IMPACT OF RETINAL FLUID-FREE MONTHS ON OUTCOMES IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Treatment Agnostic Analysis of the HAWK and HARRIER Studies.

PURPOSE: To assess the effect of the total number of fluid-free months after loading on visual and anatomical outcomes in neovascular age-related macular degeneration patients receiving anti-vascular endothelial growth factor therapy. METHODS: This post hoc analysis pooled patient-level data from the brolucizumab 6 mg (n = 718) and aflibercept 2 mg (n = 715) arms of the HAWK and HARRIER randomized clinical trials. Based on data from Weeks 12 to 96, patients were assigned to one of five categories based on fluid-free visits (FFVs; the total number of monthly visits at which they were observed to be without retinal fluid). Three definitions of "fluid-free" were explored based on the location of the fluid observed. RESULTS: Patients allocated to Categories 4 (15-21 FFV) and 5 (22 FFV, always dry) consistently had the best visual and anatomical outcomes at Week 96, whereas patients allocated to Categories 1 (0 FFV, never dry) and 2 (1-7 FFV) consistently had the worst visual and anatomical outcomes. Variability in retinal thickness over time was lowest in Categories 4 and 5. CONCLUSION: Absence of retinal fluid at more visits after loading has a positive association with visual and anatomic outcomes in neovascular age-related macular degeneration patients, regardless of fluid type.

Treatment patterns and persistence rates with anti-vascular endothelial growth factor treatment for diabetic macular oedema in the UK: A real-world study.

INTRODUCTION: Anti-vascular endothelial growth factors (anti-VEGFs) are considered standard of care therapy for diabetic macular oedema (DME). This study examined treatment patterns and outcomes in patients with DME treated with anti-VEGF therapy. METHODS: Using anonymized electronic medical record data collected from three UK sites, this retrospective cohort study assessed rates of anti-VEGF intravitreal injections in adults with treatment-naïve DME who received their first treatment between 1 September 2010 and 31 July 2018. The proportion of patients with at least one interval of at least 12 weeks between injections; the distribution of injection intervals; the discontinuation rates; and the number of anti-VEGF injection-, injection-free- and total visits were assessed during the first and second years of treatment. RESULTS: Overall, 1606 patient eyes with DME were included, with no minimum follow-up. During the first and second year of treatment, 63.2% and 73.1% of eyes had at least one anti-VEGF injection interval of at least 12 weeks, respectively. In the first and second years of treatment, the mean (standard deviation) numbers of injections were 7.7 (1.9) and 5.6 (2.2), with 14.2 (5.7) and 13.4 (6.4) total clinic visits, and 6.6 (5.0) and 7.8 (5.8) injection-free visits, respectively. In total, 27.8% of patient eyes discontinued treatment during the first 2 years. CONCLUSIONS: The high number of clinic visits and high discontinuation rates demonstrate a significant unmet need for a treatment to enable sustainable extended injection intervals, while maintaining visual acuity. This could improve patient adherence and health-related quality of life for patients with DME.

Brolucizumab 12- and 16-Week Fixed Dosing Potential in Neovascular AMD: A post hoc Evaluation of Data from the HAWK and HARRIER Trials.

INTRODUCTION: This post hoc analysis applies a fixed dosing stratification approach to patient-level brolucizumab data from the phase III HAWK and HARRIER trials to determine the proportion of patients who would have been assigned to fixed dosing regimens with treatment intervals of 8, 12, or 16 weeks (q8w, q12w, or q16w) based on the presence/absence of disease activity (DA) following the loading phase. The analysis also simulates central subfield thickness (CSFT) data to estimate the anatomical outcomes if the patients had been thus assigned. Of note, the limitations of this analysis include the post hoc nature of the work and the inability to directly compare HAWK and HARRIER with TENAYA and LUCERNE due to the differences in design. DESIGN: This study was a post hoc modelling analysis of patient-level data. METHODS: Using patient-level data from HAWK and HARRIER, patients (n = 730) were allocated to a fixed q16w, q12w, or q8w regimen based on assessment of DA at weeks 16 and 20. Two definitions of DA were used: DA 1, based on a phase II study of faricimab, and DA 2, a definition derived from common clinical consideration including visual acuity and anatomical changes. CSFT simulations were performed using a pharmacokinetic/pharmacodynamic model describing CSFT response to anti-VEGF treatment. Outcome measures were modelled patient allocation to fixed regimens and mean CSFT reduction. RESULTS: Using DA definitions 1 and 2, respectively, 78% and 76% of patients in the brolucizumab arm were allocated to a greater than or equal to q12w regimen, and 56% and 52% were allocated to a q16w regimen. Mean reduction in CSFT was similar between the two study drugs with both DA definition assumptions. CONCLUSIONS: This analysis demonstrates the potential durability of action and effectiveness of brolucizumab.

Brolucizumab: A Newly Developed Anti-VEGF Molecule for the Treatment of Neovascular Age-Related Macular Degeneration.

BACKGROUND: Despite the success of anti-vascular endothelial growth factors (anti-VEGFs), currently, there is a need for highly effective compounds that can alleviate the burden of managing neovascular age-related macular degeneration (nAMD). PURPOSE: To review the milestones in the molecular and clinical development of brolucizumab, the first single-chain antibody fragment (scFv) designed specifically for intraocular use in humans. METHODS: In this article, we summarize the preclinical and current clinical evidence of brolucizumab administration with an overview of the other treatment regimens and additional indications under investigation. RESULTS: The unique molecular design of brolucizumab led to a low molecular weight of only 26 kDa, allowing for a concentrated molar dose of 1 intravitreal injection compared with other anti-VEGF agents. Phase I and II clinical trial outcomes validated the efficacy of brolucizumab in the treatment of nAMD with signals of a more durable treatment effect. The pivotal phase III trials, HAWK and HARRIER, which included a total of 1,817 patients, established that brolucizumab can be administered every 3 months while maintaining disease control. CONCLUSIONS: The preclinical and clinical data on brolucizumab provide evidence of sustained disease control with longer injection intervals, thus potentially reducing the treatment burden in patients with nAMD.

Early Changes in eDiary COPD Symptoms Predict Clinically Relevant Treatment Response at 12 Weeks: Analysis from the CRYSTAL Study.

Early detection of treatment response is important in the long-term treatment and management of patients with chronic obstructive pulmonary disease (COPD). This analysis evaluated whether early improvement in symptoms, recorded in the first 7 or 14 days via an electronic diary (eDiary) compared with baseline, can predict clinically meaningful treatment responders at 12 weeks. CRYSTAL was a 12-week, randomized, open-label study that demonstrated the increased effectiveness of indacaterol/glycopyrronium (IND/GLY) or glycopyrronium (GLY), after a direct switch from on-going baseline therapies, in patients with symptomatic COPD and moderate airflow obstruction. The co-primary endpoints were trough forced expiratory volume in 1 second (FEV1) and transition dyspnea index (TDI) at Week 12. Patients' symptom status was recorded daily in an eDiary. Of 4,389 patients randomized, 3,936 and 3,855 reported symptoms on Days 7 and 14, respectively. Patients who reported an early decrease in symptoms on Day 7 or 14 were more likely to achieve the minimal clinically important difference of ≥100 mL in trough FEV1 or ≥ 1 point in TDI at Week 12. Using stepwise multivariate regression models we identified as best predictors of FEV1 responders the decrease in wheeze on Day 7, and nighttime symptoms and wheeze on Day 14; best predictors of TDI responders were decrease in nighttime symptoms and wheeze on Day 7, and nighttime symptoms, sputum and wheeze on Day 14. Early symptom improvement at Day 7 or 14, especially wheeze and nighttime symptoms, may identify patients with clinically important improvement in lung function and dyspnea at Week 12.

Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy).

BACKGROUND: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. METHODS: This is a post hoc analysis of the RE-LY trial. RESULTS: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16-1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88-1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56-0.95 with VHD; HR, 0.84; 95% CI, 0.71-0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64-1.06) or without VHD (HR, 0.98; 95% CI, 0.83-1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37-0.93) and those without VHD (HR, 0.67; 95% CI, 0.52-0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65-1.45; and HR, 0.88; 95% CI, 0.70-1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. CONCLUSIONS: The presence of any VHD did not influence the comparison of dabigatran with warfarin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial.

BACKGROUND: Dual bronchodilation combining a long-acting ß2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) is the preferred choice of treatment recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines for the management of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). The once-daily (q.d.) fixed-dose combination (FDC) of LABA, indacaterol 110 µg and LAMA, glycopyrronium 50 µg (IND/GLY 110/50 µg q.d.) demonstrated superior improvements in lung function, dyspnoea and overall health status and better tolerability against LABA or LAMA monotherapies and combination of LABA and inhaled corticosteroid (ICS) in more than 11,000 patients with moderate-to-severe COPD in several randomised controlled clinical trials. METHODS: The CRYSTAL study was the first, 12-week, randomised, open-label trial that evaluated the efficacy and safety of a direct switch from previous treatments to IND/GLY 110/50 µg q.d. on lung function and dyspnoea in patients with moderate COPD and a history of up to one exacerbation in the previous year. Patients were divided into 2 groups according to their background therapy and symptom scores and were randomised (3:1) to IND/GLY or to continue with their previous treatments. RESULTS: The study included 4389 randomised patients, of whom 2160 were in groups switched to IND/GLY (intention-to-treat population). The effect of IND/GLY was superior to LABA + ICS on trough forced expiratory volume in 1 s (FEV1; treatment difference, Δ = +71 mL) and transition dyspnoea index (TDI; [Δ = 1.09 units]), and to LABA or LAMA on trough FEV1 (Δ = +101 mL) and a TDI (Δ = 1.26 units). Improvements in health status and lower rescue medication use were also observed with IND/GLY. The safety profile of the study medication was similar to that observed in previous studies. CONCLUSIONS: IND/GLY demonstrated superior improvements in lung function and dyspnoea after direct switch from previous treatments. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01985334 .

Indacaterol and glycopyrronium versus indacaterol on body plethysmography measurements in COPD-a randomised controlled study.

BACKGROUND: Dual bronchodilator therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD). There are limited data on effects of a combination of two long-acting bronchodilators on lung function including body plethysmography. METHODS: This multicentre, randomised, double-blind, single-dose, cross-over, placebo-controlled study evaluated efficacy and safety of the free combination of indacaterol maleate (IND) and glycopyrronium bromide (GLY) versus IND alone on spirometric and body plethysmography parameters, including inspiratory capacity (IC), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and airway resistance (Raw) in moderate-to-severe COPD patients. RESULTS: Seventy-eight patients with FEV1 % pred. (mean ± SD) 56 ± 13% were randomised. The combination of IND + GLY versus IND presented a numerically higher peak-IC (Δ = 0.076 L, 95% confidence interval [CI]: -0.010 - 0.161 L; p = 0.083), with a statistically significant difference in mean IC over 4 h (Δ = 0.054 L, 95%CI 0.022 - 0.086 L; p = 0.001). FEV1, FVC and Raw, but not TLC, were consistently significantly improved by IND + GLY compared to IND alone. Safety profiles of both treatments were comparable. CONCLUSION: The free combination of IND + GLY improved lung function parameters as evaluated by spirometry and body plethysmography, with a similar safety profile compared to IND alone. TRIAL REGISTRATION: NCT01699685.

Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment.

Attempts at identifying patients with an elevated risk of bleeding while on anticoagulation following acute venous thromboembolism (VTE) have largely been unsuccessful thus far. We sought to develop a clinical prediction score for bleeding during stable anticoagulation treatment after acute VTE.We performed a post hoc analysis of the pooled RE-COVER studies, two double-blind randomised "sister" trials evaluating dabigatran versus standard treatment in 5107 VTE patients.A score was derived from patients randomised to dabigatran using logistic regression analysis covering the complete follow-up period. The final model, named VTE-BLEED, included six variables and yielded a c-statistic of 0.72 (95% CI 0.67-0.76). Patients from the derivation cohort in the low-risk group (<2 points; 74% of the derivation population) had a bleeding incidence of 2.8% compared to 12.6% in the elevated-risk group (OR 5.0; 95% CI 3.5-7.1). The score proved accurate for our primary end-point, i.e. prediction of major bleeding after day 30 ("stable" anticoagulation), both in patients on dabigatran (c-statistic 0.75, 95% CI 0.61-0.89) and those on warfarin (0.78, 95% CI 0.68-0.86; p=0.77 for difference).The new VTE-BLEED score accurately predicted major bleeding events in VTE patients on stable anticoagulation with both dabigatran and warfarin.

Long-term evaluation of dabigatran 150 vs. 110 mg twice a day in patients with non-valvular atrial fibrillation.

AIMS: The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively. METHODS AND RESULTS: The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELY-ABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan-Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68-0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66-0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51-1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08-1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93-2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87-1.08) (P = 0.54). CONCLUSION: Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant.

Dabigatran etexilate for thromboprophylaxis in over 5000 hip or knee replacement patients in a real-world clinical setting.

BACKGROUND: Thromboprophylaxis is recommended for patients undergoing total hip or total knee replacement (THR, TKR). An international, open-label, prospective, observational, single-arm study in a routine clinical setting was performed to assess the safety and efficacy of dabigatran etexilate 220 mg once daily in patients undergoing THR or TKR, and in subgroups of patients with potentially increased risk of bleeding or venous thromboembolism (VTE). MATERIALS AND METHODS: Patients were ≥18 years and required to be eligible to receive dabigatran 220 mg once daily (first dose 110 mg 1-4 h after THR/TKR surgery) according to the European Summary of Product Characteristics. The primary safety and efficacy outcomes were incidence of major bleeding events (MBEs), and the composite incidence of symptomatic VTE events and all-cause mortality, respectively. RESULTS: In total, 5292 patients (median age 64 years) were enrolled and received dabigatran (2734 THR and 2558 TKR). Median drug exposure was 31 days (THR 34 days; TKR 27 days). Overall incidence of MBEs was 0.72 % (95 % confidence interval [CI] 0.51, 0.98), and this rate was comparable between types of surgery and was not significantly affected by protocol-defined risk factors. The overall incidence of symptomatic VTE and all-cause mortality was 1.04 % (95 % CI 0.78, 1.35); the only significant risk factor was history of VTE events (odds ratio 5.59; 95 % CI 2.53, 11.08). A post-hoc analysis showed that the incidence of MBEs in this observational study was similar to or lower than those reported in previous phase 3 trials. CONCLUSIONS: Results from this observational study of dabigatran etexilate administered to patients undergoing THR or TKR surgery are reassuring and supportive of those obtained in dabigatran phase 3 trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00846807.

Critical appraisal of network meta-analyses evaluating the efficacy and safety of new oral anticoagulants in atrial fibrillation stroke prevention trials.

OBJECTIVES: To critically appraise published network meta-analyses (NMAs) evaluating the efficacy or safety of the new oral anticogulants (NOACs) dabigatran, rivaroxaban, and apixaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF). METHODS: A systematic literature review was performed to identify the relevant NMAs using MEDLINE, EMBASE, Cochrane Library, Database of Abstracts of Reviews of Effects, and Health Technology Assessment. The synthesis studies were evaluated using the "Questionnaire to assess the relevance and credibility of the NMA." RESULTS: Eleven NMAs evaluating NOACs among adults with nonvalvular AF were identified. Most NMAs included three large phase III randomized controlled trials, comparing NOACs to adjusted-dose warfarin (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY], Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF], and Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]). The main differences identified related to potential treatment effect modifiers regarding the mean time spent in therapeutic range (TTR) in the warfarin arm, the risk of stroke or systemic embolism across the trials (mean CHADS2 score: C = congestive heart failure, H = hypertension, A = older than age 75 years, D = diabetes mellitus, S2 = prior stroke or history of transient ischemic attack) or primary versus secondary prevention, and type of populations used in the analysis. Kansal et al. [Kansal AR, Sharma M, Bradley-Kennedy C, et al. Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada: comparative efficacy and cost-effectiveness. Thromb Haemost 2012;108:672-82] appropriately adjusted the ROCKET-AF TTR to match the RE-LY population on the basis of individual patient data. Meta-regressions are not expected to minimize confounding bias given limited data, whereas subgroup analyses had some impact on the point estimates for the treatment comparisons. CONCLUSIONS: Results of the synthesis studies were generally comparable and suggested that the NOACs had similar efficacy, although some differences were identified depending on the outcome. The extent to which differences in the distribution of TTR, CHADS2 score, or primary versus secondary prevention biased the results remains unclear.

Safety and efficacy of switching from low molecular weight heparin to dabigatran in patients undergoing elective total hip or knee replacement surgery.

BACKGROUND: The aim of this study was to assess the safety and efficacy of switching therapy from low molecular weight heparin (LMWH; enoxaparin) to dabigatran for prevention of venous thromboembolic events (VTE) in patients undergoing elective total hip or knee replacement surgery (THR/TKR). METHODS: This was a prospective, multicenter, open-label, single-arm, observational, study in patients undergoing THR or TKR who were to receive enoxaparin 40 mg for thromboprophylaxis. Enoxaparin was initiated before or after surgery according to local practice, and was switched to dabigatran 220 mg once daily at a time point chosen by the investigator. The coprimary endpoints were major bleeding events, and the composite of symptomatic VTE and all-cause mortality, from last use of enoxaparin to 24 h after last intake of dabigatran. RESULTS: Altogether, 168 (81 THR, 87 TKR) patients were enrolled, of whom 161 received both enoxaparin and dabigatran, 2 received dabigatran only and 5 received enoxaparin only. The median time of the first dabigatran tablet was 24.0 h after the last LMWH dosage and the median number of days on dabigatran treatment was 36 days. No symptomatic VTE or death occurred during the study. One major bleeding event was seen at the surgical site and required treatment cessation. Three minor bleeding events were observed. CONCLUSIONS: In the normal clinical setting, switching from LMWH to dabigatran in patients who had undergone THR and TKR was safe and effective in preventing VTE. The reported adverse events and serious adverse events were consistent with the known safety profile for dabigatran. Switching from a subcutaneous to an oral anticoagulant may offer greater convenience in the outpatient setting after discharge. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01153698.

Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.

BACKGROUND: Two phase 3 trials compared 28-35 days of treatment with oral dabigatran 220 mg or 150 mg (RE-NOVATE) or 220 mg (RE-NOVATE II) once daily with subcutaneous enoxaparin 40 mg once daily for prevention of venous thromboembolism (VTE) after elective total hip arthroplasty. METHODS: This prespecified pooled analysis compared the outcomes for the dabigatran 220 mg dose with enoxaparin, which included 4,374 patients. Total VTE (venographic and symptomatic) plus all-cause mortality (primary efficacy), major VTE (proximal deep vein thrombosis [DVT] or non-fatal pulmonary embolism) plus VTE-related death, and bleeding events were evaluated. Efficacy analysis was based on the modified intention-to-treat (ITT) population and safety analysis was based on all treated patients. The common risk difference (RD) for dabigatran versus enoxaparin was estimated using a fixed effects model. RESULTS: Total VTE and all-cause mortality occurred in 6.8 % (114/1,672) and 7.7 % (129/1,682) (RD:-0.8 %, 95 % confidence interval [CI] -2.6 to 0.9) for dabigatran and enoxaparin, respectively. Major VTE plus VTE-related mortality occurred in 2.7 % (46/1,714) and 4.0 % (69/1,711) (RD: -1.4 %, 95 % CI -2.6 to -0.2) of patients receiving dabigatran 220 mg and enoxaparin, respectively. Major bleeding occurred in 1.7 % (37/2,156) and 1.3 % (27/2,157) (RD: 0.5 %, 95 % CI -0.2 to 1.2), for dabigatran and enoxaparin respectively. CONCLUSIONS: Extended prophylaxis with oral dabigatran 220 mg once daily was as effective as enoxaparin 40 mg once daily in reducing the risk of total VTE and all-cause mortality after total hip arthroplasty, with a similar bleeding profile. The clinically relevant outcome of major VTE and VTE-related death was significantly reduced with dabigatran versus enoxaparin. TRIAL REGISTRATION: NCT00657150 and NCT00168818.

Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation: a global registry program on long-term oral antithrombotic treatment in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1% to 2% of the population and raising the risk of stroke 5-fold. Until recently, the only treatment choices for stroke prevention in patients with AF have been vitamin K antagonists (VKA) or antiplatelet drugs. With approval of novel oral anticoagulants (NOACs) antithrombotic treatment, patterns are changing. The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation is designed to investigate patient characteristics influencing choice of antithrombotic treatment of stroke prevention in patients with nonvalvular AF and to collect data on outcomes of antithrombotic therapy in clinical practice. METHODS: The GLORIA-AF is a large, international, observational registry involving patients with newly diagnosed nonvalvular AF at risk for stroke, enrolling up to 56,000 patients in nearly 50 countries. We will collect and analyze data from routine care using an inception cohort design. Phase I includes patients before approval of NOACs. Phase II, beginning early after approval of dabigatran, monitors dabigatran safety and addresses potential channeling across treatment options based on propensity scoring to assess comparability of baseline characteristics of patients treated with dabigatran or VKA. Phase III entails analysis of large treatment groups, adjusting for differences in propensity score, to provide information about the relative effectiveness and safety of NOACs and VKA in routine clinical care. CONCLUSIONS: Novel features of this registry program will add data from clinical practice to those from randomized trials to expand knowledge of antithrombotic treatment in patients with AF.

Reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat-tail bleeding model and lack of effect on assays of coagulation.

BACKGROUND: Dabigatran is a potent oral anticoagulant. Like any anticoagulant, there is an increased risk of bleeding associated with its use, and reversal may be needed in cases of severe bleeding. METHODS: In this study, six coagulation factor concentrates (CFCs) were tested for their ability to reduce bleeding induced by oral dabigatran etexilate (30 mg/kg) in a rat-tail bleeding model (n = 5 to 8 per group): three-factor (Profilnine [Grifols Biologicals Inc., Los Angeles, CA] and Bebulin [Baxter BioScience, Westlake Village, CA]) and four-factor prothrombin complex concentrates (Beriplex [CSL Behring, Marburg, Germany] and Octaplex [Octapharma AG, Lachen, Switzerland]), activated prothrombin complex concentrate (Factor Eight Inhibitor Bypassing Activity; Baxter AG, Vienna, Austria), and recombinant factor VIIa (NovoSeven; NovoNordisk, Bagsværd, Denmark). The effect of CFCs on prolongation of coagulation assays was measured. Thrombin generation after administration of each CFC was compared in vitro using human plasma (n = 5) spiked with dabigatran in concentrations corresponding to median peak (200 ng/ml) and supratherapeutic values (600 and 1,000 ng/ml). RESULTS: Dabigatran resulted in an approximately three-fold increase in bleeding time, consistent with supratherapeutic dabigatran plasma levels. Beriplex (35 and 50 IU/kg), Octaplex (40 IU/kg), Profilnine (50 IU/kg), Bebulin (60 IU/kg), Factor Eight Inhibitor Bypassing Activity (100 U/kg), and NovoSeven (500 µg/kg) significantly decreased this prolonged bleeding time over 30 min (P < 0.001). The coagulation assays were prolonged three- to eight-fold over baseline (P = 0.01). None of the CFCs produced a consistent change in these assays that was predictive of reduced bleeding. Thrombin generation reversal was dependent on the concentration of dabigatran and each CFC; normalization occurred at the lower concentration of dabigatran with most CFCs, but not at higher concentrations. CONCLUSIONS: In this animal model, bleeding induced by high doses of dabigatran can be reduced by CFCs. However, routine coagulation assays do not predict this effect.

Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference.

The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.

Efficacy and safety of brolucizumab in age-related macular degeneration: A systematic review of real-world studies.

Intravitreally injected anti-vascular endothelial growth factor (anti-VEGF) agents are first-line treatment for neovascular age-related macular degeneration (nAMD). Phase 3 trials demonstrated non-inferiority of anti-VEGF therapy with brolucizumab compared with aflibercept in best corrected visual acuity (BCVA) gains, with superior anatomical outcomes after brolucizumab. The purpose of the review was to summarize real-world efficacy and safety data on brolucizumab in patients with nAMD. The review protocol was registered with PROSPERO (ID: CRD42021290530). We conducted systematic searches in Embase, Medline and key ophthalmology congress websites (19 October 2021). Original reports of efficacy and/or safety in patients receiving brolucizumab to treat nAMD in clinical practice were eligible. The descriptive summary includes reports describing at least 10 brolucizumab-treated eyes. In total, 2907 brolucizumab-treated eyes from 26 studies were included. Outcomes were available for treatment-naive eyes (six studies), eyes switched to brolucizumab from other anti-VEGFs (16 studies), and/or treatment-naive and switch eyes combined (eight studies). Follow-up time points ranged from 4 weeks to 1 year post-brolucizumab initiation. For BCVA, significant improvements compared with brolucizumab initiation were reported in four of six studies in treatment-naive eyes (mean BCVA improvement, range: +3.7 to +11.9 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and in three of 12 studies in switch eyes (range: +9.0 to +15 ETDRS letters) (all p < 0.05); remaining studies reported no significant post-brolucizumab BCVA changes. For central subfield thickness (CST), improvements post-brolucizumab initiation were reported in all six studies in treatment-naive eyes (mean CST improvement, range: -113.4 to -150.1 µm) and in eight of 11 studies in switch eyes (range: -26 to -185.7 µm) (all p < 0.05). The 14 studies reporting on intraretinal, subretinal and/or total fluid observed improvements post-brolucizumab initiation. The four studies comparing treatment intervals observed extension of the interval between injections after switching to brolucizumab from other anti-VEGFs. Incidence of intraocular inflammation ranged from 0% to 19%. In conclusion, real-world efficacy and safety data concur with brolucizumab pivotal trials. Additionally, reduction of disease activity in anti-VEGF switch eyes was demonstrated by fluid reduction and/or visual acuity gain, along with prolongation of the interval between injections.

Does real-time artificial intelligence-based visual pathology enhancement of three-dimensional optical coherence tomography scans optimise treatment decision in patients with nAMD? Rationale and design of the RAZORBILL study.

BACKGROUND/RATIONALE: Artificial intelligence (AI)-based clinical decision support tools, being developed across multiple fields in medicine, need to be evaluated for their impact on the treatment and outcomes of patients as well as optimisation of the clinical workflow. The RAZORBILL study will investigate the impact of advanced AI segmentation algorithms on the disease activity assessment in patients with neovascular age-related macular degeneration (nAMD) by enriching three-dimensional (3D) retinal optical coherence tomography (OCT) scans with automated fluid and layer quantification measurements. METHODS: RAZORBILL is an observational, multicentre, multinational, open-label study, comprising two phases: (a) clinical data collection (phase I): an observational study design, which enforces neither strict visit schedule nor mandated treatment regimen was chosen as an appropriate design to collect data in a real-world clinical setting to enable evaluation in phase II and (b) OCT enrichment analysis (phase II): de-identified 3D OCT scans will be evaluated for disease activity. Within this evaluation, investigators will review the scans once enriched with segmentation results (i.e., highlighted and quantified pathological fluid volumes) and once in its original (i.e., non-enriched) state. This review will be performed using an integrated crossover design, where investigators are used as their own controls allowing the analysis to account for differences in expertise and individual disease activity definitions. CONCLUSIONS: In order to apply novel AI tools to routine clinical care, their benefit as well as operational feasibility need to be carefully investigated. RAZORBILL will inform on the value of AI-based clinical decision support tools. It will clarify if these can be implemented in clinical treatment of patients with nAMD and whether it allows for optimisation of individualised treatment in routine clinical care.

Anti-brolucizumab immune response as one prerequisite for rare retinal vasculitis/retinal vascular occlusion adverse events.

In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.