Major Bleeding In Patients Research Articles

Prognostic Impact of Active Cigarette Smoking on Mortality in Patients with Acute Venous Thromboembolic Events, Findings from Real World Data.

Background and Objectives: The influence of smoking habits on mortality, VTE recurrence, and major bleeding in patients receiving anticoagulant therapy for venous thromboembolism (VTE) has not been consistently evaluated. Materials and Methods: We used data from the RIETE (Registro Enfermedad TromboEmbólica) registry to compare mortality, VTE recurrence, and major bleeding risk in smoking versus non-smoking patients with acute VTE. Results: 50,881 patients (43,426 non-smoking and 7455 smoking patients) were included. After a median follow-up of 8.8 months, 7110 patients died (fatal PE 292 and fatal bleeding 281), 3243 presented VTE recurrence, and 1579 had major bleeding. At multivariate analysis, smoking behavior was associated with a higher hazard of death, (HR: 1.28; 95% CI: 1.19–1.40). The risk of VTE recurrence was marginally increased in smoking patients compared to non-smoking patients (1.14; 95% CI: 1.02–1.27). Major bleeding did not differ in smoking and non-smoking patients (1.15; 95% CI: 0.96–1.38). The presence of cancer did not appear to influence the association between smoking habits and death (HR: 1.34; 95% CI: 1.22–1.47 in cancer patients and HR: 1.23; 95% CI: 1.04, 1.45 in non-cancer patients, respectively) Conclusions: the risk of death after an acute episode of VTE appeared to be higher in smoking than in non-smoking patients and this risk is higher between patients presenting PE at the onset of symptoms.

Major bleeding during oral anticoagulant therapy associated with factor V activation by factor Xa

ObjectivePlasma thrombin generation (TG) provides important information on coagulation status; however, current TG output parameters do not predict major bleeding of patients on anticoagulants. We recently reported that factor V (FV) activation by factor X (FX)a contributes importantly to the initiation phase of TG. Here we investigated how this pathway varies in the normal population and whether FXa‐mediated activation of FV is associated with major bleeding in patients on anticoagulant therapy. ApproachWe employed TIX‐5, a specific inhibitor of FV activation by FXa, to estimate the contribution of FXa‐mediated FV activation to tissue factor (TF)–initiated TG. ResultsWe show that the contribution of this pathway to plasma TG varies considerably in the normal population, as measured by the time needed to form the first traces of thrombin (TG lag time; mean prolongation by TIX‐5 40%, range 0%–116%). Comparing patients on vitamin K antagonists (VKA) of the BLEED study (263 patients with and 538 patients without major bleeding), showed a marked prolongation in the median TG lag time in the presence of TIX‐5 in cases (12.83 versus 11.00 minutes, P = 0.0030), while the TG lag time without TIX‐5 only showed a minor although significant difference (5.83 vs. 5.67 minutes, P = 0.0198). The TIX‐5 sensitivity (lag time + TIX‐5/lag time + vehicle) in the upper quartile was associated with a 1.62‐fold (95% confidence interval 1.04–2.52) increased risk of major bleeding compared to the lowest quartile. ConclusionA greater dependence on FXa‐mediated activation of FV of TG is associated with increased risk of major bleeding during VKA therapy.

Genetic Factors of Renin-Angiotensin System Associated with Major Bleeding for Patients Treated with Direct Oral Anticoagulants.

The purpose of this study was to identify the renin–angiotensin system (RAS)-related genetic factors associated with bleeding and develop the bleeding risk scoring system in patients receiving direct oral anticoagulants (DOACs). This study was a retrospective analysis of prospectively collected samples from June 2018 to May 2020. To investigate the associations between RAS-related genetic factors and major bleeding, we selected 16 single nucleotide polymorphisms (SNPs) from five genes (namely, AGT, REN, ACE, AGTR1, and AGTR2). Multivariable logistic regression analysis was employed to investigate the independent risk factors for bleeding and to develop a risk scoring system. A total of 172 patients were included in the analysis, including 33 major bleeding cases. Both old age (≥65 years) and moderate to severe renal impairment (CrCl < 50 mL/min) increased the risk of bleeding in the multivariable analysis. Among RAS-related polymorphisms, patients carrying TT genotype of rs5050 and A allele of rs4353 experienced a 3.6-fold (95% CI: 1.4–9.3) and 3.1-fold (95% CI: 1.1–9.3) increase in bleeding, respectively. The bleeding risk increased exponentially with a higher score; the risks were 0%, 2.8%, 16.9%, 32.7%, and 75% in patients with 0, 1, 2, 3, and 4 points, respectively. Although this study is limited to a retrospective study design, this is the first study to suggest RAS-related genetic markers and risk scoring systems, including both clinical and genetic factors, for major bleeding in patients receiving DOAC treatment.

Are NOACs as safe and efficient as VKA regarding thromboembolic prophylaxis and major bleeding in patients with surgical bioprosthesis and atrial fibrillation within 3 months of surgery?

SummaryA best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: ‘Are NOACs as safe and efficient as vitamin K antagonist regarding thromboembolic prophylaxis and major bleeding in patients with surgical bioprosthesis and atrial fibrillation within 3 months of surgery?’ Altogether more than 324 papers were found using the reported search, of which 6 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The RIVER and ENAVLE trials showed non-inferiority of rivaroxaban (regarding mean time free from composite of death, major cardiovascular events or major bleeding at 12 months) and edoxaban (composite of death, clinical thromboembolic events or asymptomatic intracardiac thrombosis; and major bleeding) when compared with vitamin K antagonist. These studies include a low number of patients within 3 months of index surgery and overall low statistical power regarding this particular subgroup of patients. Data derived from lower evidence studies are compatible with the aforementioned findings. The available evidence suggests that non-vitamin K antagonist anticoagulants are as safe and as efficient as vitamin K antagonist regarding thromboembolic prophylaxis and bleeding event rates in patients with surgical bioprosthesis and atrial fibrillation within 3 months of bioprosthesis implantation. However, this evidence is derived from a limited number of studies with important methodological limitations. Expanding non-vitamin K antagonist anticoagulant recommendation to the early postoperative period warrants more confirmatory research.

Associations of anemia with death and major bleeding in patients with atrial fibrillation: A report from the Chinese Atrial Fibrillation Registry Study

BackgroundAnemia is a common comorbidity in patients with atrial fibrillation (AF). Reports on the association of anemia and adverse events in patients with AF, especially from Asia, are limited.Methods and ResultsBased on data from the Chinese Atrial Fibrillation Registry Study (CAFR), a total of 18,106 AF patients enrolled between August 2011 and December 2018 had hemoglobin (Hb) values recorded at baseline. Patients were classified into three groups according to Hb levels: 15,606 patients (86.2%) into the no anemia group (male Hb≥130 g/L; female Hb≥120 g/L), 1800 (9.9%) with mild anemia (male 110≤Hb<129 g/L; female 110≤Hb<119 g/L), and 700 (3.9%) with moderate to severe anemia (Hb≤109 g/L). Multivariable Cox regression models were used to determine if anemia was independently associated with all‐cause death, cardiovascular death, or major bleeding, after adjusting for confounders.Anemia was present in 13.8% of the population at baseline. During a median follow‐up of 4.01 years, the incidences of all‐cause death (1.8, 4.9, and 8.9 per 100 person‐years), cardiovascular death (1.0, 2.9, and 4.5 per 100 person‐years), and major bleeding (0.5, 0.6, and 0.7 per 100 person‐years) were gradually accentuated in patients with no anemia, mild anemia, and moderate to severe anemia, respectively. Compared with patients with no anemia, those with anemia had higher risks for all‐cause death (mild anemia; adjusted hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.08–1.38; moderate to severe anemia; adjusted HR: 1.53, 95% CI: 1.31–1.77); and cardiovascular death (mild anemia; adjusted HR: 1.29, 95% CI: 1.10–1.52; moderate to severe anemia; adjusted HR: 1.27, 95% CI: 1.03–1.57), but not for major bleeding. The association between anemia and all‐cause death was similar among subgroups stratified by sex, kidney function, anticoagulant, or ablation therapy.ConclusionsAnemia was associated with increased risks of all‐cause death, cardiovascular death, but no major bleeding in AF patients. The effect of anemia correction on the prognosis of patients with AF requires further study.

Simplified Academic Research Consortium for High Bleeding Risk (ARC-HBR) Definition Predicts Bleeding Events in Patients With Heart Failure.

It has recently been reported that the simplified Academic Research Consortium for High Bleeding Risk (ARC-HBR) definition, which excludes 6 rare criteria, is comparable to the original ARC-HBR definition in predicting major bleeding in patients with coronary artery disease (CAD) who undergo percutaneous coronary intervention. In this study, we investigated whether the simplified ARC-HBR definition could be applied to patients with heart failure (HF) to identify those at high bleeding risk (HBR).Methods and Results:In all, 2,437 patients hospitalized for HF were enrolled in this study. Patients were divided into 2 groups based on the simplified ARC-HBR definition: those at HBR (n=2,026; 83.1%) and those not (non-HBR group; n=411; 16.9%). The HBR group was older (72.0 vs. 61.0 years; P<0.001) and had a lower prevalence of CAD (31.1% vs. 36.5%; P=0.034) than the non-HBR group. Kaplan-Meier analysis showed that post-discharge bleeding events defined as hemorrhagic stroke or gastrointestinal bleeding were more frequent in the HBR than non-HBR group (log-rank P<0.001). The simplified ARC-HBR definition accurately predicted bleeding events (Fine-Gray model; hazard ratio 2.777, 95% confidence interval 1.464-5.270, P=0.001). The simplified ARC-HBR definition predicts a high risk of bleeding events in patients with HF.

In-Hospital Characteristics and 30-Day Readmissions for Acute Myocardial Infarction and Major Bleeding in Patients With Active Cancer

There are limited data on readmission with ischemic and major bleeding events in patients with acute myocardial infarction (AMI) with active cancer. The purpose of our study was to evaluate in-hospital characteristics and 30-day readmission rates for recurrent AMI and major bleeding by cancer type in patients with AMI and active cancer. From 2016 through 2018, patients in the Nationwide Readmission Database admitted with AMI and underlying active colon, lung, breast, prostate, and hematological cancers were included. Thirty-day readmission for recurrent AMI and major bleeding were reported. Of 1,524,677 index hospitalizations for AMI, 35,790 patients (2.2%) had cancer (0.9% hematological; 0.5% lung; 0.4% prostate; 0.2% breast; and 0.1% colon). Compared with patients without cancer, patients with cancer were about 6 to 10 years older and had a higher proportion of atrial fibrillation, valvular heart disease, previous stroke, and a greater co-morbidity burden. Of all cancer types, only active breast cancer (adjusted odds ratios 1.82, 95% CI 1.11 to 2.98) was found to be significantly associated with elevated odds of readmission for major bleeding; no such association was observed for recurrent AMI. In conclusion, AMI in patients with breast cancer is associated with significantly greater odds of readmission for major bleeding within 30 days after discharge. Management of patients with concomitant AMI and cancer is challenging but should be based on a multidisciplinary approach and estimation of an individual patient's risk of major coronary thrombotic and bleeding events.

Anticoagulation use and the risk of stroke and major bleeding in patients on hemodialysis: From the VIVALDI, a population‐based prospective cohort study

BackgroundEvidence supporting the use of anticoagulation for the prevention of stroke and thromboembolism in patients with kidney failure on hemodialysis (HD) and atrial fibrillation (AF) is limited. We prospectively assessed the incidences of stroke and major bleeding, as well as anticoagulation strategies in patients on HD with AF. MethodsWe recruited 625 prevalent HD patients into a population‐based observational cohort study. The primary prospective outcomes were thromboembolic events (stroke, transient ischemic attack, systemic embolism) and major bleeding. Secondary outcomes included a composite of thromboembolic events, major bleeding, and cardiovascular death to determine net clinical harm. ResultsA total of 238 patients (38.1%) had AF, 165 (26.4%) already at baseline and 73 (15.9%) developed AF during a median follow up of 870 days. Forty (6.4%) thromboembolic events and 89 (14.2%) major bleedings occurred. Overall, 256 patients died (41.0%). In AF patients, use of vitamin K antagonists (VKAs) in 61 patients (25.6%) was not significantly associated with reduced risk of the primary thromboembolic outcome (subdistribution hazard ratio [SHR] 1.41 adjusted for age, sex, congestive heart failure, hypertension, stroke/transient ischemic attack/thromboembolism, vascular disease, and diabetes history score and antiplatelet co‐medication (95% CI, 0.49–4.07), but with increased risk of major bleeding (SHR: 2.28; 95% CI, 1.09–4.79) compared with AF patients without anticoagulation (N = 139, 58.4%). Use of VKAs was associated with net clinical harm (adjusted SHR: 2.07; 95% CI, 1.25–3.42). ConclusionsAlthough the nonrandomized nature of the study is prone to bias, anticoagulation with VKAs was not associated with decreased thromboembolic risk, but rather with increased risk of major bleeding and may be net harmful to patients with AF on HD.

Simple risk-score model for in-hospital major bleeding based on multiple blood variables in patients with acute myocardial infarction

BackgroundIn-hospital bleeding is associated with poor prognosis in patients with acute myocardial infarction (AMI). We sought to investigate whether a combination of pre-procedural blood tests could predict the incidence of in-hospital major bleeding in patients with AMI. Methods and resultsA total of 1684 consecutive AMI patients who underwent primary percutaneous coronary intervention (PCI) were recruited and randomly divided into derivation (n = 1010) and validation (n = 674) cohorts. A risk-score model was created based on a combination of parameters assessed on routine blood tests on admission. In the derivation cohort, multivariate analysis revealed that the following 5 variables were significantly associated with in-hospital major bleeding: hemoglobin level < 12 g/dL (odds ratio [OR], 3.32), white blood cell count >10,000/μL (OR, 2.58), platelet count <150,000/μL (OR, 2.51), albumin level < 3.8 mg/dL (OR, 2.51), and estimated glomerular filtration rate < 60 mL/min/1.73 m2 (OR, 2.31). Zero to five points were given according to the number of these factors each patient had. Incremental risk scores were significantly associated with a higher incidence of in-hospital major bleeding in both cohorts (P < 0.001). Receiver operating characteristic curve analysis of risk models showed adequate discrimination between patients with and without in-hospital major bleeding (derivation cohort: area under the curve [AUC], 0.807; 95% confidence interval [CI], 0.759–0.848; validation cohort: AUC, 0.793; 95% CI, 0.725–0.847). ConclusionsOur novel laboratory-based bleeding risk model could be useful for simple and objective prediction of in-hospital major bleeding events in patients with AMI.

Abstract 10049: Outcomes, Trends and Predictors of Gastrointestinal Bleeding in Patients Undergoing Transcatheter Aortic Valve Implantation

Introduction: Gastrointestinal bleeding remains one of the most common cause of major bleeding in patients undergoing transcatheter aortic valve implantation. Hypothesis: GI bleed is associated with worse outcomes in patients undergoing TAVI Methods: We investigated trends, outcomes and predictors of major bleeding from 2011 to 2018 using the national inpatient sample database. Results: A total of 216,023 weighted hospitalizations for TAVI were included in the analysis. Among the included hospitalizations, 2188 patients had GI bleed (1%) whereas 21,385 (99%) patients did not have GI bleed. Presence of peptic ulcer disease was found to be associated with the highest odds of having a GI bleed with an OR 10.24[95% CI, 7.93-13.22] followed closely by colorectal cancer OR 8.02[CI, 185.40-11.91]. Other comorbidities associated with higher adjusted rates of GI bleed were chronic kidney disease ([OR], 1.28[confidence interval (CI), 1.15-1.42]), congestive heart failure (OR, 201.21[CI, 1.08-1.35]), liver disease (OR, 1.82[CI, 1.52-1.2.18]), end stage renal disease (OR, 212.13[CI, 1.79-2.52]), atrial fibrillation (OR, 1.64[CI, 1.50-.77.]) and lung cancer (OR, 2.68[CI, 221.70-4.24]). Over the study period, mortality in patients with a GI bleed with TAVI decreased from 13.6% in 2011 to 11.50% in 2018 along with a decrease in mortality in TAVI without GI bleed group as well. Patients with GI bleed had increased mortality rates as compared those without GI bleed, (12.1% 10 vs 2.1%, p&lt;0.01). Conclusions: In conclusion, we report that mortality is higher in TAVI patients with a GI bleed. Presence of peptic ulcer disease, colorectal cancer or baseline comorbidities like atrial fibrillation and end stage renal disease are important predictors of this adverse event.

Abstract 9726: Simplified Academic Research Consortium for High Bleeding Risk Criteria Predicts Bleeding Events in Patients with Heart Failure

Introduction: It has been reported that the simplified Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria in which six rare criteria are excluded are comparable to the original ARC-HBR criteria in predicting major bleeding in patients who undergo percutaneous coronary intervention. We aimed to evaluate the predictive value of the simplified ARC-HBR criteria for bleeding events in patients with heart failure (HF) including those with and without coronary artery disease (CAD). Methods and Results: A total of 2,437 patients hospitalized for HF were enrolled. Among them, 56.5%, 23.7%, 15.8%, 4.8%, 4.7%, and 3.0% presented with oral anticoagulation, anemia, renal dysfunction, thrombocytopenia, active malignancy, and stroke of major criteria. Patients were divided into two groups based on the simplified ARC-HBR criteria: patients who are at HBR (HBR group, n = 2,026, 83.1%) and those who are not (non-HBR group, n = 411, 16.9%). The HBR group was older (72.0 vs. 61.0 years old, P &amp;lt; 0.001) and had lower prevalence of CAD (31.1% vs. 36.5%, P = 0.034) than the non-HBR group. The Kaplan-Meier analysis showed that post-discharge hemorrhagic stroke and gastrointestinal bleeding rates were higher in the HBR group than in the non-HBR group ( Figure ). In the Cox proportional hazard analysis, the simplified ARC-HBR criteria predicted both hemorrhagic stroke (hazard ratio [HR] 2.827, 95% confidence interval [CI] 1.019-7.844, P = 0.046) and gastrointestinal bleeding (HR 3.565, 95% CI 1.560-8.145, P = 0.003) irrespectively of CAD (interaction P = 0.931 and 0.761, respectively). Conclusions: The simplified ARC-HBR criteria predicts high bleeding events in patients with HF.

Anticoagulation Use and Outcomes Among Patients with Atrial Fibrillation and Von Willebrand Disease

Intro: Von Willebrand disease (VWD) is a coagulopathy caused by deficiency or dysfunction of von Willebrand factor (VWF), resulting in prolonged and excessive bleeding. Patients are advised to avoid aspirin (ASA), P2Y12 inhibitors, or anticoagulation (AC) so as not to exacerbate this condition. However, typical treatment for atrial fibrillation (AF) includes anticoagulation, particularly if the risk of stroke by CHA 2DS 2-VASC score is 2+. Current recommendations suggest giving necessary antiplatelet (AP) or AC therapy over no treatment with assessment of bleeding risk throughout the course. However, this is a conditional recommendation based on low certainty in evidence, and there are no specific guidelines on treating AF in patients with VWD. This study aims to assess anticoagulation use, bleeding risk, and stroke risk in patients with VWF and AF.Methods: We conducted an IRB-approved analysis of coded data from institutional electronic medical records to select patients with diagnosis of VWD, low ristocetin cofactor level, or any abnormal VWF panel as well as patients with diagnosis of AF or atrial flutter. Three hundred and forty patients met criteria. Patients were manually screened for inclusion criteria and excluded for inaccurate diagnosis or insufficient data. Eighty-nine patients were included in the analysis. Primary endpoint was rate of major bleeding defined by ISTH criteria while on AC or AP. Categorical data were tested using the Fisher exact test at the nominal 0.05 two-sided significance level, and all person-time comparisons are made against the rate of bleeding on AC alone.Results: Most patients were female (64.0%; 57/89), and 28.1% (25/89) were deceased at the time of data collection. Date of diagnosis of AF ranged from 1980-2020. 42.7% (38/89) of patients were ever prescribed ASA, 43.8% (39/89) a P2Y12 inhibitor, 56.2% (50/89) AC, and 23.6% (21/89) had never been prescribed AP or AC. Of patients with a CHA 2DS 2-VASC of 2+, 57.5% (46/80) were ever prescribed AC. 32.0% (16/50) of patients ever prescribed AC and 25.6% (10/39) patients never prescribed AC had at least one major bleeding event (p=0.428). The rate of major bleeding on AC alone was 8.9 events per 100 person-years (32 events/359.2 years), 10.2 events per 100 person-years on AP alone (41 events/402.3 years) (p=0.572), and 1.06 events per 100 person-years (8 events/757.47 years) in patients never prescribed AC or AP (p=<0.0001). Notably, the rate of major bleeding on AC and AP together was 28.07 events per 100 person-years (23 events/81.94 years) (p=<0.0001) occurring in 7 patients, 6 of whom also had a diagnosis of acute coronary syndrome (ACS). Length of time to first major bleed is shown in Figure 1. 16.9% (15/89) of patients had thromboembolic strokes after diagnosis of AF, and 53.3% (8/15) of those strokes occurred when patients were not prescribed AC.Discussion: This retrospective observational study over 40 years characterizes AC and AP use in patients with VWD and AF. Only 57.5% of patients with CHA 2DS 2-VASC of 2+ received standard of care AC despite conditional recommendations to give necessary anticoagulation to patients with VWD. In parallel with the general population, AC use significantly increases the rate of major bleeding in patients with VWD, but there was no difference in bleeding rate between standard AC and AP monotherapy. However, major bleeding rates were notably elevated in patients prescribed concomitant AC and AP which most commonly occurred in the setting of ACS. This analysis is limited by its retrospective nature, the lack of granular details in the coded database, and incomplete data in older charts. Overall, these data do not support the use of AP monotherapy over standard AC to reduce bleeding rates for patients with VWD and AF. Additionally, AC and AP co-administration should be avoided due to high rates of major bleeding, but more studies are required to understand AP and AC strategies in patients with VWD, AF, and ACS. Although the rate of major bleeding is elevated with AC use in patients with VWD, there is no difference in lifetime prevalence of major bleeding events by AC vs no AC use. Finally, over half of thromboembolic strokes occurred when not prescribed AC. Shared decision-making around stroke and bleeding risk is advised in considering AC use for AF in patients with VWD. Prospective studies should further evaluate the risk of major bleeding and stroke in patients with VWD and AF on standard AC vs no AC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Bleeding Risk in Patients with Multiple Myeloma Treated for Venous Thromboembolism

▪Introduction:Multiple myeloma diagnosis is associated with a 10-15% absolute risk of venous thromboembolism (VTE) due to disease-related (i.e., vascular inflammation, hyperviscosity) and treatment-related risk factors (i.e., immunomodulatory drugs [IMiDs], high-dose dexamethasone). This has led to ongoing clinical trials to determine the best thromboprophylaxis strategy. In contrast, the risk of major bleeding following incident VTE events in patients with MM is not well described. We conducted a real-world analysis of bleeding complications in MM following anticoagulation treatment for VTE.Methods:The IBM MarketScan Commercial Claims Database was used to identify adults with MM diagnosis and an incident VTE event between 2011 and 2019. MM and VTE were defined as 1 inpatient or 2 outpatient claims based on International Classification of Diseases (ICD) 9th and 10 th Revision codes, and at least 1 prescription for anticoagulation within 31 days of first VTE claim. IMiD-related VTE was defined in subjects with an IMiD prescription prior to the VTE event. Major bleeding was defined as bleeding requiring hospitalization using inpatient ICD codes as previously validated (Cunningham algorithm). Patients were followed from index VTE and initiation of anticoagulation to first major bleeding event, disenrollment (due to death or other reasons) or December 31, 2019. Descriptive statistics were used to calculate the rate of major bleeding. Cox regression was used to determine risk factors associated with major bleeding.Results:Our population included 1,605 patients with a diagnosis of multiple myeloma and an incident VTE event requiring treatment. Anticoagulant agent of choice was warfarin in 45.7% (734), low-molecular weight heparin (LMWH) in 29% (466), and direct oral anticoagulants (DOAC) in 25.3% (405). There were no significant differences in age/sex distribution, comorbidity burden, history of significant bleeding, or use of IMiD across the different types of anticoagulation (Table 1). Hospitalized bleeding occurred in 63 (3.9%) patients during an average follow-up of 1.6 years, yielding an overall incidence rate of major bleeding in multiple myeloma patients starting anticoagulation for a new VTE event of 24.1 per 1,000 person-years. Adjusting for age and sex, risk factors significantly associated with risk of major bleeding included Charlson comorbidy index [CCI] (per standard deviation [SD] increment, HR 1.29, 95%CI 1.03 - 1.62), diabetes (HR 1.71, 95%CI 1.06 - 2.92), and liver disease (HR 1.96, 95%CI 1.04 - 3.68). The use of IMiDs was not associated with increased risk of major bleeding (Table 2). The cumulative incidence of major bleeding by VTE anticoagulation strategy in multiple myeloma was 4.8% in warfarin group and 3.2% in the LMWH and DOAC groups, though the difference was not statistically significant after adjusting for age and sex. The estimated incidence rate of bleeding was 25.7, 20.1, and 25.2 per 1,000 person-years for patients treated with warfarin, LMWH, and DOACs, respectively. In an adjusted model for age, sex, CCI, diabetes and liver disease, patients treated with LMWH and DOACs had HR for major bleeding of 0.91 and 0.82, respectively, compared to anticoagulation with warfarin, though this was not statistically significant.Discussion:In a real-world analysis of commercial claims data, the rate of major bleeding in patients with multiple myeloma receiving anticoagulation for VTE appears to be comparable to those reported in other subsets of cancer associated VTE. Surprisingly, almost half of identified patients were treated with warfarin, a non-preferred option in this setting. The point estimate of major bleeding was lower in patients treated with LMWH or DOACs compared to warfarin, though the association was not statistically significant and larger studies are needed. Higher CCI, diabetes and liver disease were clinical factors associated with higher risk of major bleeding and may be included in risk assessment models to help clinicians assess individual bleeding risk in patients with multiple myeloma treated for VTE. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk of Major Bleeding with Ibrutinib in Patients with Thrombocytopenia - a Retrospective Single-Center Canadian Study

Risk of Major Bleeding with Ibrutinib in Patients with Thrombocytopenia - a Retrospective Single-Center Canadian Study

Direct Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves

Direct Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves

Multiplex protein screening of biomarkers associated with major bleeding in patients with atrial fibrillation treated with oral anticoagulation

BackgroundOral anticoagulants (OAC) in patients with atrial fibrillation (AF) prevent thromboembolic events, but are associated with significant risk of bleeding. ObjectivesTo explore associations between a wide range of biomarkers and bleeding risk in patients with AF on OAC. MethodBiomarkers were analyzed in a random sample of 4200 patients, 204 cases with major bleedings, from ARISTOTLE. The replication cohort included 344 cases with major bleeding and 1024 random controls from RE‐LY. Plasma samples obtained at randomization were analyzed by the Olink Proximity Extension Assay cardiovascular and inflammation panels and conventional immunoassays. The associations between biomarker levels and major bleeding over 1 to 3 years of follow‐up were evaluated by random survival forest/Boruta analyses and Cox regression analyses to assess linear associations and hazard ratios for identified biomarkers. ResultsOut of 268 proteins, nine biomarkers were independently associated with bleeding in both cohorts. In the replication cohort the linear hazard ratios (95% confidence intervals) per interquartile range were for these biomarkers: TNF‐R1 1.748 (1.456, 2.098), GDF‐15 1.653 (1.377, 1.985), EphB4 1.575 (1.320, 1.880), suPAR 1.548 (1.294, 1.851), OPN 1.476 (1.240, 1.757), OPG 1.397 (1.156, 1.688), TNF‐R2 1.360 (1.144,1.616), cTnT‐hs 1.232 (1.067, 1.423), and TRAIL‐R2 1.202 (1.069, 1.351). ConclusionsIn patients with AF on OAC, GDF‐15, cTnT‐hs, and seven novel biomarkers were independently associated with major bleedings and reflect pathophysiologic processes of inflammation, apoptosis, oxidative stress, vascular calcification, coagulation, and fibrinolysis. Investigations of the utility of these markers to refine risk stratification and guide the management of patients at high risk of bleeding are warranted.

Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice.

Uncontrolled bleeding after enoxaparin (ENX) is rare but may be life-threatening. The only registered antidote for ENX, protamine sulfate (PS), has 60% efficacy and can cause severe adverse side effects. We developed a diblock copolymer, heparin-binding copolymer (HBC), that reverses intravenously administered heparins. Here, we focused on the HBC inhibitory activity against subcutaneously administered ENX in healthy mice. BALB/c mice were subcutaneously injected with ENX at the dose of 5 mg/kg. After 110 min, vehicle, HBC (6.25 and 12.5 mg/kg), or PS (5 and 10 mg/kg) were administered into the tail vein. The blood was collected after 3, 10, 60, 120, 360, and 600 min after vehicle, HBC, or PS administration. The activities of antifactors Xa and IIa and biochemical parameters were measured. The main organs were collected for histological analysis. HBC at the lower dose reversed the effect of ENX on antifactor Xa activity for 10 min after antidote administration, whereas at the higher dose, HBC reversed the effect on antifactor Xa activity throughout the course of the experiment. Both doses of HBC completely reversed the effect of ENX on antifactor IIa activity. PS did not reverse antifactor Xa activity and partially reversed antifactor IIa activity. HBC modulated biochemical parameters. Histopathological analysis showed changes in the liver, lungs, and spleen of mice treated with HBC and in the lungs and heart of mice treated with PS. HBC administered in an appropriate dose might be an efficient substitute for PS to reverse significantly increased anticoagulant activity that may be connected with major bleeding in patients receiving ENX subcutaneously.

Risk of Major Bleeding in Patients With Atrial Fibrillation Taking Dronedarone in Combination With a Direct Acting Oral Anticoagulant (From a U.S. Claims Database)

Dronedarone may increase exposure and the risk of major bleeding when prescribed with a direct oral anticoagulant (DOAC). This retrospective cohort study examined the risk of the first occurrence of major bleeding (hospitalization or emergency room visit for gastrointestinal [GI] bleeding, intracranial hemorrhage [ICH], or bleeding at other sites) among new users of apixaban, dabigatran, and rivaroxaban in patients with AF ≥18 years (January 1, 2007 to September 30, 2017) from the United States Truven Health MarketScan claims, comparing concomitant users of dronedarone to DOAC alone users in patients with atrial fibrillation (AF). No increased risk of major bleeding was associated with use of dronedarone and apixaban (adjusted Hazard Ratio [aHR]: 0.69 [95% confidence interval [CI]: 0.40, 1.17], p=0.16), a modestly increased risk of GI bleeding but not overall bleeding was associated with use of dronedarone and dabigatran (aHR bleeding: 1.18 [95% CI: 0.89, 1.56], p=0.26; aHR GI bleeding: 1.40 [95% CI: 1.01, 1.93]; p=0.04) and an increased risk of overall bleeding, driven by GI bleeding, was associated with use of dronedarone and rivaroxaban (aHR bleeding: 1.31 [95% CI: 1.01, 1.69]; p=0.04; aHR GI bleeding: 1.39 [95% CI: 0.98, 1.95]; p=0.06), compared to each DOAC respectively. There was no increased risk of ICH associated with combined use of dronedarone and any DOAC. Prospective analyses, preferably randomized controlled studies, are needed to further explore the risk of major bleeding with concomitant use of DOACs and CYP3A4/P-gp inhibitors such as dronedarone.

Influence of renal dysfunction on clinical outcomes in elderly patients with atrial fibrillation: a subanalysis of the phase 3, randomized, placebo-controlled ELDERCARE-AF trial

Abstract Background Renal dysfunction is common in elderly patients with atrial fibrillation (AF) and is thought to be associated with increased risk of thromboembolic and bleeding events. Once-daily low-dose (15 mg) edoxaban was superior to placebo in preventing stroke or systemic embolic events (S/SEE) without significantly increasing major bleeding events in very elderly (≥80 years) non-valvular AF (NVAF) patients in whom standard oral anticoagulant therapy at approved doses was inappropriate (ELDERCARE-AF trial). Little is known about how renal dysfunction affects the effects of low-dose edoxaban in these patients. Purpose We used prespecified subgroup analysis to investigate the relation between renal function (assessed by creatinine clearance, CrCl) and the efficacy and safety of edoxaban in elderly NVAF patients. Methods ELDERCARE-AF patients were divided into 3 subgroups according to baseline CrCl: normal renal function/mild dysfunction (CrCl &amp;gt;50 mL/min), moderate renal dysfunction (CrCl ≥30 to ≤50 [“30–50”] mL/min) and severe renal dysfunction (CrCl ≥15 to &amp;lt;30 [“15–30”] mL/min). Primary efficacy and safety endpoints were annualized incidence of S/SEE and ISTH-defined major bleeding, respectively. Results Of 984 patients randomized to edoxaban 15 mg or placebo (each group N=492), 681 completed the trial. The 303 discontinuations were due to withdrawal of consent (n=158), death (n=135), or other causes (n=10). Discontinuation rate was the same in the edoxaban and placebo groups. S/SEE incidence in patients with CrCl &amp;gt;50, 30–50 and 15–30 mL/min was 2.0%, 1.3% and 3.5%, respectively, in edoxaban, and 4.4%, 4.6% and 9.7%, respectively, in placebo. In those with CrCl 30–50 and 15–30 mL/min, it was significantly lower in edoxaban than in placebo (adjusted hazard ratio [HR], 0.30 [95% CI, 0.10–0.91], p=0.03; and 0.33 [95% CI, 0.16–0.71], p&amp;lt;0.01, respectively). Incidence of major bleeding in patients with CrCl &amp;gt;50, 30–50 and 15–30 mL/min was 1.0%, 1.8% and 6.2%, respectively, in edoxaban, and 0.9%, 1.5% and 2.4%, respectively, in placebo. Incidence of major bleeding in those with CrCl 15–30 mL/min was higher in edoxaban but not significantly (adjusted HR, 2.53 [95% CI, 0.96–6.72], p=0.062). Incidence of gastrointestinal bleeding in patients with CrCl 15–30 mL/min was 4.3% in edoxaban and 1.6% in placebo (adjusted HR, 2.61 [95% CI, 0.79–8.68], p=0.12). Incidence of all-cause death in patients with CrCl &amp;gt;50, 30–50 and 15–30 mL/min was 5.8%, 6.8% and 15.2%, respectively, in edoxaban, and 7.0%, 6.3% and 15.5%, respectively, in placebo (no significant intergroup differences). Conclusions Incidence of S/SEE, major bleeding and all-cause death increased with declining renal function in elderly NVAF patients. Edoxaban 15 mg remained superior to placebo in preventing S/SEE, even in those with moderate to severe renal dysfunction. Incidence of major bleeding in patients with severe renal dysfunction was higher (non-significantly) with edoxaban than with placebo. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi-Sankyo Co., Ltd.

Risk factors of recurrence and major bleeding in patients with intermediate-risk for recurrence of venous thromboembolism: from the COMMAND VTE Registry

Abstract Background/Introduction Patients with venous thromboembolism (VTE), including pulmonary embolism (PE), have a long-term risk of recurrence, and anticoagulation therapy is recommended for the prevention of recurrence. The latest 2019 European Society of Cardiology (ESC) guideline classified the risks of recurrence into low- (&amp;lt;3%/year), intermediate- (3–8%/year), and high- (&amp;gt;8%/year) risk, and recommended the extended anticoagulation therapy of indefinite duration for high-risk patients as well as intermediate-risk patients. However, extended anticoagulation therapy of indefinite duration for all of intermediate-risk patients have been a matter of active debate. Thus, additional risk assessment of recurrence in intermediate-risk patients might be clinically relevant in defining the optimal duration of anticoagulation therapy. Furthermore, bleeding risk during anticoagulation therapy should also be taken into consideration for optimal duration of anticoagulation therapy. However, there are limited data assessing the risk of recurrence as well as bleeding in patients with intermediate-risk for recurrence based on the classification in the latest 2019 ESC guideline. Purpose The current study aimed to identify the risk factors of recurrence as well as major bleeding in patients with intermediate-risk for recurrence, using a large observational database of VTE patients in Japan. Methods The COMMAND VTE Registry is a multicenter registry enrolling consecutive 3027 patients with acute symptomatic VTE among 29 centers in Japan. The current study population consisted of 1703 patients with intermediate-risk for recurrence. The primary outcome measure was recurrent VTE during the entire follow-up period, and the secondary outcome measures were recurrent VTE and major bleeding during anticoagulation therapy. Results In the multivariable Cox regression model for recurrent VTE incorporating the status of anticoagulation therapy as a time-updated covariate, off-anticoagulation therapy was strongly associated with an increased risk for recurrent VTE (HR 9.42, 95% CI 5.97–14.86). During anticoagulation therapy, the independent risk factor for recurrent VTE was thrombophilia (HR 3.58, 95% CI 1.56–7.50), while the independent risk factors for major bleeding were age ≥75 years (HR 2.04, 95% CI 1.36–3.07), men (HR 1.52, 95% CI 1.02–2.27), history of major bleeding (HR 3.48, 95% CI 1.82–6.14) and thrombocytopenia (HR 3.73, 95% CI 2.04–6.37). Conclusions Among VTE patients with intermediate-risk for recurrence, discontinuation of anticoagulation therapy was a very strong independent risk factor of recurrence during the entire follow-up period. The independent risk factors of recurrent VTE and those of major bleeding during anticoagulation therapy were different: thrombophilia for recurrent VTE, and advanced age, men, history of major bleeding, and thrombocytopenia for major bleeding. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation