BACKGROUNDThe selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODSWe randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTSDuring a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONSAmong patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo.

Purpose To compare the rates of retinal nerve fiber layer (RNFL) loss in patients suspect of having glaucoma who developed visual field damage (VFD) to those who did not develop VFD, and to determine whether the rate of RNFL loss can be used to predict who will develop VFD.. Design Prospective observational cohort study Participants Glaucoma suspects, defined as having glaucomatous optic neuropathy or ocular hypertension (Intraocular pressure (IOP)>21 mmHg) without repeatable VFD at baseline from the Diagnostic Innovations in Glaucoma Study, and the African Descent and Glaucoma Evaluation Study. Methods Global and quadrant RNFL thickness (RNFLT) were measured with the Spectralis spectral-domain optical coherence tomography (SD-OCT). VFD was defined as having 3 consecutive abnormal visual fields. The rate of RNFL loss in eyes developing VFD was compared with eyes not developing VFD using multivariable linear mixed-effects models. A joint longitudinal survival model utilized the estimated RNFLT slope to predict the risk of developing VFD, while adjusting for potential confounding variables. Main Outcome Measures The rate of RNFL thinning and the probability of developing VFD. Results Four hundred and fifty-four eyes of 294 glaucoma suspects were included. The average number of SD-OCT examinations was 4.6 (range, 2–9) with median follow-up time of 2.2 (0.4–4.1) years. Forty eyes (8.8%) developed VFD. The estimated mean rate of global RNFL loss was significantly faster in eyes developing VFD compared with eyes that did not (−2.02μm/year vs. −0.82μm/year, P<0.001). The joint longitudinal survival model showed that each 1μm/year faster rate of global RNFL loss corresponded to a 2.05 times higher risk of developing VFD (Hazards Ratio (HR)=2.05, 95% Confidence Interval (CI): 1.14–3.71; p=0.017). Conclusions The rate of global RNFL loss was more than twice as fast in eyes developing VFD compared with eyes that did not develop them. Joint longitudinal survival model showed that a 1μm/year faster rate of RNFLT loss corresponded to a 2.05 times higher risk of developing VFD. These results suggest that measuring the rate of SD-OCT RNFL loss may be a useful tool to help identify patients who are at a high risk of developing visual field loss.

Purpose To evaluate 6-month and 1-year outcomes of every 8 weeks (Q8W) aflibercept in patients with resistant neovascular age-related macular degeneration (AMD). Design Retrospective, interventional, consecutive case series. Methods Retrospective review of patients with resistance (multiple recurrences or persistent exudation) to every 4 weeks (Q4W) ranibizumab or bevacizumab that were switched to Q8W aflibercept. Results Sixty-three eyes of 58 patients had a median of 13 (interquartile range (IQR), 7-22) previous anti Vascular Endothelial Growth Factor (anti-VEGF) injections. At 6-months after changing to aflibercept, 60.3% of eyes were completely dry, which was maintained up to one-year. The median maximum retinal thickness improved from 355 microns to 269 microns at 6 months (p<0.0001) and 248 microns at one year (p<0.0001). There was no significant improvement in ETDRS visual acuity at 6 months (p=0.2559) and one-year follow-up (p=0.1081) compared with baseline. The mean difference in ETDRS visual acuity compared to baseline at 6 months was −0.05 logMAR (+2.5 letters) and 0.04 logMAR at 1 year (−2 letters). Conclusion Sixty percent of eyes with resistant AMD while on Q4W ranibizumab or bevacizumab were completely dry after changing to Q8W aflibercept at the 6-month and 1-year follow-ups, but visual acuity did not significantly improve. Only a third of eyes needed to be switched from Q8W to Q4W aflibercept due to persistence of fluid; Q8W dosing of aflibercept without the initial 3 monthly loading doses may be a good alternative in a select group of patients who may have developed ranibizumab or bevacizumab resistance.

Aims The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and results Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N‐terminal pro‐B‐type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC‐HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594). Conclusions GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation.

Purpose To evaluate racial differences in the development of visual field (VF) damage in glaucoma suspects. Design Prospective, observational cohort study. Methods Six hundred thirty six eyes from 357 glaucoma suspects with normal VF at baseline were included from the multicenter African Descent and Glaucoma Evaluation Study (ADAGES). Racial differences in the development of VF damage were examined using multivariable Cox Proportional Hazard models. Results Thirty one (25.4%) of 122 African descent participants and 47 (20.0%) of 235 European descent participants developed VF damage (p=0.078). In multivariable analysis, worse baseline VF mean deviation, higher mean arterial pressure during follow up, and a race *mean intraocular pressure (IOP) interaction term were significantly associated with the development of VF damage suggesting that racial differences in the risk of VF damage varied by IOP. At higher mean IOP levels, race was predictive of the development of VF damage even after adjusting for potentially confounding factors. At mean IOPs during follow-up of 22, 24 and 26 mmHg, multivariable hazard ratios (95%CI) for the development of VF damage in African descent compared to European descent subjects were 2.03 (1.15–3.57), 2.71 (1.39–5.29), and 3.61 (1.61–8.08), respectively. However, at lower mean IOP levels (below 22 mmHg) during follow-up, African descent was not predictive of the development of VF damage. Conclusion In this cohort of glaucoma suspects with similar access to treatment, multivariate analysis revealed that at higher mean IOP during follow-up, individuals of African descent were more likely to develop VF damage than individuals of European descent.

Purpose To evaluate and compare the diagnostic accuracy of the global and sector analyses for detection of early visual field damage using the retinal nerve fiber layer (RNFL) reference databases of the Spectralis and Cirrus spectral-domain optical coherence tomography (SD-OCT) devices. Methods Healthy subjects and glaucoma suspects from the Diagnostic Innovations in Glaucoma Study (DIGS) and African Descent and Glaucoma Evaluation Study (ADAGES) with at least 2 years of follow-up were included. Global and sectoral RNFL measures were classified as within normal limits, borderline and outside normal limits based on the device reference databases. The sensitivity of outside normal limits classification was estimated in glaucoma suspect eyes that developed repeatable visual field (VF) damage. Results 353 glaucoma suspect eyes and 279 healthy eyes were included. 34 (9.6%) of glaucoma suspect eyes developed VF damage. In glaucoma suspect eyes, Spectralis and Cirrus outside normal limits classification was present in 47 eyes (13.3%) and 24 eyes (6.8%), respectively. The sensitivity of the global RNFL outside normal limits classification among eyes that developed VF damage was 23.5% for Cirrus and 32.4% for Spectralis. The specificity of within normal limits global classification in healthy eyes was 100% for Cirrus and 99.6% for Spectralis. There was moderate to substantial agreement between Cirrus and Spectralis classification as outside normal limits. Conclusions The Spectralis and Cirrus reference databases have a high specificity for identifying healthy eyes, and good agreement for detection of eyes with early glaucoma damage.

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Background and objective Retrospective claims data in patients with chronic obstructive pulmonary disease (COPD) initiating maintenance therapy with inhaled fixed-dose combinations of long-acting muscarinic antagonist/long-acting β 2 -agonist (LAMA/LABA) versus inhaled corticosteroid (ICS)/LABA have not been reported. Methods Retrospective observational study in a COPD-diagnosed population of commercial and Medicare Advantage with Part D (MAPD) enrollees aged ≥40 years from a US health insurer database. Patients initiated umeclidinium/vilanterol (UMEC/VI [62.5/25 µg]) or fluticasone propionate/salmeterol (FP/SAL [250/50 µg]) between April 1, 2014 and August 31, 2016 (index date) and had 12 months continuous enrollment pre- and post-index. Exclusion criteria included an asthma diagnosis in the pre-index period/index date; ICS-, LABA-, or LAMA-containing therapy during the pre-index period; or pharmacy fills for both UMEC/VI and FP/SAL, multiple-inhaler triple therapy, a non-index therapy, or COPD exacerbation on the index date. Adherence (proportion of days covered [PDC] ≥80%) was modeled using weighted logistic regression following inverse probability of treatment weighting (IPTW). Weighted Kaplan–Meier and Cox proportional hazards regression following IPTW were performed for incidence of COPD exacerbation and escalation to multiple-inhaler triple therapy. Results The study population included 5306 patients (1386 initiating UMEC/VI and 3920 initiating FP/SAL). Adjusted odds of adherence were 2.00 times greater among UMEC/VI than FP/SAL initiators (95% confidence interval [CI]: 1.62─2.46; P <0.001). The adjusted hazard ratio (HR) for first exacerbation was 0.87 (95% CI: 0.74–1.01; P =0.067) among UMEC/VI versus FP/SAL initiators. UMEC/VI initiators had 35% lower adjusted risk of escalation to multiple-inhaler triple therapy (HR 0.65; 95% CI: 0.47–0.89; P =0.008) versus FP/SAL. On-treatment, UMEC/VI initiators had an adjusted 30% reduced risk of a first moderate/severe COPD exacerbation (HR 0.70; 95% CI: 0.54–0.90; P =0.006). Conclusion Patients with COPD initiating UMEC/VI had higher adherence and longer time before escalation to multiple-inhaler triple therapy than FP/SAL initiators.