Direct Oral Anticoagulants Usage Research Articles

Heparin-Induced Thrombocytopenia (HIT) in the Direct Oral Anticoagulants (DOAC) Era

Heparin-induced thrombocytopenia (HIT) is an uncommon complication of heparin therapy with significant risk for severe morbidity and mortality. We investigated the role and outcome of direct oral anticoagulants (DOACs) for the management of HIT. After institutional review board (IRB) approval, a retrospective review was performed identifying all patients with positive HIT serotonin-release assays between 2020 and 2022 at two hospitals. The demographic and clinical variables were collected as follows: initial anticoagulant, dosing and indication, interval before onset of HIT, thrombotic complications, platelet nadir and recovery, direct thrombin inhibitor (DTI) and DOAC usage, and clinical outcomes. 15 patients were included in the study. 8 underwent a vascular procedure, 3 had cardiac surgery, 1 patient had both and was included in both groups, and 5 patients had either noncardiac, nonvascular surgery, or no surgery. 14 patients received unfractionated heparin (93% with therapeutic dosing), and 1 received prophylactic enoxaparin prior to diagnosis of HIT. The average time to diagnosis of HIT was 10.77days after initial anticoagulation. In-hospital mortality was 27%, related to Covid-19 infection (3/4) and intracranial hemorrhage (1/4). 40% developed thrombosis (67% venous, 33% arterial) after the diagnosis of HIT. 8/11 survivors were discharged on a DOAC. With DOAC therapy, platelet counts rebounded to an average of 265K (±104.6K) within an average of 2.3days and 364K (±273.9K) within 30days after initiation of a DOAC. No recurrent thrombosis occurred after DOAC administration and only one patient had persistent thrombocytopenia within 30days. Mortality and thrombosis (arterial and venous) are common complications in patients diagnosed with HIT. In patients who survive to discharge, DOACs are the most common discharge antithrombotic agent, with low rates of recurrent thrombosis and thrombocytopenia.

Changes in anticoagulation practice in subjects admitted with stroke associated with atrial fibrillation, following introduction of direct oral anticoagulants over 2013-2021.

The adoption of direct oral anticoagulants (DOACs) has changed practice in prevention of stroke in atrial fibrillation (AF). We used Irish data national data on stroke and anticoagulation therapy over 9 years to investigate changes in anticoagulation practice and potential consequences on stroke prevalence and thrombolysis. AF, anticoagulation, thrombolysis, and stroke data from the Irish National Audit of Stroke (INAS) 2013-2021 were reviewed. The proportion of patients with ischemic stroke (IS) and intracerebral hemorrhage (IH) with known AF admitted on anticoagulation was determined. Effects on age distribution in the population and thrombolysis practice were assessed. AF data were available on 34,630 of 35,241 individuals (98.3%) included in INAS; median age was 74 years and 56% were male. AF was found in 10,016 (28.9%, 9059 IS, 957 IH). 6313 had known AF prior to stroke (63.1%). The proportion all total IS due to AF decreased by 15.3% (31.3%-26.5%, chi-square = 24.6, p < 0.0001). The proportion of IH did not change significantly (21.6%-20.2%, chi-square = 1.8, p = 0.18). Over the 9 years, 3875 (38.6%) of the subjects with AF were recorded as receiving anticoagulants at admission. In 2013, 4.4% of AF-associated strokes were admitted on a DOAC and 21.4% on warfarin; by 2021, 44.1% were receiving a DOAC and 6.2% warfarin. There was a strong inverse correlation between the proportion of anticoagulated stroke patients and the total proportion of AF-associated strokes over time (r = -0.82, p = 0.006). In contrast, no correlation was found between increasing DOAC usage and IH (r = 0.14, p = 0.71). Increased anticoagulation usage correlated with a reduction in patients ⩾ 80 years (r = -0.83, p = 0.006) and also correlated with a relative reduction of 30.1% in subjects thrombolysed <4 h from onset (r = -0.89, p = 0.001). DOACs have led to increased use of anticoagulation, but warfarin use fell by two-thirds. There has been a reduction in the proportion of AF-associated IS without a noticeable increase in IH. Increased anticoagulation correlated with reduced numbers of strokes in those >80 years and in the proportion of patients thrombolysed.

Direct oral anticoagulant agents might be safe for patients undergoing endovenous radiofrequency and laser ablation

ObjectiveStudies assessing the effect of the use of anticoagulant agents on endovenous thermal ablation (ETA) have been limited to patients taking warfarin. Thus, the aim of the present study was to assess the efficacy and safety of ETA for patients taking direct oral anticoagulants (DOACs). We hypothesized that the outcome of ETA for patients taking DOACs would not be superior to the outcomes for patients taking DOACs. MethodsWe performed a retrospective review to identify patients who had undergone radiofrequency ablation or endovenous laser ablation with 1470-nm diode laser fibers for symptomatic great or small saphenous venous reflux from 2018 to 2020. The patients were dichotomized into those who had received a therapeutic dose of DOACs periprocedurally and those who had not (control group). The outcomes of interest included the rates of treated vein closure at 7 days and 9 months and the incidence of deep vein thrombosis (DVT), endothermal heat-induced thrombosis (EHIT), and bleeding periprocedurally. ResultsOf the 301 patients (382 procedures), 69 patients (87 procedures) had received DOACs and 232 control patients (295 procedures) had not received DOACs. The patients receiving DOACs were more often older (mean age, 65 years vs 55 years; P < .001) and male (70% vs 37%; P < .001), with a higher prevalence of venous thromboembolism and more severe CEAP (clinical, etiologic, anatomic, pathophysiologic) classification (5 or 6), than were the control patients. Those receiving DOACs were more likely to have had a history of DVT (44% vs 6%; P < .001), pulmonary embolism (13% vs 0%; P < .001), and phlebitis (32% vs 15%; P < .001). Procedurally, radiofrequency ablation had been used more frequently in the control group (92% vs 84%; P = .029), with longer segments of treated veins (mean, 38 mm vs 35 mm, respectively; P = .028). No major or minor bleeding events nor any EHIT had occurred in either group. Two patients in the control group (0.7%) developed DVT; however, no DVT was observed in those in the DOAC group (P = .441). At 9 months, the treated vein had remained ablated after 94.4% of procedures for patients receiving DOACs and 98.4% of the control group (P = .163). On multivariable analysis, DOAC usage was not associated with an increased risk of vein recanalization (hazard ratio, 5.76; 95% confidence interval, 0.57-58.64; P = .139). An increased preprocedural vein diameter and the use of endovenous laser ablation were associated with an increased risk of recanalization. ConclusionsIn our study of patients who had undergone ETA for symptomatic saphenous venous reflux, the periprocedural use of DOACs did not adversely affect the efficacy of endovenous ablation to ≥9 months. Furthermore, DOAC use did not confer an additional risk of bleeding, DVT, or EHIT periprocedurally. DOACs may be safely continued without affecting the efficacy and durability of ETA.

Heparin: The Journey from Parenteral Agent to Nasal Delivery.

Although the worldwide usage of direct oral anticoagulants has continuously increased over the past decade, heparin remains an important weapon in the current arsenal of anticoagulant drugs. Parenteral heparin administration (i.e., either intravenously or subcutaneously) has represented for decades the only possible route for generating a significant anticoagulant effect, although being notoriously associated with some important drawbacks such as discomfort and risk of low compliance, thus paving the way to searching for more amenable means of administration. We provide here an updated analysis of animal and human studies that have explored the feasibility, suitability, and efficiency of heparin administration through the unconventional nasal route, as a possible alternative to the more traditional parenteral injection. The major hurdles that contribute to impair intranasal absorption and systemic delivery of heparin are represented by its relatively high molecular weight and negative charge. Therefore, although pure drug administration would not be associated with efficient nasal adsorption, or by systemic biological activity (i.e., anticoagulant effect), the combination of low molecular weight heparins and absorption enhancers such as surfactants, mucoadhesive, cyclodextrins, polyethylenimines and encapsulation into (nano)carriers seems effective to at least partially improve drug transport through the nasal route and allow systemic delivery in animals. Besides generating anticoagulant effects, intranasal heparin administration can also produce local pleiotropic effects, mostly related to anti-inflammatory properties, such as attenuating airway allergic inflammation or inhibiting the binding of the spike protein of some coronaviruses (including severe acute respiratory syndrome coronavirus 2) to their host cell receptors. This preliminary evidence represents a valuable premise for planning future studies in humans aimed at establishing the pharmacokinetics and biological activity of locally and systemically delivered intranasal heparin formulations.

ACOD en pacientes con fibrilación auricular e intervención quirúrgica sobre la válvula mitral

Introduction and objectivesAlthough the usage of direct oral anticoagulants (DOAC) in patients with atrial fibrillation (AF) and intervention on the mitral valve (biological valve prosthesis or repair) is included in the clinical practice guidelines as an alternative to vitaminK antagonists (VKA), real world data in this scenario remain scarce. MethodsOur study included all patients who underwent mitral valve replacement by biological prosthesis or mitral valve repair in our hospital between 2014 and 2020, with indication of anticoagulation due to AF. We compared rates of cerebrovascular events, major and minor bleeding, and mortality, between those treated with DOACs and VKAs. ResultsWe selected 105 patients: 75 submitted to biological replacement and 30 to repair. After a mean follow-up of 2.8years, 41 patients were treated exclusively with VKA, and 64 started DOACs —34 as anticoagulant from the beginning, and 30 after switching from VKA. There were no significant differences in their baseline clinical characteristics in terms of age, sex, kidney function, or embolic or bleeding risk scales between groups. There were no differences in the rate of stroke and major bleeding between patients with VKA or DOAC (major bleeding, VKA n=6, 8.4% vs DOAC n=4, 11.7%; stroke/TIA, VKA n=5, 7.04% vs DOAC 2, 5.8%), with 2 intracranial hemorrhages under VKA (2.8%). ConclusionsThe use of DOACs in a real-life cohort of patients with mitral valve surgery (biological prosthesis or repair) is an effective and safe alternative to the use of VKAs, without differences in the rate of ischemic or hemorrhagic events.

Prior direct oral anticoagulant dosage and outcomes in patients with acute ischemic stroke and non-valvular atrial fibrillation: A sub-analysis of PASTA registry study

Background and purposePrescribing under-dose direct oral anticoagulants (DOACs) for non-valvular atrial fibrillation (NVAF) is alerted to increase cardiovascular events or death. However, the association between dose selection of DOACs and the clinical course remains unclear. This study aimed to propose a novel criterion for selecting the DOAC dose and investigate clinical characteristics of ischemic stroke (IS) under this criterion. MethodsWe assessed the pooled prospective multicenter registry data of stroke patients taking anticoagulant agents, including IS patients with NVAF and prior DOAC usage. The recommended dose according to the reduction criteria of each DOAC and the selected dose were identified for each patient, and patients were categorized into four groups: no alternative low-dose, selecting low-dose appropriately with all DOACs applicable for reduction criteria; selected low-dose, selecting low-dose appropriately or inappropriately despite at least one DOAC inapplicable for reduction criteria; selected standard-dose, appropriate standard-dose use; and absolute over-dose, inappropriate standard-dose regardless of criteria. We investigated the effects of dose selection of DOACs on short-term poor functional outcomes. Results322 patients were included in the analysis. The prevalence of no alternative low-dose, selected low-dose, selected standard-dose, and absolute over-dose was 74 (23%), 144 (45%), 89 (27%), and 15 (5%), respectively. Multivariable analysis found that the selected low-dose group showed significantly poorer functional outcomes than the selected standard-dose group only in patients without renal dysfunction (OR, 2.60; 95% CI, 1.17–6.00; P = 0.0186). ConclusionsSelecting a low dose DOAC might be associated with poor functional outcomes in patients without renal dysfunction.

Experience with direct oral anticoagulants in pregnancy – a systematic review

The experience and use of the new direct oral anti coagulants (DOACs) in pregnancy is limited, but as they offer many practical advantages compared to low molecular weight heparin (LMWH), the pursue of their safety is challenging. Systematic review of studies in which DOACs were used during pregnancy and the puerperal period (PROSPERO registry-CRD42021237688). Searches were performed on MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library databases, until July 2021 and secondary sources using the MeSH terms 'pregnancy', 'pregnancy complications', 'venous thrombosis', 'congenital abnormalities', 'Factor Xa Inhibitors,' and names of specific DOACs. Search was limited to human studies, with English or French as languages of report. Literature search yielded 1,989 results which, after duplicate exclusion, resulted in 672 publications. Studies were then screened using the specified eligibility criteria described and studies that did not meet the criteria were excluded, resulting in 21 full text studies to an in-depth analysis and data extraction. Overall, 339 cases of DOACs usage during pregnancy were reported until now. The data demonstrated 56% live births but a miscarriage rate of 22.2% and an elective termination of pregnancy in 21.8%; fetal abnormalities related to DOACs occurred in 3.6%. Our meta-analysis displayed a higher rate of fetal loss and fetal abnormalities with DOACs use compared to LMWH, notwithstanding similar bleeding complications. The current information available for the 339 cases herein reported does not allow a conclusion that DOACs can be safely used in pregnancy.

Direct oral anticoagulants are associated with potentially bleeding lesions in suspected mid-gastrointestinal bleeding

Background and aim Direct oral anticoagulants (DOACs) became a widespread alternative in anticoagulant therapy. Nevertheless, concerns are raised about their safety, with increased gastrointestinal bleeding rates being described. There are scarce studies regarding DOACs effect on small-bowel capsule endoscopy (SBCE) findings. We aimed to assess if the detection of lesions with high bleeding potential on SBCE was significantly different in patients treated with DOACs when compared to non-anticoagulated patients and to patients anticoagulated with other agents. Methods Cohort study including consecutive patients who underwent SBCE for suspected mid-gastrointestinal bleeding (MGIB) in 2019 and 2020. Results From 148 patients, 38 (25.7%) were anticoagulated, of which 26 (68.4%) with DOACs. P2 lesions were detected in 36.5% (n = 54) of the patients. These lesions were more frequently detected in patients under DOACs treatment when compared to non-anticoagulated patients (69.2% vs. 29.1%; p=.001), and also when compared to patients treated with other anticoagulants (69.2% vs. 33.3%; p=.037). No differences in P2 lesions detection were observed between patients treated with other anticoagulants and non-anticoagulated patients (33.3% vs. 29.1%; p=.747). In multivariate analysis, DOACs usage was significantly associated with higher detection rates of P2 lesions on SBCE, when adjusted for classical risk factors for MGIB (OR: 3.38; 95%CI = 1.23–9.26; p=.018). Conclusions Despite their undeniable cardiovascular benefits and easy applicability, DOACs should still be considered with caution. These drugs were significantly associated with higher risk of potentially bleeding lesions on SBCE when compared to other anticoagulants and represent an independent risk factor for MGIB when adjusted for other variables.

Two Cases of Acute Direct Oral Anticoagulant Overdose Without Adverse Effect.

We report 2 pediatric patients who had acute overdoses of the direct oral anticoagulants medications. Both patients were managed conservatively; neither required reversal agents or blood products nor had any major or minor bleeding events. With therapeutic usage of direct oral anticoagulants, routine coagulation studies typically are considered insufficient measures of anticoagulation and the preferred chromogenic anti-Factor Xa assay is recommended but not widely available. Using a routine hybrid heparin anti-Factor Xa assay, 1 patient demonstrated a strong linear correlation up to a serum rivaroxaban concentration of 940 ng/mL.

Current Opinion on the use of Direct Oral Anticoagulants for the Prophylaxis of Venous Thromboembolism among Medical Inpatients.

Venous thromboembolism (VTE) is a known cause of morbidity and mortality, especially among acutely ill medical patients. Although VTE prophylaxis is part of post-discharge clinical care in surgical patients, there is controversy regarding its use in acutely ill medical patients and the current guideline statements suggest against its routine use. Recent clinical trials (APEX, MAGELLAN and MARINER) compared the safety and efficacy of direct oral anticoagulants (including betrixaban and rivaroxaban) with the standard of the care, enoxaparin, to identify the risk–benefit tradeoff. In this review, we summarized the key findings from these trials and substudies and recent updates in society guidelines regarding VTE prevention. In addition, we discussed the potential barriers, cost-effectiveness, and COVID-19 with respect to the implementation of extended-duration or post-discharge usage of direct oral anticoagulants.

Risk of postpolypectomy bleeding in patients taking direct oral anticoagulants or clopidogrel

The usage of direct oral anticoagulants (DOACs) to prevent and treat thromboembolic events is gradually increasing. We aimed to evaluate the outcomes of patients taking DOACs after polypectomy. We retrospectively reviewed 131 patients taking DOACs and 270 taking clopidogrel who underwent polypectomy between November 2010 and December 2017. The risk of delayed postpolypectomy bleeding (PPB) was evaluated and compared. A total of 989 polyps were removed (320 polyps in the DOAC and 669 polyps in the clopidogrel group). DOACs and clopidogrel were discontinued for 2.8 ± 1.7 days and 5.8 ± 2.5 days before polypectomy, respectively. DOACs and clopidogrel were restarted on 1.6 ± 2.9 days and 1.7 ± 1.1 days after polypectomy, respectively. According to per polyp analysis, delayed PPB rate was 1.6% in both groups (p = 0.924). Logistic regression analysis was performed after propensity score matching and revealed that DOACs did not increase the delayed PPB risk compared to clopidogrel (OR 0.929, 95% CI 0.436–1.975, p = 0.847). With the majority following the antithrombotic discontinuation guidelines, the incidence of delayed PPB was 3.1% in the patients taking DOACs. The delayed PPB risk was not greater in those taking DOACs than in those taking clopidogrel.

ACOD frente a AVK en pacientes con fibrilación auricular y recambio valvular aórtico por bioprótesis

Introduction and objectivesAlthough the usage of direct oral anticoagulants (DOAC) in patients with atrial fibrillation (AF) and bioprosthesis is already accepted in recent guidelines as an alternative to vitamin K antagonists (VKA), real world data in this scenario remain scarce, even more in our country. MethodsA retrospective single-center study that included all consecutive patients who underwent aortic valve replacement with bioprosthetic heart valve from 2013 to 2018, with oral anticoagulation initiated because of AF. The rates of occurrence of thromboembolic events (ischemic stroke, transient ischemic attack), major and minor although clinically relevant bleed, intracranial hemorrhage and death were assessed in patients on DOAC vs VKA. ResultsA total of 132 patients on VKA (62.6%) and 79 on DOACs (37.4%; apixaban 20%, edoxaban 10%, rivaroxaban 6% and dabigatran 3%) were included in the study. There were no significant differences in baseline clinical characteristics (age, sex, renal function or embolic risk scales). Mean follow-up was 32.85±15 months. The incidence-rates of cerebrovascular/thromboembolic events were 1.5/100 persons-year in the DOAC group 1.32 in the VKA group. The incidence-rates of major bleed 2.02/100 persons-year in DOACs group vs 3.7 in VKA group. Patients in the VKA group experienced 6 intracranial hemorrhages vs none in the DOAC group. ConclusionsAccording to our data from clinical practice, DOAC in patients with AF and a bioprosthetic heart valve seem to be a safe and effective alternative to VKA.

Anticoagulant Usage Patterns for Acute Venous Thromboembolism in Patients with Advanced Liver Disease

Introduction: Management of acute venous thromboembolism (VTE) in patients with chronic liver diseases is challenging due to the risk of bleeding and thrombotic complications. No clinical trials have studied vitamin K antagonists (VKA) or low molecular weight heparins (LMWH) use in this population. Pivotal clinical trials evaluating direct oral anticoagulants (DOAC) such as apixaban, edoxaban, rivaroxaban, and dabigatran lead to the U.S. Food and Drug Administration approval for VTE treatment but these studies excluded patients with clinically significant liver disease. Methods: We conducted a single-center retrospective chart review of anticoagulant practice patterns in adult patients with cirrhosis (Child-Pugh Class A-C) diagnosed with acute VTE managed between January 1, 2010 through January 2, 2020. Acute VTE was defined as pulmonary embolism, deep vein thrombosis (DVT), and splanchnic vein thrombosis (SVT), which included portal vein thrombosis (PVT). Primary outcomes were recurrent VTE, bleeding events, and anticoagulant practice patterns and were calculated in the study population, as well as a subset excluding patients with only PVT. Cirrhosis, VTE, and bleeding diagnoses were based on ICD-9 and ICD-10 codes. Anticoagulant prescribing patterns were recorded in both the inpatient and outpatient setting, along with demographic, VTE risk factors, and key laboratory data. Baseline laboratory data were determined as the closest measured lab ≤180 days from the acute VTE diagnosis date. Child-Pugh score was calculated using the closest laboratory data and ICD-9 and ICD-10 codes ±180 days from the VTE diagnosis date. Anticoagulant usage was considered if ≥1 dose was administered. Statistical analysis was performed using SAS® version 9.4. Results: Baseline characteristics of the 1335 patients in the study are listed (Table 1-3). Median age was 65 years (range 19-98) with 845 male patients (63.3%). Following acute VTE, 467 patients (35.0%) received therapeutic anticoagulation, 114 patients (8.5%) received prophylactic anticoagulation, and 754 patients (56.5%) did not receive anticoagulation. Of patients that received therapeutic anticoagulation, 78 received apixaban, 1 received argatroban, 2 received bivalirudin, 7 received dabigatran, 1 received dalteparin, 0 received edoxaban, 180 received therapeutic enoxaparin, 19 received therapeutic fondaparinux, 231 received unfractionated heparin, 28 received rivaroxaban, and 159 received warfarin. Of patients that received prophylactic anticoagulation, 59 received enoxaparin, 10 received fondaparinux, and 246 received heparin. Of 599 patients with acute VTE without PVT only, 287 patients (47.9%) received therapeutic anticoagulation, 64 patients (10.7%) received only prophylactic anticoagulation, and 248 patients (41.4%) did not receive any anticoagulation. Many patients received more than one type of anticoagulant. Therapeutic anticoagulant usage patterns by year are depicted (Figure 1-2). Recurrent VTE occurred in 329 of all patients (24.6%). Recurrent VTE occurred in 196 of 467 patients (42.0%) on therapeutic anticoagulation, 33 of 114 patients (28.9%) on prophylactic anticoagulation, and 100 of 754 patients (13.3%) who did not receive any anticoagulation. Bleeding occurred in 721 of all patients (54.0%). Bleeding occurred in 288 of 467 patients (61.7%) on therapeutic anticoagulation, 67 of 114 patients (58.8%) on prophylactic anticoagulation, and 366 of 754 patients (48.5%) who did not receive any anticoagulation. Conclusion: Management of anticoagulant medications in patients with advanced liver disease has marked practice variation. Anticoagulant usage patterns changed over time with the approval of DOACs and increasing familiarity with these drugs. VKA and LMWH usage appeared to decrease over time as DOAC usage rose. Close to half of all patients did not receive any anticoagulation, even when excluding patients with only PVT from the population due to the common practice of monitoring PVT patients without anticoagulation. Further analysis of recurrent VTE and bleeding events based on individual anticoagulant medications and rationale for prescribed anticoagulant regimens is underway. We hope these findings will guide and encourage future studies evaluating safety and efficacy of anticoagulant medications in patients with advanced liver disease and VTE. Disclosures Kelkar: Acorn AI by Medidata, a Dassault Systemes Company: Current Employment. Rajasekhar:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma Plasma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxter: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Use of direct oral anticoagulants in cerebral venous thrombosis: a systematic review.

: We are here to review the efficacy and safety of direct oral anticoagulants (DOACs) in the treatment of Cerebral Venous Thrombosis (CVT). A search strategy was developed with a research librarian. All published articles including trials, studies, case series, and case reports were reviewed from NCBI/PubMed up to May 2019 by two independent reviewers. A total of 11 studies were identified, which included 70 patients with CVT on DOACs. After 6 months follow-up more than 86.7% of these patients had a good outcome on the Modified Rankin Scale (mRS) of 0--1 at 6 months and no recurrence of venous thromboembolic events (VTE) at 12 months. Recanalization rate at 6 months varied from 55 to 100%. Only two patients had a side effect of minor bleeding because of DOAC usage. Although the current American Heart Association/American Stroke Association and European Stroke Organization guidelines do not endorse the use of DOACs for treatment of CVT because of lack of evidence from large randomized clinical trials, Use of DOACs in CVT appears to be well tolerated and efficacious with favorable outcomes. Further evidence is needed to establish their use in CVT.

Mo1754 POST-POLYPECTOMY BLEEDING IN PATIENTS ON DIRECT-ACTING ORAL ANTICOAGULANTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Since coming into practice in 2010, direct oral anticoagulants (DOACs) have become an increasingly popular form of anticoagulation. However, it is unclear which form of polypectomy intervention or peri-procedural anticoagulation management is best for reducing post-polypectomy bleeding (PPB) risk in the setting of DOAC usage. The aim of our study was to assess the efficacy of polypectomy approaches and management of anticoagulation in minimizing PPB in patients on DOACs. A systematic review of electronic databases was performed through September 2019, including PubMed, MEDLINE, EMBASE, and Cochrane. Two authors independently screened manuscripts and extracted data using Covidence. We included prospective, retrospective, case-control, cohort, and randomized controlled trials that evaluated PPB in patients on DOACs who underwent colonoscopy with polypectomy. The primary outcome was overall PPB rate in patients undergoing snare polypectomy versus endoscopic mucosal resection. We compared approaches to anticoagulation which included heparin bridge, no heparin bridge, and continuation of DOAC. Random effect analyses and 95% confidence intervals (CI) were calculated for all outcomes. Between-study heterogeneity was quantified using the Q statistic and I2 (p<0.05 was considered significant). 973 citations were reviewed, of which 9 were included in the final analysis. The majority were retrospective cohort studies. In total, the studies comprised 2,977 patients with average age of 72.4 years and study follow-up period ranging from 2 to 6 years. Studies defined PPB as hematochezia requiring endoscopic hemostasis occurring 14 to 30 days post endoscopy. Endoscopic submucosal dissection was associated with a significantly higher rate of PPB compared to snare polypectomy. There was a tendency towards higher PPB rates in hot snare versus cold snare polypectomy cases, though this did not reach statistical significance. There were no statistically significant bleeding rates amongst various anticoagulation management strategies. However, PPB effects sizes did tend to be larger in cases where anticoagulation was continued peri-procedurally (Table 1). There was insufficient data to determine the role of prophylactic clips after polypectomy. PPB is a serious adverse effect of colonoscopy. We found that in patients on DOACs, performing endoscopic submucosal dissection is associated with higher PPB rates compared to snare polypectomy. However, for patients at high risk of thromboembolism, our results suggest that continuation of DOAC may not increase the risk of PPB as compared to heparin bridging or discontinuation of anticoagulation altogether. More high-quality studies are needed to further discern amongst various anticoagulation and PPB-prevention strategies.

P4750Uninterrupted and minimally-interrupted direct oral anticoagulant therapy in patients undergoing catheter ablation for atrial fibrillation. An updated meta-analysis

Abstract Background Adequate anticoagulation in catheter ablation of atrial fibrillation (AF) is crucial in preventing both thromboembolic events and life-threatening bleeding. As clinicians gain more experience and reassurance with data from clinical trials, the usage of Direct Oral Anticoagulants (DOAC) in patients undergoing catheter ablation of AF has rapidly increased over the last years. The purpose of this updated meta-analysis was to assess the latest evidence and compare the safety and efficacy of uninterrupted and minimally interrupted periprocedural DOAC anticoagulation protocols with uninterrupted Vitamin K Antagonists (VKA) in this setting. Methods Randomized or prospective controlled observational studies comparing DOACs to VKAs were identified with multiple databases (Embase, PubMed, Cochrane, and Scopus). Uninterrupted and minimally interrupted DOAC (single dose of dabigatran or apixaban withheld) were distinguished, VKA therapy was always uninterrupted. The primary outcomes were stroke or transient ischemic attack (TIA), major bleeding, and net clinical benefit. Results 32 studies were included in the final analysis, encompassing a total of 19.437 patients. The incidence of thromboembolic events was rare (less than 0.2%), with no significant difference between groups. Occurrence of major bleeding and net clinical benefit were significantly improved in patients assigned to uninterrupted DOAC treatment compared to VKAs (1.5% vs 2.2%, POR: 0.74, CI: 0.56–0.98, I2=0,0% and 1.7% vs 2.4%, POR: 0.76; CI: 0.59–0.99, I2=0,0%, respectively). Net clinical benefit Conclusion This updated meta-analysis, based on a large database, showed that DOAC therapy is equally effective as VKA in preventing stroke and TIA. Minimally-interrupted DOAC therapy is a non-inferior peri-procedural anticoagulation strategy, however, uninterrupted DOAC therapy showed superiority when compared to VKA regarding major, life-threatening bleeding. Our findings showed that uninterrupted periprocedural DOAC therapy is a safe and preferable alternative to VKAs in patients undergoing catheter ablation for atrial fibrillation. Acknowledgement/Funding This study was supported by an Economic Development and Innovation Operative Programme Grant (GINOP 2.3.2-15-2016-00048).

Coagulation Signalling and Metabolic Disorders: Lessons Learned from Animal Models.

Nutrient excess in obesity drives metabolic reprogramming in multiple tissues involving extensive interorgan and intercellular crosstalk. Experimental and clinical studies show that prolonged nutrient excess often compromises metabolic adaptation propagating proobesogenic and proinflammatory responses. Chronic inflammation further promotes insulin resistance and associated comorbidities. Obesity and type 2 diabetes are characterized by a hypercoagulable state and clinical studies show a strong correlation of markers of coagulation activation in metabolic disorders. Coagulation protease-dependent signalling via protease-activated receptors is intimately associated with inflammation. The experimental evidence supports roles of tissue factor and G protein coupled protease-activated receptor-2 signalling in the regulation of insulin resistance and metabolic inflammation in diet-induced obesity. Likewise, increases in plasminogen activator inhibitor-1 levels and fibrin-driven inflammation promote insulin resistance in obesity. Additionally, impaired thrombomodulin-dependent protein C activation is mechanistically linked to diabetic kidney disease. Given the increased usage of direct oral anticoagulants, understanding the role of specific coagulation proteases in regulation of metabolic inflammation is highly relevant and might provide insights into the design of novel treatment regimens for patients suffering from thromboinflammatory and cardiometabolic disorders.

Comparison of Drug Switching and Discontinuation Rates in Patients with Nonvalvular Atrial Fibrillation Treated with Direct Oral Anticoagulants in the United States.

IntroductionContinuous usage of direct oral anticoagulants (DOACs) among nonvalvular atrial fibrillation (NVAF) patients is essential to maintain stroke prevention. We examined switching and discontinuation rates for the three most frequently initiated DOACs in NVAF patients in the USA.MethodsPatients who initiated apixaban, rivaroxaban, or dabigatran (index event/date) were identified from the Pharmetrics Plus claims database (Jan 1, 2013–Sep 30, 2016, includes patients with commercial and Medicare coverage) and grouped into cohorts by index DOAC. Patients were required to have a diagnosis of NVAF and continuous health plan enrollment for 12 months prior to the index date (baseline period) and at least 3 months during the follow-up period. Drug switching rates to any other DOAC or warfarin and index DOAC discontinuation rate were evaluated separately with descriptive statistics, Kaplan–Meier analysis, and multivariable Cox regression analysis.ResultsOf the NVAF study population (n = 41,864), 37% initiated apixaban (n = 15,352; mean age 62 years), 51% initiated rivaroxaban (n = 21,250; mean age 61 years), and 13% initiated dabigatran (n = 5262; mean age 61 years). During the follow-up period, the unadjusted drug switching rates of patients treated with apixaban, rivaroxaban, and dabigatran were 3.6%, 6.3%, and 11.1%, respectively (p < 0.001 across the three cohorts); while the index DOAC discontinuation rates were 52.8%, 60.3%, and 62.9%, respectively (p < 0.001). After we controlled for differences in patient characteristics, patients treated with rivaroxaban (HR 1.8; 95% CI 1.6–2.0; p < 0.001) and dabigatran (HR 3.4; 95% CI 3.0–3.8, p < 0.001) had a significantly greater likelihood for drug switching than patients treated with apixaban. Also, both rivaroxaban (HR 1.1; 95% CI 1.1–1.2, p < 0.001) and dabigatran (HR 1.3; 95% CI 1.2–1.3, p < 0.001) treated patients were more likely to discontinue treatment.ConclusionIn the real-world setting, patients with NVAF newly treated with apixaban were less likely to switch or discontinue treatment compared to patients treated with rivaroxaban or dabigatran.FundingPfizer and Bristol-Myers Squibb.

291 Incidence of Delayed Intracranial Hemorrhage Among Patients Using Direct Oral Anticoagulants

Head injury as a cause for ED visits has been increasing significantly over the past decade in the US, which parallels the increasing usage of direct oral anticoagulants over recent years. A larger percent of patients on anticoagulation are choosing direct oral anticoagulants (DOAC), also known as novel oral anticoagulants, as their anticoagulant of choice since the approval of their use 4 years ago by the Federal Drug Administration. Both of these trends compel practitioners to determine how best to care for head injury patients who are on a DOAC. Incidence of delayed intracranial hemorrhage (DICH) has been reported for warfarin in many studies, albeit with some controversy. No previous literature to date has reported on the rate of DICH for patients on DOAC. The current study seeks to investigate this prevalence in order to identify head trauma patients who may need to be managed with repeat head CT (HCT) imaging, and to provide future studies with data for power calculations. This was a multicenter retrospective study using a Level II trauma registry, at a community hospital with an ED annual volume of approximately 50,000 and a large geriatric population, supplemented with medical record data. All cases of head injuries from March 2014 to December 31, 2017 were included if the patient was on a DOAC, and a CT was obtained. DICH was defined as negative initial CT scan, but positive repeat scan performed within 24 hours of the original imaging, or the patient presented >12 hours received only 1 CT scan. Demographic data used descriptive statistics. Patients were included if they had a negative initial CT, were not on any other concomitant anticoagulants or antiplatelets. DOAC were defined as factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and direct thrombin inhibitor (dabigatran, bivalirudin, argatroban). Exclusion criteria are patients who had a positive initial head; patients who had a second traumatic event prior to repeat head CT. 53 patients had repeat HCT or presented >12 hours after trauma event with single HCT. Four resulted in DICH for an incidence-proportion of 5.66%. The distribution of agents was: Apixaban 23, Dabigatran 10, Rivaroxaban 19. The cases with DICH included: Apixaban 2 and Dabigatran 1. In this analytic observational study of direct oral anticoagulants, we found an incidence of delayed intracranial hemorrhage. Further studies are needed to gain an accurate measure of a generalizable incidence of delayed intracranial hemorrhage, such as multicenter retrospective studies and prospective cohort studies.

Better clinical outcome with direct oral anticoagulants in hospitalized heart failure patients with atrial fibrillation

BackgroundAtrial fibrillation (AF) is common in patients with heart failure and is associated with higher mortality. Although previous studies have reported that direct oral anticoagulants (DOACs) reduce the risk of cardiovascular events in out-patients with AF, it remains unclear whether DOACs reduce mortality in hospitalized heart failure (HHF) patients with AF. Therefore, we examined the impact of DOACs on mortality in this group of patients.MethodsConsecutive 497 HHF patients with AF were retrospectively registered and divided into three groups on the basis of the presence of anticoagulant therapy: non-anticoagulant group (Non, n = 90), Vit K antagonists (VKAs) group (n = 257) and DOACs group (n = 150). We followed up all the patients for mortality.ResultsIn the Kaplan-Meier analysis (mean follow-up of 1093 days), all-cause mortality was significantly lower in the VKAs and DOACs groups than in the Non group (31.1% and 15.3% vs. 43.3%, log-rank P < 0.001). In the multivariable Cox proportional hazard analysis after adjusting for other potential confounding factors, usage of DOACs and VKAs were independently associated with lower mortality in HHF patients AF (DOACs, HR 0.356, P = 0.001; VKAs, HR 0.472, P = 0.002). Furthermore, the propensity-matched 1:1 cohort was assessed based on the propensity score (DOACs, n = 114 and VKAs, n = 114). All-cause mortality was significantly lower in the DOACs group than in the VKAs group in the post-matched cohort (12.3% vs. 35.1%, log-rank P = 0.038). In the Cox proportional hazard analysis, the use of DOACs was associated with lower mortality in the post-matched cohort (HR 0.526, P = 0.041).ConclusionAppropriate use of anticoagulants in HHF patients with AF is important, and DOACs potentially improve all-cause mortality in such patients.