAI group and 128.0 μm in the laser group (P<0.0001). Traumatic cataract in an IAI patient was the only ocular serious adverse event (SAE) that occurred. There were no cases of intraocular inflammation or endophthalmitis. The incidence of nonocular SAEs was 8.8% in the IAI group and 9.8% in the laser group. One Anti-Platelet Trialists' Collaboration-defined event of nonfatal stroke (1.1%) and 1 death (1.1%) due to pneumonia occurred during the 24 weeks of the study, both in patients in the laser group. Monthly IAI provided significantly greater visual benefit and reduction in CRT at 24 weeks than grid laser photocoagulation in eyes with macular edema after BRVO.

Intravitreal Aflibercept for Diabetic Macular Edema

A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME). Two similarly designed, double-masked, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement. Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation. The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained ≥ 15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography. Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P < 0.0001) in VIVID. The corresponding proportions of eyes gaining ≥ 15 letters were 41.6% and 31.1% versus 7.8% (P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 μm (P < 0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 μm (P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events and vascular deaths, were similar across treatment groups. At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated.

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia

IntroductionGout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and...

Oral antiplatelet therapy for acute ischaemic stroke.

In people with acute ischaemic stroke, platelets become activated and can cause blood clots to form and block an artery in the brain, resulting in damage to part of the brain. Such damage gives rise to the symptoms of stroke. Antiplatelet therapy might reduce the volume of brain damaged by ischaemia and also reduce the risk of early recurrent ischaemic stroke, thereby reducing the risk of early death and improving long-term outcomes in survivors. However, antiplatelet therapy might also increase the risk of fatal or disabling intracranial haemorrhage. To assess the efficacy and safety of immediate oral antiplatelet therapy (that is started as soon as possible and no later than two weeks after stroke onset) in people with acute presumed ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched 16 October 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2013), MEDLINE (June 1998 to May 2013), and EMBASE (June 1998 to May 2013). In 1998, for a previous version of this review, we searched the register of the Antiplatelet Trialists' Collaboration, MedStrategy and contacted relevant drug companies. Randomised trials comparing oral antiplatelet therapy (started within 14 days of the stroke) with control in people with definite or presumed ischaemic stroke. Two review authors independently applied the inclusion criteria and assessed trial quality. For the included trials, they extracted and cross-checked the data. We included eight trials involving 41,483 participants. No new trials have been added since the last update.Two trials testing aspirin 160 mg to 300 mg once daily, started within 48 hours of onset, contributed 98% of the data. The risk of bias was low. The maximum follow-up was six months. With treatment, there was a significant decrease in death or dependency at the end of follow-up (odds ratio (OR) 0.95, 95% confidence interval (CI) 0.91 to 0.99). For every 1000 people treated with aspirin, 13 people would avoid death or dependency (number needed to treat 79). Antiplatelet therapy was associated with a small but definite excess of symptomatic intracranial haemorrhages, but this small hazard was significantly outnumbered by the benefit, the reduction in recurrent ischaemic stroke and pulmonary embolus. Antiplatelet therapy with aspirin 160 mg to 300 mg daily, given orally (or by nasogastric tube or per rectum in people who cannot swallow) and started within 48 hours of onset of presumed ischaemic stroke, reduced the risk of early recurrent ischaemic stroke without a major risk of early haemorrhagic complications; long-term outcomes were improved.

Intravitreal Aflibercept Injection for Neovascular Age-related Macular Degeneration: Ninety-Six–Week Results of the VIEW Studies

To determine efficacy and safety of intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) during a second year of variable dosing after a first-year fixed-dosing period. Two randomized, double-masked, active-controlled, phase 3 trials. Two thousand four hundred fifty-seven patients with neovascular AMD. From baseline to week 52, patients received 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks. Proportion of eyes at week 96 that maintained best-corrected visual acuity (BCVA; lost <15 letters from baseline); change from baseline in BCVA. Proportions of eyes maintaining BCVA across treatments were 94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96. Mean BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Proportions of eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6% to 54.4%), and more 2q4 eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference of 10.4% [95% confidence interval {CI}, 4.9-15.9] and 9.0% [95% CI, 3.0-15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the 2q4 and 2q8 groups versus the Rq4 group (differences of-0.64 [95% CI,-0.89 to-0.40] and-0.55 [95% CI,-0.79 to-0.30]; P < 0.0001, post hoc analysis). Incidences of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events were similar across groups (2.4% to 3.8%) from baseline to week96. All aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA loss at 96 weeks. The 2q8 aflibercept group was similar to ranibizumab in visual acuity outcomes during 96weeks, but with an average of 5 fewer injections. Small losses at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of losses commonly observed with variable dosing.

Aspirin in the secondary prevention of unprovoked thromboembolism: the WARFASA and ASPIRE studies

The treatment of unprovoked venous thromboembolism (VTE) is anticoagulant therapy for at least 3 months [1]. As VTE recurs frequently and about 20 % of the patients with an unprovoked VTE develop recurrence within the first 2 years [2], extended vitamin K antagonist (VKA) treatment is often considered. The decision to prolong VKA therapy after the initial treatment period is a dilemma, since longer term therapy reduces the risk of recurrent thromboembolism, but increases the risk of bleeding. The last American College of Chest Physicians (ACCP) EvidenceBased Clinical guidelines suggest a strategy to balance the benefits and risks of different durations of anticoagulant therapy; in unprovoked VTE, ACCP guidelines suggest extended anticoagulant therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high. When extended anticoagulant therapy is contraindicated, aspirin might be appealing. In fact the annual risk of major bleeding is only 0.1 % in patients on long-term low-dose aspirin therapy, thus lower than VKA therapy [3]. A large meta-analysis by the Antiplatelet Trialists’ Collaboration shows that antiplatelet therapy significantly reduces the risk of fatal or non-fatal pulmonary embolism (PE) by 25 % [3]. Moreover, a large trial involving patients undergoing surgery for hip fracture shows a 36 % risk reduction in VTE in the aspirin therapy group, [4] suggesting that antiplatelet therapy may be an alternative to prolonged VKA therapy. Two randomized controlled studies were conducted to evaluate the use of ASA for the prevention of venous thromboembolism recurrence: the Aspirin for the Prevention of Recurrent Venous Thromboembolism (Warfarin and Aspirin [WARFASA]) [5] and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study [6].

Prasugrel

The unequivocal importance of platelet inhibition for prevention of secondary occlusive vascular events in patients with coronary heart disease is well established. Yet the scientific debates on the preferred agents for platelet inhibition have reached new heights. Recent antiplatelet clinical trials, such as Aspirin and Clopidogrel Compared With Clopidogrel Alone After Recent Ischaemic Stroke or Transient Ischaemic Attack in High-Risk Patients (MATCH),1 Clopidogrel and Aspirin Versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA),2 Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel (TRITON),3 and Platelet Inhibition and Patient Outcomes (PLATO),4 have raised concerns with regard to vascular antithrombotic efficacy in the investigated, more potent combination antiplatelet regimens, which at the same time increase the bleeding risks. In a different conceptual approach, researchers have attempted to link high-risk cohorts and worsened clinical outcomes to the degree of platelet inhibition by individual tailoring of antiplatelet therapy. However, trials, such as the Gauging Responsiveness With A VerifyNow Assay—Impact on Thrombosis And Safety (GRAVITAS),5 Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel (TRIGGER-PCI),6 Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention Patients (INNOVATE-PCI),7 Assessment by a Double …

Vascular Protection in People with Diabetes

Vascular Protection in People with Diabetes

Abstract TP380: Increasing the Sample Size in the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial: What Did We Gain?

Introduction: The NIH-funded SPS3 study assessed whether combination antiplatelet therapy (AC) was superior to aspirin alone (AP) in preventing recurrent stroke among patients with a lacunar stroke at baseline. Due to lower than expected overall rates of recurrent stroke, the sample size was increased from 2500 to 3000 to ensure adequate power to detect a 25% reduction in recurrent stroke. The antiplatelet trial was terminated early due to lack of efficacy, coupled with safety concerns. We conducted a retrospective analysis to assess the gains achieved by the sample size re-estimation. Methods: We assessed the difference in stroke recurrence among the first 2500 patients recruited, assuming follow-up ended when the antiplatlet arm terminated, and compared the results to those obtained with the complete 3020 patients. Results: Among the first 2500 patients, we observed 248 events, over an average of 3.9 years follow-up. The recurrent stroke rate for the AC and AP groups was 2.5% and 2.7% per year, respectively. The hazard ratio for AC vs. AP was 0.92 (95% CI: 0.72-1.18). Including the additional 520, only 15 more patients had primary events, and recurrent stroke rates (2.7%, and 2.5% year), and the HR of 0.92 (95% CI: 0.72-1.16) were similar. Conclusions: Despite an increase in sample size in SPS3, there was no appreciable difference in the results obtained for the antiplatelet trial had the study adjustment not been made. While sample size re-estimation is an important tool for ensuring adequate power for detecting treatment effects of interest, there is a potential to add unnecessary cost and complexity when no effect exists. More post-hoc examinations of studies using adaptive designs are warranted to understand their strengths and weaknesses.