Long-Term Triple Therapy De-escalation to Indacaterol/Glycopyrronium in Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized, Double-Blind, Triple-Dummy Clinical Trial.

RATIONALE: There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations. OBJECTIVES: To evaluate the efficacy and safety of direct de-escalation from long-term triple therapy to indacaterol/glycopyrronium in nonfrequently exacerbating patients with chronic obstructive pulmonary disease (COPD). METHODS: This 26-week, randomized, double-blind, triple-dummy study assessed the direct change from long-term triple therapy to indacaterol/glycopyrronium (110/50 µg once daily) or continuation of triple therapy (tiotropium [18 µg] once daily plus combination of salmeterol/fluticasone propionate [50/500 µg] twice daily) in nonfrequently exacerbating patients with moderate-to-severe COPD. Primary endpoint was noninferiority on change from baseline in trough FEV1. Moderate or severe exacerbations were predefined secondary endpoints. MEASUREMENTS AND MAIN RESULTS: A total of 527 patients were randomized to indacaterol/glycopyrronium and 526 to triple therapy. Inhaled corticosteroids withdrawal led to a reduction in trough FEV1 of -26 ml (95% confidence interval, -53 to 1 ml) with confidence limits exceeding the noninferiority margin of -50 ml. The annualized rate of moderate or severe COPD exacerbations did not differ between treatments (rate ratio, 1.08; 95% confidence interval, 0.83 to 1.40). Patients with ≥300 blood eosinophils/µl at baseline presented greater lung function loss and higher exacerbation risk. Adverse events were similar in the two groups. CONCLUSIONS: In patients with COPD without frequent exacerbations on long-term triple therapy, the direct de-escalation to indacaterol/glycopyrronium led to a small decrease in lung function, with no difference in exacerbations. The higher exacerbation risk in patients with ≥300 blood eosinophils/µl suggests that these patients are likely to benefit from triple therapy. Clinical trial registered with www.clinicaltrials.gov (NCT 02603393).

Comparison of peak inspiratory flow rate via the Breezhaler®, Ellipta® and HandiHaler® dry powder inhalers in patients with moderate to very severe COPD: a randomized cross-over trial.

BACKGROUND: The chronic and progressive nature of chronic obstructive pulmonary disease (COPD) requires self-administration of inhaled medication. Dry powder inhalers (DPIs) are increasingly being used for inhalation therapy in COPD. Important considerations when selecting DPIs include inhalation effort required and flow rates achieved by patients. Here, we present the comparison of the peak inspiratory flow rate (PIF) values achieved by COPD patients, with moderate to very severe airflow limitation, through the Breezhaler®, the Ellipta® and the HandiHaler® inhalers. The effects of disease severity, age and gender on PIF rate were also evaluated. METHODS: This randomized, open-label, multicenter, cross-over, Phase IV study recruited patients with moderate to very severe airflow limitation (Global Initiative for Obstructive Lung Disease 2014 strategy), aged ≥40 years and having a smoking history of ≥10 pack years. No active drug or placebo was administered during the study. The inhalation profiles were recorded using inhalers fitted with a pressure tap and transducer at the wall of the mouthpiece. For each patient, the inhalation with the highest PIF value, out of three replicate inhalations per device, was selected for analysis. A paired t-test was performed to compare mean PIFs between each combination of devices. RESULTS: In total, 97 COPD patients were enrolled and completed the study. The highest mean PIF value (L/min ± SE) was observed with the Breezhaler® (108 ± 23), followed by the Ellipta® (78 ± 15) and the HandiHaler® (49 ± 9) inhalers and the lowest mean pressure drop values were recorded with the Breezhaler® inhaler, followed by the Ellipta® inhaler and the HandiHaler® inhaler, in the overall patient population. A similar trend was consistently observed in patients across all subgroups of COPD severity, within all age groups and for both genders. CONCLUSIONS: Patients with COPD were able to inhale with the least inspiratory effort and generate the highest mean PIF value through the Breezhaler® inhaler when compared with the Ellipta® and the HandiHaler® inhalers. These results were similar irrespective of patients' COPD severity, age or gender. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov NCT02596009 on 4 November 2015.

Visual benefit versus visual gain: what is the effect of baseline covariants in the treatment arm relative to the control arm? A pooled analysis of ANCHOR and MARINA.

BACKGROUND: This study aimed to elucidate visual benefits of ranibizumab in patients with neovascular age-related macular degeneration (nAMD) compared with control arms and identify factors affecting response. METHODS: This is a post-hoc pooled analysis of two phase III studies, ANCHOR and MARINA, of ranibizumab for the treatment of nAMD. ANCHOR included 83 international sites. MARINA included 96 sites in the USA. Analysis included patients (control, n=323; ranibizumab, n=332) with nAMD and a baseline best-corrected visual acuity (BCVA) of ≥35-<85 letters. RESULTS: Patients receiving ranibizumab achieved an adjusted mean BCVA superiority of 18.9 and 21.2 letters over 12 and 24 months, respectively, compared with control. Ranibizumab treatment, higher baseline BCVA, lower age and smaller lesion size were positively associated with the ability to achieve BCVA >69 letters. Patients with the highest baseline BCVA had lowest BCVA gains. Ranibizumab treatment, lower baseline BCVA, lower age and smaller lesion size were identified as significant predictors of BCVA gain from baseline at month 24 (all p<0.0001). However, the difference in mean BCVA gains at month 24 between treatment and control groups was similar for all baseline BCVA subgroups (≥35-<55 letters, 21.9 letters; ≥55-<70 letters, 25.2 letters; ≥70-<85 letters, 19.3 letters). CONCLUSIONS: Higher baseline BCVA is associated with lower BCVA gains but a greater likelihood of achieving good final BCVA >69 letters due to smaller gains needed to achieve response. Visual benefits, including maintenance of visual acuity (VA), final VA achieved and relative gain compared with natural disease progression, should be considered when assessing treatment response in nAMD.

Global Differences in Characteristics, Precipitants, and Initial Management of Patients Presenting With Acute Heart Failure.

Importance: Acute heart failure (AHF) precipitates millions of hospital admissions worldwide, but previous registries have been country or region specific. Objective: To conduct a prospective contemporaneous comparison of AHF presentations, etiologic factors and precipitants, treatments, and in-hospital outcomes among global regions through the International Registry to Assess Medical Practice with Longitudinal Observation for Treatment of Heart Failure (REPORT-HF). Design, Setting, and Participants: A total of 18 553 adults were enrolled during a hospitalization for AHF. Patients were recruited from the acute setting in Western Europe (WE), Eastern Europe (EE), Eastern Mediterranean and Africa (EMA), Southeast Asia (SEA), Western Pacific (WP), North America (NA), and Central and South America (CSA). Patients with AHF were approached for consent and excluded only if there was recent participation in a clinical trial. Patients were enrolled from July 23, 2014, to March 24, 2017. Statistical analysis was conducted from April 18 to June 29, 2018; revised analyses occurred between August 6 and 29, 2019. Main Outcomes and Measures: Heart failure etiologic factors and precipitants, treatments, and in-hospital outcomes among global regions. Results: A total of 18 553 patients were enrolled at 358 sites in 44 countries. The median age was 67.0 years (interquartile range [IQR], 57-77), 11 372 were men (61.3%), 9656 were white (52.0%), 5738 were Asian (30.9%), and 867 were black (4.7%). A history of HF was present in more than 50% of the patients and 40% were known to have a prior left-ventricular ejection fraction lower than 40%. Ischemia was a common AHF precipitant in SEA (596 of 2329 [25.6%]), WP (572 of 3354 [17.1%]), and EMA (364 of 2241 [16.2%]), whereas nonadherence to diet and medications was most common in NA (306 of 1592 [19.2%]). Median time to the first intravenous therapy was 3.0 (IQR, 1.4-5.6) hours in NA; no other region had a median time above 1.2 hours (P < .001). This treatment delay remained after adjusting for severity of illness (P < .001). Intravenous loop diuretics were the most common medication administered in the first 6 hours of AHF management across all regions (65.4%-89.9%). Despite similar initial blood pressure across all regions, inotropic agents were used approximately 3 times more often in SEA, WP, and EE (11.3%-13.5%) compared with NA and WE (3.1%-4.3%) (P < .001). Older age (odds ratio [OR], 1.0; 95% CI, 1.00-1.02), HF etiology (ischemia: OR, 1.65; 95% CI, 1.11-2.44; valvular: OR, 2.10; 95% CI, 1.36-3.25), creatinine level greater than 2.75 mg/dL (OR, 1.85; 95% CI, 0.71-2.40), and chest radiograph signs of congestion (OR, 2.03; 95% CI, 1.39-2.97) were all associated with increased in-hospital mortality. Similarly, younger age (OR, -0.04; 95% CI, -0.05 to -0.02), HF etiology (ischemia: OR, 0.77; 95% CI, 0.26-1.29; valvular: OR, 2.01; 95% CI, 1.38-2.65), creatinine level greater than 2.75 mg/dL (OR, 1.16; 95% CI, 0.31-2.00), and chest radiograph signs of congestion (OR, 1.02; 95% CI, 0.57-1.47) were all associated with increased in-hospital LOS. Conclusions and Relevance: Data from REPORT-HF suggest that patients are similar across regions in many respects, but important differences in timing and type of treatment exist, identifying region-specific gaps in medical management that may be associated with patient outcomes.

Patient perception of Breezhaler® and Ellipta® device feedback mechanisms in COPD: The ADVANTAGE Study.

OBJECTIVES: The primary objective of the ADVANTAGE study was to compare device-naïve chronic obstructive pulmonary disease (COPD) patients' perception of the Breezhaler® and Ellipta® devices' feedback mechanisms of dose delivery confirmation. The secondary objective was to assess comfort with the inhalers' mouthpiece in terms of ease to form a tight seal around the mouthpiece. These objectives were achieved by using a novel, patient perception of inhaler questionnaire developed and tested during cognitive interviews of patients by Evidera, London, United Kingdom. METHODS: Ten COPD patients were interviewed to collect feedback on the interpretation, relevance and language of the questionnaire. This questionnaire was then used in ADVANTAGE to compare patients' perception (n = 100) of both devices. Patients completed the questionnaire after a single inhalation of placebo through each inhaler. RESULTS: Using the final questionnaire, patients reported being more confident of the feedback mechanism of Breezhaler than that of the Ellipta device (mean score 4.3 versus 3.6 respectively, estimated difference [95% CI]: 0.75 [0.51, 0.99], p < .0001). Patients also reported better comfort (ease to form a tight seal with the lips) with the Breezhaler mouthpiece than the Ellipta mouthpiece (mean score 4.3 versus 3.9 respectively, estimated difference [95% CI]: 0.41 [0.21, 0.61], p < .0001). There were no safety concerns associated with either device. CONCLUSION: COPD patients showed greater preference for the Breezhaler over the Ellipta inhaler for confidence of dose delivery and comfort of the mouthpiece. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (ClinicalTrials.gov number NCT02551224).

Efficacy and safety of ranibizumab monotherapy versus ranibizumab in combination with verteporfin photodynamic therapy in patients with polypoidal choroidal vasculopathy: 12-month outcomes in the Japanese cohort of EVEREST II study.

PURPOSE: To compare the efficacy and safety of ranibizumab 0.5 mg with or without verteporfin photodynamic therapy in Japanese patients with polypoidal choroidal vasculopathy over 12 months. STUDY DESIGN: EVEREST II was a 24-month, Phase IV, multicenter, randomized, double-masked study in Asian patients with symptomatic macular polypoidal choroidal vasculopathy. METHODS: Of the 322 enrolled patients, 84 patients, including 46 patients who received ranibizumab + verteporfin photodynamic therapy (combination therapy arm) and 38 patients who received ranibizumab/sham PDT (monotherapy arm), were Japanese who were evaluated in this subanalysis. Mean change in best-corrected visual acuity (BCVA) and complete polyp regression at Month 12, ranibizumab treatment exposure, and safety over 12 months were assessed. RESULTS: Baseline demographics were well balanced between the arms. At Month 12, mean change in BCVA letter score was +8.5 with combination therapy versus +6.4 with monotherapy. Complete polyp regression was higher with combination therapy than with monotherapy at Month 12 (70.5% vs 27.3%). Over 12 months, patients in the combination arm received a median of 4.0 ranibizumab injections vs 7.0 in the monotherapy arm. Serious adverse events were generally low in both arms, and retinal hemorrhage, an adverse event, was reported in one patient (2.2%). CONCLUSION: The results from the Japanese cohort were in agreement with the EVEREST II study. Combination therapy was effective in improving BCVA and achieving a higher rate of complete polyp regression with a lower number of ranibizumab injections than monotherapy. No new safety signals were reported, and safety events were comparable between both arms over 12 months.

Predictive imaging biomarkers relevant for functional and anatomical outcomes during ranibizumab therapy of diabetic macular oedema.

BACKGROUND/AIMS: The objective is to identify imaging biomarkers in optical coherence tomography predicting functional/anatomical outcomes in diabetic macular oedema (DMO). METHODS: The presented study is a post hoc analysis of the RESTORE/RESTORE-extension studies. Best-corrected visual acuity (BCVA) was analysed using general estimating equation models using treatment group/morphological features as predictor variables. In addition, linear multiple regression models analysed BCVA gain up to 12 and 36 months with BCVA/morphological baseline characteristics as independent predictor variables. The correlations between central retinal thickness (CRT)/BCVA were calculated as Spearman's/Pearson's correlation coefficients. RESULTS: A weak negative linear correlation between CRT/BCVA was observed in all study arms at baseline (r=-0.34, p<0.001) and at month 36 (r=-0.26, p<0.001). Patients with baseline height of intraretinal cystoid fluid (IRC) ≤380 µm had better baseline BCVA compared with patients with IRC height >380 µm (64.84±10.63 vs 61.66±9.92 letters; p=0.0071, respectively), which was maintained until the end of month 12 (70.5±12.33 vs 67.0±14.09 letters; p=0.0252, respectively). With laser, there was a trend for patients with subretinal fluid (SRF) at baseline to lose BCVA letters at month 12 (-5.38±16.54 vs 2.49±9.72 letters; p=0.1038), whereas ranibizumab patients trended towards higher BCVA gains (10.28±7.14 vs 6.76±7.67; p=0.0563), compared with those without SRF. With combined therapy, all patients had similar BCVA gains regardless of SRF (p=0.3768). CONCLUSION: With ranibizumab treatment, the height of IRC spaces at baseline was a better predictor of functional/anatomical improvement than CRT alone. There was also a trend for SRF to show a positive impact on ranibizumab therapy response and a negative impact on laser therapy response.

Association of Changes in Macular Perfusion With Ranibizumab Treatment for Diabetic Macular Edema: A Subanalysis of the RESTORE (Extension) Study.

Importance: Anti-vascular endothelial growth factor treatment is the first-line therapy in the treatment of center-involving diabetic macular edema. Data on capillary perfusion changes under repeated treatment in a possibly compromised vascular network are limited. Objective: To evaluate the association of repeated ranibizumab injections on macular perfusion in patients with diabetic macular edema. Design, Setting, and Participants: This study analyzed prospectively collected data from the 12-month RESTORE core study and the 24-month open label RESTORE extension study, which assessed the efficacy and safety of ranibizumab in patients with visual impairment due to diabetic macular edema. Of 345 patients with center-involving diabetic macular edema who had enrolled in the 12-month RESTORE core study, 240 entered the 24-month RESTORE extension study. Of these, 83 (34.6%) received ranibizumab, 83 (34.6%) received ranibizumab and laser combination therapy, and 74 (30.8%) received laser monotherapy in the first year of the study; 208 completed the 24-month extension study. Fluorescence angiography images were taken from each participant twice each year graded by Vienna Reading Center on severity of capillary loss in the parafoveal area, regularity of the foveal avascular zone outline, and measurement of the size of the foveal avascular zone, following a standardized protocol. Data analysis took place from July 2014 through December 2017. Main Outcomes and Measures: Change in 3 fluorescence angiography perfusion parameters over the course of treatment. Results: Mean (SD) patient age was 62.6 (8.8) years; 124 of 208 (59.2%) were male and 197 of 208 (94.6%) were white. The number of patients with definite altered foveal avascular zone regularity at baseline was 103 of 240 patients (42.9%); another 118 patients (49.2%) had questionably altered regularity at baseline. Definitive capillary loss was found in 65 of 240 patients (27.1%) at baseline. Mean (SD) foveal avascular zone size at baseline was 0.261 (0.232) mm2 in ranibizumab monotherapy, 0.231 (0.219) mm2 in ranibizumab and macular laser combination therapy, and 0.201 (0.13) mm2 in laser monotherapy. No treatment arm experienced significant increase in foveal avascular zone size at any time in the study period. At month 36, ranibizumab monotherapy resulted in a mean increase of 0.073 mm2 (95% CI, 0.005-0.142 mm2) and combination therapy resulted in a mean increase of 0.117 mm2 (95% CI, 0.045-0.188 mm2), but no changes were statistically significant. No changes occurred in foveal avascular zone regularity in any treatment group, and no differences were found in capillary loss around the fovea in the 3 treatment groups; neither element could be correlated with visual acuity or central retinal thickness. Conclusions and Relevance: Repeated ranibizumab treatment was not associated with impaired macular perfusion in our study cohort. Because our data do not suggest a harmful effect of anti-vascular endothelial growth factor therapy on capillary integrity, patients with severe microangiopathy and advanced capillary dropout should not be denied these treatments.