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.
Objective Certain races are known to be at increased risk for stroke, and the prevalence of carotid artery stenosis (CAS) is thought to vary by race. The goal of this report was to study the ...prevalence of CAS in different races by analyzing a population of subjects who underwent vascular screening examinations. Methods The study data were provided by Life Line Screening. The cohort consists of self-referred individuals who paid for vascular screening tests. Subjects <40 and >100 years of age and those who reported a prior stroke or carotid artery intervention were excluded. Of the remaining 3,291,382 subjects, 3.7% did not self-identify a race. CAS was defined as stenosis in either internal carotid artery ≥50% by duplex ultrasound velocity criteria. Results The 3,291,382 subjects available for analysis consisted of Caucasian (2,845,936 90%), African American (97,502 3.1%), Hispanic (75,240 2.4%), Asian (60,982 1.9%), and Native American (87,757 2.8%) individuals. The prevalence of CAS was 3.4% in females and 4.2% in males ( P ≤ .001). Controlling for gender and age, there was marked variation in the prevalence of CAS ( P < .001) by race. Native American subjects had the highest prevalence of CAS across all age categories and in both sexes. Caucasian subjects had the second highest prevalence of CAS across most age decades and in both sexes. Among males, African American individuals had the lowest prevalence of CAS in nearly all age categories. In contrast to males, Asian females had the lowest prevalence of CAS compared with females of other races in most age groups. Multivariate analysis adjusting for atherosclerotic risk factors in addition to age confirmed race as a significant independent predictor of CAS. Compared with Caucasian subjects, African American (odds ratio OR, 0.65), Asian (OR, 0.69), and Hispanic (OR, 0.74) subjects had a significantly lower risk of CAS, whereas Native American (OR, 1.3) subjects had a significantly higher risk of CAS. Conclusions The prevalence of clinically significant CAS varies significantly by race. Native American and Caucasian individuals have the highest prevalence of CAS, whereas African American males and Asian females appear to have the lowest prevalence. This information adds evidence to the hypothesis that the increased stroke rate in African American subjects is likely not related to extracranial cerebrovascular disease. Furthermore, this is a novel report of an extremely high prevalence of CAS in the Native American population.
Background The benefit of carotid endarterectomy (CEA) in female patients has been questioned by various randomized, prospective trials, particularly in asymptomatic cases; several have noted an ...increase in perioperative stroke among women after CEA. The outcome of carotid angioplasty and stenting (CAS) has not been extensively examined in women. This study examined the outcome of CEA and CAS in women vs men by using a national database. Methods Outcomes of CEA and CAS were stratified by sex using discharge data from the Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality. The NIS was used to identify patient discharges that occurred during 2004 and 2005. Appropriate International Classification of Diseases, 9th Revision (ICD-9) procedure and diagnosis codes were used to identify CEA and CAS cases. Outcome measures included in-hospital perioperative stroke and death. Comparisons of demographics, procedures, and outcome were performed between men and women. Additional analysis was performed among women alone to attempt to identify whether improved outcome was noted with either procedure. Results Of 54,658 procedures, 94.2% were CEA and 5.8% were CAS. Women comprised 42.3% of the analyzed cases. Women and men were equally likely to be symptomatic (5.3% vs 5.3%, P = .8). Women were significantly less likely to undergo CAS than men (5.4% vs 6.1%, P < .001). Women and men had equivalent rates of perioperative stroke when undergoing CEA (1.0% vs 1.0%, P = .9) and CAS (2.7% vs 2.0%, P = .2). Symptomatic women had a significantly higher rate of perioperative stroke overall than did symptomatic men (3.8% vs 2.3%, P = .03). Asymptomatic women had a significantly lower perioperative stroke rate after CEA than after CAS (0.9% vs 2.1%, P < .001). Rates of perioperative showed a trend favoring CEA vs CAS among symptomatic women (3.4% vs 6.2%, P = .1). Conclusions The concern regarding an increased perioperative stroke rate after CEA among asymptomatic women appears to be unfounded. The perioperative stroke rate among symptomatic women was higher than that of symptomatic men, but still well within the acceptable range for symptomatic patients undergoing a cerebrovascular intervention. Nationally, women underwent CAS significantly less frequently than did men. Outcome among women for perioperative stroke favored CEA over CAS, particularly in asymptomatic patients. CEA may be the preferred treatment in women seeking intervention for cerebrovascular disease, unless compelling reasons exist to perform CAS.
Abstract Background Patients with atrial fibrillation receiving dialysis are at a high risk of ischemic stroke. The role of warfarin in mitigating this risk in patients with atrial fibrillation ...receiving dialysis is uncertain. Our objective was to examine the safety and efficacy of warfarin in patients who have atrial fibrillation and are receiving dialysis. Methods We used Medline, Embase, and the Cochrane Library to conduct a systematic review and meta-analysis of published and unpublished observational and interventional studies relating to the use of warfarin in patients with atrial fibrillation receiving dialysis, which provided data on the risk of stroke and/or bleeding outcomes relative to placebo or no anticoagulation therapy. A random effects model was used to calculate pooled adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for these outcomes. Results No randomized controlled trials met the criteria for inclusion. Fourteen observational studies (20,398 participants) were included in the analysis. The use of warfarin was not associated with ischemic stroke (14 studies; 20,398 participants, aHR 0.77, 95% CI 0.55 to 1.07), intracranial hemorrhage (hemorrhagic stroke) (4 studies; 15,726 participants, aHR 1.93, 95% CI 0.93-4.00), gastrointestinal bleeding (3 studies, 14,693 participants, aHR 1.19, 95% CI 0.8-1.76) or all-cause mortality (7 studies; 16,172 participants, aHR 0.89, 95% CI 0.72-1.11). Conclusion Observational studies suggest that warfarin was not associated with a clear benefit or harm among patients who have atrial fibrillation and are receiving dialysis. These estimates were limited by study heterogeneity including the inability to account for a number of important confounders such as the time in the therapeutic range. Given the high prevalence of atrial fibrillation, stroke, and bleeding complications in this population, well-designed clinical trials of warfarin and other anti-coagulants are urgently needed.
Summary Background Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In ...a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. Methods In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov , number NCT01495585. Findings Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were −0·73 log IU/mL in group 1 (95% CI 0·17–1·31; p=0·03) and −1·54 log IU/mL in group 2 (1·21–1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change ( r2 =0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days SE 0·24), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 SE 0·06 vs 0·739 0·05, p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Interpretation Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. Funding National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health , and Eiger Biopharmaceuticals Inc.
Objective To determine if temperature regulation is improved during neonatal transport using a servo-regulated cooling device when compared with standard practice. Study design We performed a ...multicenter, randomized, nonmasked clinical trial in newborns with neonatal encephalopathy cooled during transport to 9 neonatal intensive care units in California. Newborns who met institutional criteria for therapeutic hypothermia were randomly assigned to receive cooling according to usual center practices vs device servo-regulated cooling. The primary outcome was the percentage of temperatures in target range (33°-34°C) during transport. Secondary outcomes included percentage of newborns reaching target temperature any time during transport, time to target temperature, and percentage of newborns in target range 1 hour after cooling initiation. Results One hundred newborns were enrolled: 49 to control arm and 51 to device arm. Baseline demographics did not differ with the exception of cord pH. For each subject, the percentage of temperatures in the target range was calculated. Infants cooled using the device had a higher percentage of temperatures in target range compared with control infants (median 73% IQR 17-88 vs 0% IQR 0-52, P < .001). More subjects reached target temperature during transport using the servo-regulated device (80% vs 49%, P <.001), and in a shorter time period (44 ± 31 minutes vs 63 ± 37 minutes, P = .04). Device-cooled infants reached target temperature by 1 hour with greater frequency than control infants (71% vs 20%, P < .001). Conclusions Cooling using a servo-regulated device provides more predictable temperature management during neonatal transport than does usual care for outborn newborns with neonatal encephalopathy.
Background Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective ...contributions to heritability are unknown. Objective To quantify the risk associated with genes and environment on familial clustering of EoE. Methods Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree “Nuclear-Family” relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE “Twins” probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined. Results Analysis of the Nuclear-Family–based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P < .001) than in sisters, mothers, and females, respectively. The risk of EoE for other siblings was 2.4%. In the Nuclear-Family cohort, combined gene and common environment heritability was 72.0% ± 2.7% ( P < .001). In the Twins cohort, genetic heritability was 14.5% ± 4.0% ( P < .001), and common family environment contributed 81.0% ± 4% ( P < .001) to phenotypic variance. Probandwise concordance in monozygotic co-twins was 57.9% ± 9.5% compared with 36.4% ± 9.3% in dizygotic co-twins ( P = .11). Greater birth weight difference between twins ( P = .01), breast-feeding ( P = .15), and fall birth season ( P = .02) were associated with twin discordance in disease status. Conclusions EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).
To compare the effect of intravitreal aflibercept or ranibizumab drug type and frequency on visual acuity outcomes in eyes with neovascular age-related macular degeneration (NVAMD) and early ...persistent retinal fluid after 3 initial monthly injections.
A post hoc analysis of eyes enrolled in VIEW 1 and VIEW 2, 2 similarly designed, randomized, phase 3 trials.
A total of 1815 eyes with NVAMD from VIEW 1 and VIEW 2.
Analyses included patients with known fluid status at baseline and weeks 4, 8, and 12 in 3 treatment groups: ranibizumab 0.5 mg every 4 weeks (Rq4) (n = 595), intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4) (n = 613), and IAI 2 mg every 8 weeks (2q8) after 3 monthly injections (n = 607).
Mean best-corrected visual acuity (BCVA) change from baseline over weeks 16 to 52 and the proportion of eyes that gained ≥15 letters or lost ≥5 letters were evaluated in eyes with and without persistent fluid (cystic intraretinal or subretinal fluid at all 4 initial visits). Visual outcomes also were assessed in eyes with persistent fluid by fluid type (intraretinal and subretinal fluid).
The proportions of eyes with persistent fluid were 29.4%, 18.8%, and 20.3% in the Rq4, 2q4, and 2q8 groups, respectively. In these eyes, mean BCVA gain from baseline to week 52 was greater with 2q4 compared with Rq4 (P < 0.01) and 2q8 (P < 0.05), whereas it was similar with Rq4 and 2q8 (P = 0.294). At week 52, similar proportions of eyes gained ≥15 letters (31.5%–35.2%), whereas fewer eyes lost ≥5 letters with 2q4 compared with Rq4 and 2q8 (6.5% vs. 16.6% and 16.2%). The pattern of visual outcomes was similar regardless of fluid type. In eyes without persistent fluid, BCVA changes were similar across treatment groups.
In patients with early persistent fluid, 2q4 may provide additional clinical benefit over 2q8 or Rq4.
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