Abstract In the ENSURE-AF study (NCT 02072434), edoxaban was compared to enoxaparin–warfarin in 2199 patients undergoing electrical cardioversion of non-valvular atrial fibrillation (AF). In this ...multicenter PROBE trial, we analyzed patients randomized to enoxaparin–warfarin. We determined time to achieve therapeutic range (TtTR), time in therapeutic range (TiTR), their clinical determinants, relation to SAMe-TT2 R2 score, and impact on primary endpoints (composite of stroke, systemic embolic event SEE, myocardial infarction MI, and cardiovascular death CVD and composite of major + clinically relevant non-major CRNM bleeding). Among 1104 patients randomized to enoxaparin––warfarin, 27% were oral anticoagulant naïve. Mean age was 64.2±11 years and mean CHA2 DS2 -VASc score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching INR 2.0–3.0 was 71%. In 695 patients with INR <2.0 prior to first dose and who reached ≥2.0, 436 had a SAMe-TT2 R2 score ≤2 and 259 a score of >2. On multivariate regression, an independent predictor of extended TtTR was creatinine clearance (CrCl) P =0.02. TtTR was marginally related to stroke/SEE/MI/CVD ( P =0.06; OR=0.23, 95% CI 0.02–1.17) but not to any bleeding. Independent predictors of TiTR were prior VKA experience ( P <0.01) and low HAS-BLED score ( P =0.02). TiTR was related to any bleeding ( P =0.02; OR=0.39, 95% CI 0.16–0.88), but not stroke/SE/MI/CVD. In this cohort of warfarin users with a high TiTR no difference was seen between TtTR and TiTR in relation to SAMe-TT2 R2 score. In conclusion, even in this short-term study, TiTR was significantly related to bleeding events.
Background Women with acute coronary syndromes (ACS) are less likely to undergo invasive revascularization than men, but sex-specific differences in long-term outcomes and platelet reactivity among ...medically managed ACS patients remain uncertain. We examined sex-specific differences in long-term ischemic and bleeding outcomes and platelet reactivity for medically managed ACS patients randomized to prasugrel versus clopidogrel plus aspirin. Methods Data from 9,326 patients enrolled in TRILOGY ACS were analyzed to determine differences in long-term ischemic and bleeding outcomes between women (n = 3,650 39%) and men (n = 5,676 61%) randomized to prasugrel 10 mg/d (5 mg/d for patients ≥75 years and/or <60 kg) versus clopidogrel 75 mg/d. Sex-specific differences in 30-day platelet reactivity were analyzed in 2,564 (27%) patients participating in a platelet function substudy. Results Compared with men, women were older, weighed less, were less likely to have prior myocardial infarction or revascularization, and had lower baseline creatinine clearance and hemoglobin level values. Rates of the composite of cardiovascular death/myocardial infarction/stroke (20.2% vs 19.1%; P = .56), all-cause mortality (12.2% vs 11.7%; P = .88), and Global Use of Strategies to Open Occluded Arteries severe/life-threatening/moderate bleeding (3.8% vs 2.8%; P = .74) through 30 months were similar in women versus men. After adjustment, women had significantly lower risk for ischemic outcomes and all-cause mortality. There were no sex-specific, treatment-related differences in 30-day platelet reactivity. Conclusions Long-term ischemic and bleeding outcomes in medically managed ACS patients were similar for women versus men, as was treatment-related platelet reactivity. Women had a higher baseline risk profile and, after adjustment, significantly lower risk of the primary composite end point and all-cause death through 30 months.
Background To further explore the impact of smoking on antiplatelet activity and treatment response, we evaluated time-dependent relationships between smoking status with on-treatment platelet ...reactivity and clinical outcomes for prasugrel vs. clopidogrel in patients with acute coronary syndromes managed medically without revascularization. Methods and Results A total of 7062 patients aged <75 years from the primary TRILOGY ACS cohort randomized to prasugrel vs. clopidogrel were evaluated through 30 months by baseline and time-dependent smoking status with adjusted proportional-hazards models. A total of 1613 participants (23%) were included in a platelet function sub-study evaluating serial P2Y12 reaction unit (PRU) measurements. Current smokers (n = 1566 22%) at baseline had fewer comorbidities compared with non-smokers; nearly half quit smoking during follow-up. Although median on-treatment PRU values were lower with prasugrel vs. clopidogrel, persistent smokers had lower serial PRU values in both treatment groups compared with non-smokers, with no differential interaction of treatment response by smoking status. The frequency of cardiovascular death, myocardial infarction, or stroke in current smokers was significantly lower with prasugrel (11.7%) vs. clopidogrel (18.6%), but there was no difference in non-smokers (13.8% vs. 13.7%), with significant interaction between treatment and baseline smoking status ( P = .0002). Bleeding events occurred more frequently in prasugrel-treated patients with no significant interaction between treatment and baseline smoking status. Conclusions Among medically managed ACS patients <75 years of age, the risk of ischemic outcomes was significantly reduced with prasugrel vs. clopidogrel among smokers vs. non-smokers. No interaction between on-treatment platelet reactivity and smoking status was found.
Summary Background Edoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than ...well controlled enoxaparin–warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available. Methods We did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparing edoxaban 60 mg per day with enoxaparin–warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15–50 mL/min, low bodyweight ≤60 kg, or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)—stratified by cardioversion approach (transoesophageal echocardiography TEE or not), anticoagulant experience, selected edoxaban dose, and region—was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov , number NCT02072434. Findings Between March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n=1095) or enoxaparin–warfarin (n=1104). The mean age was 64 years (SD 10·54) and mean CHA2 DS2 -VASc score was 2·6 (SD 1·4). Mean time in therapeutic range on warfarin was 70·8% (SD 27·4). The primary efficacy endpoint occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin–warfarin group (odds ratio OR 0·46, 95% CI 0·12–1·43). The primary safety endpoint occurred in 16 (1%) of 1067 patients given edoxaban versus 11 (1%) of 1082 patients given enoxaparin–warfarin (OR 1·48, 95% CI 0·64–3·55). The results were independent of the TEE-guided strategy and anticoagulation status. Interpretation ENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups. Funding Daiichi Sankyo provided financial support for the study.
We designed a prospective, randomized, open-label, blinded end point evaluation parallel group Phase 3b clinical trial comparing edoxaban (a new oral factor Xa inhibitor) with enoxaparin/warfarin ...followed by warfarin alone in subjects undergoing planned electrical cardioversion of non-valvular atrial fibrillation. The primary efficacy end point is the composite end points of stroke, systemic embolic event, myocardial infarction, and cardiovascular (CV) mortality, from randomization until the end of follow-up (day 56 post cardioversion). The primary safety end point is the composite of major and clinically-relevant non-major bleeding, from the first administration of study drug to end of treatment (Day 28 post cardioversion) +3 days. The primary efficacy analysis will be conducted on the intention-to-treat population whereas the primary safety analysis, on the safety population. The study includes stratification on the following levels: (i) approach to cardioversion (transoesophagel echocardiography or non-transoesophagel echocardiography) as determined by the Investigator; (ii) subject’s experience in taking anticoagulants at the time of randomization (anticoagulant-experienced or anticoagulant-naïve); and (iii) assigned edoxaban dose (full 60 mg QD or reduced 30 mg dose QD). A subject with one or more factors (CrCl ≥15 mL/min and ≤50 mL/min, low body weight ≤60 kg, and concomitant use of p-pg inhibitors (excluding amiodarone) will receive a reduced dose (30 mg) of edoxaban if the subject is randomized to the edoxaban group. ENSURE-AF will be the largest prospective randomised trial of anticoagulation for cardioversion, also involving a N on-VKA O ral A nti c oagulant—edoxaban.
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