Major Bleeding in Adults Undergoing Peripheral Extracorporeal Membrane Oxygenation (ECMO): Prognosis and Predictors

Background. Major bleeding has been a common and serious complication with poor outcomes in ECMO patients. With a novel, less-invasive cannulation approach and closer coagulation monitoring regime, the incidence of major bleeding is currently not determined yet. Our study aims to examine the incidence of major bleeding, its determinants, and association with mortality in peripheral-ECMO patients. Method. We conducted a single-center retrospective study on adult patients undergoing peripheral-ECMO between January 2019 and January 2020 at a tertiary referral hospital. Determinants of major bleeding were defined by logistic regression analysis. Risk factors of in-hospital mortality were determined by Cox proportional hazard regression analysis. Results. Major bleeding was reported in 33/105 patients (31.4%) and was associated with higher in-hospital mortality [adjusted hazard ratio (aHR) 3.56, 95% confidence interval (CI) 1.63–7.80, p < 0.001 ). There were no significant difference in age, sex, ECMO indications, ECMO modality, pre-ECMO APACHE-II and SOFA scores between two groups with and without major bleeding. Only APTT >72 seconds [adjusted odds ratio (aOR) 7.10, 95% CI 2.60–19.50, p < 0.001 ], fibrinogen <2 g/L [aOR = 7.10, 95% CI 2.60–19.50, p < 0.001 ], and ACT >220 seconds [aOR = 3.9, 95% CI 1.20–11.80, p = 0.017 ] on days with major bleeding were independent predictors. Conclusions. In summary, major bleeding still had a fairly high incidence and poor outcome in peripheral-ECMO patients. APTT > 72 seconds, fibrinogen < 2 g/L were the strongest predicting factors for major bleeding events.

Left Atrial Appendage Closure Yields Favorable Cardio- and Cerebrovascular Outcomes in Patients With Non-valvular Atrial Fibrillation and Prior Stroke

Introduction: Patients with non-valvular atrial fibrillation (NVAF) and previous stroke are at significantly higher risk of stroke recurrence. Data on the efficacy of left atrial appendage closure (LAAC) on these patients is limited. The aim of this study was to investigate the differences of LAAC efficacy on long-term cardio- and cerebrovascular outcomes in NVAF patients with vs. without prior stroke.Methods: Three hundred and seventy consecutive NVAF patients who underwent LAAC were enrolled and divided into stroke and non-stroke groups based on history of previous stroke. Endpoints, such as thromboembolism, major bleeding, and mortality post-LAAC, were followed up among groups.Results: Patients in the stroke group had higher mean CHA2DS2-VASc and HAS-BLED scores compared to the non-stroke group (5.1 vs. 3.6 and 4.1 vs. 3.4, both P &lt; 0.001, respectively). Over a median follow-up of 2.2 years, there were no significant differences in incidence rates of thromboembolism, device-related thrombus (DRT), major bleeding, and combined efficacy endpoints between the two groups. In both stroke and non-stroke groups, LAAC decreased the risk of thromboembolism [relative risk reduction (RRR) 87.5%, P = 0.034, and 74.6%, P = 0.004, respectively] and major bleeding (RRR 68.8%, P = 0.034, and 68.6%, P = 0.007, respectively) compared with predicted risk. The RRR in thromboembolism was greater in patients with vs. without prior stroke (OR 2.45, 95% CI: 1.20–5.12, P = 0.016). The incidence rates of all-cause mortality and non-cardiovascular death were similar between the two groups, but the risks of cardiovascular death post-LAAC both before (1.4% vs. 8.1%, respectively, P = 0.038) and after adjustment for confounding factors (P = 0.048) were significantly decreased in the stroke group.Conclusions: Patients with vs. without prior stroke did not exhibit a worse clinical prognosis after LAAC. LAAC may provide an increased benefit in cardio-cerebrovascular outcomes in patients with previous stroke compared to those without previous stroke. Further research is necessary to evaluate the efficacy of LAAC in this field.

Andexanet Alfa for Specific Anticoagulation Reversal in Patients with Acute Bleeding during Treatment with Edoxaban

Background Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban. Methods Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients. Results Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population (n = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3–202.4) ng/mL at baseline to 24.0 (IQR: 77.7–83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1–77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0–91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died. Conclusion In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.

Direct Oral Anticoagulants versus Warfarin in Patients with Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials with Interaction Testing by Age and Sex

Background: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation (AF). Meta-analyses using individual patient data offer significant advantages over study-level data. Methods: We used individual patient data from the COMBINE AF database, which includes all patients randomized in the 4 pivotal trials of DOACs vs warfarin in AF (RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (95% CIs) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex. Results: A total of 71,683 patients were included (29,362 on standard-dose DOAC, 13,049 on lower-dose DOAC, 29,272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke/systemic embolism (883/29312 [3.01%] vs 1080/29229 [3.69%]; HR 0.81, 95% CI 0.74-0.89), death (2276/29312 [7.76%] vs 2460/29229 [8.42%]; HR 0.92, 95% CI 0.87-0.97) and intracranial bleeding (184/29270 [0.63%] vs 409/29187 [1.40%]; HR 0.45, 95% CI 0.37-0.56), but no statistically different hazard of major bleeding (1479/29270 [5.05%] vs 1733/29187 [5.94%]; HR 0.86, 95% CI 0.74-1.01), whereas lower-dose DOACs were associated with no statistically different hazard of stroke/systemic embolism (531/13049 [3.96%] vs 1080/29229 [3.69%]; HR 1.06, 95% CI 0.95-1.19) but a lower hazard of intracranial bleeding (55/12985 [0.42%] vs 409/29187 [1.40%]; HR 0.28, 95% CI 0.21-0.37), death (1082/13049 [8.29%] vs 2460/29229 [8.42%]; HR 0.90, 95% CI 0.83-0.97), and major bleeding (564/12985 [4.34%] vs 1733/29187 [5.94%]; HR 0.63, 95% CI 0.45-0.88). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke/systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (p=0.01) and lower creatinine clearance (p=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (p=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction p=0.02) and lower-dose DOACs (interaction p=0.01) versus warfarin. Conclusions: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with AF.

Associations of Atrial Fibrillation Patterns With Mortality and Cardiovascular Events: Implications of the MISOAC-AF Trial

Aim: This retrospective cohort study aimed to evaluate the prognostic implications of the distinct atrial fibrillation (AF) temporal patterns: first diagnosed, paroxysmal, and persistent or permanent AF. Methods: In this post hoc analysis of the MISOAC-AF trial (NCT02941978), a total of 1052 patients with AF (median age 76 years), discharged from the cardiology ward between 2015 and 2018, were analyzed. Kaplan-Meier and Cox-regression analyses were performed to compare the primary outcome of all-cause mortality, the secondary outcomes of stroke, major bleeding and the composite outcome of cardiovascular (CV) mortality or hospitalization among AF patterns. Results: Of patients, 121 (11.2%) had first diagnosed, 356 (33%) paroxysmal, and 575 (53.2%) persistent or permanent AF. During a median follow-up of 31 months (interquartile range 10 to 52 months), 37.3% of patients died. Compared with paroxysmal AF, patients with persistent or permanent AF had higher mortality rates (adjusted hazard ratio (aHR), 1.37; 95% confidence interval [CI], 1.08-1.74, P = .009), but similar CV mortality or hospitalization rates (aHR, 1.09; 95% CI, 0.91-1.31, P = .35). Compared with first diagnosed AF, patients with persistent or permanent AF had similar mortality (aHR, 1.26; 95% CI, 0.87-1.82, P = .24), but higher CV mortality or hospitalization rates (aHR, 1.35; 95% CI, 1.01-1.8, P = .04). Stroke and major bleeding events did not differ across AF patterns (all P > .05). Conclusions: In conclusion, in recently hospitalized patients with comorbid AF, the presence of persistent or permanent AF was associated with a higher incidence of mortality and morbidity compared with paroxysmal and first diagnosed AF.

Trade-off of major bleeding versus myocardial infarction on mortality after percutaneous coronary intervention

BackgroundThe choice of antithrombotic therapy after percutaneous coronary intervention (PCI) is heavily dependent on the relative trade-off between major bleeding (MB) and myocardial infarction (MI). However, the mortality trade-off was mostly described in Western populations and remained unknown in East Asians.MethodThis was a retrospective cohort study from 14 hospitals under the Hospital Authority of Hong Kong between 2004 and 2017. Participants were patients undergoing first-time PCI and survived for the first year. Patients were stratified by the presence of MB and MI during the first year. The primary endpoint was all-cause mortality between 1 and 5 years after PCI. The secondary endpoint was cardiovascular mortality.ResultsA total of 32 180 patients were analysed. After adjustment for baseline characteristics and using patients with neither events as reference, the risks of all-cause mortality were increased in patients with MI only (HR, 1.63; 95% CI 1.45 to 1.84; p<0.001), further increased in those with MB only (HR, 2.11, 95% CI 1.86 to 2.39; p<0.001) and highest in those with both (HR, 2.92; 95% CI 2.39 to 3.56; p<0.001). In both Cox regression and propensity score analyses, MB had a stronger impact on all-cause mortality than MI, but similar impact on cardiovascular mortality.ConclusionsBoth MB and MI within the first year after PCI were associated with increase in all-cause and cardiovascular mortality in Chinese patients, but the impact was stronger with MB.