Objectives This study sought to characterize major bleeding on the basis of the components of the major bleeding definition, to explore major bleeding by location, to define 30-day mortality after a ...major bleeding event, and to identify factors associated with major bleeding. Background Apixaban was shown to reduce the risk of major hemorrhage among patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Methods All patients who received at least 1 dose of a study drug were included. Major bleeding was defined according to the criteria of the International Society on Thrombosis and Haemostasis. Factors associated with major hemorrhage were identified using a multivariable Cox model. Results The on-treatment safety population included 18,140 patients. The rate of major hemorrhage among patients in the apixaban group was 2.13% per year compared with 3.09% per year in the warfarin group (hazard ratio HR 0.69, 95% confidence interval CI: 0.60 to 0.80; p < 0.001). Compared with warfarin, major extracranial hemorrhage associated with apixaban led to reduced hospitalization, medical or surgical intervention, transfusion, or change in antithrombotic therapy. Major hemorrhage followed by mortality within 30 days occurred half as often in apixaban-treated patients than in those receiving warfarin (HR 0.50, 95% CI: 0.33 to 0.74; p < 0.001). Older age, prior hemorrhage, prior stroke or transient ischemic attack, diabetes, lower creatinine clearance, decreased hematocrit, aspirin therapy, and nonsteroidal anti-inflammatory drugs were independently associated with an increased risk. Conclusions Apixaban, compared with warfarin, was associated with fewer intracranial hemorrhages, less adverse consequences following extracranial hemorrhage, and a 50% reduction in fatal consequences at 30 days in cases of major hemorrhage.
Background Patients with atrial fibrillation (AF) are prone to cardiovascular events and anticoagulation-related bleeding complications. We hypothesized that patients with anemia are at increased ...risk for these outcomes. Methods We performed a post hoc analysis of the ARISTOTLE trial, which included >18,000 patients with AF randomized to warfarin (target international normalized ratio, 2.0-3.0) or apixaban 5 mg twice daily. Multivariable Cox regression analysis was used to determine if anemia (defined as hemoglobin <13.0 in men and <12.0 g/dL in women) was associated with future stroke, major bleeding, or mortality. Results Anemia was present at baseline in 12.6% of the ARISTOTLE population. Patients with anemia were older, had higher mean CHADS2 and HAS-BLED scores, and were more likely to have experienced previous bleeding events. Anemia was associated with major bleeding (adjusted hazard ratio HR, 1.92; 95% CI, 1.62-2.28; P < .0001) and all-cause mortality (adjusted HR, 1.68; 95% CI, 1.46-1.93; P < .0001) but not stroke or systemic embolism (adjusted HR, 0.92; 95% CI, 0.70-1.21). The benefits of apixaban compared with warfarin on the rates of stroke, mortality, and bleeding events were consistent in patients with and without anemia. Conclusions Chronic anemia is associated with a higher incidence of bleeding complications and mortality, but not of stroke, in anticoagulated patients with AF. Apixaban is an attractive anticoagulant for stroke prevention in patients with AF with or without anemia.
Abstract Background The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart ...disease (VHD) is of substantial interest. Objectives This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF–TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin. Methods Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards. Results After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio HR: 1.40; 95% confidence interval CI:1.26 to 1.56; p <0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p <0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction pint = 0.26; and for less major bleeding, HR: 0.74; 95% CI: 0.53 to 1.02 in patients with VHD, and HR: 0.82; 95% CI: 0.71 to 0.94, in patients with no VHD; pint = 0.57). Conclusions The presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation ENGAGE AF-TIMI 48; NCT00781391 )
Abstract Background Non-vitamin K oral anticoagulants (NOACs) are proven alternatives to vitamin K antagonists (VKAs) for the prevention of thromboembolism in patients with nonvalvular atrial ...fibrillation. However, there are few data on the efficacy and safety of NOAC therapy after cardioversion, where the risk of thromboembolic events is heightened. Methods We performed a random-effects meta-analysis of patients who underwent both electrical and pharmacologic cardioversion for atrial fibrillation in the RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF–TIMI 48, and X-VeRT trials. We assessed Mantel-Haenszel pooled estimates of risk ratio (RR) and 95% confidence intervals (CIs) for stroke/systemic embolism and major bleeding at ≤42 days of follow-up. Results The analysis pooled 3949 patients in whom a total of 4900 cardioversions for atrial fibrillation were performed. Compared with VKAs, NOAC therapy was associated with a similar risk of stroke/systemic embolism (RR 0.84; 95% CI, 0.34-2.04) and major bleeding (RR 1.12; 95% CI, 0.52-2.42); no significant statistical heterogeneity was found among studies (Cochrane Q P = .59, I2 = 0% for stroke/systemic embolism; P = .47; I2 = 0% for major bleeding). Conclusions The short-term incidences of thromboembolic and major hemorrhagic events after cardioversion on NOACs were low and comparable to those observed on dose-adjusted VKA therapy. Non-vitamin K oral anticoagulants are a reasonable alternative to VKAs in patients undergoing cardioversion.
Abstract Background Valvular heart disease (VHD) and atrial fibrillation (AF) often coexist. Phase III trials comparing non–vitamin K antagonist oral anticoagulants (NOACs) with warfarin excluded ...patients with moderate/severe mitral stenosis or mechanical heart valves, but variably included patients with other VHD and valve surgeries. Objectives This study aimed to determine relative safety and efficacy of NOACs in patients with VHD. Methods We performed a meta-analysis of the 4 phase III AF trials of the currently available NOACs versus warfarin in patients with coexisting VHD to assess pooled estimates of relative risk (RR) and 95% confidence intervals (CIs) for stroke/systemic embolic events (SSEE), major bleeding, intracranial hemorrhage (ICH), and all-cause death. Results Compared with warfarin, the rate of SSEE in patients treated with higher-dose NOACs was lower and consistent among 13,585 patients with (RR: 0.70; 95% CI: 0.58 to 0.86) or 58,098 without VHD (RR: 0.84; 95% CI: 0.75 to 0.95; interaction p = 0.13). Major bleeding in patients on higher-dose NOACs versus warfarin was similar and consistent among patients with (RR: 0.93; 95% CI: 0.68 to 1.27) or without VHD (RR: 0.85; 95% CI: 0.70 to 1.02; interaction p = 0.63 for VHD/no-VHD difference). Intracranial hemorrhage was lower with higher-dose NOACs than with warfarin irrespective of VHD (RR: 0.47; 95% CI: 0.24 to 0.93, and 0.49; 95% CI: 0.41 to 059, respectively; interaction p = 0.91). No protective effect of higher-dose NOACs in preventing all-cause death seemed to be present in patients with VHD versus without VHD (RR:1.01; 95% CI: 0.90 to 1.14 vs. RR: 0.88; 95% CI: 0.82 to 0.94, respectively; interaction p = 0.03). Conclusions High-dose NOACs provide overall efficacy and safety similar in AF patients with or without VHD.
Endothelial progenitor cells (EPCs) may concur to endogenous vascular repair. Previous studies have reported that statin treatment increases EPC levels. We investigated whether this occurs in ...patients on long-term statin treatment who underwent percutaneous coronary interventions (PCIs). In a phase A study, 53 patients (atorvastatin reload AR 80 mg 12 hours before + 40 mg 2 hours before PCI, n = 27; placebo P, n = 26) were evaluated for EPC mobilization as CD45dim/CD34+/CD133+/KDR+ cell number by flow cytometry. Assays were run at randomization (12 hours before PCI, R), immediately before PCI (T0) at 8 (T8) and 24 hours (T24). In phase B study, 50 patients (AR, n = 25; P, n = 25) were evaluated for early colony formation by Hill colony forming unit (CFU) assay, with sampling at randomization and 24 hours later. In phase A, EPCs levels were similar at randomization between 2 arms (0.23% 0.14 to 0.54 of total events in AR vs 0.22% 0.04 to 0.37 in P group; p = 0.33). At PCI, EPC levels were higher in AR arm (0.42% 0.06 to 0.30 vs 0.19% 0.06 to 030; p = 0.009). Higher EPC levels in AR group were also found at 8 and 24 hours. In phase B, EPC CFUs/well numbers at randomization were similar in the 2 arms (8 6 to 12 in AR vs 12 6 to 20 in P group, p = 0.109). EPC CFU/well at 24 hours became significantly higher in AR arm (17 10 to 23 vs 5 2 to 13, p = 0.002). In conclusion, high-dose AR before PCI in patients on long-term statin therapy promptly increases EPCs mobilization, which are capable of early colony formation and may contribute to cardioprotection.
Angina and myocardial ischemia without obstructive coronary artery disease are common clinical findings, often neglected for the assumption of a good prognosis. Most often, such patients are neither ...further investigated nor offered specific treatment beyond reassurance. However, the absence of significant coronary stenoses on angiography does not necessarily imply a “healthy” coronary tree. In such cases, myocardial ischemia may result from different types of functional disease involving the epicardial coronary arteries, the coronary microcirculation, or both; an accurate assessment of these components should be systematically performed after exclusion of organic epicardial disease because a correct diagnosis has relevant prognostic and therapeutic implications. Here we discuss the basic principles of diagnostic tests in this setting and propose a diagnostic sequence of reasonable practical implementation that may help identify patients at risk of future cardiac events.
Abstract Background Bleeding limits anticoagulant treatment in patients with acute coronary syndromes (ACS). Objectives We investigated whether background concomitant antiplatelet therapy influences ...the effects of apixaban after ACS. Methods This study examined high-risk ACS patients who were treated with aspirin or aspirin plus clopidogrel and who were randomized to apixaban 5 mg twice daily or placebo. In a post-hoc analysis, we assessed whether the effect of apixaban on efficacy and safety outcomes varied by the concomitant antiplatelet regimen by using simple Cox modeling and marginal structural models with propensity scores and antiplatelet therapy as a time-dependent covariate. Results At baseline, of 7,364 patients, 16.3% (n = 1,202) were on aspirin alone, and 79.0% (n = 5,814) were on aspirin plus clopidogrel. A total of 19.2% (n = 1,415) switched antiplatelet therapy during follow-up. No differential effect of apixaban versus placebo was observed for the composite endpoint of cardiovascular death, myocardial infarction, and ischemic stroke in patients taking aspirin (12.21 per 100 patient-years vs. 13.21 per 100 patient-years; adjusted hazard ratio HR: 0.91; 95% confidence interval CI: 0.62 to 1.32) or aspirin plus clopidogrel (13.22 vs. 14.24; adjusted HR: 0.95; 95% CI: 0.78 to 1.14; pinteraction = 0.84). Compared with placebo, apixaban increased Thrombolysis In Myocardial Infarction major bleeding in patients taking aspirin (1.48 vs. 0.25; adjusted HR: 6.62; 95% CI: 0.75 to 51.73) and in patients taking aspirin plus clopidogrel (2.58 vs. 1.02; adjusted HR: 2.44; 95% CI: 1.34 to 4.45; pinteraction = 0.41). Similar results were obtained with marginal structural models and in patients treated with and without percutaneous coronary intervention. Conclusions Post-ACS treatment with apixaban versus placebo showed no efficacy, but it increased bleeding regardless of concomitant therapy with aspirin alone or aspirin plus clopidogrel. (Apixaban for Prevention of Acute Ischemic Events 2 APPRAISE-2; NCT00831441 )
Abstract Objectives We tested the noninferiority of a fast-track rule-out protocol for the diagnosis of non-ST-segment elevation myocardial infarction vs noncoronary chest pain based on the ...single-sampling combined assessment of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin compared with the serial assessment of medium-sensitivity cardiac troponin I. Methods Ultra-sensitive copeptin and medium-sensitivity cardiac troponin I levels were measured at presentation in 196 consecutive patients admitted to the emergency department for acute nontraumatic chest pain within 6 hours from symptoms onset and without ST-segment elevation on a 12-lead electrocardiogram. The diagnostic performance for non-ST-segment elevation myocardial infarction diagnosis of the dual-marker single-sampling strategy with medium-sensitivity cardiac troponin I and ultra-sensitive copeptin on admission was compared with that of the serial 0- and 3-hour medium-sensitivity cardiac troponin I sampling in reference to the adjudicated postdischarge diagnosis, using both the comparison of area under the curve (AUC) receiver operating characteristic and the McNemar chi-square test. Results The diagnosis of non-ST-segment elevation myocardial infarction was adjudicated in 29 patients (14.8%). The combination of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin generated an AUC of 0.87 (95% confidence interval, 0.82-0.91), which was noninferior with respect to the 3-hour interval medium-sensitivity cardiac troponin I serial sampling ( P = .194 for AUC difference). The combination of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin also yielded a numerically higher diagnostic sensitivity (100% vs 89.7%; P = not significant). Conclusions A single-sampling strategy of combined ultra-sensitive copeptin and medium-sensitivity cardiac troponin I is noninferior to a 0- and 3-hour serial medium-sensitivity cardiac troponin I sampling in ruling out non-ST-segment elevation myocardial infarction and thus may allow an earlier discharge of patients who are ruled out for non-ST-segment elevation myocardial infarction ( ClinicalTrials.gov Identifier NCT01962506).
Abstract Background Non-vitamin K oral anticoagulants are now proven alternatives to vitamin K antagonists for stroke prevention in atrial fibrillation. However, there are few data on the efficacy ...and safety of their use for cardioversion, in which the risk of thromboembolic events is heightened. Methods We performed a random-effects meta-analysis of patients undergoing both electrical and pharmacologic cardioversion for atrial fibrillation in the RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF-TIMI 48, X-VeRT, and ENSURE-AF trials. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% confidence intervals (CIs) for stroke/systemic embolism and major bleeding at ≤42 days of follow-up. Results The analysis pooled 6148 patients in whom 6854 cardioversions for atrial fibrillation were performed. Compared with vitamin K antagonists, non-vitamin K antagonist oral anticoagulant therapy was associated with a similar risk of stroke/systemic embolism (RR, 0.82; 95% CI, 0.38-1.75) and major bleeding (RR, 0.98; 95% CI, 0.51-1.87). We found no significant statistical heterogeneity among studies (Cochrane Q P = .75, I2 = 0% for stroke/systemic embolism; P = .54; I2 = 0% for major bleeding). Conclusions The short-term incidence of thromboembolism and major bleeding after cardioversion on non-vitamin K antagonist oral anticoagulants was comparable to the incidence observed on dose-adjusted vitamin K antagonist therapy. Non-vitamin K antagonist oral anticoagulants are a reasonable alternative to vitamin K antagonists in patients undergoing cardioversion.
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