Risk Factors For Major Bleeding Research Articles

Standalone transcatheter left atrial appendage closure or combined with cryoballoon pulmonary vein isolation

Abstract Background Head-to-head comparisons between stand-alone left atrial appendage closure (LAAC) and a same-procedure LACC + cryoballoon (CB) pulmonary vein isolation (PVI) (combined procedure) are currently lacking. Purpose To compare acute and long-term outcomes between stand-alone LAAC vs a LAAC+CB-PVI combined procedure. Methods All patients undergoing LAAC at our institution, having at least 2 years follow-up, were analyzed to assess the impact of additional CB-PVI. The primary efficacy and safety endpoints of our study were the acute procedural success rate and the peri-procedural complications rate. As secondary endpoints, major bleeding, and ischemic events, as well as sinus rhythm rate at 2 years follow-up were assessed. Results Among 126 LAAC patients meeting inclusion criteria (males=64.2%), n=55 (43.7%) underwent a combined procedure. LAAC-only patients were older (72.5±7.2 vs 68.9±8.6, p<0.05) and less frequently having paroxysmal AF (23.9% vs 47.3%, p<0.05). Baseline CHA2DS2-VASc was similar among groups (3.3±1.3 vs 2.9±1.1, p=0.07) while LAAC-only patients had higher HAS-BLED at enrollment (3.4±1.1 vs 3.0±1.0, p=0.04). Additional CB-PVI was not a risk factor for incomplete LAA occlusion (OR 0.24–3.78, p=0.96), presence of residual lateral flow (OR 0.26–4.05; p=0.96), intraprocedural need for occluder device resizing compared to pre-procedural assessment (OR 0.27–3.05; p=0.884), and peri-procedural complications (OR 0.25–6.74, p=0.749). At 3-month post-procedural trans-esophageal echocardiography, a combined procedure was not associated with higher risk of incomplete occlusion (OR 0.33–1.59, p = 0.432), nor larger peri-device leakages (coefficient k: -0.65–+0.20, p=0.291). Overall and by-group ischemic (red) and bleeding (blue) relative risk reduction from CHA2DS2-VASc and HAS-BLED predicted yearly rates during follow-up was reported in Figure1. Over a median follow-up of 40 [26–56] months, a combined procedure was not a risk factor for major bleeding (OR 0.31–5.48, p=0.715) or ischemic (OR 0.11–3.56, p=0.599) events. As expected, additional CB-PVI was strongly associated with a reduction of AF recurrences (OR 0.16–0.86, p<0.05), after excluding permanent AF patients from the analysis. Conclusion Combined LAAC + CB-PVI procedure does not appear to be a risk factor for worse LAAC-related outcomes, while reducing AF recurrences in non-permanent AF patients.Figure 1

#430 Risk factors for major bleeding in patients with non-valvular atrial fibrillation and CKD G3-G5D on oral anticoagulants

Abstract Background and Aims We previously published a register-based cohort study comparing direct oral anticoagulants (DOAC) and warfarin in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) GFR category 3-5 (G3-G5) including patients on dialysis (G5D) (1). This study showed that DOAC was associated with lower risk of major bleeding but similar risk of ischemic stroke compared to warfarin. Bleedings were however more common than strokes, especially in advanced CKD (G5-G5D) where the risk of major bleeding was up to 10 times higher than the risk of stroke. Subsequently, the stroke- and bleeding risk in patients with AF and advanced CKD must be carefully evaluated when deciding on whether to prescribe oral anticoagulants (OAC) or not. Available stroke- and bleeding scoring systems do not perform well in CKD (2, 3). This study aims to present risk factors associated with major bleeding in a Swedish cohort of OAC-treated patients with CKD G3-G5D. Method Data was collected from high quality Swedish healthcare registers including Swedish Renal Registry and Auricula, a register for atrial fibrillation and oral anticoagulants and the National Patient Register. Patients with eGFR<60 ml/min/1.73m2 and non-valvular atrial fibrillation and either DOAC (apixaban, rivaroxaban, edoxaban and dabigatran) or warfarin treatment between 2009-2018 where included. DOAC treatment periods were collected from the Swedish Prescribed Drug Register (PDR), starting from dispense date covering assumed standard pill use and an additional 30 days grace period. Warfarin treatment periods were collected directly from Auricula. An undefined treatment was a period of no OAC or a period of warfarin from PDR not matching a treatment period in Auricula. All periods of OAC treatment with either DOAC or warfarin were evaluated in a multivariate Cox regression model regarding the risk of major bleeding requiring inpatient care. Time-dependent covariates adjusted for in the model were age, sex, years from study start, GFR category, congestive heart failure, diabetes mellitus, hypertension, excessive alcohol use, liver disease, vascular disease, previous gastrointestinal bleeding, intracranial bleeding, other bleeding, ischemic stroke/ transient ischemic attack (TIA), myocardial infarction, PCI and exposures (DOAC, warfarin and periods of undefined treatment). Results Of 2453 included patients, 59% had warfarin (time in therapeutic range, TTR, 67%) and 41% DOAC at inclusion, predominantly apixaban (81% of DOAC users). The mean age was 77 years, 28.3% had G3, 45.4% G4, 9.1% G5 and 17.3% G5D (Table 1). Mean follow up was 2.2 years. During follow up 424 major bleedings occurred yielding 8.9 (95% confidence interval 8.1-9.8) bleedings per 100 patient-years. Table 2 shows effect estimates of each covariate on the outcome major bleeding. Covariates, besides warfarin, associated with increased risk of major bleeding were GFR category, G5/5D versus G3, hazard ratio 1.92 (95% CI 1.43-2.56), previous GI bleeding, 1.77 (1.39-2.25) and previous other bleeding 1.33 (1.09-1.62). Other factors associated with major bleeding were congestive heart failure 1.36 (1.11-1.68), male sex 1.28 (1.03-1.60) and vascular disease, 1.35 (1.01-1.79). Conclusion Patients with non-valvular atrial fibrillation and CKD G3-G5D on OAC are at high risk of major bleeding. Previous major bleeding and kidney failure are strongly associated with major bleeding, this reiterates the results of many previous studies. The present study also shows an association between OAC-associated major bleeding in CKD and male sex, congestive heart failure and vascular disease. Similar associations have been showed in non-CKD cohorts previously but is inadequately studied in CKD. Knowledge about risk factors for major bleeding on OAC in advanced CKD is essential when deciding on when to anticoagulate or not.

Clinical Characteristics and Incidence of Hemorrhagic Complications in Patients Taking Factor Xa Inhibitors in Spain: A Long-Term Observational Study.

Objective. To analyze the clinical characteristics of patients taking Factor Xa inhibitors (FXai), either direct FXai or enoxaparin (only in active cancer patients), and to estimate the incidence of and risk factors for major bleeding during FXai use. Methods. A retrospective cohort study, which included secondary data from computerized health records of primary care centers and hospitals in seven Spanish Autonomous Communities. Results. 9374 patients were analyzed, with 8972 taking direct FXai and 402 enoxaparin. At baseline, the mean age (SD) was 71.8 (9.4) years, 56.0% were women, 76.3% had hypertension, 33.6% had type 2 diabetes, and 25.5% had heart failure. The most common indication for FXai use was atrial fibrillation (72.3%), followed by venous thromboembolism (22.2%) and non-mechanical cardiac-valve replacement (5.6%). At the end of the follow-up period, the incidence rates of major bleeding overall, gastrointestinal, and intracranial were 10.2, 9.0, and 0.8 per 100 person-years, respectively. The total incidence of fatal major bleeding was 0.5 per 100 person-years. Incidence rates of all bleedings progressively decreased over time, with 62.5% of the first events occurring in the initial three months and reaching 76.8% within six months following initiation of treatment. Only 4.8% of the 1st major bleedings led to death, 2.3% in the case of major gastrointestinal bleeding, and 30.8% after an intracranial bleeding. 65.9% of patients discontinued anticoagulation after experiencing major bleeding. Conclusions. In Spain, patients taking FXai were old and had many comorbidities. Despite incidence rates of major bleeding were high, incidence rates of intracranial and fatal bleedings were low, but more efforts are required due to their relevant clinical impact.

Prevention of Perioperative Bleeding in Patients With Chronic Limb-Threatening Ischemia

Materials and methods: At stage I, we retrospectively studied histories and outpatient medical records of 766 patients with chronic limb-threatening ischemia (from 2006 to 2020) to identify hemorrhagic complications and potential risk factors for their development. We analyzed the effectiveness of different scores for assessment of the bleeding risk. Based on the obtained data, measures to prevent hemorrhagic complications in this cohort of patients were improved. During stage II, 114 patients with 1 or several risk factors for major bleeding underwent surgery between 2021 and 2023. We used the proposed and improved preventive measures for all the patients. Follow-up periods were during the hospital stay and in 6 and 12 months.Results: At stage I, 44 (5.74%) patients were found to have hemorrhagic complications in the early postoperative period: retroperitoneal hematoma, bleeding from an operating wound, and pulsating hematoma (15.9%); gastrointestinal hemorrhage (31.8%); gross hematuria (13.7%), and hemorrhagic stroke (6.8%). The most significant risk factors for bleeding were endovascular intervention using brachial and femoral approaches (P = .000), hybrid intervention (P = .000), dual antiplatelet therapy (P = .014), surgery duration above 60 minutes (P = .001), triple antithrombotic therapy (P = .001), and significant vascular calcification (P = .023). The PRECISE-DAPT score has proven to be of prognostic value (P = .073; odds ratio, 2.88). At stage II, due to the proposed preventive measures, bleeding that required blood transfusion was found in 5 (4.38%) of 114 patients: of them, 1 (0.9%) patient had acute coronary syndrome. There were no major amputations, whereas 3 (2.63%) patients underwent minor amputation. In 6 and 12 months of the follow-up, the total frequency of major cardiovascular complications (cardiac death, myocardial infarction), major and minor amputation was 0.9% and 2.6%, 0% and 1.75%, and 0.9% and 2.6%, respectively.Conclusions: Surgical treatment of patients with chronic limb-threatening ischemia and risk factors for hemorrhagic complications who underwent surgery with the proposed preventive measures demonstrated high efficiency in reducing the number of hemorrhages and associated cardiac complications and low frequency of major and minor amputations in the long-term follow-up.

Prognostic Significance of Heart Failure in Acute Pulmonary Embolism: A Comprehensive Assessment of 30-Day Outcomes.

Patients with heart failure (HF) are known to have an increased risk of pulmonary embolism (PE), but there is limited evidence regarding the prognostic implications of HF in patients with acute PE and the relationship between PE prognosis and left ventricular ejection fraction (LVEF). The primary objective of this study was the development of a composite outcome (mortality, major bleeding, and recurrence) within the first 30 days. The secondary objective was to identify the role of LVEF in predicting the development of early complications in patients with both HF and reduced LVEF. A prospective study was conducted at two tertiary hospitals between January 2012 and December 2022 to assess differences among patients diagnosed with acute PE based on the presence or absence of a history of HF. Cox regression models were employed to assess the impact of HF and reduced LVEF on the composite outcome at 30 days. Out of 1991 patients with acute symptomatic PE, 7.13% had a history of HF. Patients with HF were older and had more comorbidities. The HF group exhibited higher mortality (11.27% vs. 4.33%, p < 0.001) and a higher incidence of major bleeding (9.86% vs. 4.54%, p = 0.005). In the multivariate analysis, HF was an independent risk factor for the development of the composite outcome (HR 1.93; 95% CI 1.35-2.76). Reduced LVEF was independently associated with a higher risk of major bleeding (HR 3.44; 95% CI 1.34-8.81). In patients with acute pulmonary embolism, heart failure is independently associated with a higher risk of early complications. Additionally, heart failure with reduced LVEF is an independent risk factor for major bleeding.

Event rates and risk factors for venous thromboembolism and major bleeding in a population of hospitalized adult patients with acute medical illness receiving enoxaparin thromboprophylaxis

BackgroundWe aimed to describe the event rates and risk-factors for symptomatic venous thromboembolism (VTE) and major bleeding in a population of hospitalized acutely ill medical patients. MethodsPatients ≥40 years old and hospitalized for acute medical illness who initiated enoxaparin prophylaxis were selected from the US Optum research database. Rates of symptomatic VTE and major bleeding at 90-days were estimated via the Kaplan-Meier (KM) method. Risk factors were identified via the Cox proportional hazards model. ResultsA total of 123,022 patients met the selection criteria. The KM rates of VTE and major bleeding at 90-days were 3.5 % and 2.2 %, respectively. Among subgroups, the risk of VTE varied from 3.0 % in patients with ischemic stroke to 6.9 % in patients with a cancer-related hospitalization, and the risk of major bleeding varied from 1.9 % in patients with inflammatory conditions to 3.6 % in patients with ischemic stroke. Key risk factors for VTE were prior VTE (HR=4.15, 95 % confidence interval [CI] 3.80–4.53), cancer-related hospitalization (HR=2.35, 95 % CI 2.10–2.64), and thrombophilia (HR=1.64, 95 % CI 1.29–2.08). Key risk factors for major bleeding were history of major bleeding (HR=2.17, 95 % CI 1.72–2.74), history of non-major bleeding (HR=2.46, 95 % CI 2.24–2.70), and hospitalization for ischemic stroke (2.42, 95 % CI 2.11–2.78). ConclusionThere is substantial heterogeneity in the event rates for VTE and major bleeding in acute medically ill patients. History of VTE and cancer related hospitalization represent profiles with a high risk of VTE, where continued VTE prophylaxis may be warranted.

Bleeding and Thrombotic Outcomes in Adults with Cancer-Associated Splanchnic Vein Thrombosis and Thrombocytopenia

Introduction: Splanchnic vein thrombosis (SVT) can arise as a complication in patients with underlying cancers, especially gastrointestinal malignancies, as well as other comorbidities such as liver disease. In patients with cancer-associated thrombosis, thrombocytopenia is a common co-occurrence that can complicate management decisions around anticoagulation. Data on the optimal management of SVT in patients with malignancies is limited, and the risk of bleeding and recurrent thrombosis in patients with cancer-associated SVT and thrombocytopenia is unclear. Methods: We identified patients with radiographic diagnosis of cancer-associated SVT at our institution between 2010 and 2021. Exclusion criteria included squamous and basal cell carcinomas and myeloproliferative neoplasms. We manually reviewed all medical records to determine baseline clinical data and clinical outcomes. We performed log-binomial regression to identify independent risk factors for major bleeding, using age at thrombosis (continuous), gender, prior major bleed, baseline creatinine (continuous), use of antiplatelets, and use of anticoagulants as covariates. We present these data as adjusted risk ratios (RR) and 95% confidence intervals (CI). We subsequently used Cox models with inverse probability of treatment weighting with propensity scores for thrombocytopenia (platelet count less than 100,000/uL within 15 days before or after diagnosis of SVT) to calculate hazard ratios (HR) and 95% CIs for our outcomes of interest. Independent variables used in propensity scoring included all variables included in the adjusted models plus type of cancer (hematologic, solid tumor). Outcomes included major bleeding, clinically relevant non major bleeding (CRNMB), clinically relevant bleeding (major bleeding + CRNMB), progression and recurrence of SVT, and development of usual-site VTE (DVT or PE) up to one year following the initial SVT. Progression was defined as extension of the thrombus contiguously into a new vein, and recurrence was defined as a new interval thrombus which was non-contiguous with the initial thrombus. Results: A total of 581 patients with cancer and SVT were identified. Baseline demographics, clinical history, laboratory data, and details of SVT are shown in Table 1. Of note, 44.2% of patients had cirrhosis, and the most common cancer types were hepatobiliary (55.2%) and pancreatic (22.0%); 40.7% of patients had metastatic disease. Of 512 patients with available platelet count data, 39.5% of patients had platelet count &amp;lt;100,000/uL; of these 512, 14.1% were &amp;lt;75,000/uL, and 12.7% were &amp;lt;50,000/uL. Most (70.6%) SVT were bland thrombi based on radiology interpretation, 19.9% were tumor thrombi, and 5.5% were mixed type, with the remainder being of uncertain etiology. Survival at one year was 41.5%, and median follow-up time was 5.5 months (interquartile range: 1.4-22.2). Only 4.0% of patients received a thrombectomy, and 39.2% were treated with anticoagulation within two weeks of diagnosis. The cumulative incidence of major bleeding event within one year of SVT diagnosis was 11.0% (95% CI: 8.5-13.5). This was primarily upper GI bleeding (70.3% of major bleeds). Multivariate regression analysis identified only male gender as an independent predictor of major bleeding (aRR: 0.91, 95% CI: 0.84-0.99), as shown in Table 2. In the propensity score-weighted Cox models, thrombocytopenia was not associated with an increased risk of major bleeding within one year (aHR: 1.65, 95% CI: 0.32-8.41). The cumulative incidence of CRNMB at one year was 6.7% (95% CI: 4.7-8.7), and cumulative incidence of clinically relevant bleeding was 17.7% (95% CI: 14.6-20.8). The cumulative incidence of progression or recurrence of SVT at one year was 16.3% (95% CI: 13.3-19.3). In the weighted Cox models, patients with thrombocytopenia did not impact the risk of progression or recurrence of SVT (aHR: 1.15, 95% CI: 0.58-2.26). The cumulative incidence of usual-site VTE at one year was 5.7% (95% CI: 3.8-7.5). Conclusion: Thrombocytopenia was a common co-occurrence in cancer-associated SVT. Major bleeding- especially upper GI bleeding- was a common complication of cancer-associated SVT. Recurrent or progressive SVT was also frequent, which highlights the challenges of optimal management in this high-risk population. We found that thrombocytopenia was not an independent risk factor for major bleeding in this population.

Influence of thrombocytopenia on bleeding and vascular events in atrial fibrillation

AbstractWhether thrombocytopenia substantively increases the risk of hemorrhage associated with anticoagulation in patients with atrial fibrillation (AF) is not established. The purpose of this study was to compare rates of bleeding in patients with AF and thrombocytopenia (platelet count < 100 000/μL) to patients with AF and normal platelet counts (>150 000/μL). We performed a propensity score–matched, retrospective cohort study of adults (n = 1070) with a new diagnosis of AF who received a prescription for an oral anticoagulant between 2015 and 2020. The thrombocytopenia cohort was defined as having at least 2 platelet counts <100 000/μL on separate days in the period spanning the 12 weeks preceding the initiation of anticoagulation to 6 weeks after the initiation of anticoagulation. The primary end point was the 1-year cumulative incidence of major bleeding; secondary end points included clinically relevant bleeding, arterial and venous thrombotic events, and all-cause mortality. Patients with AF and thrombocytopenia experienced a higher 1-year cumulative incidence of major bleeding (13.3% vs 5.7%; P < .0001) and clinically relevant bleeding (24.5% vs 16.7%; P = .005) than the controls. Thrombocytopenia was identified as an independent risk factor for major bleeding (hazard ratio, 2.20; confidence interval, 1.36-3.58; P = .001), with increasing risk based on the severity of thrombocytopenia. The cumulative incidence of arterial thrombosis at 1 year was 3.6% in the group with thrombocytopenia and 1.5% in controls (Gray test, P = .08). These findings suggest that baseline platelet counts are an important biomarker for hemorrhagic outcomes in AF and that the degree of thrombocytopenia is an important factor in determining the level of risk.

Prediction of major bleeding events in 1381 patients with essential thrombocythemia.

The goal of therapy in essential thrombocythemia (ET) is reducing thrombotic risk. No algorithm to predict hemorrhage risk exists. The impact ofanti-platelet, cytoreductive and anticoagulation therapies on risk of major bleeding (MB) was evaluated. MB events were retrospectively analyzed in 1381 ET from 10 European centers. There were 0.286MB events/person-year. Neither the International Thrombosis Prognostic Score for thrombosis in essential thrombocythemia (IPSET-t) nor the revised IPSET-t (r-IPSET-t) was predictive for hemorrhage-free survival at 10years (p = 0.092 vs p = 0.1). Ageand leukocyte count were MB risk factors, while low hemoglobin was protective. For ET with extreme thrombocytosis (ExtT) and leukocytosis cytoreduction was not protective. MB were more frequent in ET with ExtT who received anticoagulation. Antiplatelet therapy was not, while anticoagulation was a risk factor for MB (HR 3.05, p = 0.016, CI 1.23-7.56), in particular vitamin K antagonists (22.6% of those treated had a MB event, HR 2.96, p = 0.004, CI 1.41-6.22). Survival at 10years was associated with hemorrhage (OR 2.54, p < 0.001) but not thrombosis (HR 0.95, p = 0.829). Hemorrhage has a higher risk of mortality than thrombosis. Improved risk stratification for MB is necessary. The choice of anticoagulation, cytoreduction and antiplatelet therapies is an important area of research in ET.

Incidence of thromboembolic events in glioblastoma multiforme: The first Middle Eastern study risk stratifying patients from this region.

e14044 Background: Prophylactic anticoagulation for Glioblastoma Multiforme patients remains an area of high controversy with no definite guidelines and with clinical practice recommendations depending mainly on individual center based strategies. Considering that the middle eastern population is known to be associated with increased incidence of thrombophilia due to the high prevalence of factor V R506Q Mutation-Leiden and with no studies reporting incidence of VTE with GBM patients in this region, we aimed to conduct the first middle east based study to see if the incidence of VTE in GBM patient will be higher than the other overall reported incidence worldwide and we looked whether using the Khorana score will be a good predictor for assessing the need for VTE prophylaxis in these patients. Methods: we conducted a retrospective chart review to determine the incidence of initial VTE in GBM patients who received treatment at a tertiary care center in Beirut. Results: The total patient population was 132 with males constituting 71.2% of our population compared to 28.8 % females. Preexisting risk factors included: 34.8 % for hypertension, 65.2% for diabetes, and 25% were smokers, 0.8% had history of thrombophilia, and 7.6% had preexisting episode of VTE while 94% of the population had craniotomy. The incidence of deep vein thrombosis (DVT) was 15.4%, while 7.2 % developed a pulmonary embolism (PE). Recurrent VTEs affected 34.8% of those who had a previous VTE, and 7.4% of patients had the recurrent VTE while they were on anticoagulation. Regarding complications, 7.3% developed bleeding, 66% of those had intracranial bleeding while 33 % had a gastrointestinal bleed. Out of all of those who developed bleeding, only 3.4% were on anticoagulation so anticoagulation was not a major risk factor for bleeding. 57.6% of the patients had a Khorana score of 0, 28.8% had a score of 1,7.6% had a score of 2,1.6% had a score of 3, while 8% had a Khorana score of 4. In our cohort, all patients with a Khorana score of 3 and 4 developed VTE which indicated that this could be used as a risk assessment tool for our GBM patients. Conclusions: In conclusion in our study, with its retrospective limitation, we could not prove that our middle eastern populations, though known to have higher incidence of congenital thrombophilia, is associated with much higher incidence of VTE when compared to many studies involving different populations in the world however our cohort of patients with GBM undergoing craniotomy are still at increased risk of thrombotic events with low risk of bleeding despite anticoagulation and the Khorana score could be a risk stratifying method to help us establish the patients who have the highest risk of developing VTE. Prospective studies involving higher number of patients with thrombophilia testing should be explored to risk stratify our patients.

Relation between laxative use and risk of major bleeding in patients with atrial fibrillation and heart failure

Constipation has been reported to increase the risk of cardiovascular mortality. Patients with atrial fibrillation (AF) and heart failure (HF) have more comorbidities and an increased bleeding risk. However, it remains unclear whether constipation is associated with an increased risk of incident bleeding complications in AF with HF. Here, we investigated the association between constipation requiring laxatives and major bleeding in AF and HF. We retrospectively analyzed the medical records of 370 consecutive patients hospitalized for AF and congestive HF. Constipation was defined as regularly taking laxatives or having at least two prescriptions for a ≥ 30-day supply of laxatives. Sixty patients experienced major bleeding events during a median follow-up of 318 days. The most common sites of bleeding were lower gastrointestinal (28%, 17/60), upper gastrointestinal (27%, 16/60), and intracranial (20%, 12/60). There were 33 (55%) patients with constipation in the bleeding group and 107 (35%) in the non-bleeding group (P = 0.004). Multivariate Cox regression analysis adjusted for HAS-BLED score, hemoglobin, and direct oral anticoagulant use showed that constipation (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.11–3.08; p = 0.019) was a significant risk factor for major bleeding. We found a significant association between constipation requiring laxatives and major bleeding in patients with AF and HF. These findings indicate the need for constipation prevention in these patients to avoid reliance on invasive defecation management, including laxatives.

New score for predicting major bleeding in patients with atrial fibrillation using direct oral anticoagulants

PurposeOur aim was to identify factors associated with major bleeding in patients with atrial fibrillation (AF) on direct oral anticoagulants (DOACs) and to construct and externally validate a predictive model that would provide a validated tool for clinical assessment of major bleeding. MethodsIn the development cohort, prediction model was built by logistic regression, the area under the curve (AUC), and Nomogram. External validation, analytical identification and calibration of the model using AUC, calibration curves and Hosmer-Lemeshow test. ResultsThe development cohort consisted of 4209 patients from 7 centers and the external validation cohort consisted of 1800 patients from 12 centers. Multifactorial analysis showed that age > 65 years, history of bleeding, anemia, vascular disease, antiplatelet therapy/non-steroidal anti-inflammatory drugs and rivaroxaban were independent risk factors for major bleeding, and gastrointestinal protective agents was a protective factor. The Alfalfa-MB model was constructed using these seven factors (AUC = 0.807), and in the external validation cohort, the model showed good discriminatory power (AUC = 0.743) and good calibration (Hosmer-Lemeshow test P value of 0.205). The predictive power of the six bleeding scores was ORBIT (AUC = 0.706), HAS-BLED (AUC = 0.648), ATRIA (AUC = 0.645), HEMORR2 HAGES (AUC = 0.632), ABC (AUC = 0.619) and Shireman (AUC = 0.599) in descending order. ConclusionBased on 7 factors, we derived and externally validated a predictive model for major bleeding with DOACs in patients with AF (Alfalfa-MB). The model has good predictive value and may be an effective tool to help reduce the occurrence of major bleeding in patients with DOACs.

Risk factors for recurrence and major bleeding in patients with cancer-associated venous thromboembolism

Risks of recurrence and treatment-emergent bleeding are high in patients with cancer-associated venous thromboembolism (VTE) but factors associated with these risks remain substantially undefined.The aim of this analysis in patients with cancer-associated VTE included in the Caravaggio study was to identify risk factors for recurrent VTE and major bleeding. Variables potentially predictive for recurrent VTE or major bleeding were evaluated in a Cox proportional hazard multivariable analysis with backward variable selection.Recurrent VTE occurred in 78 patients (6.8%) and major bleeding in 45 (3.9%). Independent risk factors for recurrent VTE were deep vein thrombosis (DVT) as index event (Hazard ratio (HR) 1.84, 95% CI 1.17–2.88), ECOG status of 1 or more (HR 1.95, 95% CI 1.11–3.43), pancreatic or hepatobiliary cancer site (HR 2.20, 95% CI 1.19–4.06), concomitant anti-cancer treatment (HR 1.98, 95% CI 1.03–3.81) and creatinine clearance (HR 1.10, 95% CI 1.00–1.20 for every 10 ml/min absolute increase). Independent risk factors for major bleeding were ECOG status of 2 (HR 2.31, 95% CI 1.24–4.29), genitourinary cancer site (HR 2.72, 95% CI 1.28–5.77), upper gastrointestinal cancer site (HR 3.17, 95% CI 1.22–8.23), and non-resected luminal gastrointestinal cancer (HR 2.77, 95% CI 1.38–5.56).This analysis of the Caravaggio study in patients with cancer-associated VTE who were on standardized anticoagulant treatment identified five independent predictors for recurrent VTE and four independent predictors of treatment-emergent major bleeding. Considering these risks could help clinicians to optimize the anticoagulant treatment in patients with cancer-associated VTE.

Systemic thrombolytic and ultrasound-assisted catheter-directed thrombolysis for treatment of acute pulmonary embolism: a 7-year, multicenter experience.

Treatment of acute pulmonary embolism (PE) varies based upon risk stratification and ranges from outpatient oral anticoagulation to emergency surgical embolectomy. Patients with high-risk PE can be considered for systemic thrombolytic (ST) based upon guideline recommendations, but intermediate-risk PE does not currently have strong evidence to guide primary reperfusion strategies via thrombolytic administration. Ultrasound-assisted catheter-directed thrombolysis (USAT) is an alternative reperfusion option to ST but is not currently recommended as first line in any key guidelines due to limited available evidence. This retrospective, multicenter, observational study compares 210 patients treated with USAT (n = 105) or ST (n = 105) for acute high- or intermediate-risk PE in three hospitals. Baseline characteristics were significant in that severity of illness was higher in those that received ST, which limited comparisons of outcomes. The primary outcome of major bleeding in patients receiving USAT was 15.2% and 22.9% in those that received ST. Efficacy of reperfusion strategy was observed to be 86.7% of patients in USAT group and 65.7% in ST group. Reperfusion strategies had no difference in in-hospital death, intensive care length of stay, or hospital length of stay. Predefined subgroup analysis found that high-risk PE had higher mortality (14.7%) than intermediate-risk PE (0%) regardless of reperfusion strategy. Upon multivariate analysis, high-risk PE was the only independent risk factor for major bleeding while USAT therapy and intermediate-risk PE were independent predictors of efficacy. Due to the difference in baseline severity of illness, direct comparisons in primary outcomes to each group was not performed. We have described real world usage of both USAT and ST and which patients were likely to receive each therapy at these institutions.

Polypharmacy and adverse events in atrial fibrillation: Main cause or reflection of multimorbidity?

BackgroundPrevious evidence indicated that atrial fibrillation (AF) patients with polypharmacy presented increased probability of adverse events. We investigated the prevalence of polypharmacy, risk factors for polypharmacy, and the impact of polypharmacy in clinical outcomes in a ‘real-world’ cohort of AF patients starting vitamin K antagonists (VKAs). MethodsProspective study including AF outpatients starting VKA therapy from July, 2016 to June, 2018. At inclusion, all concomitant drugs were carefully collected and recorded. Polypharmacy was defined as the intake of ≥ 5 concomitant drugs. During 2-years of follow-up, ischemic strokes/transient ischemic attacks (TIAs), fatal/nonfatal myocardial infarctions (MIs), bleeding events, venous thromboembolisms, and all-cause deaths were recorded. Results1050 patients (51.5 % females, median age 77 [69–83] years) were included, and the prevalence of polypharmacy was 32.9 % (345). Female sex (OR 1.5; 95 % CI 1.11–2.03), hypertension (OR 2.53; 95 % CI 1.51–4.22), diabetes (OR 3.11; 95 % CI 2.31–4.17), vascular disease (OR 3.08; 95 % CI 2.19–4.33), heart failure (OR 1.86; 95 % CI 1.35–2.58) and dyslipidemia (OR 2.61; 95 % CI 1.9–3.58) were independently associated to the polypharmacy. Patients with polypharmacy showed significantly higher incidence of major bleeding, net clinical outcomes (composite of major bleeding, ischemic stroke/TIA, and mortality), MACE (composite of ischemic stroke/TIA, MI, and cardiovascular death), and composite thrombotic/thromboembolic events; being an independent risk factor for major bleeding (HR 1.77, 95 % CI 1.07–2.92), and composite thrombotic/thromboembolic events (HR 1.55, 95 % CI 1.05–2.31). ConclusionIn this “real world” AF cohort, polypharmacy was highly prevalent and conditioned worse prognosis due to its association with bleeding and thromboembolic events.

Impact of baseline blood pressure on adverse outcomes in Japanese patients with non-valvular atrial fibrillation: the J-RISK AF.

This study aimed to investigate the impact of baseline blood pressure (BP) on adverse outcomes in patients with atrial fibrillation (AF), using a pooled analysis performed on data from J-RISK AF, a large-scale cohort of Japanese patients with AF. Of the 16 918 patients from five major AF registries including the J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry, 15 019 non-valvular AF (NVAF) patients with baseline BP values (age, 70.0 ± 11.0 years; men, 69.1%) were analysed. Incidence rates of adverse events were evaluated between patients divided into baseline systolic BP quartiles or at 150 mmHg. During the follow-up period of 730 days, ischaemic stroke, major bleeding, all-cause death, and cardiovascular death occurred in 277, 319, 718, and 275 patients, respectively. Hazard ratios (HRs) for ischaemic stroke and major bleeding were comparable among the quartiles, whereas HRs for all-cause and cardiovascular deaths in the lowest quartile with systolic BP <114 mmHg were significantly higher [HR 1.43, 95% confidence interval (CI) 1.13-1.81; and HR 1.47, 95% CI 1.01-2.12, respectively] than in the third quartile, even after adjusting for known confounding factors. In patients with a systolic BP of ≥150 mmHg, adjusted HR for major bleeding was significantly higher than that of <150 mmHg (HR 1.64, 95% CI 1.12-2.40). In Japanese patients with NVAF, a baseline systolic BP <114 mmHg was significantly associated with higher all-cause and cardiovascular mortality. In contrast, a systolic BP ≥150 mmHg was an independent risk factor for major bleeding.

Clinical Presentation, Risk Factors and Outcome of Splanchnic Venous Thrombosis: A Report on 305 Cases

Background and Aims: Splanchnic vein thrombosis (SVT) is a manifestation of unusual site venous thromboembolism. Most common predisposing factors for SVT include liver cirrhosis, solid abdominal cancer, myeloproliferative neoplasms (MPN), and abdominal infection or inflammatory diseases. Complex balance between bleeding risk and the risk of thrombus extension or recurrence makes the management of SVT a clinical challenge. In this study, we reported clinical presentation and outcome data of patients with SVT followed in our center from January 2000 to December 2021, with a focus on MPN and cirrhotic patients. Methods: We performed a retrospective review of clinical reports of 305 SVT patients. According to PLT count in patients with no active bleeding, anticoagulation treatment was started as soon as possible with: no treatment for a platelet count <30.000/μl; prophylactic dose of LMWH or related drugs for a platelet count range 30.000 -50.000/μl and therapeutic dose low-molecular-weight heparin (LMWH) followed by early initiation of vitamin-K antagonist (VKA; INR range 1.8-2.5) for a platelet count >50.000/μl. Moreover, cytoreductive therapy was administered in MPN patients and prophylaxis with beta-blockers and endoscopic therapies were applied in cirrhotic SVT. Cox regression analysis was used to identify independent predictors of recanalization and overall survival. The Kaplan-Meier method was performed to estimate the overall survival and the time to reach vessel recanalization. Results: In a median follow up of 16.1 months (range, 1-346), 305 patients experienced a SVT (median age 59 years; 68.2% males). Isolated portal vein thrombosis was the most common site of thrombosis (55.1%), followed by multiple venous involvement (28.9%). Six patients developed a Budd-Chiari syndrome. SVT were associated to chronic liver disease, solid cancer and abdominal infections in 212 (69.5%), 100 (32.8%) and 34 (11.5%) patients, respectively. Ninety-seven patients had splenomegaly. MPN was identified in 38 (12.5%) patients. Among these patients, JAK2 and CALR mutation were detected in 81.6% and 13.2%, respectively, and abnormal karyotype in 10.5%. Ascites and esophageal varices were present in 47.5% and 48.8% of patients, respectively. Therapeutic decisions were taken as a multidisciplinary team, involving the use of VKA and LMWH in 70 and 163 patients, respectively. In addition, trans-jugular intrahepatic portosystemic (TIPS) or other surgical shunting was undertaken in 12% and variceal banding in 11%. In a median duration therapy of 9.6 months, bleeding complications and recanalization were reported in 9.5% and 35.4% of patients, respectively. At univariate analysis, VKA exposure was associated with a significantly lower risk of bleeding events compared to LMWH (p=0.039), while esophageal varices (p=0.049), leukocytosis at time of thrombosis (p=0.048), liver cirrhosis (p=0.010) and solid tumor (p=0.021) were associated with lack of recanalization. Only one death was attributed to fatal bleeding, whereas 76 patients died for causes not related to anticoagulation (cirrhosis, cancer, MPN evolution) with a median OS was not reached (range, 107,89-NR). Factors associated with poor survival included age (p<0.001), MPN (p=0.047), recurrent thrombosis (p=0.041), alkaline phosphatase (p=0.013), gamma-GT (p<0.001), albumin (p=0.021), MELD score (p=0.004), lack of recanalization (p<0.001), bleeding event (p=0.043), ascites (p=0.009), and antithrombotic therapy (p=0.006, Figure 1). Among MPN patients, poor survival outcome was also associated with driver mutations (p=0.034), hemoglobin level at thrombosis (p<0.001), splenomegaly (p=0.019), and cytoreductive therapy (p=0.019). Conclusions: Outcome in SVT patients mostly depends on the presence of an underlying MPN, liver failure, active bleeding, recurrence and recanalization rate. Moreover, the anticoagulant treatment was associated with a low bleeding incidence also in patients with major risk factors for bleeding (i.e. liver cirrhosis, cancer or esophageal varices). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Oral Anticoagulants in Very Elderly Nonvalvular Atrial Fibrillation PatientsWith High Bleeding Risks: ANAFIE Registry.

Data on the effectiveness and safety of oral anticoagulant (OAC) agents in very elderly nonvalvular atrial fibrillation patients with high bleeding risk are lacking. This study examined 2-year outcomes and effects of OAC agents among these patients using the ANAFIE (All Nippon Atrial Fibrillation in the Elderly) registry (N=32,275) data. Patients were classified into high-risk (age:≥80 years; CHADS2 score:≥2; and presence of≥1 bleeding risk factor: creatinine clearance of 15-30mL/minute, prior bleeding at critical sites, body weight of≤45kg, or continuous antiplatelet use) and reference groups. In the high-risk (n=7,104) and reference (n=25,171) group patients, 89.0% and 93.4%, respectively, used OAC agents. Of these, respectively, 30.1% and 24.2% used warfarin, and 58.9% and 69.1% used direct-acting OAC (DOAC) agents. Compared with the reference group, the high-risk group had higher incidences of stroke/systemic embolism, major bleeding, intracranial hemorrhage, gastrointestinal bleeding, cardiovascular events, and all-cause death. In the high-risk group, DOAC agent use vs nonuse of OAC agents was associated with reduced incidences of stroke/systemic embolism (HR: 0.53; 95%CI: 0.36-0.79) and all-cause death (HR: 0.65; 95%CI: 0.52-0.81) but not with major bleeding (HR: 1.09; 95%CI: 0.63-1.89). DOAC agents were superior to warfarin in effectiveness and safety. For high-risk patients, history of major bleeding, severe liver dysfunction, and falls within 1 year were independent risk factors for major bleeding. High-risk elderly nonvalvular atrial fibrillation patients had higher event incidences. DOAC agents were associated with reduced risk of stroke/systemic embolism and all-cause death vs nonuse of OAC agents or warfarin. (Prospective Observational Study in Late-Stage Elderly Patients With Nonvalvular Atrial Fibrillation [ANAFIE registry]; UMIN000024006).

In-hospital major bleeding in patients with acute coronary syndrome medically treated with dual anti-platelet therapy: Associated factors and impact on mortality.

Major bleeding is associated with poor hospital prognosis in patients with acute coronary syndrome (ACS). Despite its clinical importance, there are limited studies on the incidence and risk factors for major bleeding in ACS patients with dual anti-platelet therapy (DAPT) without access to revascularization. We analyzed data from 19,186 patients on DAPT after ACS with no access to revascularization from Clinical Pathway for Acute Coronary Syndrome in China Phase 3 (CPACS-3) cohort, which was conducted from 2011 to 2014. Major bleeding included intracranial hemorrhage, clinically significant bleeding, or bleeding requiring blood transfusion. Factors associated with in-hospital major bleeding were assessed using Poisson regressions with generalized estimating equations to account for the clustering effect. A total of 75 (0.39%) patients experienced major bleeding during hospitalization. Among subtypes of ACS, 0.65% of patients with STEMI, 0.33% with NSTEMI, and 0.13% with unstable angina had in-hospital major bleeding (p < 0.001). The patients who experienced major bleeding had a longer length of stay (median 12 vs. 9 days, p = 0.011) and a higher all-cause in-hospital death rate (22.7 vs. 3.7%, p < 0.001). Multivariable analysis showed advancing age (RR = 1.52 for every 10 years increase, 95% CI: 1.13, 2.05), impaired renal function (RR = 1.79, 95% CI: 1.10, 2.92), use of fibrinolytic drugs (RR = 2.93, 95% CI: 1.55, 5.56), and severe diseases other than cardiovascular and renal diseases (RR = 5.56, 95% CI: 1.10, 28.07) were associated with increased risk of major bleeding, whereas using renin-angiotensin system inhibitors (RR = 0.54, 95% CI: 0.36, 0.81) was associated with decreased risk of major bleeding. These independent factors together showed good predictive accuracy with an AUC of 0.788 (95% CI: 0.734, 0.841). Among ACS patients on DAPT, advancing age, impaired renal function, thrombolytic treatment, and severe comorbidities were independently associated with a higher risk of in-hospital major bleeding.

Incidence and risk factors for major bleeding events in atrial fibrillation patients on direct oral anticoagulant therapy: data from the National Patient-Centered Clinical Research Network

Abstract Background Direct oral anticoagulation (DOACs) prevent stroke in patients with atrial fibrillation (AF) and have a superior safety profile compared with vitamin K antagonists (VKA). Yet, better definition of incidence and risk factors for major bleeding associated with DOACs in clinical practice may be important given emerging stroke prevention technologies, both pharmacologic and nonpharmacologic. Purpose To describe the incidence of and risk factors for major bleeding in individuals with AF on DOAC therapy. Methods We reviewed electronic health record data for two patient cohorts with AF prescribed DOACs: (1) Duke University Health System (DUHS) (2010–2018) and (2) Sites within the Patient-Centered Clinical Research Network (PCORnet) (2015–2019) which had ≥6 years assimilated data from both inpatient and outpatient encounters (7 sites). In each cohort, we assessed the 5-year incidence of major bleeding events defined as hospitalization for intracranial hemorrhage, or hospitalization for gastro-intestinal bleeding or procedure to control bleeding accompanied by transfusion within ±7 days or death within 30 days. Multivariable Fine-Gray proportional hazards modeling in each cohort was performed to evaluate independent risk factors for major bleeding on DOAC therapy. Results The cohorts included 10,625 patients (DUHS) and 58,321 patients (PCORnet) with AF. Major bleeding events occurred within 5 years of diagnosis in 639 (7.9%) of DUHS patients and 2568 (6.6%) of PCORnet patients (Table 1). The DUHS model predicted time to first major bleeding event with a C-index of 0.756 (95% CI 0.737, 0.775) and the PCORNet model had a c-index of 0.745 (0.736, 0.755) (Table 2). Independent factors associated with major bleeding consistent across both models (p&amp;lt;0.001 in PCORnet for all unless noted) were higher CHA2DS2-VASc scores, lower eGFR, anemia (HR per 1-point increase in hemoglobin up to 12 g/dL 0.79 [0.76, 0.82]), prior major bleeding (HR 2.70 [2.22, 3.30]), cancer (HR 1.23 [1.12, 1.36]), recent cardiac surgery (HR 0.70 [0.51, 0.97]; p=0.030), alcohol use (HR 1.56 [1.29, 1.88]), aspirin use (HR 1.44 [1.32, 1.57]), and selective serotonin reuptake inhibitor use (HR 1.30 [1.19, 1.42]). Conclusions Across a large and geographically diverse contemporary population, risk of bleeding on DOAC for stroke prevention in AF remains a frequent and important clinical problem. There is an unmet need for stroke prevention therapies with improved safety profiles. We identified risk factors for major bleeding events on DOAC therapy, some of which are not represented in traditional risk scores, which may inform shared decision making for stroke prevention. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer Pharmaceuticals