Risk Of Anticoagulant-related Bleeding Research Articles

Risk Factors Associated with Anticoagulant-Related Bleeding in Patients with Cancer-Associated Thrombosis

Background: Patients with cancer-associated thrombosis (CAT) have a high risk of recurrent venous thromboembolism as well as anticoagulant-related major bleeding. Thus, initiation and maintenance of anticoagulant therapy requires careful consideration of the risk versus benefit of therapy. Prior literature demonstrates that existing bleeding risk models have mediocre to moderate predictive performance for anticoagulant-related bleeding in patients with cancer. Patients with cancer have unique risk factors for bleeding that are absent in many of these models. Thus, we aimed to evaluate the association candidate traditional and cancer-specific risk factors with anticoagulant-related bleeding in a large cohort of patients with CAT. Methods : Using a nationwide cohort of US Veterans, we identified patients diagnosed with CAT with a new prescription for anticoagulant therapy between 2012 and 2020. Eligible anticoagulant therapy included a prescription for at least 30 days of: direct oral anticoagulants (DOACs), direct selective factor Xa inhibitors, low molecular-weight-heparin (LMWH), or vitamin K antagonists (VKA). Patients with outpatient prescriptions for anticoagulation within the six months preceding CAT were excluded. We further identified a subgroup of patients on chemotherapy around the time of CAT diagnosis, chemotherapy cohort. Using the methods of Fine and Gray, we assessed the association between candidate risk factors and clinically significant anticoagulant-related bleeding using competing risk analyses to account for the competing risk of death. Anticoagulant related bleeding was identified using previously validated international classification of disease (ICD) coding, with position dependent on site of bleed. Results : We identified a cohort of 11,731 patients with CAT, of whom 4,298 patients received anti-cancer systemic therapy within 6 months before to 12 months after CAT diagnosis. The most common malignancies represented in the full cohort included lung (23%), gastrointestinal (14%), and prostate (11%). Most patients received anticoagulant therapy with LMWH (47.7%), followed by DOACs (26.8%), VKAs (24.5%), and fondaparinux (1%). When assessing anticoagulant trends over time, DOACs were the treatment of choice by 2018 with 45.3% of patients receiving initial therapy with a DOAC and further increased to 78.1% by 2020. The 6-month and 12-month cumulative incidence of bleeding in the full cohort was 7% (CI 6.5-7.5) and 9.5% (CI 8.9-10.1), respectively. In the chemotherapy cohort, 6-month and 12-month cumulative incidence of bleeding was 7.9% (CI 7.1-8.8) and 12% (CI 10.8-13.2). In both the chemotherapy and full cohorts, the most frequent sites of clinically significant bleeding included gastrointestinal (GI) tract (57.2%, 54.5%), genitourinary (GU) tract (excluding microscopic hematuria) (20.2%, 21.2%), and intracranial hemorrhage (10.4%, 11.4%) respectively. Of the traditional candidate variables assessed in the full cohort, history of bleeding, estimated glomerular filtration rate (eGFR), uncontrolled hypertension, predisposition to falling, history of ischemic stroke, alcohol abuse, anemia (defines as hemoglobin < 13g/dL in men and < 12 g/dL in women), and liver disease had the highest association with anticoagulant-related bleeding. In addition, use of chemotherapy was associated with an increased risk of bleeding. Findings were similar in the chemotherapy cohort, history of ischemic stroke, alcohol abuse, and anemia were no longer associated with bleeding risk. Of cancer specific candidate variables, GI cancer, GU cancer and metastatic cancer was most predictive. Full results of the analyses are in Table 1 for both the full and chemotherapy cohorts. Conclusions : In this study, many candidate variables in available risk prediction models for anticoagulant-related bleeding were not associated with bleeding risk. This may explain the performance of these models in patients with cancer on anticoagulant therapy. We identified cancer-specific candidate variables that were associated with risk of anticoagulant-related bleeding. Incorporation of these cancer-specific variables into available models could improve predictive performance.

Discriminating Risk of Anticoagulant-Related Bleeding in Ambulatory Cancer Patients on Thromboprophylaxis

Introduction: Among patients taking anticoagulants, those with cancer have double the risk of major bleeding (MB). Because they also have a risk of VTE, two large randomized-control trials, AVERT and CASSINI, demonstrated effectiveness of low-dose direct oral anticoagulants (DOACs) for primary prevention of VTE in patients with cancer at high-risk for VTE based on a validated prediction model. Despite demonstrated efficacy, there is limited uptake of primary thromboprophylaxis in clinical practice. This apprehension may, in part, be due to concerns about the risk of bleeding. We aimed to determine the predictive performance of available risk prediction scores for anticoagulant-related bleeding in cancer patients randomized to thromboprophylaxis during participation in the AVERT randomized trial. Methods: Using patients in the modified intent-to-treat analysis in the AVERT randomized controlled trial, we conducted a post-hoc analysis to assess the performance of three available risk prediction scores for anticoagulant-related bleeding in 288 patients randomized to apixaban. We selected scores based on availability of candidate variables: RIETE, VTE Bleed, and Kuijer et al. scores. The primary outcome of interest was development of a MB or clinically relevant non-major bleed (CRNMB). A second analysis was conducted limiting the bleeding event to either a MB or a CRNMB that required a medical intervention. Each bleeding risk score was applied to the cohort with clinical point assignments as in the original papers (Table) . Using a Fine and Gray competing risk model, we tested the association between each score and development of first bleed following anticoagulant prescription. Patients were censored after a MB. The performance of each model was evaluated using time-dependent ROC (model discrimination) and Brier score (model calibration/discrimination). All analyses were conducted using R (4.2.3) and SAS (9.4) statistical software. Results: Between 2014 and 2018, 574 patients were randomized with 563 receiving at least one dose of study medication. A total of 288 patients received apixaban 2.5mg twice daily and 275 received placebo. The mean age was 61 years and mostly women (58.2%). Frequent cancers included: gynecologic (25.8%), lymphoma (25.3%), and pancreatic cancer (13.6%). The median duration of follow-up for the cohort was 183 days with adherence rates of 83.6% and 84.1% with apixaban and placebo respectively. There were 10 MBs and 18 CRNMBs when censoring patients at the time of first bleed. Of the 18 CRNMB events, 6 required a medical intervention. There was no significant association between each 1-point increase in the Kuijer et al. score and risk of MB+CRNMB (subdistribution hazard ratio (sHR) 0.97, p 0.85). However, for each 1-point increase in score in RIETE and VTE BLEED, there was a 72% (sHR 1.72, p <0.0001) and 26% (sHR 1.26, p 0.05) increase in risk of MB+CRNMB respectively. Discrimination of each score at 180 days was 0.69 for RIETE, 0.50 for Kuijer et al., and 0.61 for VTE BLEED. Results of calibration for each score was similar at 180 days was 0.056 for RIETE, 0.059 for Kuijer et al., and 0.058 for VTE BLEED. When limiting analyses to MB+CRNMB that required medical intervention, results remained consistent for the RIETE and Kuijer et al. scores, with a loss of association for the VTE BLEED score. Conclusions: Of the scores analyzed, the RIETE score performed best with moderate discrimination. There is a need to improve the performance of these scores. The ability to quantify risk of anticoagulant-related bleeding in patients who are candidates for primary thromboprophylaxis can allow providers and patients to make informed decisions about primary thromboprophylaxis based on the risk of VTE versus risk of anticoagulant-related bleeding.

External validation of PE-SARD bleeding score for early major bleeding in patients with acute pulmonary embolism: Insight from the COMMAND VTE Registry-2

Abstract Background/Introduction The current guidelines and existing bleeding risk scores focus on assessing the risk of anticoagulant-related bleeding in patients with pulmonary embolism (PE) who are candidates for extended anticoagulation therapy. However, there is no consensus on the risk of bleeding in the acute phase. The Syncope, Anemia, Renal Dysfunction (PE-SARD) bleeding score has been developed to predict early major bleeding in acute PE patients. However, the score has not yet been externally validated. Purpose The present study aimed to externally validate the PE-SARD bleeding score, using a large-scale multicenter observational database of patients with venous thromboembolism (VTE). Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. The present study population was consisted of 2722 patients with PE who received anticoagulation therapy during the acute phase and had a calculated PE-SARD bleeding score. The eligible patients were classified into three groups: high-risk group with a PE-SARD score >2.5 points, intermediate-risk group with a score of 1–2.5 points, and low-risk group with a score of 0 point. The discriminatory and calibration ability of the PE-SARD score for 30-day major bleeding were assessed by calculating the area under the receiver operating characteristic curve and creating a calibration plot, respectively. Results The high-risk group accounted for 537 patients (20%), intermediate-risk group for 1381 (51%), and low-risk group for 804 (30%). The proportion of thrombolysis use did not significantly differ across the groups. Among the patients who received direct oral anticoagulants (DOACs), the proportion of high-dose DOAC initiation was highest (54%) in the low-risk group and lowest in the high-risk group (29%). During the first 30 days of anticoagulation therapy, major bleeding occurred in 118 patients. The cumulative 30-day incidence of major bleeding substantially increased in the higher risk categories by the PE-SARD bleeding score (high-risk group: 8.2% [95% CI, 6.2%–10.9%], intermediate-risk group: 4.5% [95% CI, 3.5%–5.8%], and low-risk group: 1.8% [95% CI, 1.0%–3.0%], long-rank P<0.001). The discriminating power of the score was modest with a C-statistic of 0.65 (95%CI 0.61–0.70). Based on the calibration plot, the PE-SARD bleeding score was well calibrated. A sensitivity analysis excluding 275 outpatients showed similar results. Conclusions The risks of 30-day major bleeding in patients with PE substantially increased in the higher risk categories by using the PE-SARD bleeding score. The score is potentially helpful for management of anticoagulation therapy in the acute phase.The Kaplan-Meier curves

OC 21.5 Risk of Anticoagulant-Related Bleeding in Patients with Venous Thromboembolism. Results from a Large Non-Interventional Cohort

OC 21.5 Risk of Anticoagulant-Related Bleeding in Patients with Venous Thromboembolism. Results from a Large Non-Interventional Cohort

Recurrent Thrombosis and Bleeding in Patients with Cancer-Associated Venous Thromboembolism Receiving Anticoagulation: Are These Modifiable Risk Factors for Mortality?

Patients with cancer associated venous thromboembolism (VTE) have a higher risk of recurrent VTE than those without cancer and require long-term anticoagulation, but these patients are also at higher risk of anticoagulant-related bleeding because of the frequent presence of disease- or treatment-related predispositions for bleeding.

Available Risk Scores Modestly Predict Hemorrhage in Patients with Atrial Fibrillation and Cance

Background: Patients with cancer have an increased risk of developing atrial fibrillation (AF). Patients with cancer who develop AF have an increased risk of cardiovascular-related death at 12-months. Use of anticoagulant therapy may benefit these patients. However, patients with cancer are at increased risk of anticoagulant-related bleeding. Several risk prediction models are available to estimate the risk of anticoagulant-related bleeding in patients with AF. However, these models were developed predominately in patients without cancer. Thus, the utility of these models in cancer is unknown. We aimed to evaluate the performance of existing bleeding risk models in a cohort of patients with active cancer and AF starting on anticoagulant therapy. Methods: Using a nationwide cohort of US Veterans, we identified patients with active cancer and AF with a new prescription for anticoagulant therapy between 2012 and 2018. Cancer was defined as active if the diagnosis of AF occurred within 3 months prior to up to 6 months after new cancer diagnosis or in the setting of incurable hematological cancers (e.g., multiple myeloma, chronic myelogenous leukemia) or metastatic solid tumors. We identified anticoagulant-related major bleeding (MB) within 6 months of anticoagulant start by the presence of inpatient ICD-9/10 codes in any position as previously validated. Patients were censored 30-days after last anticoagulant prescription. We evaluated the predictive performance of six models. The association per standard deviation increase in the score and MB within 6 months of anticoagulant start was estimated using Fine-Gray subdistribution survival analysis to account for the competing risk of death≥÷A sensitivity analysis limiting inpatient ICD-9/10 codes for MB to the first two positions was also performed. We evaluated model discrimination using Harrell's c-statistic. Results: 5716 patients met inclusion criteria into the cohort. The most common types of cancer included: hematological malignancies (24%), lung (20%), prostate (18%), non-prostate genitourinary (11%), and gastrointestinal (10%) cancer. Mean age at the start of anticoagulant therapy was 73.4 years and median overall survival 41.1 months. Of the cohort, anticoagulant therapy was as follows: 2040 warfarin, 179 LMWH, 5 fondaparinux, and 3495 DOAC. 328 (5.7%) patients had a MB within 6 months of anticoagulant start and 439 (7.7%) within 12 months. The most common type of bleeds within the first 6 months of anticoagulant therapy was gastrointestinal (47%), followed by hematuria (28%) and hemoptysis (13.7%). 2.4% of bleeding events (n=8) were intracranial hemorrhage. The increase in hazard of bleeding per each standard deviation increase in bleeding score is in Table 1. For model discrimination, Harrell's c-statistic for each score is also listed in Table 1. Conclusions: In this cohort of 5716 patients with active cancer and atrial fibrillation starting on anticoagulant therapy, available clinical risk models moderately predicted bleeding. The addition of cancer-specific risk factors might improve accuracy of the available models. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Unanswered questions in cancer-associated thrombosis.

Cancer-associated venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. Treatment of cancer-associated VTE comes with a heightened risk of anticoagulant-related bleeding that differs by choice of anticoagulant as well as by patient- and disease-specific risk factors. Available data from randomized controlled trials and observational studies in cancer-associated VTE suggest that direct oral anticoagulants are effective, continuing anticoagulation beyond six months is indicated in those with active cancer and that patients who develop 'breakthrough' thrombotic events can be effectively treated. We review the evidence that addresses these key clinical questions and offer pragmatic approaches in individualizing care. While significant investigative efforts over the past decade have made impactful advances, future research is needed to better define the factors that contribute to anticoagulant-related bleeding and VTE recurrence, in order to aid clinical decision-making that improves the care of patients with cancer-associated VTE.

Off-label reduced-dose apixaban does not reduce hemorrhagic risk in Taiwanese patients with nonvalvular atrial fibrillation: A retrospective, observational study.

East Asians are reportedly at high risk of anticoagulant-related bleeding; therefore, some physicians prefer to prescribe low-dose direct oral anticoagulants (DOACs). Little is known about the therapeutic effectiveness and safety of off-label reduced-dose apixaban in East Asians with nonvalvular atrial fibrillation (AF). We aimed to investigate the effectiveness and safety of off-label reduced-dose apixaban in Taiwanese patients with nonvalvular AF.This retrospective cohort study enrolled 1073 patients with nonvalvular AF who took apixaban between July 2014 and October 2018 from 4 medical centers in southern Taiwan. The primary outcomes included thromboembolic events (stroke/transient ischemic attack or systemic embolism), major bleeding, and all-cause mortality.Among all patients, 826 (77%) patients were classified as the “per-label adequate-dose” treatment group (i.e., consistent with the Food and Drug Administration label recommendations) while 247 (23%) patients were the “off-label reduced-dose” treatment group. The mean follow-up period was 17.5 ± 13 months. The “off-label reduced-dose” group did not have a lower major bleeding rate than the “per-label adequate-dose” group (4.8% vs 3.8%, adjusted hazard ratio [HR] 1.20, 95% confidence interval [CI] 0.69–2.09), but had a nonsignificantly higher incidence of thromboembolic events (4.23% vs 3.05%, adjusted HR: 1.29, 95% CI: 0.71–2.34).An off-label reduced-dose apixaban treatment strategy may not provide incremental benefits or safety for Taiwanese patients with nonvalvular AF.

Risk Assessment Models for Thrombosis and Anticoagulant-Related Bleeding in Ambulatory Cancer Patients.

Cancer patients have a high risk of developing venous thromboembolism and arterial thrombosis, along with an increased risk of anticoagulant-related bleeding with primary and secondary prophylaxis of cancer-associated thrombosis. Decisions on initiation, dosing, and duration of anticoagulant therapy for prevention and treatment of cancer-associated thrombosis are challenging, as clinicians have to balance patients' individual risk of (recurrent) thrombosis against the risk of bleeding complications. For this purpose, several dedicated risk assessment models for venous thromboembolism in cancer patients have been suggested. However, most of these scores perform poorly and have received limited to no validation. For bleeding and arterial thrombosis, no risk scores have been developed specifically for cancer patients, and treatment decisions remain based on clinical gestalt and rough and unstructured estimation of the risks. The aims of this review are to summarize the characteristics and performance of risk assessment scores for (recurrent) venous thromboembolism and discuss available data on risk assessment for bleeding and arterial thrombosis in the cancer population. This summary can help clinicians in daily practice to make a balanced decision when considering the use of risk assessment models for cancer-associated venous thromboembolism. Future research attempts should aim at improving risk assessment for arterial thrombosis and anticoagulant-related bleeding in cancer patients.

Thromboembolism in Older Adults.

Arterial and venous thromboembolism are both more common in older adults. The use of anticoagulants, the mainstay to prevent thromboembolism, requires consideration of the balance between risk and benefit. Such consideration is even more important in the very elderly in whom the risk of anticoagulant-related bleeding and thrombosis are higher. This review will focus on the challenges of implementing and managing anticoagulant therapy in older patients in an era when the options for anticoagulants include not only vitamin K antagonists (VKAs), but also direct-acting oral anticoagulants (DOACs).

Consumer-led screening for atrial fibrillation using consumer-facing wearables, devices and apps: A survey of health care professionals by AF-SCREEN international collaboration

AimA variety of consumer-facing wearables, devices and apps are marketed directly to consumers to detect atrial fibrillation (AF). However, their management is not defined. Our aim was to explore their role for AF screening via a survey. Methods and ResultsAn anonymous web-based survey was undertaken by 588 health care professionals (HCPs) (response rate 23.7%). Overall, 57% HCPs currently advise wearables/apps for AF detection in their patients: this was much higher for electrophysiologists and nurses/allied health professionals (74–75%) than cardiologists (57%) or other physicians (34–38%). Approximately 46% recommended handheld (portable) single-lead dedicated ECG devices, or, less frequently, wristband ECG monitors with similar differentials between HCPs . Only 10–15% HCPs advised photoplethysmographic wristband monitors or smartphone apps. In over half of the HCP consultations for AF detected by wearables/apps, the decision to screen was entirely the patient's. About 45% of HCPs perceive a potential role for AF screening in people aged >65 years or in those with risk factors. Almost 70% of HCPs believed we are not yet ready for mass consumer-initiated screening for AF using wearable devices/apps, with patient anxiety, risk of false positives and negatives, and risk of anticoagulant-related bleeding perceived as potential disadvantages, and perceived need for appropriate management pathways. ConclusionsThere is a great potential for appropriate use of consumer-facing wearables/apps for AF screening. However, it appears that there is a need to better define suitable individuals for screening and an appropriate mechanism for managing positive results before they can be recommended by HCPs.

Periprocedural Interruption of Anticoagulation in Patients with Cancer-Associated VTE: An Analysis of Thrombotic and Bleeding Outcomes

Background: Approximately 10-20% of patients with venous thromboembolic events (VTE) have underlying malignancy. VTE is considered the second leading cause of death in patients with cancer, and patients with cancer-associated VTE are at higher risk of anticoagulant-related bleeding. Although patients with cancer often undergo diagnostic or therapeutic invasive procedures, there is a paucity of data on adverse outcomes following the periprocedural interruption of anticoagulation in this patient population.Methods: We did a single-center, retrospective chart review of consecutive patients with cancer-associated VTE who had periprocedural interruption of anticoagulation for invasive procedures between November 2015 and March 2018. Perioperative interruption of warfarin/low-molecular-weight heparin was done as per CHEST guidelines (Douketis et al. Chest 141(2 Suppl). Heparin bridging anticoagulation was used only for patients with recent (< 3 months) VTE. Perioperative interruption of direct oral anticoagulants (DOACs) was done as per Thrombosis Canada guidelines, with anticoagulation held for 3 half-lives prior to low bleeding risk procedures and 5 half-lives for high bleeding risk procedures. Active cancer was defined as per the HOKUSAI VTE CANCER trial (Raskob et al. NEJM 378(7)). Primary outcomes were 30-day post-operative rates of VTE and major bleeding. Secondary outcomes were 30-day post-operative rates of clinically relevant non-major bleeding (CRNMB) and mortality. Major bleeding and CRNMB were defined according to ISTH definitions. Data are reported on a per-interruption basis. Herein, we present an interim analysis of results.Results: To date, 82 perioperative interruptions are included, of whom 69.5% were receiving a DOAC. Mean age of the cohort was 65.8 years, 62.2% were male, 92.6% had active cancer and 41.5% had metastatic cancer. Thrombocytopenia (platelet count < 100 x 106/L) was present in 12.2% of interruptions. Procedures were stratified as high bleeding risk in 65.9% of cases. The 30-day rates of thromboembolism and major bleeding were both 3.70 % (95% confidence interval [CI] 1.25 to 10.2%), as was the 30-day rate of CRNMB. There were no deaths during the 30-day follow-up period.Conclusions: The periprocedural interruption of anticoagulation in patients with cancer-associated VTE appears to be associated with high rates of post-operative thrombotic and bleeding complications. Prospective studies are required to better quantify the risks of periprocedural anticoagulation interruption in this patient population. DisclosuresShaw:Portola Pharmaceuticals: Research Funding. Douketis:BMS: Other: Advisory Board; Janssen: Consultancy; Bayer: Other: Advisory Board; Pfizer: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Portola: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Biotie: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board. Carrier:Pfizer: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; Leo Pharma: Research Funding.

Evaluation of the predictive performance of bleeding risk scores in patients with non-valvular atrial fibrillation on oral anticoagulants.

Bleeding risk scores (BRSs) aid in the assessment of oral anticoagulant-related bleeding risk in patients with atrial fibrillation. Ideally, the applicability of a BRS needs to be assessed, prior to its routine use in a population other than the original derivation cohort. Therefore, we evaluated the performance of 6 established BRSs to predict major or clinically relevant bleeding (CRB) events associated with the use of oral anticoagulant (OAC) among Malaysian patients. The pharmacy supply database and the medical records of patients with non-valvular atrial fibrillation (NVAF) receiving warfarin, dabigatran or rivaroxaban at two tertiary hospitals were reviewed. Patients who experienced an OAC-associated major or CRB event within 12months of follow-up, or who have received OAC therapy for at least 1year, were identified. The BRSs were fitted separately into patient data. The discrimination and the calibration of these BRSs as well as the factors associated with bleeding events were then assessed. A total of 1017 patients with at least 1-year follow-up period, or those who developed a bleeding event within 1year of OAC use, were recruited. Of which, 23 patients experienced a first major bleeding event, whereas 76 patients, a first CRB event. Multivariate logistic regression results show that age of 75 or older, prior bleeding and male gender are associated with major bleeding events. On the other hand, prior gastrointestinal bleeding, a haematocrit value of less than 30% and renal impairment are independent predictors of CRB events. All the BRSs show a satisfactory calibration for major and CRB events. Among these BRSs, only HEMORR2 HAGES (C-statistic=0.71, 95% CI 0.60-0.82, P<.001) and ATRIA score (C-statistic=0.70, 95% CI 0.58-0.82, P<.001) show acceptable discrimination performance for major bleeding events. All the 6 BRSs, however, lack acceptable predictive performance for CRB events. To the best of our knowledge, this is the first evaluation study of the predictive performance of these 6 BRSs on clinically relevant bleeding events applied to the same cohort consisting of mainly Asian novel oral anticoagulant users. These BRSs show poor to acceptable predictive performance on OAC-induced major or CRB events. An improvement in the existing BRSs for OAC users is warranted.

Clinical and economic impact of rivaroxaban on the burden of atrial fibrillation: The case study of Japan

Objectives: Atrial fibrillation (AF) affects an estimated 1.5 million individuals in Japan, increasing their stroke risk and imposing considerable costs on the Japanese healthcare system. To reduce stroke incidence, guidelines recommend using anticoagulants in moderate-to-high risk non-valvular AF (NVAF) patients; however, many patients receive no treatment, aspirin only, or remain poorly-controlled on vitamin K antagonists (VKAs) due to high VKA discontinuation rates and non-adherence to guidelines. A prevalence-based Markov model was developed to estimate the clinical and budgetary impact of treating these patients with XareltoTM (rivaroxaban, Bayer AG) in Japan.Methods: Population, baseline risk of events, and associated management costs were estimated using data from Japanese publications where available. Treatment efficacy and safety were derived from published data and the J-ROCKET AF trial. Drug and physician visit costs were based on data from the Ministry of Health, Labor, and Welfare, the J-ROCKET AF trial, and Japanese clinical guidelines.Results: This model demonstrates that increased use of rivaroxaban in inadequately-managed NVAF patients could avoid 456 081 non-fatal ischemic strokes (IS) and 76 975 cardiovascular deaths over 10 years in Japan. This clinical benefit offsets the increased incidence of myocardial infarctions and anticoagulant-related bleeding. Decreased event costs could lead to a ¥188.4 billion decrease in net spending over the analysis time horizon.Conclusions: Introducing rivaroxaban may decrease the burden of NVAF in Japanese society. From a clinical perspective, the reduction in IS and embolic events outweighs the increased risk of anticoagulant-related bleeding; from an economic perspective, reduced event costs offset drug and physician visit costs, resulting in cost savings.

Duration of Diabetes Mellitus and Risk of Thromboembolism and Bleeding in Atrial Fibrillation: Nationwide Cohort Study.

Guidelines advocate anticoagulant treatment to all patients with atrial fibrillation and concomitant diabetes mellitus. The potential refinement to thromboembolic risk stratification that may spring from subdividing diabetes mellitus is unexplored. The purpose was to investigate duration of diabetes mellitus as a predictor of thromboembolism and anticoagulant-related bleeding in patients with atrial fibrillation. Using nationwide Danish registries, we identified all patients discharged from hospital with an incident diagnosis of atrial fibrillation from 2000 to 2011. Hazard ratios with 95% confidence intervals for thromboembolism and bleeding according to years of diabetes mellitus duration in categories (0-4, 5-9, 10-14, and ≥15) and as a continuous variable using cubic splines were calculated by Cox regression. The study population comprised 137 222 patients with atrial fibrillation, of which 12.4% had diabetes mellitus. Compared with patients without diabetes mellitus and after adjustment for anticoagulant treatment and CHA2DS2-VASc components (congestive heart failure, hypertension, age, previous stroke, vascular disease, and sex), the risk of thromboembolism was lowest in the 0 to 4 years duration category (hazard ratio, 1.11; 95% confidence interval, 1.03-1.20), and highest in the longest duration category of ≥15 years (hazard ratio, 1.48; 95% confidence interval, 1.29-1.70). When analyzed as a continuous variable, duration of diabetes mellitus was associated with risk of thromboembolism in a dose-response-dependent manner, but not with a higher risk of bleeding during anticoagulant treatment. In patients with atrial fibrillation, longer duration of diabetes mellitus was associated with a higher risk of thromboembolism, but not with a higher risk of anticoagulant-related bleeding. Considering the critical balance between preventing thromboembolism and avoiding bleeding, longer duration of diabetes mellitus may favor initiation of anticoagulant therapy.

Physical Activity Reduces Risk for Anticoagulant-Associated Bleeding

Anticoagulant therapy is associated with major, even fatal, hemorrhage in elderly patients who fall or experience other trauma. Physical activity reduces the risk for falls in such patients, but whether it increases their risk for anticoagulant-related bleeding has been unclear. To examine this issue, Swiss investigators conducted a prospective, multicenter …

Addressing Disparities in Stroke Prevention for Atrial Fibrillation: Educational Opportunities.

Disparities in atrial fibrillation (AF)-related stroke and mortality persist, especially racial disparities, within the US "Stroke Belt." This study identified barriers to optimal stroke prevention to develop a framework for clinician education. A comprehensive educational needs assessment was developed focusing on clinicians within the Stroke Belt. The mixed qualitative-quantitative approach included regional surveys and one-on-one clinician interviews. Identified contributors to disparities included implicit racial biases, lack of awareness of racial disparities in AF stroke risk, and lack of effective multicultural awareness and training. Additional barriers affecting disparities included patient medical mistrust and clinician-patient communication challenges. General barriers included lack of consistency in assessing stroke and anticoagulant-related bleeding risk, underuse of standardized risk assessment tools, discomfort with novel anticoagulants, and patient education deficiencies. Effective cultural competency training is one strategy to reduce disparities in AF-related stroke and mortality by improving implicit clinician bias, addressing medical mistrust, and improving clinician-patient communication.

Inherited and Secondary Thrombophilia

Case Presentation 1: A healthy 19-year-old man presented with new chest pain and near syncope. Computed tomography pulmonary angiography showed a saddle pulmonary embolus. The patient denied recent travel, trauma, surgery, or hospitalization. His mother had 2 miscarriages at 10 weeks of gestation, and his maternal grandfather had deep venous thrombosis at 60 years of age. Case Presentation 2: A healthy 45-year-old woman reported new dyspnea and left calf pain. Computed tomography pulmonary angiography and compression venous duplex ultrasonography showed bilateral pulmonary emboli and acute left leg deep vein thrombosis, respectively. The patient denied exogenous hormone use, recent travel, trauma, surgery, or hospitalization. Her health maintenance was current, and she gave a family history of pernicious anemia, Grave disease, and amyotrophic lateral sclerosis. Laboratory analyses showed reduced hemoglobin (11.4 g/dL; normal, 12.0–15.5 g/dL), increased red blood cell distribution width (18.9%; normal, 11.9%–15.5%), and mild thrombocytopenia. Neither patient had previous venous thromboembolism, and both were referred to the Mayo Clinic Thrombophilia Center for apparent idiopathic venous thromboembolism. Thrombophilia is defined as a predisposition (susceptibility) to thrombosis. Thrombophilia is not a disease per se, but may be associated with a disease (eg, cancer), drug exposure (eg, oral contraceptives) or condition (eg, pregnancy or postpartum, secondary thrombophilia; Table 1), and thrombophilia may be inherited (Table 2).1 This concept is important because disease susceptibility does not imply an absolute requirement for primary or secondary prevention, or for treatment. Most persons with a thrombophilia do not develop thrombosis. Thus, thrombophilia must be considered in the context of other risk factors for incident thrombosis, or predictors of recurrent thrombosis, when estimating the need for primary or secondary prophylaxis, respectively. View this table: Table 1. Secondary Thrombophilia1 View this table: Table 2. Inherited Thrombophilia1 The role of special coagulation testing for an acquired or inherited thrombophilia is controversial. Thrombophilia testing should only be done if …

Use Of Novel Oral Anticoagulants For Treatment Of Venous Thromboembolism (VTE) In Patients With Malignancy: Meta-Analysis Of Randomized Controlled Trials

AbstractUse of Novel oral anticoagulants for treatment of venous thromboembolism (VTE) in patients with malignancy: meta-analysis of randomized controlled trials BackgroundVenous thromboembolism (VTE) is a frequent complication of cancers. Patients with cancer have at least a 6 fold increased risk for VTE compared to those without cancer, and the diagnosis of VTE in cancer patient is associated with a 2-4 fold decreased survival during the first year. The mainstays of anticoagulant treatment in cancer patients remain unfractionated heparin, LMWH, and the Vitamin K antagonists (VKAs), with current guideline favoring the use of LMWH. Novel oral anticoagulants (NOAs) that directly inhibit factor Xa and thrombin, including dabigatran, rivaroxaban, and apixaban, represents a milestone in the prevention and treatment of VTE. However, there have been no clinical trials to test the efficacy of NOAs in cancer patients, therefore, use of these agents in cancer population is an extrapolation of published results with general population. ObjectivesDetermine the efficacy of novel oral anticoagulants (thrombin inhibitor; dabigatran, and direct factor Xa inhibitors; rivaroxaban and apixaban) in VTE treatment in patients with cancer. Data sourceA systematic review was conducted using MEDLINE and EMBASE up to July 2013. Key words used included venous thromboembolism, pulmonary embolism, deep venous thrombosis, cancer, dabigatran, rivaroxaban, and apixaban. Due to the fact that no randomized controlled trials (RCTs) in cancer population, we combined data that were extracted from major RCTs that include cancer patients and performed a sub-group analysis. ResultsThree randomized controlled trials (RCTs) were reviewed, and a total of 550 patients with cancers were analyzed. NOAs are not inferior to the current standard anticoagulant therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist, to prevent symptomatic recurrent venous thromboembolism. Odd ratio (OR) is 0.988 (95% CI, 0.51-1.94). There is no significant heterogeneity. The major bleeding events were not analyzed due to lack of sub-group data in the trials. ConclusionCancer patients have different hemodynamics and unique features that make the treatment of VTE challenging. These includes: tumor-associated pro-coagulant, venous stasis and endothelial damage from chemotherapy and catheters, an increased risk of anticoagulant-related bleeding, and the complexity of anticoagulant control because of the occurrence of urgent procedures. The development of NOAs provided new modalities to treat VTEs in cancer patients, as it showed that NOAs is non-inferior to the current standard anticoagulant therapy. However, large scale randomized controlled trials specifically targeted cancer patients are needed. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Performance of the HEMORR2HAGES, ATRIA, and HAS-BLED Bleeding Risk–Prediction Scores in Patients With Atrial Fibrillation Undergoing Anticoagulation: The AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) Study

The objective of this study was to compare the predictive performance of bleeding risk-estimation tools in a cohort of patients with atrial fibrillation (AF) undergoing anticoagulation. Three bleeding risk-prediction schemes have been derived for and validated in patients with AF: HEMORR(2)HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol). Τhe relative predictive values of these bleeding scores have not previously been compared. We analyzed the dataset from the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial, a multicenter, randomized, open-label noninferiority study that compared fixed-dose idraparinux with adjustable-dose oral vitamin K antagonist therapy in patients with AF. The principal safety outcome was any clinically relevant bleeding event, which was a composite of major bleeding plus clinically relevant nonmajor bleeding. The HAS-BLED score performed best in predicting any clinically relevant bleeding, reflected both in net reclassification improvement (10.3% and 13% improvement compared with HEMORR(2)HAGES and ATRIA, respectively) and receiver-operating characteristic (ROC) analyses (c-indexes: 0.60 vs. 0.55 and 0.50 for HAS-BLED vs. HEMORR(2)AGES and ATRIA, respectively). Using decision-curve analysis, the HAS-BLED score demonstrated superior performance compared with ATRIA and HEMORR(2)HAGES at any threshold probability for clinically relevant bleeding. HAS-BLED was the only score that demonstrated a significant predictive performance for intracranial hemorrhage (c-index: 0.75; p = 0.03). An ATRIA score >3 was not significantly associated with the risk for any clinically relevant bleeding on Cox regression or on ROC analysis (c-index: 0.50; p = 0.87). All 3 tested bleeding risk-prediction scores demonstrated only modest performance in predicting any clinically relevant bleeding, although the HAS-BLED score performed better than the HEMORR(2)HAGES and ATRIA scores, as reflected by ROC analysis, reclassification analysis, and decision-curve analysis. Only HAS-BLED demonstrated a significant predictive performance for intracranial hemorrhage. Given its simplicity, the HAS-BLED score may be an attractive method for the estimation of oral anticoagulant-related bleeding risk for use in clinical practice, supporting recommendations in international guidelines.