Anticoagulant-related Hemorrhage Research Articles

Mechanical versus Bioprosthetic Aortic Valve Replacement in Patients Aged 50 to 70 Years.

This study compared the outcomes of surgical aortic valve replacement (AVR) in patients aged 50 to 70 years based on the type of prosthetic valve used. We compared patients who underwent mechanical AVR to those who underwent bioprosthetic AVR at our institution between January 2000 and March 2019. Competing risk analysis and the inverse probability of treatment weighting (IPTW) method based on propensity score were employed for comparisons. A total of 1,580 patients (984 patients with mechanical AVR; 596 patients with bioprosthetic AVR) were enrolled. There was no significant difference in early mortality between the mechanical AVR and bioprosthetic AVR groups (0.9% vs. 1.7%, p=0.177). After IPTW adjustment, the risk of all-cause mortality was significantly higher in the bioprosthetic AVR group than in the mechanical AVR group (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.07-1.80; p=0.014). Competing risk analysis revealed lower risks of stroke (sub-distributional hazard ratio [sHR], 0.44; 95% CI, 0.28-0.67; p<0.001) and anticoagulation- related bleeding (sHR, 0.35; 95% CI, 0.23-0.53; p<0.001) in the bioprosthetic AVR group. Conversely, the risk of aortic valve (AV) reintervention was higher in the bioprosthetic AVR group (sHR, 6.14; 95% CI, 3.17-11.93; p<0.001). Among patients aged 50 to 70 years who underwent surgical AVR, those receiving mechanical valves showed better survival than those with bioprosthetic valves. The mechanical AVR group exhibited a higher risk of stroke and anticoagulation-related bleeding, while the bioprosthetic AVR group showed a higher risk of AV reintervention.

Telemedicine-based medical care compared to in-person medical care for warfarin follow-up: A retrospective propensity score matching cohort study.

Telemedicine is underutilized in Saudi Arabia, which is a matter of concern, especially since previous literature has showed its equivalence with office visits in providing access to care and convenience for patients while reducing anticoagulation-related bleeding events when appropriate measures are followed. The purpose of this study is to analyze the efficacy of telehealth-based care compared to in-person visit care for warfarin follow-up. The authors conducted a retrospective chart review comparing the mean percentage of time in the therapeutic range (TTR) of international normalized ratio (INR) values among patients prescribed warfarin from July 2019 to November 2020 at King Faisal Specialist Hospital & Research Center - Jeddah Branch whose anticoagulant therapy was managed via telemedicine or through in-person clinic visits. A subcohort analysis of outcomes in the telemedicine and in-person groups was performed using propensity score matching, and descriptive analysis was done for the entire cohort. A total of 350 patient records were included in this retrospective study. Matched analysis for 148 patients using propensity score matching showed that the mean (SD) percentages of TTR were 62.82% (19.46%) and 70.61% (19.83%) in the telemedicine and in-person groups, respectively (P = 0.017). There was no statistical difference in the incidence of major or minor bleeding events, thromboembolic events, and hospital readmission between the two groups. The study results showed that patients on oral anticoagulation therapy managed through a telemedicine method had a lower overall TTR percentage than a matched group of patients managed through in-person anticoagulant clinic visits, thus demonstrating that using a telemedicine approach alone for warfarin follow-up may not help patients to maintain their INR target level.

Risk factors for anticoagulant-associated gastrointestinal hemorrhage: a systematic review and meta-analysis.

There may be many predictors of anticoagulation-related gastrointestinal bleeding (GIB), but until now, systematic reviews and assessments of the certainty of the evidence have not been published. We conducted a systematic review to identify all risk factors for anticoagulant-associated GIB to inform risk prediction in the management of anticoagulation- related GIB. A systematic review and meta-analysis were conducted to search PubMed, EMBASE, Web of Science, and Cochrane Library databases (from inception through January 21, 2022) using the following search terms: anticoagulants, heparin, warfarin, dabigatran, rivaroxaban, apixaban, DOACs, gastrointestinal hemorrhage, risk factors. According to inclusion and exclusion criteria, studies of risk factors for anticoagulation-related GIB were identified. Risk factors for anticoagulant-associated GIB were used as the outcome index of this review. We included 34 studies in our analysis. For anticoagulant-associated GIB, moderate-certainty evidence showed a probable association with older age, kidney disease, concomitant use of aspirin, concomitant use of the antiplatelet agent, heart failure, myocardial infarction, hematochezia, renal failure, coronary artery disease, helicobacter pylori infection, social risk factors, alcohol use, smoking, anemia, history of sleep apnea, chronic obstructive pulmonary disease, international normalized ratio (INR), obesity et al. Some of these factors are not included in current GIB risk prediction models. such as anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction, etc. The study found that anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction et al. were associated with anticoagulation-related GIB, and these factors were not in the existing prediction models. This study informs risk prediction for anticoagulant-associated GIB, it also informs guidelines for GIB prevention and future research.

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 &amp;lt; 13g/dL in men and &amp;lt; 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 &amp;lt;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.

All-Cause Mortality after Major Gastrointestinal Bleeding Among Patients Receiving Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis

Background: Bleeding is the major complication of anticoagulant use, including direct oral anticoagulants (DOACs). Although major gastrointestinal (GI) bleeding represents the single most frequent site of anticoagulant-related bleeding, outcomes after major GI bleeding including mortality are not well characterized and, as a result, severity may be underappreciated with resulting implications for clinical practice. We conducted a systematic review and meta-analysis to quantify the risk for 30-day all-cause mortality after major GI bleeding among DOAC treated patients. Methods: The systematic review protocol was registered with PROSPERO (CRD42022295815). We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception to November 26 th, 2021 for studies that met the following inclusion criteria: (i) were randomized controlled trials, or prospective and retrospective cohort studies, (ii) included adults treated with a DOAC for venous thromboembolism (VTE) or atrial fibrillation; and (iii) reported 30-day all-cause mortality after major GI bleeding. Two reviewers independently performed study screening and data extraction in duplicate. Summary estimates for 30-day all-cause mortality were calculated using the random-effects inverse-variance method. Statistical heterogeneity was evaluated using the I 2 statistic and by providing 95% prediction intervals. In a sensitivity analysis, we included only studies that defined major GI bleeding based on the International Society on Thrombosis and Haemostasis (ISTH) criteria. Subgroup analyses were performed according to indication for anticoagulation and type of DOAC. Risk of bias was assessed using a modified version of the QUIPS tool for prognostic studies. Results: Of 6548 unique studies identified in our search, we included 17 studies which comprised a total of 3910 DOAC-treated patients with major GI bleeds. The pooled estimate of 30-day mortality after a major GI bleed was 9% (95% CI, 7-13%; I 2=76%) (Figure). In a sensitivity analysis, limited to 15 studies (1846 major GI bleeds) that used the ISTH major GI bleeding definition, the pooled estimate of 30-day mortality was 9% (95% CI, 6-13%; I 2=75%; 95% prediction interval, 2-29%). Studies deemed to be at high risk of bias (5 studies, 228 major GI bleeds) had higher mortality (14%; 95% CI, 8-24%; I 2=8%) than those at low risk of bias (11 studies, 3644 major GI bleeds) where mortality was 8% (95% CI, 6-12%; I 2=81%). In patients receiving a DOAC for either VTE or atrial fibrillation (14 studies, 2764 major GI bleeds), the pooled estimate of 30-day mortality was 11% (95% CI, 7-16%; I 2=10%), and in those receiving a DOAC for atrial fibrillation (3 studies, 1119 major GI bleeds), it was 5% (95% CI, 2-14%; I 2=84%). The pooled estimate of 30-day mortality was 9% (95% CI, 6-14%; I 2=80%) in patients on any DOAC (15 studies, 3747 major GI bleeds), 13% (95% CI, 8-20%; I 2=0%) among those on dabigatran (2 studies, 125 major GI bleeds), and 3% (95% CI, 0-13%) among those rivaroxaban (only 1 study, 38 major GI bleeds). Conclusion: DOAC related major GI bleeding is associated with a significant risk of 30-day mortality. We found substantial heterogeneity across studies which limits the certainty of summary estimates and the ability to compare between DOACs and indications for treatment. Studies reporting on anticoagulation usage should more report on outcomes such as all-cause mortality after bleeding events to better characterize the potential harms of therapy.

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 &amp;gt;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&amp;lt;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

Extracranial anticoagulant related bleedings admitted to intensive care units: a French multicenter retrospective study

BackgroundAnticoagulants are widely used but can lead to iatrogenic events such as bleeding. Limited data exists regarding the characteristics and management of patients admitted to intensive care units (ICU) for severe anticoagulant-related extracranial bleeding.MethodsA retrospective observational study was conducted in five French ICUs. From January 2007 to December 2018, all patients aged over 18 years admitted to ICU for extracranial bleeding while receiving therapeutic anticoagulation were included.Results486 patients were included, mainly male (61%) with an average age of 73 ± 13 years. Most patients had comorbidities, including hypertension (68%), heart disease (49%) and diabetes (33%). Patients were treated by vitamin K antagonists (VKA, 54%), heparins (25%) and direct oral anticoagulants (DOAC, 7%). The incidence of patients admitted to ICU for anticoagulant-related bleeding increased from 3.2/1000 admissions in 2007 to 5.8/1000 in 2018. This increase was particularly high for DOAC class. Upon admission, patients exhibited severe organ failure, as evidenced by a high SOFA score (7 ± 4) and requirement for organ support therapies such as vasopressors (31.5%) and invasive mechanical ventilation (34%). Adherence to guidelines for the specific treatment of anticoagulant-related bleeding was generally low. ICU mortality was 27%. In multivariate analysis, five factors were independently associated with mortality: chronic hypertension, need for vasopressors, impaired consciousness, hyperlactatemia and prolonged aPTT > 1.2.ConclusionAnticoagulant-related extracranial bleeding requiring ICU admission is a serious complication responsible for organ failure and significant mortality. Its incidence is rising. The therapeutic management is suboptimal and could be improved by educational programs.

Standardizing periprocedural anticoagulation management: a stewardship initiative.

Study data indicates anticoagulant interruption peri-procedurally can increase the risk of anticoagulation-related bleeding and thrombosis. Management of anticoagulated patients during the peri-procedural period poses clinical challenges given the potential for thrombosis and bleeding in this complex, high risk population. As such, there is a need for enhanced emphasis on anticoagulated patient care throughout the peri-procedural period with the goal of optimizing patient safety and efficacy. To operationalize an effective, efficient, comprehensive, and standardized anticoagulation management peri-procedural process housed within the electronic health record (EHR). The IPRO-MAPPP clinical decision support logic was adapted into a nurse-managed protocol to guide anticoagulation therapy use during the elective peri-procedural period at Bassett Medical Center, an Anticoagulation Forum Center of Excellence. A second phase of this initiative endorsed peri-procedural warfarin and bridging management by the Anticoagulation Management Service. Outcomes revealed 30-day hospital or emergency department admissions remained at or below 1% of the surgical patient population, and below the published national standards for both phases of implementation. Further, no emergent anticoagulation reversal agent use was attributed to peri-procedural care during the assessment period. The phased implementation of this Anticoagulation Stewardship initiative in elective peri-procedural anticoagulation management successfully describes the operationalization and demonstration of high-quality care and low provider practice variation from policy. The integration of clinical decision support systems, in consort with effective communication, via the EHR, provides stability, sustainability, and drives high quality care to optimize patient outcomes.

Are Ischemic Strokes the Same? The Special Case Argument of Atrial Fibrillation

A comprehensive evaluation is necessary to identify the etiologic factors in order to select optimal stroke-prevention measures. Atrial fibrillation is one of the most important stroke causes. Although anticoagulant therapy is the treatment of choice for patients with nonvalvular atrial fibrillation, it should not be considered uniformly to treat all patients given the high mortality associated with anticoagulant-related hemorrhages. The authors propose a risk-stratified individualized approach for stroke prevention in patients with nonvalvular atrial fibrillation by considering nonpharmacologic approaches for patients at high hemorrhage risk or otherwise unsuitable for lifelong anticoagulation.

Bleeding related to oral anticoagulants: Trends in US emergency department visits, 2016-2020

BackgroundClinical trials suggest lower rates of major bleeding with direct-acting oral anticoagulants (DOACs) than with warfarin, but anticoagulant-related bleeding remains one of the most common outpatient adverse drug events. MethodsWe estimated the number of emergency department (ED) visits and subsequent hospitalizations for oral anticoagulant-related bleeding in 2016–2020 based on active surveillance in a nationally representative, size-stratified probability sample of 60 U.S. hospitals. We estimated rates of ED visits using a nationally-projected retail prescription dispensing database. ResultsBased on 19,557 cases, oral anticoagulant-related bleeding resulted in an estimated 1,270,259 (95 % Confidence Interval [CI], 644,686-1,895,832) ED visits for the five years 2016–2020, of which 47.8 % (95 % CI, 40.6 %–55.0 %) resulted in hospitalization. Oral anticoagulant-related bleeding resulted in an estimated 230,163 (95% CI, 109,598-350,728) ED visits in 2016 and 301,433 (95% CI, 138,363-464,503) in 2020. During 2016–2020, ED visits for DOAC-related bleeding increased by an average of 27.9 % (95 % CI, 24.0 %–32.0 %; p < .001) per year, while ED visits for warfarin-related bleeding decreased by an average of 8.8 % (95 % CI, −10.7 % to −7.0 %; p = .001) per year. The estimated rate of bleeding visits per 100 patients dispensed oral anticoagulants at least once in 2016–2020 was highest for patients aged ≥ 80 years (13.1; 95 % CI, 6.2–20.0) and lowest for those aged <45 years (4.0; 95 % CI, 2.6–5.5); it was 5.9 visits per 100 patients dispensed DOACs [95 % CI, 2.5–9.2] and 13.0 visits per 100 patients dispensed warfarin [95 % CI, 7.4–18.7]. ConclusionsAlthough the rates of ED visits for anticoagulant-related bleeding may be lower for DOACs than for warfarin, persistently large numbers of patients requiring ED visits for anticoagulant-related bleeding despite increased use of DOACs and declining use of warfarin suggest that efforts to improve appropriate prescribing and monitoring of anticoagulants remain important.

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia

Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative. To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies. The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis-114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023. Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days. A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death). Among the study population of 334 individuals (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men and 108 [32.3%] women), use of HD-PA and SD-PA had similar probabilities of favorable outcome (47.3% [95% CI, 39.9% to 54.8%] vs 52.7% [95% CI, 45.2% to 60.1%]; P = .48), as did TA compared with SD-PA (50.9% [95% CI, 43.4% to 58.3%] vs 49.1% [95% CI, 41.7% to 56.6%]; P = .82) and TA compared with HD-PA (53.5% [95% CI 45.8% to 60.9%] vs 46.5% [95% CI, 39.1% to 54.2%]; P = .37). Net clinical outcome was met in 29.8% of patients receiving SD-PA (20.2% thrombosis, 2.6% bleeding, 14.0% death), 16.4% receiving HD-PA (5.5% thrombosis, 3.6% bleeding, 11.8% death), and 20.0% receiving TA (5.5% thrombosis, 3.6% bleeding, 12.7% death). Moreover, HD-PA and TA use significantly reduced thrombosis compared with SD-PA (absolute difference, -14.7 [95% CI -6.2 to -23.2] and -14.7 [95% CI -6.2 to -23.2], respectively). Use of HD-PA significantly reduced net clinical outcome compared with SD-PA (absolute difference, -13.5; 95% CI -2.6 to -24.3). This randomized clinical trial found that compared with SD-PA, neither HD-PA nor TA use improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemic COVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis. ClinicalTrials.gov Identifier: NCT04808882.

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.

Genetic Risk Score Improves Risk Stratification for Anticoagulation-Related Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is the most devastating adverse outcome for patients on anticoagulants. Clinical risk scores that quantify bleeding risk can guide decision-making in situations when indication or duration for anticoagulation is uncertain. We investigated whether integration of a genetic risk score into an existing risk factor-based CRS could improve risk stratification for anticoagulation-related ICH. We constructed 153 genetic risk scores from genome-wide association data of 1545 ICH cases and 1481 controls and validated them in 431 ICH cases and 431 matched controls from the population-based UK Biobank. The score that explained the largest variance in ICH risk was selected and tested for prediction of incident ICH in an independent cohort of 5530 anticoagulant users. A CRS for major anticoagulation-related hemorrhage, based on 8/9 components of the HAS-BLED score, was compared with a combined clinical and genetic risk score incorporating an additional point for high genetic risk for ICH. Among anticoagulated individuals, 94 ICH occurred over a mean follow-up of 11.9 years. Compared with the lowest genetic risk score tertile, being in the highest tertile was associated with a two-fold increased risk for incident ICH (hazard ratio, 2.08 [95% CI, 1.22-3.56]). Although the CRS predicted incident ICH with a hazard ratio of 1.24 per 1-point increase (95% CI [1.01-1.53]), adding a point for high genetic ICH risk led to a stronger association (hazard ratio of 1.33 per 1-point increase [95% CI, 1.11-1.59]) with improved risk stratification (C index 0.57 versus 0.53) and maintained calibration (integrated calibration index 0.001 for both). The new clinical and genetic risk score showed 19% improvement in high-risk classification among individuals with ICH and a net reclassification improvement of 0.10. Among anticoagulant users, a prediction score incorporating genomic information is superior to a clinical risk score alone for ICH risk stratification and could serve in clinical decision-making.

Survival Implications of Thrombus Recurrence or Bleeding in Cancer Patients Receiving Anticoagulation for Venous Thromboembolism Treatment.

Study aims were to analyze prospectively collected data from patients with cancer-associated venous thromboembolism (VTE) to determine the impact of VTE recurrence and anticoagulant-related bleeding on all-cause mortality. Consecutive cancer patients with acute VTE treated with anticoagulants (March 1, 2013-November 30, 2021) were included in this analysis. Anticoagulant therapy-associated VTE recurrences, major bleeding, and clinically relevant nonmajor bleeding (CRNMB) were assessed for their impact on all-cause mortality outcomes. This study included 1,812 cancer patients with VTE. Of these, there were 97 (5.4%) with recurrent VTE, 98 (5.4%) with major, and 104 (5.7%) with CRNMB while receiving anticoagulants. Recurrent VTE (hazard ratio [HR]: 1.52; 95% confidence interval [CI]: 1.16-2.00; p = 0.0028), major bleeding (HR: 1.82; 95% CI: 1.41-2.31; p = 0.006), and CRNMB (HR; 1.38; 95% CI: 1.05-1.81; p = 0.018) each adversely influenced mortality outcomes. Deep vein thrombosis as the incident thrombotic event type was associated with VTE recurrence (HR: 1.78; 95% CI: 1.08-2.89; p = 0.02). Neither cancer type nor stage, chemotherapy, or Ottawa risk category influenced VTE recurrence. Higher body weights (HR: 1.01; 95% CI: 1.00-1.01; p = 0.005) were associated with increased major bleeding, while high Ottawa scores (HR: 0.66; 95% CI: 0.46-0.96; p = 0.03) and apixaban treatment (HR: 0.62; 95% CI: 0.45-0.84; p = 0.002) were associated with fewer major bleeding outcomes. Among cancer patients receiving anticoagulant therapy for VTE, adverse outcomes such as VTE recurrence, major bleeding, or CRNMB increase mortality risk by 40 to 80%. Identifying variables predicting these outcomes may help risk-stratify patients with poor prognosis.

All-cause mortality after major gastrointestinal bleeding among patients receiving direct oral anticoagulants: a protocol for a systematic review and meta-analysis

BackgroundGastrointestinal (GI) bleeding represents the single most frequent site of anticoagulant-related bleeding. Adverse outcomes after major GI bleeding including mortality are not well characterized and, as a result, may be underappreciated in clinical practice. We aim to conduct a systematic review and meta-analysis of the risk for 30-day all-cause mortality after major GI bleeding among patients receiving DOACs.MethodsElectronic databases including MEDLINE, EMBASE, and Cochrane CENTRAL will be systematically searched to identify randomized controlled trials and prospective and retrospective cohort studies reporting 30-day all-cause mortality in adults with DOAC-related major GI bleeding. At least two investigators will independently perform study selection, risk of bias assessment, and data extraction. The proportion of deaths following a major GI event relative to the number of major GI bleeding events will be calculated for each individual study, and results across studies will be pooled using random-effects meta-analysis. We will assess risk of bias using criteria proposed by the GRADE group for prognostic studies.DiscussionThe findings of this systematic review and meta-analysis will provide clinicians and patients with estimates of mortality after the most common major bleeding event to support shared decision making about anticoagulation management.Trial registrationPROSPERO CRD42022295815.

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

Medsafe reviews risk of anticoagulant-related abnormal uterine bleeding

Medsafe reviews risk of anticoagulant-related abnormal uterine bleeding

Thrombotic Events and Anticoagulation-Related Bleeding Complications in Critically Ill Patients with Coronavirus Disease 2019

Background: Thrombosis (T) is common in coronavirus disease 2019 (COVID-19) patients, and d-dimer concentrations correlate with outcomes. Controversy exists with regards to anticoagulation (AC) for patients. We implemented a full-heparinization AC protocol from the onset of the pandemic and hypothesized that a safety signal would be undetectable. Patients and Methods: Prospective evaluation of 111 patients with COVID-19 critical illness hospitalized from March to June 2020. All patients received therapeutic heparinoid-based AC from admission. Incidences of T, bleeding (B), or both (BT) were noted. The primary outcome was mortality. Kruskal-Wallis test and logistic regression were performed. Results are expressed as n (%), median (interquartile range) and odds ratios with 95% confidence intervals. Alpha was set at 0.05. Results: Thirty-two patients (28%) had T, 23 (20%) had B, and 14 (12%) had BT; 42 (40%) patients were unaffected. Two logistic regression models (outcome = mortality) evaluated BT as T, or BT as B. For BT as T, neither T, B, nor male gender predicted mortality; similarly, for BT as B, neither T, B, nor male gender predicted mortality. Factors associated with higher odds of death included higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00-1.13; p = 0.0045), higher d-dimer concentration (OR, 1.00; 95% CI, 1.00-1.01; p = 0.043), and higher activated partial thromboplastin time (aPTT; OR, 1.09; 95% CI, 1.02-1.16; p = 0.010). Conclusions: Neither T nor B predicted mortality in this prospective cohort of anticoagulated patients with COVID-19 critical illness. These data support continued full-dose heparinoid prophylaxis.