Direct Oral Anticoagulants Cohorts Research Articles

Tolerability of Direct Oral Anticoagulants and Low Molecular Weight Heparin in Patients with Brain Tumors or CNS Metastases

Background: Despite the increase in the use of direct oral anticoagulants (DOACs) for cancer-associated thrombosis, limited data exists regarding the safety of DOACs in patients with brain metastases or primary brain tumors. The purpose of this retrospective cohort study is to describe overall tolerability of DOACs compared to low-molecular weight heparin (LMWH) for the treatment of venous thromboembolism (VTE) or for stroke prevention in atrial fibrillation (AF), in patients with brain tumors or CNS metastases. Methods: This is a single center, institutional review board approved retrospective cohort study at New York University Langone Health of patients with primary brain tumors or CNS metastasis that received therapeutic dosed anticoagulation with either a DOAC or LMWH (enoxaparin) between December 1, 2018 and August 19, 2022. Electronic medical records were reviewed for pertinent data. The primary outcome was tolerability of anticoagulation, which included continuation of initial anticoagulation therapy and absence of any switches in anticoagulation, dose adjustments or temporary interruptions. Reasons for discontinuations included bleeding events, intolerance/patient preference (such as the need for subcutaneous administration or cost of therapy), provider preference, or a change in clinical status such as transition to hospice or unable to determine based on chart review. Secondary outcomes included the incidence of anticoagulation discontinuations secondary to an intracerebral hemorrhage (ICH). Results: A total of 153 patients were included (DOAC n = 105, 69%; enoxaparin n = 48, 31%). The study population was predominantly White (74%), male (59%), with a median BMI≥30 kg/m2 in 40% of the cohort and age of 65 (IQR 56-73) years; however, the enoxaparin group was younger than the DOAC group at 59.5 years vs. 67 years (p <0.001), respectively at the time of anticoagulation initiation. Primary brain tumors were the most prevalent in the total cohort at 89%, with enoxaparin most commonly prescribed at 71% versus a DOAC at 47%, p = 0.005. Other primary malignancies included anaplastic astrocytoma, glioma, anaplastic oligodendroglioma, and tanycytic ependymoma. Non-small cell lung cancer was the most common malignancy that resulted in CNS metastasis (7.2%). The most common indication for anticoagulation was for the treatment of VTE at 70%, followed by stroke prevention in AF at 28%, with the remainder 2% as off-label. The primary outcome of remaining on initial anticoagulant chosen without any anticoagulant therapy changes occurred in only 52% of the cohort. There were more changes in therapy in the enoxaparin cohort at 29, 60% vs. 44, 42% for the DOAC cohort, p = 0.033, driven by provider preference in 48% of the cohort and patient intolerance in 29% of the cohort. More patients in the enoxaparin cohort were switched to a DOAC (n = 17) and more patients in the DOAC cohort had their initial anticoagulation discontinued for non- ICH reasons (n = 14). The median time to any anticoagulation switch was 2.12 months (IQR 0.35-4.27 months). Discontinuations in patients who were still alive was primarily driven by completion of therapy, deemed by the treatment team, intolerance or patient preference, and provider preference (Table 1). Though the reason for provider preference was not always clearly elucidated upon chart review, this trend supports the movement towards increasing DOAC use. The secondary outcome of the incidence of ICH was also lower in the DOAC cohort compared to enoxaparin at 3.8 vs 14.6% (p = 0.037). (Figure 1) Conclusions: Our study demonstrates real world prescribing practice of anticoagulants for the treatment of VTE or stroke prevention in AF in patients with primary brain tumors or metastases. Although initial anticoagulants chosen were either discontinued or switched to an alternative agent, we observed a shift towards a preference for DOACs, similar to the shift towards DOACs for cancer associated thrombosis. We also observed a lower incidence of ICH with DOACs compared to LMWH. However, these results should be confirmed in a randomized controlled trial to account for the inherent selection biases we could not account for, which may have favored the initial anticoagulant chosen, the reason for switch, and overall tolerability.

The efficacy and safety of direct oral anticoagulants compared with low-molecular-weight heparin for venous thromboembolism prophylaxis after surgical resection of primary lower extremity bone or soft-tissue sarcoma.

The incidence of postoperative venous thromboembolism (VTE)and wound complications is greater after sarcoma resection. We sought to identify differences in postoperative VTE and bleeding complications with direct oral anticoagulants (DOACs)versus low-molecular-weight heparin (LMWH)following resection of lower extremity primary bone or soft tissue sarcoma. We retrospectively identified 2083 patients from the PearlDiver database who underwent resection of primary bone or soft tissue sarcoma of the lower extremity from January 2010 to October 2021 and prescribed LMWH or DOAC within 90-days postoperatively. The primary outcomes were comparison of postoperative incidence and odds of deep venous thrombosis(DVT), pulmonary embolism(PE), and bleeding complications within 90-days following resection. Patients prescribed DOACs had a greater odds of DVT (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.06-2.41;p = 0.024) and PE (OR: 3.38;95% CI: 1.96-5.86;p < 0.001) within 90-days following resection of bone sarcoma when compared withthe LMWH cohort. Patients undergoing resection of soft tissue sarcomas also had greater odds DVT (OR: 1.65;95% CI: 1.09-2.49;p = 0.016) and PE (OR: 2.62;95% CI: 1.52-4.54;p < 0.001) in the DOAC cohort. There was no difference in the odds of bleeding complications. This study demonstrated an increased incidence and odds of VTE, but not bleeding complications, when using DOACs versus LMWH after primary bone or soft tissue sarcoma resection. Level III.

Effectiveness and Safety of Direct Oral Anticoagulants Among Patients with Non-valvular Atrial Fibrillation and Multimorbidity.

In the USA, there is a steady rise of atrial fibrillation due to the aging population with increased morbidity. This study evaluated the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) among elderly patients with non-valvular atrial fibrillation (NVAF) and multimorbidity prescribed direct oral anticoagulants (DOACs). Using the CMS Medicare database, a retrospective observational study of adult patients with NVAF and multimorbidity who initiated apixaban, dabigatran, or rivaroxaban from January1, 2012 to December31, 2017 was conducted. High multimorbidity was classified as having ≥ 6 comorbidities. Cox proportional hazard models were used to evaluate the hazard ratios of S/SE and MB among three 1:1 propensity score matched DOAC cohorts. All-cause healthcare costs were estimated using generalized linear models. Overall 36% of the NVAF study population had high multimorbidity, forming three propensity score matched (PSM) cohorts: 12,511 apixaban-dabigatran, 60,287 apixaban-rivaroxaban, and 12,567 dabigatran-rivaroxaban patients. Apixaban was associated with a lower risk of stroke/SE and MB when compared with dabigatran and rivaroxaban. Dabigatran had a lower risk of stroke/SE and a similar risk of MB when compared with rivaroxaban. Compared to rivaroxaban, apixaban patients incurred lower all-cause healthcare costs, and dabigatran patients incurred similar all-cause healthcare costs. Compared to dabigatran, apixaban patients incurred similar all-cause healthcare costs. Patients with NVAF and ≥ 6 comorbid conditions had significantly different risks for stroke/SE and MB when comparing DOACs to DOACs, and different healthcare expenses. This study's results may be useful for evaluating the risk-benefit ratio of DOAC use in patients with NVAF and multimorbidity.

Safety of apixaban and rivaroxaban compared to warfarin after cardiac surgery

Direct oral anticoagulants (DOACs) are frequently prescribed for the management of atrial fibrillation and venous thrombosis. There is a lack of published data on the utilization of DOACs in individuals who have undergone recent cardiac surgery. The purpose of this study was to evaluate the safety and efficacy of apixaban and rivaroxaban compared to warfarin in patients postcardiac surgery. In this retrospective cohort study, patients were separated into a DOAC cohort or a warfarin cohort based on the agent they received after cardiac surgery. Patients could be included if they were ≥18 years of age and received or were discharged on either rivaroxaban, apixaban, or warfarin within 7 days after cardiac surgery. The primary outcome for the study was the rate of International Society on Thrombosis and Hemostasis (ISTH) major bleeding during hospitalization and for 30 days following discharge or until first follow-up appointment. There were a total of 194 patients included in the analysis, 97 in the DOAC cohort and 97 in the warfarin cohort. Four patients (4.1%) in the DOAC group experienced ISTH major bleeding, while 2 patients (2.1%) in the warfarin cohort experienced ISTH major bleeding (p = 0.68). No patients in the DOAC cohort experienced a thrombotic event, whereas 2 patients (2.1%) in the warfarin cohort experienced a thrombotic complication (p = 0.5). Apixaban and rivaroxaban demonstrated similar safety when compared to a matched cohort of warfarin patients. Larger prospective randomized studies are needed to confirm these findings.

Risk of intracranial hemorrhage between different direct oral anticoagulants in older patients seen in the emergency department with a head injury: A population-based cohort study

IntroductionPatients taking direct oral anticoagulants (DOACs) are increasingly managed in emergency departments (ED). It is unknown whether the risk of traumatic intracranial hemorrhage (ICH) after a head injury differs between DOACs. The objective of this study was to compare risk of ICH at the index ED visit among older adults presenting to the ED with a head injury prescribed different DOACs. MethodsRetrospective cohort study using population-based administrative databases from Ontario, Canada between 2016 and 2018 of patients age 65 years and older prescribed DOACs who were seen in the ED with a head injury. Patients were matched on the propensity score to create three pairwise-matched cohorts based on the DOAC prescribed (dabigatran vs rivaroxaban; dabigatran vs apixaban; rivaroxaban vs apixaban). For each cohort, relative risk (RR) and 95% confidence intervals (CI) of ICH diagnosed at the index ED visit were calculated. ResultsWe identified 9230 older adults presenting with a head injury prescribed a DOAC. There were 1274 (13.8%) patients with a prescription for dabigatran, 3136 (34.0%) patients with a prescription for rivaroxaban, and 4820 (52.2%) patients with a prescription for apixaban. Overall, 5.9% of patients had an ICH at the index ED visit. After matching, there were no significant differences in the risk of ICH between any matched DOAC cohorts. ConclusionIn patients aged 65 years and older with a prescription for a DOAC seen in the ED for a head injury, there were no differences in the risk of ICH between DOACs.

Association of Vitamin K and Non-Vitamin K Oral Anticoagulant Use and Cancer Incidence in Atrial Fibrillation Patients.

The association between the use of vitamin K antagonists (VKAs) and cancer risk reduction remains unclear. We aimed to assess the association between the use of VKAs or direct oral anticoagulants (DOACs) and the incidence of cancer in a large cohort of patients with atrial fibrillation (AF) by means of a population‐based, propensity‐weighted cohort study using population‐wide databases including patients diagnosed with nonvalvular AF (NVAF) followed for up of 5 years (median 2.94 years). We created two cohorts based on the initiation therapy (VKA or DOAC). Initiation with VKA or DOAC was defined as filling a prescription with no previous exposure in the preceding 12 months. Cancer diagnoses of any type and for specific tumors (lung, colon, prostate, bladder, and breast). We included 39,989 patients, 31,200 (78.0%) in the VKA cohort. Incidence rate for any cancer was 12.45 per 1,000 person‐year in the DOAC cohort vs. 14.55 in the VKA cohort (adjusted hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.02–1.32). In secondary outcomes, no differences were found for specific types of cancer, such as lung (HR: 1.28, CI: 0.89–1.83), colon (HR: 0.84, CI: 0.62–1.13), prostate (HR: 1.40, CI: 0.94–2.10), bladder (HR: 1.07, CI: 0.76–1.52), and breast (HR: 1.05, CI: 0.66–1.69). Sensitivity analyses yielded similar results. Subgroup analyses also produced consistent findings, except for men, for whom VKA was associated with a lower risk of colon cancer (HR: 0.68, 95% CI: 0.48–0.96). Our results do not confirm a chemoprotective effect of VKA when compared with DOAC in a large, real‐world cohort of patients with NVAF followed for up to 5 years.

Safety and Efficacy of Direct Oral Anticoagulants in Comparison to Low Molecular Weight Heparin in Hematological Malignancies

Introduction: The association between malignancies and venous thromboembolism (VTE) is a well established and significant cause of mortality in cancer patients. Compared to warfarin, low molecular weight heparin (LMWH) was found to be superior in preventing VTEs in the CLOT trial (Lee, et al. NEJM, 2003). Current guidelines recommend LMWH in patients with malignancies (Kearon, et al. Chest. 2016) however it is often difficult for patients to continue this long term given it is a subcutaneous injection that needs to be administered twice a day. Patients generally prefer direct oral anticoagulants (DOACs) due to ease of administration. When DOACs were compared to warfarin in non-cancer patients (RE-COVER, EINSTEIN, AMPLIFY, HOKUSAI-VTE trials), they had similar efficacy and safety profiles. There are limited studies looking at DOACs in malignancies, particularly in those with hematological malignancies who often present with cytopenias, making anticoagulation challenging. We performed a retrospective analysis to evaluate the efficacy and safety of DOACs compared to LMWH in patients with hematological malignancies.Methods: We performed a retrospective analysis of patients diagnosed with a hematological malignancy who were placed on either a DOAC or LMWH for a VTE or atrial fibrillation (AF) from January 2011 to May 2017. We classified leukemia as those with AML, ALL, or CML and categorized CLL with other lymphoma subtypes. We also included multiple myeloma, MGUS, MDS, and Waldenstrom's macroglobulinemia. We primarily assessed efficacy and safety of DOACs in comparison to LMWH. Efficacy was based on incidence of a new VTE while on anticoagulation, and safety was measured by incidence of a bleeding event while on anticoagulation. CTCAE grading was used for bleeding events. 168 patients on DOACs and 70 patients on LMWH were available for analysis.Results: Of the 168 patients on a DOAC, 108 (64%) were started for a VTE and 60 (36%) were started for AF. Of the 70 patients on LMWH, 67 (96%) were started for a VTE and 3 (4%) were started for AF. Median follow-up in the DOAC and LMWH group was 11 and 22 months, respectively. The groups were similar in median age, gender distribution, race, ethnicity, and malignancy types. Average weight between the DOAC and LMWH groups were 87 versus 90.5 kg, respectively. Estimated glomerular filtration rate was 81.2 mL/min/1.73m2 in the DOAC group and 86.6 mL/min/1.73m2 in the LMWH group. The majority of patients were diagnosed with either a lymphoma or leukemia (61.9% of patients with lymphoma/19.6% with a leukemia in the DOAC cohort, and 54.2% of patients with lymphoma/30% with leukemia in the LMWH cohort). The majority of patients had not yet achieved remission at time of DOAC/LMWH initiation (60.1% versus 58.6%, respectively). Apixaban was the most commonly prescribed DOAC (60.7%).Incidence of a new VTE was 11.3% (n=18) in the DOAC group versus 11.4% (n=8) in the LMWH group. Of those who experienced a new VTE in the DOAC group, the majority developed a new extremity DVT (72.2%, n=13). Only two patients developed a new pulmonary embolism (PE), both of which were non-life-threatening. Of the 8 patients who developed a VTE in the LMWH group, 4 developed a recurrent extremity DVT (50%), 2 developed a thrombus in the IJ (25%), 1 developed a portal vein thrombus (12.5%), and 1 developed a submassive PE (12.5%).The incidence of a bleeding complication on DOAC therapy was 10.7% (n=19) versus 11.4% (n=8) on LMWH therapy. Of the 19 bleeding events in the DOAC group, there were two intracranial bleeds, one grade 2 in the setting of a new stroke and the second considered Grade 4 after a mechanical fall. There were 6 gastrointestinal (GI) bleeding complications (3 grade 2, 3 grade 3). There were 3 grade 2 epistaxis and 3 grade 3 hemoptysis. There were two extremity hematomas and one abdominal hematoma after a trauma, all grade 3. Lastly, there were 2 grade 3 pericardial bleeding complications related to pacemaker exchanges.Of the 8 bleeding events in the LMWH group, there was one grade 4 intracranial bleed after a new stroke and one grade 4 upper GI bleed in the setting of esophageal varices. Otherwise there were 4 extremity hematomas, (3 grade 2, 1 grade 3), one grade 3 leg hematoma and one grade 3 hemoptysis.Conclusion: In those with hematological malignancies, DOACs appear to be non-inferior to the standard of care, LMWH, with similar efficacy and safety. [Display omitted] DisclosuresPortell:Infinity: Research Funding; TG-Therapeutics: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Roche/Genentech: Research Funding.

From a DOAC to Warfarin: Reasons Why Patients Switch

1. IntroductionThe introduction of direct oral anticoagulants (DOACs) has led to their widespread use for stroke prevention in patients with non-valvular atrial fibrillation (AF) and as first-line treatment in acute venous thromboembolism (VTE), and also as secondary thromboprophylaxis in patients with a history of VTE. In addition, many patients previously taking vitamin K antagonists (VKAs) have switched to a DOAC for reasons including erratic international normalised ratio (INR) control, medication interactions, convenience, possible lower major bleeding risk and possible improved stroke prevention rates. Although DOACs are well tolerated, little is known about the numbers of patients switching from a DOAC to (or back to) a VKA or the reasons for doing so.2. MethodsThis study was an analysis of prospectively-collected data from a four-year period surveying a computer-based VKA (warfarin) dose adjustment clinic in a large city centre hospital. The primary objective was to identify the reasons for patients switching from a DOAC to warfarin. Secondary objectives included assessing indication for anticoagulant therapy and choice of DOAC. The time in therapeutic range (TTR) once switched back to VKA and clinical events following commencement of warfarin were also determined.3. ResultsIn our VKA clinic with 1791 patients annually under review, 39 patients were identified as having switched from a DOAC to warfarin. The mean age of the patients was 68.5 years +/- 13.8 and the majority (N=24) were female. AF was the most common condition necessitating anticoagulation (N=24); VTE accounted for 12 cases; arterial thromboembolism (N=2) and cardiac thrombus (N=1) were less common causes and one patient had been started on a DOAC in the setting of valvular replacement. Of the patients who were switched to warfarin, seven (17.9%) had originally been anticoagulated with a VKA prior commencing on a DOAC. In terms of anticoagulant choice, the majority of patients (N = 27) were taking rivaroxaban with 6 patients each on dabigatran and apixaban. The causes for switching in this cohort are outlined in table 1. Interesting cases of note include one patient who had a splenic infarction while taking rivaroxaban for atrial fibrillation and one patient who developed a new thumb arterial embolus while taking rivaroxaban for a PE.Following warfarin commencement, there was a total of eight clinical events reported (21.1% of patients). There were seven bleeding events recorded with two serious events necessitating hospital admission and five minor events; in five of these (71.4%), the original reason for switching back to warfarin had been a bleed while on a DOAC. One further patient had a high INR necessitating administration of vitamin K. The mean TTR of this cohort was 61.4% +/- 22.3. 33 patients (84.6%) of patients still attend the warfarin clinic, with cessation of anticoagulant therapy having occurred in three patients (7.7%) and death occurring in one patient (2.6%); two patients (5.1%) have been recommenced on a DOAC.4. DiscussionDOACs have several advantages over warfarin for many patients; they do not require monitoring and the dose remains stable. Index trials have demonstrated at least non-inferiority to warfarin in stroke prevention in non-valvular AF and treatment of VTE, with at least no significant difference in bleeding outcomes. However, warfarin can be an attractive option in complicated cases as it can be rapidly reversed, and there continues to be greater levels of clinician experience with its use. In the present study, we report data regarding the switch back to warfarin in a DOAC cohort, an area into which little research has been conducted. There were only 39 patients reported over a four-year period; this represents only a small minority of the full cohort. As expected, the majority of patients required a switch because of re-thrombosis or a bleeding event. Patients also required an appropriate switch in situations outside of the licence of the DOACs i.e. renal deterioration or valvular AF. The authors are not aware of any data regarding arterial embolisation in rivaroxaban users, and acute hepatitis has been rarely described in rivaroxaban use. These data confirm that switching from a DOAC to warfarin is seldom deemed necessary by clinicians. However, familiarity and experience may guide therapy in complicated cases, and vigilance is required to ensure adherence to the licence when prescribing a DOAC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mortality and Hepatic Decompensation in Patients With Cirrhosis and Atrial Fibrillation Treated With Anticoagulation

Outcomes with anticoagulation (AC) are understudied in advanced liver disease. We investigated effects of AC with warfarin and direct oral anticoagulants (DOACs) on all-cause mortality and hepatic decompensation as well as ischemic stroke, major adverse cardiovascular events, splanchnic vein thrombosis, and bleeding in a cohort with cirrhosis and atrial fibrillation (AF). This was a retrospective, longitudinal study using national data of U.S. veterans with cirrhosis at 128 medical centers, including patients with cirrhosis with incident AF, from January 1, 2012 to December 31, 2017 followed through December 31, 2018. To assess the effects of AC on outcomes, we applied propensity score (PS) matching and marginal structural models (MSMs) to account for confounding by indication and time-dependent confounding. The final cohort included 2,694 veterans with cirrhosis with AF (n=1,694 and n=704 in the warfarin and DOAC cohorts after PS matching, respectively) with a median of 4.6 years of follow-up. All-cause mortality was lower with warfarin versus no AC (PS matched: hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.55-0.76; MSM models: HR, 0.54; 95% CI, 0.40-0.73) and DOACs versus no AC (PS matched: HR, 0.68; 95% CI, 0.50-0.93; MSM models: HR, 0.50; 95% CI, 0.31-0.81). In MSM models, warfarin (HR, 0.29; 95% CI, 0.09-0.90) and DOACs (HR, 0.23; 95% CI, 0.07-0.79) were associated with reduced ischemic stroke. In secondary analyses, bleeding was lower with DOACs compared to warfarin (HR, 0.49; 95% CI, 0.26-0.94). Warfarin and DOACs were associated with reduced all-cause mortality. Warfarin was associated with more bleeding compared to no AC. DOACs had a lower incidence of bleeding compared to warfarin in exploratory analyses. Future studies should prospectively investigate these observed associations.

Mortality Rate and Functional Outcomes Among Patients Presenting with Anticoagulation- Associated Intracranial Hemorrhage

Background Oral anticoagulants are the recommended therapy for prophylaxis and treatment of venous thromboembolism and for stroke prevention among patients with non-valvular atrial fibrillation. Given their widespread use, clinicians must balance efficacy and anticoagulation associated bleeding risks. Intracranial hemorrhage (ICH) has been the most feared complication, as this form of bleeding has been associated with the greatest morbidity and mortality. Clinical trials suggest a lower incidence of ICH among patients prescribed the direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs). While reassuring, the clinical impact on functional outcomes once an anticoagulant-associated ICH does occur is needed. The aim of this study was to evaluate the role of anticoagulation use on in-hospital mortality rates, and functional outcomes among survivors presenting with ICH. Methods In this study, we present data from a retrospective chart review of patients who presented to The Ottawa Hospital, Ottawa, Canada with ICH between January 2016 and December 2017. Patients were identified from the Ottawa Hospital Data Warehouse using ICD-10 codes. Patient demographics, type of anticoagulant/antiplatelet agent and indication for therapy were collected. The primary outcome was in-hospital mortality rates among patients prescribed oral anticoagulants compared with those not anticoagulated or on antiplatelet therapy. A secondary outcome was functional assessment of survivors at hospital discharge using the modified Rankin Scale (mRS), a validated tool used widely in contemporary stroke research to measure the degree of disability after a neurological event. Results 1457 patients were identified in the Ottawa Hospital Data and 1331 patients with ICH were confirmed by manual review. 195 patients were on an oral anticoagulant, and the primary indication for anticoagulation was atrial fibrillation (Table 1). Intraparenchymal bleeding was most common among patients on DOACs, while patients on warfarin tended to have more subdural hematomas (Table 2). In-hospital mortality was 37.7% in DOAC-related ICH, 36.4% in warfarin-related ICH and 16.8% in patients not on an antithrombotic therapy. The average modified Rankin Scale (excluding death as a competing factor) at the time of discharge was 3.4 in DOAC-related ICH, 3.6 in warfarin-related ICH and 3.2 in patients not on an anticoagulant or antiplatelet (Table 3). The majority of patients with a DOAC-related ICH were on Apixaban or Rivaroxaban. The in-hospital mortality for patients on Apixaban (N=31) and Rivaroxaban (N=39) was 29.0% and 46.2%, respectively (Table 4). Conclusions In this cohort of patients presenting with ICH to a large academic hospital, the in-hospital mortality rate was higher in patients receiving oral anticoagulation compared to those not on anticoagulants. DOAC-related ICH tended to have similar in-hospital mortality when compared to warfarin; however, among survivors, functional outcomes at discharge tended to be more favourable in the DOAC cohort. Although the DOACs are reported in the literature to have an overall lower incidence of ICH, prospective studies are needed to understand the clinical impact when a bleeding event does occur. Disclosures Castellucci: Servier: Honoraria; Bayer: Honoraria; BMS-Pfizer: Honoraria; LEO Pharma: Honoraria.

Bleeding and thrombotic complications during treatment with direct oral anticoagulants or vitamin K antagonists in venous thromboembolic patients included in the prospective, observational START2-register

ObjectiveThe proportion and characteristics of Italian patients affected by venous thromboembolism (VTE) treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs), and complications occurring during follow-up.DesignA prospective cohort...

Dental extractions on direct oral anticoagulants vs. warfarin: The DENTST study

BackgroundConflicting recommendations exist addressing the management of direct oral anticoagulants (DOACs) for invasive dental procedures. ObjectivesTo determine the safety of DOAC continuation compared to warfarin continuation for dental extractions with regards to bleeding outcomes. MethodsA single‐center, prospective, cohort study was performed to compare 7‐day bleeding outcomes between patients who continued their DOAC, and patients on warfarin with an International Normalized Ratio (INR) between 2.0 and 4.0. Blood tests including oral anticoagulant drug levels were measured immediately prior to extraction. The gauze used to apply pressure to the socket was weighed before and after extraction to estimate blood loss. Patients were contacted by phone 2 and 7 days after extraction. ResultsEighty‐six patients on a DOAC had a total of 145 teeth extracted, and 21 patients on warfarin had 50 teeth extracted. There were no major bleeding events. The rate of minor plus clinically relevant nonmajor bleeding was comparable between the DOAC and warfarin cohorts (36% and 43%, respectively; odds ratio, 0.75; 95% confidence interval, 0.29‐1.98). Preextraction apixaban and dabigatran levels were comparable between bleeders and nonbleeders, while rivaroxaban levels were higher in those who bled. The weight change of gauze used to tamponade the socket was similar between the 2 cohorts. ConclusionDental extractions on patients continuing DOACs led to bleeding rates similar to patients on warfarin with an INR between 2.0 and 4.0. There is no need to adjust DOAC dosing prior to dental extractions.

Perioperative interruption of direct oral anticoagulants and vitamin K antagonists in patients with atrial fibrillation: A comparative analysis

BackgroundThere is a paucity of studies comparing postoperative thromboembolic and major bleeding complications following perioperative interruption of the direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs). Objective/MethodsWe conducted a retrospective cohort study to compare postoperative thromboembolic and major bleeding outcomes following perioperative interruption of DOACs and VKAs in patients with atrial fibrillation. The primary efficacy and safety outcomes were the 30‐day postoperative rates of arterial thromboembolic events (ATEs) and major bleeding, respectively. The secondary outcomes included the 30‐day rates of clinically relevant nonmajor bleeding (CRNMB) and overall mortality. Thromboembolic, major bleeding, and mortality outcomes were independently adjudicated. Multivariable mixed‐effects logistic‐regression models were used to adjust for potential confounding variables between the DOAC and VKA cohorts. ResultsA total of 325 DOAC patients undergoing 351 procedures and 199 VKA patients undergoing 221 procedures were included. The 30‐day ATE rate was 0.57% (95% confidence interval [CI], 0.27‐0.8) in the DOAC cohort. There were no ATEs in the VKA cohort. The 30‐day rates of major bleeding were 0.57% (95% CI, 0.27‐0.8) and 3.62% (95% CI, 0‐7.3) in the DOAC and the VKA cohorts, respectively. There were significantly more postoperative major bleeding events in the VKA cohort. The 30‐day rate of CRNMB was 4.27% (95% CI, 4.15‐4.42) in the DOAC cohort and 4.52% (95% CI, 3.67‐5.38) in the VKA cohort. There were 2 deaths in the VKA cohort, one of which was deemed to be a fatal nonsurgical bleeding event. ConclusionsThe perioperative interruption of VKAs may be associated with higher postoperative major bleeding rates as compared to DOACs. Careful postoperative reinitiation and monitoring of VKA anticoagulation may be warranted following surgical procedures.

Efficacy and Safety of Direct Oral Factor Xa Inhibitors in Patients after Bariatric Surgery

Background: Over 200,000 people underwent weight loss surgery in the United States in 2017. The absorption of numerous drugs has been shown to be altered in patients after bariatric procedures, as gastrointestinal absorptive surface, food volume, and gastric pH all affect bioavailability. Dosing of warfarin, which is commonly used for the treatment of venous thromboembolism (VTE), often needs to be adjusted, based on INR, after bariatric surgery. Since direct oral anticoagulants (DOACs), which are rapidly replacing warfarin as standard anticoagulant therapy, are not monitored, there is concern regarding their efficacy and safety in patients who have had bariatric surgery, particularly rivaroxaban, which is absorbed primarily in the stomach and must be taken with food at therapeutic doses. One study found that 9 out of 9 apixaban patients (but only 2 of 7 rivaroxaban patients) had levels that fell within the expected range after bariatric surgery. Effects of bariatric surgery on DOACs may be further complicated by baseline obesity and subsequent weight loss of the patients. The goal of our current study is to determine whether DOACs are safe and effective in preventing recurrent VTE in patients who have undergone bariatric surgery. Methods: Using our institutional database, we identified all adult patients (age ≥18 years) with a history of bariatric surgery (gastric banding, sleeve gastrectomy, and Roux-en-Y gastric bypass) who were started on anticoagulation with apixaban or rivaroxaban for VTE, between July 1, 2013 and June 30, 2018. We performed retrospective chart review to obtain information on patient demographics, BMI and type of bariatric surgery. We documented clinical outcomes of recurrent VTE and bleeding from the first prescription date to the earliest of a thrombotic event, discontinuation of medication, death, or the end of study period, June 30, 2018. VTE events were confirmed by a review of imaging studies (compression ultrasonography, ventilation/perfusions scans, and CT scans). Bleeding events were included if they met criteria for clinically relevant non-major bleeding and/or major bleeding according to the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Safety outcomes included major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). We also compared VTE recurrence and bleeding rates between the post-bariatric surgery patients and patients with BMI &gt;40 from our prior study. Chi- squared tests were used to assess statistical significance of the differences in recurrent VTE and bleeding rates between anticoagulant cohorts. Results: Data on 102 patients were collected: 42 patients on apixaban and 60 patients on rivaroxaban. Our population was predominantly female (82.4%) with a mean age of 48.5 years and a median BMI of 35.7 at initiation of anticoagulation. Gastric bypass was the most common bariatric procedure (51%), followed by sleeve gastrectomy (37.3%), and gastric banding (11.8%). There were no recurrent VTE events in the apixaban cohort with a median follow-up duration of 137 days. Among patients on rivaroxaban, with a median follow-up of 232 days, there was one recurrent VTE (1.7%) in a patient with a BMI of 54 at the time of event. When we compared VTE recurrence rates of our combined DOAC cohort (apixaban + rivaroxaban) between our general morbidly obese population, from a prior study at our institution, and post-bariatric surgery patients, there was no statistically significant difference (2.0% vs. 1.0%, respectively, p=0.5). In bariatric surgery patients, one CRNMB event was recorded in apixaban group (2.4%) while 4 major bleeding events occurred on rivaroxaban (6.7%), p=0.3. There was no significant difference in the rate of composite MB and CRNMB between the general obesity and bariatric surgery patients (8.0% vs. 4.9%, respectively, p=0.3). Conclusions: In a review of post-bariatric surgery patients on anticoagulation for VTE, we found low rates of recurrent VTE for patients on DOACs. Although we had a relatively small sample size, the incidence of VTE recurrence was not higher in this cohort than was found in our previously published study of general obesity population. Prospective studies are needed to further investigate the efficacy and safety of direct oral anticoagulants in patients after bariatric surgery. Table. Disclosures Kushnir: Janssen Pharmaceuticals: Research Funding. Billett:Janssen: Research Funding.

Predictors of Bleeding in the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study

Introduction In the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study a simplified, standardized, pharmacokinetic based perioperative interruption scheme was stablished for patients with non-valvular atrial fibrillation taking direct oral anticoagulants (DOACs). The rate of bleeding and thromboembolic outcomes was low, yet better awareness of bleeding predictors will aid the informed decision making for both clinicians and patients. Thus, we aimed to define the factors associated with perioperative bleeding events in the PAUSE cohorts. Methods The standardized interruption scheme is depicted in figure 1. We analyzed bleeding as the composite of major and clinically relevant non-major bleeding (MB/CRNM) according to the ISTH criteria. Putative predictors of bleeding were prospectively collected during the PAUSE recruitment. For patients taking dabigatran the dilute thrombin time was measured from a pre-operative blood sample. A DOAC-calibrated anti-factor Xa level was assessed preoperatively for patients taking factor Xa inhibitors. Continuous numeric variables were reported as means with SD; frequencies were reported when appropriate. We used stratified logistic regression models for analysis. All statistical analyses were performed in R version 3.6.0. Results There were 3007 patients requiring perioperative DOAC interruption, distributed in the apixaban (A) (N = 1,257), dabigatran (D) (N = 668), and rivaroxaban (R) (N = 1,082) cohorts. Characteristics of the patients who developed MB/CRNM are reported in table 1. More than one third of included patients underwent a high bleeding risk procedure. The rates of MB/CRNM were 3.02% in group A, 2.84% in group D, and 4.16% of group R patients from the point of DOAC interruption to 30 days after the procedure. In the univariate analysis, surgery bleeding risk was significantly associated with MB/CRNM (low vs high, OR 0.56, 95% CI 0.36-0.86; p=0.008). Multivariate analysis stratified by region found hypertension (OR 1.81, 95%CI 1.07-3.07; p=0.027), prior bleed or bleed predisposition (OR 1.62, 95% CI 1.02-2.58; p=0.043) were significantly associated with MB/CRNM (table 2); whereas surgery bleeding risk was not significant after adjusting other covariates. Female gender was associated with lower MB/CRNM risk (This result seems to be mainly driven by the rate of CRNM, 2.21% male had CRNM and 1.57% female had CRNM, and the signal disappeared in the model for MB). [Hypertension (OR 3.93, 95%CI 1.40-11.07; p=0.010), active cancer (OR 2.30, 95% CI 1.10-4.81; p=0.026) were significantly associated with MB (table 3)] Aspirin use was more prevalent among males (13.78%) than females (7.75%), but this did not fully explain the gender effect. The model for MB/CRNM had an area under the curve (AUC) of 0.65 (standard error 0.03). Drug level analysis was available for 2541 (84.5%) patients. In the stratified analysis with the DOAC level (&amp;gt;50ng/dL vs £50ng/dL) as a single predictor, there was no significant association with MB/CRNM observed (OR 1.07, 95% CI 0.38-2.96; p=0.902). In the multivariate model, adding DOAC level to the model did not improve the AUC. Discussion A standardized interruption scheme results in low risk of bleeding for patients with atrial fibrillation interrupting DOACs for surgery/invasive procedures. The protocol-defined surgical bleed risk in PAUSE was valid, and selected to numerically higher bleeding rates, but it was not independent predictor of bleeding when the interruption scheme and covariates are accounted for. Hypertension was the only potentially modifiable predictor of perioperative MB/CRNM bleeding. Likely selecting for a frail population, active cancer and hypertension were predictors of MB events. In the exploratory analyses, residual levels did not improve the predictive model. The multivariate model had a low performance and we do not advocate modification of the PAUSE-proposed interruption schema based on these results. The PAUSE trial is the first large scale study enabled to investigate the factors governing perioperative bleed among DOAC-Anticoagulated patients. Nonetheless, we did not have power to analyze DOAC cohorts independently due to the paucity outcomes. Overall, the results strengthen the validity of the PAUSE-proposed DOAC interruption scheme for atrial fibrillation patients who need surgery. Disclosures Tafur: Recovery Force: Consultancy; Janssen: Other: Educational Grants, Research Funding; BMS: Research Funding; Idorsia: Research Funding; Daichi Sanyo: Research Funding; Stago: Research Funding; Doasense: Research Funding. Spyropoulos:Bayer: Consultancy; Ingelheim: Consultancy; Portola: Consultancy; Janssen: Research Funding; Boehringer INgelheim: Research Funding; Janssen: Consultancy. Douketis:Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Portola: Other: Consultant ; Janssen: Other: Consultant ; The Merck Manual: Patents &amp; Royalties; Up-to-Date: Patents &amp; Royalties.

Comparative Effectiveness of Direct Oral Anticoagulants and Warfarin for the Treatment of Left Ventricular Thrombus

Introduction Left ventricular (LV) thrombus is a complication of acute endomyocardial injury and chronic ventricular wall hypokinesis (e.g. dilated cardiomyopathy), resulting in increased risk of thromboembolic complications. Historically, observational studies support the general safety and efficacy of warfarin for this indication. To date, limited data exists regarding the use of the direct oral anticoagulants (DOACs) for LV thrombus. Methods A retrospective cohort study utilizing electronic medical records was conducted from September 2012 - October 2018 at the University of Colorado Hospital System. Patients were included if they had any diagnosis of LV thrombus and received either a DOAC or warfarin within 90 days of diagnosis. The primary outcome was to determine the incidence of thromboembolic stroke in patients receiving a DOAC compared to warfarin. Secondary outcomes consisted of the composite incidence of thromboembolic events (stroke and systemic embolism), bleeding rates defined by the The Global Use of Strategies to Open Occluded Arteries (GUSTO) criteria, and blood product administration. Chi square test was used to analyze categorical variables and the student's t-test and Wilcoxon Rank Sum test for continuous data. All statistical analyses were conducted using SAS. Results A total of 949 patients met inclusion, of whom 180 (19%) received a DOAC and 769 (81%) warfarin. Of the DOAC cohort, 77 (41.6%) received rivaroxaban, 79 (42.7%) apixaban, and 29 (15.7%) dabigatran. For baseline demographic information, see table 1. For the primary endpoint of new onset thromboembolic stroke on or within 90 days of LV thrombus diagnosis, no difference existed between treatment groups (DOAC: 7.8% vs warfarin: 11.7%, p=0.524). When compared to warfarin, no difference existed in the composite of thromboembolic events (33.1% vs 30.6%, P=0.524, respectively) or in GUSTO bleeding (11.1% vs 7.8%, p=0.397, for DOAC vs. warfarin, respectively). However, more patients on warfarin received blood products compared to those taking a DOAC (25.8% vs 13.9%, p Conclusions Compared to warfarin, DOACs may be safe and efficacious for the treatment of LV thrombus, however further studies are warranted.

Effectiveness and safety of direct oral anticoagulants compared to warfarin in treatment na\xefve non-valvular atrial fibrillation patients in the US Department of defense population

BackgroundClinical trials have demonstrated that direct oral anticoagulants (DOACs) are at least non-inferior to warfarin in reducing the risk of stroke/systemic embolism (SE) among patients with non-valvular atrial fibrillation (NVAF), but the comparative risk of major bleeding varies between DOACs and warfarin. Using US Department of Defense (DOD) data, this study compared the risk of stroke/SE and major bleeding for DOACs relative to warfarin.MethodsAdult patients with ≥1 pharmacy claim for apixaban, dabigatran, rivaroxaban, or warfarin from 01 Jan 2013–30 Sep 2015 were selected. Patients were required to have ≥1 medical claim for atrial fibrillation during the 12-month baseline period. Patients with a warfarin or DOAC claim during the 12-month baseline period were excluded. Each DOAC cohort was matched to the warfarin cohort using propensity score matching (PSM). Cox proportional hazards models were conducted to evaluate the risk of stroke/SE and major bleeding of each DOAC vs warfarin.ResultsOf 41,001 identified patients, there were 3691 dabigatran-warfarin, 8226 rivaroxaban-warfarin, and 7607 apixaban-warfarin matched patient pairs. Apixaban was the only DOAC found to be associated with a significantly lower risk of stroke/SE (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.39, 0.77; p < 0.001) and major bleeding (HR: 0.65; 95% CI: 0.53, 0.80; p < 0.001) compared to warfarin. Dabigatran and rivaroxaban initiation were associated with similar risk of stroke/SE (dabigatran: HR: 0.68; 95% CI: 0.43, 1.07; p = 0.096; rivaroxaban: HR: 0.83; 95% CI: 0.64, 1.09; p = 0.187) and major bleeding (dabigatran: HR: 1.05; 95% CI: 0.79, 1.40; p = 0.730; rivaroxaban: HR: 1.07; 95% CI: 0.91, 1.27; p = 0.423) compared to warfarin.ConclusionAmong NVAF patients in the US DOD population, apixaban was associated with significantly lower risk of stroke/SE and major bleeding compared to warfarin. Dabigatran and rivaroxaban were associated with similar risk of stroke/SE and major bleeding compared to warfarin.

Comparative clinical outcomes between direct oral anticoagulants and warfarin among elderly patients with non-valvular atrial fibrillation in the CMS medicare population

Atrial fibrillation (AF) prevalence increases with age; > 80% of US adults with AF are aged ≥ 65 years. Compare the risk of stroke/systemic embolism (SE), major bleeding (MB), net clinical outcome (NCO), and major adverse cardiac events (MACE) among elderly non-valvular AF (NVAF) Medicare patients prescribed direct oral anticoagulants (DOACs) vs warfarin. NVAF patients aged ≥ 65 years who initiated DOACs (apixaban, dabigatran, and rivaroxaban) or warfarin were selected from 01JAN2013-31DEC2015 in CMS Medicare data. Propensity score matching was used to balance DOAC and warfarin cohorts. Cox proportional hazards models estimated the risk of stroke/SE, MB, NCO, and MACE. 37,525 apixaban–warfarin, 18,131 dabigatran–warfarin, and 55,359 rivaroxaban–warfarin pairs were included. Compared to warfarin, apixaban (HR: 0.69; 95% CI 0.59–0.81) and rivaroxaban (HR: 0.82; 95% CI 0.73–0.91) had lower risk of stroke/SE, and dabigatran (HR: 0.88; 95% CI 0.72–1.07) had similar risk of stroke/SE. Apixaban (MB: HR: 0.61; 95% CI 0.57–0.67; NCO: HR: 0.64; 95% CI 0.60–0.69) and dabigatran (MB: HR: 0.79; 95% CI 0.71–0.89; NCO: HR: 0.84; 95% CI 0.76–0.93) had lower risk of MB and NCO, and rivaroxaban had higher risk of MB (HR: 1.08; 95% CI 1.02–1.14) and similar risk of NCO (HR: 1.04; 95% CI 0.99–1.09). Compared to warfarin, apixaban had a lower risk for stroke/SE, MB, and NCO; dabigatran had a lower risk of MB and NCO; and rivaroxaban had a lower risk of stroke/SE but higher risk of MB. All DOACs had lower risk of MACE compared to warfarin.

Switching to Another Oral Anticoagulant and Drug Discontinuation Among Elderly Patients With Nonvalvular Atrial Fibrillation Treated With Different Direct Oral Anticoagulants.

We compared the risks of switching to another oral anticoagulant (OAC) and discontinuation of direct oral anticoagulants (DOACs) among elderly patients with nonvalvular atrial fibrillation (NVAF) who were prescribed rivaroxaban or dabigatran versus apixaban. Patients (≥65 years of age) with NVAF prescribed DOACs (January 1, 2013 to September 30, 2017) were identified from the Humana research database and grouped into DOAC cohorts. Cox regression analyses were used to evaluate whether the risk for switching to another OAC or discontinuing index DOACs differed among cohorts. Of the study population (N = 38 250), 55.9% were prescribed apixaban (mean age: 78.6 years; 49.8% female), 37.3% rivaroxaban (mean age: 77.4 years; 46.7% female), and 6.8% dabigatran (mean age: 77.0 years; 44.0% female). Compared to patients prescribed apixaban, patients prescribed rivaroxaban (hazard ratio [HR]: 2.08; 95% confidence interval [CI], 1.92-2.25; P < .001) or dabigatran (HR: 3.74; 95% CI, 3.35-4.18, P < .001) had a significantly higher risk of switching to another OAC during the follow-up; compared to patients prescribed apixaban, the risks of discontinuation were also higher for patients treated with rivaroxaban (HR: 1.10; 95% CI, 1.07-1.13, P < .001) or dabigatran (HR: 1.29; 95% CI, 1.23-1.35, P < .001).

Efficacy and Safety of Direct Oral Factor Xa Inhibitors in 795 Morbidly Obese Patients

Background: Studies of acute venous thromboembolism (VTE) and non-valvular atrial fibrillation (AF) have shown comparable therapeutic efficacy and similar or lower bleeding risk for direct oral anticoagulants (DOACs) compared to warfarin. Because the representation of morbidly obese patients (BMI ≥40 kg/m2) in pivotal clinical trials has been minimal, efficacy and safety of DOACs in this population are unclear. Our goal was to investigate whether direct oral factor Xa inhibitors, apixaban and rivaroxaban, are as effective and safe as warfarin in morbidly obese (BMI ≥40) patients.Methods: Using our institutional database, we identified all adult patients at Montefiore Medical Center with BMI ≥40 who were started on anticoagulation with apixaban, rivaroxaban or warfarin, for either AF or VTE, between March 1, 2013 and March 1, 2017. We reviewed charts to obtain detailed information on patient demographics and to document clinical outcomes of recurrent VTE, ischemic stroke (CVA) and bleeding from the first prescription date to the earliest of a thrombotic event, discontinuation of medication, death, or June 30, 2017. VTE and CVA episodes were confirmed by imaging (compression sonography, CT scans, ventilation/perfusion scans, MRIs). Bleeding events were classified according to criteria from the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis. Analyses were stratified by anticoagulation indication. Chi-squared tests or Fisher's exact tests were used to assess statistical significance of the differences in VTE, CVA and bleeding rates between anticoagulant cohorts. Differences in times from first prescription date to VTE, CVA and bleeding were analyzed with Kaplan-Meier curves, Log-rank tests, and Cox proportional hazards models. Data were adjusted for age, CHA2DS2-VASc, and Charlson scores. Subgroup analyses were performed for patients with BMI ≥50 kg/m2.Results: Data on 795 patients were collected. In 366 patients with a history of VTE, the rates of recurrent VTE were low and comparable among the apixaban, rivaroxaban and warfarin cohorts [1/47 (2.1%), 3/152 (2%), and 2/167 (1.2%), respectively, p=0.74]. In the subgroup of individuals with BMI ≥50 kg/m2 (n=92), none of the 40 DOAC patients had recurrent VTE. The rates of clinically relevant bleeding, including major bleeding, among VTE patients, were comparable between the three cohorts.Among the 429 patients with AF, stroke rates were also low and similar among anticoagulant cohorts [1/103 (1%) for apixaban, 4/174 (2.3%) for rivaroxaban, and 2/152 (1.3%) for warfarin, p=0.71]. CVAs were similarly rare in patients with BMI ≥50 (1/19 patients on apixaban, 0/37 on rivaroxaban and 1/44 patients on warfarin). In the AF sample, there was no statistically significant difference in the rate of bleeding, including major bleeding, among the 3 cohorts. In an analysis with combined DOAC cohort (apixaban + rivaroxaban vs. warfarin), the recurrent VTE and stroke rates were still low and comparable. There were more major bleeding events in AF patients on warfarin than the combined DOAC cohort (7.9% vs. 2.9%, p=0.02), a finding that became non-significant when adjusted for age, CHA2DS2-VASc, and Charlson scores (p=0.06). The rates of bleeding, including major bleeding, were comparable among the three anticoagulants in both VTE and AF patients with BMI ≥50.Conclusions: Our study is the largest study examining morbidly obese patients on DOACS and provides further evidence of comparable efficacy and safety of the direct oral anti-Xa inhibitors, compared to warfarin, in morbidly obese patients with AF and VTE. [Display omitted] DisclosuresKushnir:Janssen: Research Funding. Billett:Bayer: Consultancy; Janssen: Research Funding.