Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: An analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.

BACKGROUND: Edoxaban is a specific anti-Xa inhibitor that, in comparison to warfarin, has been found to be noninferior for the prevention of stroke or systemic embolism (SSE) and to reduce bleeding significantly in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration (FDA) approved the higher-dose edoxaban regimen (60/30 mg) in patients with AF and a creatinine clearance of ≤95 mL/min. We report for the first time the clinical characteristics, efficacy, and safety of the FDA-approved population in the ENGAGE AF--TIMI 48 trial. METHODS: The patients included had been treated with either warfarin or edoxaban 60/30 mg and had a creatinine clearance of ≤95 mL/min. The primary efficacy was SSE, and the principal safety end point was major bleeding (International Society on Thrombosis and Haemostasis classification). Median follow-up was 2.8 years. RESULTS: Patients in the FDA-approved cohort were older, were more likely female, and had higher CHADS2 and HAS-BLED scores, as compared with patients not included in the FDA label. The primary end point occurred in 1.63%/y with edoxaban vs 2.02%/y with warfarin (hazard ratio [HR] 0.81, 95% CI 0.67-0.97, P = .023). Edoxaban significantly reduced the rate of hemorrhagic stroke (HR 0.47, 95% CI 0.31-0.72, P < .001) and cardiovascular death (HR 0.84, 95% CI 0.73-0.97, P = .015). Ischemic stroke rates were similar between the treatment groups (1.31%/y vs 1.39%/y, P = .97). Major bleeding was significantly lower with edoxaban (3.16%/y vs 3.77%/y; HR 0.84, 95% CI 0.72-0.98, P = .023). CONCLUSION: In the FDA-approved cohort of the ENGAGE AF--TIMI 48 trial, treatment with edoxaban 60/30 mg was superior to warfarin in the prevention of SSE and significantly reduced cardiovascular death and bleeding, especially fatal bleeding and hemorrhagic stroke.

Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data.

BACKGROUND: Cangrelor is a potent, rapid-acting, reversible intravenous platelet inhibitor that was tested for percutaneous coronary intervention (PCI) in three large, double-blind, randomised trials. We did a pooled analysis of data from three trials that assessed the effectiveness of cangrelor against either clopidogrel or placebo in PCI. METHODS: This prespecified, pooled analysis of patient-level data from three trials (CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX) compared cangrelor with control (clopidogrel or placebo) for prevention of thrombotic complications during and after PCI. Trial participants were patients undergoing PCI for ST-elevation myocardial infarction (11.6%), non-ST-elevation acute coronary syndromes (57.4%), and stable coronary artery disease (31.0%). Efficacy was assessed in the modified intention-to-treat population of 24,910 patients, with a prespecified primary efficacy composite of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis at 48 h. The primary safety outcome was non-coronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe or life-threatening bleeding at 48 h. FINDINGS: Cangrelor reduced the odds of the primary outcome by 19% (3.8% for cangrelor vs 4.7% for control; odds ratio [OR] 0.81, 95% CI 0.71-0.91, p=0.0007), and stent thrombosis by 41% (0.5% vs 0.8%, OR 0.59, 95% CI 0.43-0.80, p=0.0008). Cangrelor reduced the odds of the secondary triple composite (all-cause death, myocardial infarction, or ischaemia-driven revascularisation at 48 h) by 19% (3.6% vs 4.4%, OR 0.81, 95% CI 0.71-0.92, p=0.0014). Efficacy outcomes were consistent across the trials and main patient subsets. These benefits were maintained at 30 days. There was no difference in the primary safety outcome (0.2% in both groups), in GUSTO moderate bleeding (0.6% vs 0.4%), or in transfusion (0.7% vs 0.6%), but cangrelor increased GUSTO mild bleeding (16.8% vs 13.0%, p<0.0001). INTERPRETATION: Compared with control (clopidogrel or placebo), cangrelor reduced PCI periprocedural thrombotic complications, at the expense of increased bleeding. FUNDING: The Medicines Company.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

AIMS: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). METHODS AND RESULTS: A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. CONCLUSIONS: Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.