Direct Oral Anticoagulants Intake Research Articles

Overdosing of direct oral anticoagulants

Direct oral anticoagulants (DOAC) are increasingly used for prophylaxis and treatment of thromboembolic events. Incorrectly dosed DOAC treatment is associated with excess mortality. This article aims at raising awareness of DOAC overdosing and its causes as well as presenting adiagnostic and therapeutic work-up. Based on acase presentation, astructured review of the current literature on DOAC overdosing was performed and treatment recommendations were extracted. In addition to wittingly or unwittingly increased DOAC intake, common causes of overdose are inadequate dose adjustment for concomitant medication or comorbidities. Global coagulation testing should be supplemented with DOAC-specific testing. Severe bleeding and the need for invasive diagnostics or urgent surgery represent indications for treating DOAC overdoses. Based on the cause of an DOAC overdose, active charcoal, endoscopic pill rescue, antagonization with idarucizumab or andexanet alfa and the targeted substitution of coagulation factors represent treatment options. The sensitization of clinicians is important to ensure atimely diagnosis and adequate treatment of DOAC overdosing. This report provides an overview of current knowledge on diagnostics and treatment; however, further studies are necessary to improve the existing algorithms.

Intravenous thrombolysis in patients with recent intake of direct oral anticoagulants: A target trial analysis after the liberalization of institutional guidelines.

This study aimed to report the safety and efficacy of off-label intravenous thrombolysis (IVT) with alteplase after sequentially liberalizing our institutional guidelines allowing IVT for patients under direct oral anticoagulants (DOACs) regardless of plasma levels, time of last intake, and without prior anticoagulation reversal therapy. We utilized the target-trial methodology to emulate hypothetical criteria of a randomized controlled trial in our prospective stroke registry. Consecutive DOAC patients (06/2021-11/2023) otherwise qualifying for IVT were included. Safety and efficacy outcomes (symptomatic intracranial hemorrhage [ICH], any radiological ICH, major bleeding, 90-day mortality, 90-day good functional outcome [mRS 0-2 or return to baseline]) were assessed using inverse-probability-weighted regression-adjustment comparing patients with versus without IVT. Ninety eight patients fulfilled the target-trial criteria. IVT was given in 49/98 (50%) patients at a median of 178 (interquartile range 134-285) min after symptom onset with median DOAC plasma level of 77 ng/ml (15 patients had plasma levels > 100 ng/ml; 25/49 [51%] were treated within 12 h after last DOAC ingestion). Endovascular therapy was more frequent in patients without IVT (73% vs 33%). Symptomatic ICH occurred in 0/49 patients receiving IVT and 2/49 patients without IVT (adjusted difference -2.5%; 95% CI -5.9 to 0.8). The rates of any radiological ICH were comparable. Patients receiving IVT were more likely to have good functional outcomes. After liberalizing our approach for IVT regardless of recent DOAC intake, we did not experience any safety concerns. The association of IVT with better functional outcomes warrants prospective randomized controlled trials.

Clinical guideline on reversal of direct oral anticoagulants in patients with life threatening bleeding.

Anticoagulation is essential for the treatment and prevention of thromboembolic events. Current guidelines recommend direct oral anticoagulants (DOACs) over vitamin K antagonists in DOAC-eligible patients. The major complication of anticoagulation is serious or life-threatening haemorrhage, which may necessitate prompt haemostatic intervention. Reversal of DOACs may also be required for patients in need of urgent invasive procedures. This guideline from the European Society of Anaesthesiology and Intensive Care (ESAIC) aims to provide evidence-based recommendations and suggestions on how to manage patients on DOACs undergoing urgent or emergency procedures including the treatment of DOAC-induced bleeding. A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process. So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%. DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given. In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings.

Potential of Direct Oral Anticoagulant in Bleeding After Gastric Endoscopic Submucosal Dissection: A Systematic Review and Meta-Analysis.

An increasing number of patients are undergoing gastric endoscopic submucosal dissection (ESD) with active prescriptions of direct oral anticoagulants (DOACs). Only a few reports have described the effects of DOAC intake on postoperative bleeding. We aimed to investigate the bleeding risk associated with DOACs after gastric ESD. Clinical studies published up to April 2022 showing bleeding rates after gastric ESD in patients taking DOACs were identified using electronic searches. The primary outcome was the rate of bleeding after gastric ESD in patients receiving DOACs compared to those not receiving antithrombotic therapy. In this meta-analysis, odds ratios (ORs) were calculated and pooled using a random effects model. The secondary outcome was the difference in the bleeding rate between patients treated with DOACs and those treated with warfarin and antiplatelet drugs. Seven studies were included in this meta-analysis. The pooled analysis showed that DOACs had a higher bleeding rate than non-thrombotic therapy (17.0% vs. 3.4%; OR 5.72; 95% confidence interval [CI], 4.33-7.54; I2 = 0%). The bleeding risk associated with DOAC administration was similar to that associated with warfarin (17.0% vs. 20.0%; OR 0.83; 95% CI 0.59-1.18; I2 = 0%), whereas it was higher than that associated with antiplatelet administration (16.9% vs. 11.0%; OR 1.63; 95% CI 1.14-2.34; I2 = 8%). This meta-analysis reveals that the bleeding risk of DOACs is higher than that of non-antithrombotics and antiplatelets, whereas it is comparable to that of warfarin. Gastric ESD in patients on anticoagulants requires careful postoperative management.

Urine-based point-of-care testing for factor-Xa-inhibitors in acute ischemic stroke patients: a feasibility study.

Direct oral anticoagulants (DOACs) have become widely used in clinical practice for preventing thromboembolic events. Point-of-care testing methods, particularly those based on urine samples, offer a promising approach for rapid and accurate assessment of DOAC presence. This pilot study aims to evaluate the utility of a urine-based DOAC dipstick test as a point-of-care tool for identifying DOAB presence in acute ischemic stroke (AIS) or transient ischemic attack (TIA) patients. This prospective pilot study included patients with AIS/TIA eligible for DOAC-measurement. After exclusion of 3 patients, 23 patients with DOAC-intake (DOAC group; factor-Xa-inhibitors; n = 23) and 21 patients without DOAC-intake (control-group) remained for analyses. The urine-based DOAC dipstick test and parallel blood-based specific DOAC-level assessment were performed in all patients. Time-intervals of sampling urine/blood sampling and result of DOAC-test were recorded to analyze a potential time benefit based on dipstick evaluation. The urine-based DOAC dipstick test demonstrated high sensitivity (100%) and specificity (100%), correctly identifying all patients with anticoagulatory activity due to DOAC intake (i.e., anti-Xalevel ≥30 ng/mL). Moreover, the visual readout of the test provided semiquantitative information on drug-specific anti-Xa levels, showing a sensitivity of 83% and specificity of 93% to detect anti-Xa levels ≥120 ng/mL. The dipstick test exhibited a median time-benefit of 2:25 h compared to standard blood-based DOAC-level testing. The results of this pilot study underline the efficacy of urine-based point-of-care testing as a rapid and reliable method for assessing DOAC presence in patients with acute ischemic stroke. The value of this tool for clinical decision-making in stroke management needs to be established in future trials.Clinical Trial Registration: Clinicaltrails.org identifier [NCT06037200].

Influence of perioperative antiplatelet and anticoagulant medication management on bleeding events in dermatosurgery-A prospective observational study.

Perioperative management of antiplatelet and anticoagulant (AP/AC) therapy is a matter of balancing the risks of bleeding and thromboembolic events. Reliable data for dermatosurgery are still lacking, especially for direct oral anticoagulants (DOAC). The aim was to prospectively evaluate the influence of AP/AC-medication on bleeding risk in dermatosurgery with focus on exact intervals between DOAC intake and procedure performed on post-operative bleeding. Patients with or without AP/AC-therapy were included in the study without randomization. Exact times of DOAC-intake, procedure performed and post-operative bleeding were documented. Data collection was prospectively and standardized done by one person. We evaluated 1852 procedures in 675 patients. Post-operative bleeding occurred after 15.93% (n = 295) of all procedures, but only a few of them were severe (1.57%, n = 29). Compared to patients without AP/AC-medication, severe post-operative bleeding occurred significantly more often under dual antiplatelet therapy (11.76%, n = 2; p = 0.0166) and bridging of either vitamin K antagonist (9.09%, n = 2; p = 0.0270) or DOAC (15.38%, n = 2; p = 0.0099). There was no significant difference in the frequency of severe bleeding regarding to the preoperative DOAC-free period. Although AP/AC-therapy is associated with a significant higher rate of post-operative bleeding, no life-threatening bleeding was recorded. Long preoperative pausing or bridging of DOAC does not lead to significantly less severe bleeding events.

Safety of recanalization therapy in patients with acute ischemic stroke on direct oral anticoagulants: A sub-analysis of PASTA registry study

BackgroundThe safety of intravenous recombinant tissue plasminogen activator (rtPA) and mechanical thrombectomy (MT) in patients treated with direct oral anticoagulants (DOACs) before stroke has not been fully investigated. Therefore, we aimed to investigate the safety of recanalization therapy in patients receiving DOACs. MethodsWe assessed data from a prospective multicenter registry of patients with stroke, including those with acute ischemic stroke (AIS) treated with rtPA and/or MT who were administered DOACs. We evaluated the safety of recanalization considering the DOACs dosage and interval between the last DOAC intake and recanalization. ResultsThe final analysis included 108 patients (women, n = 54; median age, 81 years; DOAC overdose, n = 7; appropriate dose, n = 74; and inappropriate low dose, n = 27). The rate of any ICH differed significantly among overdose-, appropriate dose-, and inappropriate-low dose DOACs groups (71.4, 23.0, and 33.3%, respectively; P = 0.0121), whereas no significant difference was observed in respect of symptomatic ICH (P = 0.6895). Multivariate analysis showed that the National Institutes of Health Stroke Scale score on admission (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 1.01–1.11; P = 0.0267) and overdose-DOAC (OR: 8.40, 95% CI: 1.24–56.88; P = 0.0291) were independently associated with any ICH. No relationship was observed between the timing of the last DOAC intake and occurrence of ICH in patients treated with rtPA and/or MT (all P > 0.05). ConclusionRecanalization therapy during DOAC treatment may be safe in selected patients with AIS, if it is performed >4 h after the last DOAC intake and the patient is not overdosed with DOACs. Registrationhttps://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034958

A retrospective study of indications and consequences of monitoring direct oral anticoagulant plasma concentrations on patient care in a university hospital: The Retro-AOD study

IntroductionThe use of direct oral anticoagulants (DOAC) is increasing. Specific concentrations are available and have been proven to be reliable and reproducible in optimising patient care. This retrospective, monocentric study aimed to describe the indications and consequences of monitoring DOAC plasma levels on patient care. Materials and methodsWe collected data of patients hospitalised at the Bordeaux University Hospital between January 2017 and December 2018. These included demographics, indications, type, dose of DOAC, standard coagulation tests, creatinine clearance and DOAC plasma concentration using specifically calibrated rivaroxaban and apixaban anti-Xa and dabigatran anti-IIa assays. The date of last DOAC intake, the time between intake and plasma level measurement were also collected and analysed. ResultsA total of 2197 DOAC assays in 1488 patients were obtained in various clinical situations: urgent or elective procedures, context of acute renal failure, suspicion or occurrence of ischemic strokes, intra-cranial and other bleeding sites. Interpretation of these assays led physicians to maintain, postpone or cancel invasive and high haemorrhagic risk procedures in 757, 261 and 56 cases respectively. The remaining 1123 assays were associated with no significant modification of patient care. DOAC plasma concentration was ≤30 ng ml-1 (sensitivity 85.4%, specificity 73.6%, positive predictive value 71.1%, negative predictive value 86.7%, AUC 0.81) after a last intake of at least 2 days. ConclusionsOur study is, to date, the largest report of real-life measurement of specific DOAC plasma level at a single institution. Patient care was not modified in more than half of the assays.

Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants.

The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess. This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level. Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC-apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12hours after starting DOAC for quantification of drug levels and TG. The baseline TG before DOAC intake showed inter-individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti-Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti-Xa inhibitors. All DOACs showed a nonlinear dose-response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels. The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient-specific baseline TG level and the drug-specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation.

Management of Patients Receiving Direct Oral Anticoagulants Scheduled for Radical Prostatectomy: An Update of a Prospective Assessment

BackgroundIn the perioperative setting, temporary interruption of direct oral anticoagulants (DOACs) is mandatory. However, the safety of these recommendations is largely based on nonurological surgical experiences. ObjectiveTo verify the safety of these recommendations in patients undergoing radical prostatectomy (RP). Design, setting, and participantsA total of 5317 patients underwent RP in our tertiary care centre between December 2017 and February 2020. Of them, 107 consecutive patients had DOACs in standard preoperative medication. DOAC intake was stopped 2–3 d before RP. Postoperatively, patients received weight- and risk-adapted low-molecular-weight heparin (LMWH). DOAC intake was restarted, and administration of LMWH was stopped the 3rd day after surgery. For comparison, we performed 1:2 propensity-score matching (DOAC:non-DOAC), which resulted in 321 consecutive patients. Outcome measurements and statistical analysisPerioperative outcomes and 30-d morbidity were compared between both cohorts. The Wilcoxon rank sum test and the Pearson’s chi-square test were used. Results and limitationsThe median age of patients with DOACs was 68 yr. Sixty-six patients (61.7%) stopped DOAC intake 48 h and 41 patients (38.3%) 72 h before RP. In comparison with the matching cohort, the median blood loss during RP, median duration of surgery, and median duration of hospitalisation did not differ in a statistically significant fashion. Similarly, there was no significant difference in 30-d morbidity between groups. Importantly, the rate of bleeding and thromboembolic complications did likewise not differ significantly, though it is a nonrandomised and retrospective study. ConclusionsStandardised perioperative management of DOACs is important to minimise bleeding and thromboembolic complications. RP can be performed with a low perioperative complication risk if patients are adherent to our presented algorithm. Patient summaryWe looked at peri- and postoperative complications and compared direct oral anticoagulant (DOAC) and non-DOAC patients. We found no significant difference in thromboembolic and bleeding complications between the groups. We conclude that our regime is safe.

The Effect of Direct Oral Anticoagulants on Antithrombin Activity Testing Is Abolished by DOAC-Stop in Venous Thromboembolism Patients.

Direct oral anticoagulants (DOACs) may cause false negative results of antithrombin (AT) deficiency screening. To evaluate the impact of DOAC-Stop, an agent reversing in vitro effects of DOACs, on AT testing in anticoagulated patients. We assessed 130 venous thromboembolism patients aged 46.7 ± 13.5 years. Blood samples were collected 2 to 27 hours after DOAC intake from 49 patients on rivaroxaban, 54 on apixaban, and 27 on dabigatran. Antithrombin activity was assessed using the activated factor X (FXa)-based and the activated factor II (FIIa)-based method twice, before and after DOAC-Stop treatment, together with plasma DOAC levels using coagulometric assays. The use of DOAC-Stop did not influence AT activity measured using the FIIa-based assay, whereas there was a marked decrease in AT activity determined using the FXa-based assay (ΔAT = 16.9%; 95% CI, 12.9%-19.1%). The AT-FIIa assay revealed decreased AT level (<79%) in all 10 (7.7%) genetically confirmed AT-deficient patients treated with rivaroxaban or apixaban (n = 5 each), whereas the AT-FXa assay showed decreased AT activity (<83%) in 2 subjects on rivaroxaban and 1 on apixaban with low plasma DOAC concentrations (<90 ng/mL). After DOAC-Stop median AT-FXa activity lowered from 83.5% (interquartile range, 66%-143%) to 65.5% (interquartile range, 57%-75%; P = .005; ΔAT = 18%) in AT-deficient patients, without any false negative results. The ΔAT in the FXa-based assay correlated with rivaroxaban and apixaban concentrations in the AT-deficient patients (r = 0.99, P < .001). Application of DOAC-Stop enables reliable evaluation of AT deficiency screening in patients taking rivaroxaban or apixaban and tested using the FXa-based method.

Inhibition of thrombin generation 12 hours after intake of direct oral anticoagulants

BackgroundThe residual antithrombotic activity 12 hours after intake of direct oral anticoagulants (DOACs) is of clinical relevance in the setting of bleeding or urgent surgery. ObjectiveTo evaluate the effects of DOACs on thrombin generation 12 hours after DOAC intake in comparison to baseline and a healthy control group. MethodsEighty patients were recruited, 20 patients for each approved DOAC: apixaban, edoxaban, rivaroxaban, and dabigatran. The patients were either to be put on anticoagulation for the first time or had stopped taking oral anticoagulation for at least 48 hours. Blood plasma was sampled before (baseline) and 12 hours after starting DOAC for quantification of drug levels and thrombin generation assayed using an automated system (ST Genesia). Sixty‐one blood donors served as control group. ResultsThe factor Xa inhibitors significantly increased lag time (137%‐219%) and reduced thrombin peak (47%‐76%) and velocity index (17%‐44%) after 12 hours compared to baseline. Dabigatran showed prolongation of lag time to 133% and time to peak to 119%. All patients had residual antithrombotic activity, with reduced thrombin generation parameters 12 hours after DOAC intake compared to baseline and to the healthy control group. This effect remained significant in patients with low residual DOAC plasma levels <50 ng/mL. ConclusionThrombin generation remains reduced 12 hours after DOAC intake. While thrombin peak is particularly modified by factor Xa inhibitors, all DOACs prolong the lag time and time to thrombin peak. In the setting of bleeding or urgent surgery, the automated thrombin generation assay may assist in decision making and antidote administration.

Direct oral anticoagulant plasma levels and thrombin generation on ST Genesia system

BackgroundMonitoring of anticoagulant activity of direct oral anticoagulants (DOACs) can be necessary in special situations. DOAC plasma levels have a high inter‐ and intraindividual variation and do not necessarily reflect the coagulation status of the patient. Thrombin generation (TG) is a global hemostatic assay with the capacity to overcome this limitation. The aim of this study was to show correlations between DOAC plasma levels and TG parameters using the fully automated ST Genesia system. MethodsA total of 380 blood samples (120 with apixaban, 79 with dabigatran, 79 with edoxaban, and 102 with rivaroxaban) from patients at different time points after DOAC intake were included in the analysis. DOAC plasma levels were analyzed using calibrated anti‐Xa or anti‐IIa tests. Thrombin generation was measured using the ST Genesia system and STG‐DrugScreen reagent. ResultsThere was a significant correlation between the drug levels of all DOACs and the TG parameters’ lag time and time to peak. Peak thrombin and velocity index show a negative correlation following an exponential regression curve with all anti‐Xa DOACs but not with dabigatran. Apart from a weak correlation with rivaroxaban, there was no correlation between drug levels of all other DOACs and endogenous thrombin potential. ConclusionTG parameters measured with ST Genesia correlate with the drug levels of anti‐Xa DOACs. Peak thrombin and velocity index are of special interest for the determination of residual anticoagulant effect at low drug levels. For dabigatran‐treated patients, only lag time shows a correlation with the dabigatran plasma levels.

Safety of direct oral anticoagulants in patients with atrial fibrillation and high risk of stroke (review of literature)

Review discusses the problem of non-vitamin K antagonist oral anticoagulants safety in patients with non-valvular atrial fibrillation. Bleeding risk assessment while applying anticoagulant therapy, preventive methods for major bleeding (intracranial, gastro-intestinal) during this therapy as well as the strategy of treating patients with bleedings occurring on direct oral anticoagulants intake are discussed in this review. Special attention is paid to the choice of direct oral anticoagulant, the importance of specific antagonist of dabigatran – idarucizumab and indications for its clinical application.

Endovascular Stroke Treatment and Risk of Intracranial Hemorrhage in Anticoagulated Patients.

Background and Purpose- We aimed to determine the safety and mortality after mechanical thrombectomy in patients taking vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). Methods- In a multicenter observational cohort study, we used multiple logistic regression analysis to evaluate associations of symptomatic intracranial hemorrhage (sICH) with VKA or DOAC prescription before thrombectomy as compared with no anticoagulation. The primary outcomes were the rate of sICH and all-cause mortality at 90 days, incorporating sensitivity analysis regarding confirmed therapeutic anticoagulation. Additionally, we performed a systematic review and meta-analysis of literature on this topic. Results- Altogether, 1932 patients were included (VKA, n=222; DOAC, n=98; no anticoagulation, n=1612); median age, 74 years (interquartile range, 62-82); 49.6% women. VKA prescription was associated with increased odds for sICH and mortality (adjusted odds ratio [aOR], 2.55 [95% CI, 1.35-4.84] and 1.64 [95% CI, 1.09-2.47]) as compared with the control group, whereas no association with DOAC intake was observed (aOR, 0.98 [95% CI, 0.29-3.35] and 1.35 [95% CI, 0.72-2.53]). Sensitivity analyses considering only patients within the confirmed therapeutic anticoagulation range did not alter the findings. A study-level meta-analysis incorporating data from 7462 patients (855 VKAs, 318 DOACs, and 6289 controls) from 15 observational cohorts corroborated these observations, yielding an increased rate of sICH in VKA patients (aOR, 1.62 [95% CI, 1.22-2.17]) but not in DOAC patients (aOR, 1.03 [95% CI, 0.60-1.80]). Conclusions- Patients taking VKA have an increased risk of sICH and mortality after mechanical thrombectomy. The lower risk of sICH associated with DOAC may also be noticeable in the acute setting. Improved selection might be advisable in VKA-treated patients. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496064. Systematic Review and Meta-Analysis: CRD42019127464.

Laboratory bleeding predictors in elderly patients with atrial fibrillation taking direct oral anticoagulants

Atrial fibrillation (AF) is one of the most common arrhythmias in patients ≥75 years of age. The increased risk of thrombosis due to age and the large number of concomitant diseases makes it evident that anticoagulant therapy is necessary. However, the same factors increase the risk of hemorrhagic complications, which are among the most dangerous side effects of anticoagulant therapy. That is why it is very important to identify patients with the highest probability of bleeding, whether large or small clinically significant and minor. The purpose of our study was to study the prognostic value of laboratory methods of examination with regard to the development of hemorrhagic events in elderly patients with AF taking direct oral anticoagulants (DOAC). The study enrolled 102 patients ≥75 years of age with AF of non-valve etiology taking dabigatran, apixaban, rivaroxaban at full or reduced doses. Anticoagulants were administered by outpatient and inpatient physicians. Both previous experience with DOAC prior to inclusion in the trial (if DOAC was previously prescribed) and prospective patient monitoring after inclusion in the trial were analyzed. The minimum analyzed period of DOAC intake was 18 months. Patients who underwent (n = 19) and did not undergo (n = 83) hemorrhagic events (all events were considered small by ISTH criteria) did not differ in any of the laboratory indicators potentially considered as predictors of hemorrhagic events.

Perioperative management of direct oral anticoagulants in patients undergoing radical prostatectomy: results of a prospective assessment.

In the perioperative setting, temporary interruption of direct oral anticoagulants (DOACs) is recommended. However, the safety of these recommendations is based on non-urological surgical experiences. Our objective was to verify the safety of these recommendations in patients undergoing radical prostatectomy (RP). Patients regularly receiving a DOAC and scheduled for RP at our institution were prospectively assessed. DOAC intake was usually stopped 48h before surgery without any preoperative bridging therapy. Postoperatively, patients received risk-adapted low-molecular weight heparin (LMWH). On the third day after unremarkable RP, DOAC intake was restarted and the administration of LMWH was stopped. We assessed perioperative outcomes and 30-day morbidity. Thirty-two consecutive patients receiving DOAC underwent RP at our institution between 12/2017 and 07/2018. Time of surgery (median, 177min) and intraoperative blood loss (median, 500mL) were unremarkable. DOACs were restarted on the third postoperative day in 30 patients (94%). No patient had a significant hemoglobin level reduction after DOAC restart. Overall, 28% of patients experienced complications within 30days after surgery. Most of which were minor (Clavien ≤ 2), three patients (9%), however, had Clavien ≥ 3 complications. Our report is the first to prospectively assess current guideline recommendations regarding DOAC restarting after major urological surgery. RP can safely be performed, if DOACs are correctly paused before surgery. Moreover, in case of an uneventful postoperative clinical course, DOACs can be safely restarted on the third postoperative day. A 9% Clavien ≥ 3 30-day morbidity warrants attention and should be further explored in future studies.

Management of Patients with Acute Subdural Hemorrhage During Treatment with Direct Oral Anticoagulants.

Anticoagulation therapy is a major risk factor for unfavorable patient outcomes following (traumatic) intracranial hemorrhage. Direct oral anticoagulants (DOAC) are increasingly used for the prevention and treatment of thromboembolic diseases. Data on patients treated for acute subdural hemorrhage (SDH) during anticoagulation therapy with DOAC are limited. We analyzed the medical records of consecutive patients treated at our institution for acute SDH during anticoagulation therapy with DOAC or vitamin K antagonists (VKA) during a period of 30months. Patient characteristics such as results of imaging and laboratory studies, treatment modalities and short-term patient outcomes were included. A total of 128 patients with preadmission DOAC (n = 65) or VKA (n = 63) intake were compared. The overall 30-day mortality rate of this patient cohort was 27%, and it did not differ between patients with DOAC or VKA intake (26% vs. 27%; p = 1.000). Similarly, the rates of neurosurgical intervention (65%) and intracranial re-hemorrhage (18%) were comparable. Prothrombin complex concentrates were administered more frequently in patients with VKA intake than in patients with DOAC intake (90% vs. 58%; p < 0.0001). DOAC treatment in patients with acute SDH did not increase in-hospital and 30-day mortality rates compared to VKA treatment. These findings support the favorable safety profile of DOAC in patients, even in the setting of intracranial hemorrhage. However, the availability of specific antidotes to DOAC may further improve the management of these patients.

Appropriateness of DOAC Prescribing Before and During Hospital Admission and Analysis of Determinants for Inappropriate Prescribing.

Background and Objectives: Appropriate dosing of direct oral anticoagulants (DOACs) is required to avoid under- and overdosing that may precipitate strokes or thromboembolic events and bleedings, respectively. Our objective was to analyze the appropriateness of DOAC dosing according to the summaries of product characteristics (SmPC). Furthermore, determinants for inappropriate prescribing were investigated.Methodology: Retrospective cohort study of hospitalized patients aged ≥60 years with at least one DOAC intake during hospital stay. Descriptive analyses were used to summarize the characteristics of the study population. Chi-square test was used to evaluate differences between DOACs. Binary logistic regression analysis was performed to assess determinants for inappropriate prescribing.Results: For the 772 included patients, inappropriate dosing occurred in 25.0% of hospitalizations with 23.4, 21.9, and 29.7% for dabigatran, rivaroxaban, and apixaban, respectively (p = 0.084). Underdosing was most prevalent for apixaban (24.5%) compared to dabigatran (14.0%) and rivaroxaban (12.8%), p < 0.001. In 67.1% (apixaban), 26.7% (dabigatran), and 51.2% (rivaroxaban) of underdosed DOAC cases according to the SmPC, the dose would be considered appropriate according to the European Heart Rhytm Association (EHRA) guidelines. Overdosing was observed in 4.5% (apixaban), 4.7% (dabigatran), and 7.7% (rivaroxaban) of patients. For all DOACs, our analysis showed an age ≥80 years (p = 0.036), use of apixaban (p = 0.026), DOAC use before hospitalization (p = 0.001), intermediate renal function (p = 0.014), and use of narcotic analgesics (p = 0.019) to be associated with a higher rate of inappropriate prescribing. Undergoing surgery was associated with a lower odds of inappropriate prescribing (p = 0.012). For rivaroxaban, use of medication for hypothyroidism (p = 0.027) and the reduced dose (p < 0.001) were determinants for inappropriate prescribing. Treatment of venous thromboembolism was associated with less errors (p = 0.002). For apixaban, severe renal insufficiency (p < 0.001) and initiation in hospital (p = 0.016) were associated with less and the reduced dose (p < 0.001) with more inappropriate prescribing. No determinants were found in the dabigatran subgroup.Conclusions: Inappropriate DOAC prescribing is frequent with underdosing being the most common drug related problem when using the SmPC as reference. More appropriate prescriptions were found when taking the EHRA guidelines into account. Analysis of determinants of inappropriate prescribing yielded insights in the risk factors associated with inappropriate DOAC prescriptions.

Direct Oral Anticoagulants and Medical Comorbidities in Patients Needing Dental Extractions: Management of the Risk of Bleeding

The purpose of this study was to measure the frequency of bleeding during and after tooth extraction in patients exposed to direct oral anticoagulants (DOACs) and identify risk factors for prolonged or excessive bleeding. This retrospective cohort study involved 100 patients who underwent tooth extractions according to the European Heart Rhythm Association protocol: continuation of DOAC therapy for extractions of up to 3 teeth in the same session performed at the (presumed) time of DOAC trough concentration. We respected an interval of at least 4hours between extraction and last DOAC intake. The outcome of interest was incidence of mild, moderate, and severe bleeding during the intervention and in the 7-day follow-up period. Data analysis considered the presence of comorbidities as the primary predictor for bleeding; additional predictors were age, gender, type of comorbidity, indication for DOAC therapy, DOAC agent, and extraction of contiguous teeth. Of the patients, 64 had comorbidities (diabetes in 50%). The distributions of demographic, clinical, and dental variables were similar for patients with and without comorbidities. We observed 4 bleeding episodes (1 moderate episode 1hour after the extraction and 3 mild episodes the day after the extraction) in the comorbidity group and none in the non-comorbidity group (4 of 64 vs 0 of 36, P=.29; overall bleeding rate, 4 of 100). The factor significantly triggering bleeding in patients with comorbidity was extractions of couples and triplets of multirooted teeth (P=.004). Tooth extractions in patients with comorbidities taking DOACs may be safely managed as long as they are performed at least 4hours after the last DOAC intake and do not involve 2 or 3 contiguous premolars and molars.