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Background: D-Dimer testing is sensitive but not specific for diagnosing deep venous thrombosis (DVT). Changing the use of testing and the threshold level for a positive test result on the basis of risk for DVT might improve the tradeoff between sensitivity and specificity and reduce the need for testing. Objective: To determine whether using a selective D-dimer testing strategy based on clinical pretest probability (C-PTP) for DVT is safe and reduces diagnostic testing compared with using a single D-dimer threshold for all patients. Design: Randomized, multicenter, controlled trial. Patients were allocated using a central automated system. Ultrasonographers and study adjudicators but not other study personnel were blinded to trial allocation. (ClinicalTrials.gov: NCT00157677) Setting: 5 Canadian hospitals. Patients: Consecutive symptomatic patients with a first episode of suspected DVT. Intervention: Selective testing (n = 860), defined as D-dimer testing for outpatients with low or moderate C-PTP (DVT excluded at D-dimer levels <1.0 µg/mL [low C-PTP] or <0.5 µg/mL [moderate C-PTP]) and venous ultrasonography without D-dimer testing for outpatients with high C-PTP and inpatients, or uniform testing (n = 863), defined as D-dimer testing for all participants (DVT excluded at D-dimer levels <0.5 µg/mL). Measurements: The proportion of patients not diagnosed with DVT during initial testing who had symptomatic venous thromboembolism during 3-month follow-up and the proportion of patients undergoing D-dimer testing and ultrasonography. Results: The incidence of symptomatic venous thromboembolism at 3 months was 0.5% in both study groups (difference, 0.0 percentage point [95% CI, -0.8 to 0.8 percentage points]). Selective testing reduced the proportion of patients who required D-dimer testing by 21.8 percentage points (CI, 19.1 to 24.8 percentage points). It reduced the proportion who required ultrasonography by 7.6 percentage points (CI, 2.9 to 12.2 percentage points) overall and by 21.0 percentage points (CI, 14.2 to 27.6 percentage points) in outpatients with low C-PTP. Limitation: Results may not be generalizable to all D-dimer assays or patients with previous DVT, study personnel were not blinded, and the trial was stopped prematurely. Conclusion: A selective D-dimer testing strategy seems as safe as and more efficient than having everyone undergo D-dimer testing when diagnosing a first episode of suspected DVT. Primary Funding Source: Heart and Stroke Foundation of Ontario. [ABSTRACT FROM AUTHOR]

Rationale: We report a new method to diagnose acute pulmonary embolism (PE) by single photon emission computerized tomography (SPECT) after administration of (99m)Tc-labeled anti-D-dimer (DI-80B3) monoclonal antibody Fab' fragments. This novel technique provides an additional approach to diagnosing PE in patients for whom other methods are nondiagnostic or contraindicated. Objectives: We performed a prospective, multicenter study to investigate the sensitivity and specificity of (99m)Tc-DI-80B3/SPECT in patients with suspected acute PE. Methods: Subjects with a moderate to high clinical probability of PE or a positive D-dimer test underwent a PE-protocol contrast-enhanced multidetector thoracic computed tomography (CT) scan as well as (99m)Tc-DI-80B3/SPECT (0.5 mg (99m)Tc-DI-80B3 intravenously followed by a thoracic SPECT 2.5 h later). Separate and independent adjudication committees, blinded to clinical data and other test results, interpreted the (99m)Tc-DI-80B3/SPECT scans (PE detected as foci of abnormally increased (99m)Tc uptake) and the thoracic CT scans using Prospective Investigation of Pulmonary Embolism Diagnosis II criteria. Measurements and Main Results: Of the 52 patients who were enrolled and completed both tests, 42 had both evaluable SPECT scans and thoracic CT scans. Using the criterion standard (thoracic CT scan) there were 21 patients with PE and 21 without. (99m)Tc-DI-80B3/SPECT had a sensitivity of 76.2% (95% confidence interval, 52.8-91.8%) and a specificity of 90.5% (95% confidence interval, 69.8-98.8%). Treatment-related serious adverse events did not occur. Conclusions: (99m)Tc-DI-80B3/SPECT was sensitive and specific for acute PE in subjects with moderate to high clinical probability of PE or a positive D-dimer test. (99m)Tc-DI-80B3/SPECT demonstrated an acceptable safety profile and avoids exposure to contrast. [ABSTRACT FROM AUTHOR]

Background: Patients who are receiving vitamin K antagonist (VKA) therapy pose challenges when they require surgery or invasive procedures because the risk for bleeding during the procedure must be balanced against the risk of an atherothrombotic event if the VKA is interrupted. However, it may be possible to safely perform some procedures, such as coronary angiography with or without percutaneous coronary intervention (PCI), without VKA interruption.Methods: We undertook a systematic review and metaanalysis to assess the safety of a periprocedural management strategy of uninterrupted VKA (U-VKA) vs interrupted VKA (I-VKA) with or without bridging with low-molecular-weight heparin in patients undergoing elective coronary angiography with or without PCI.Results: Eight studies were included in the review. Most were of moderate to very low quality. A strategy of U-VKA appears to confer approximately one-half the risk (odds ratio, 0.43; 95% CI, 0.26-0.73) of experiencing an access site bleeding complication within 1 week of the procedure compared with a strategy of I-VKA. The U-VKA strategy was associated with a pooled access site bleeding complication rate of 4.0% (95% CI, 3.0-7.0), and although high heterogeneity precluded pooling of such a rate in the I-VKA group, these rates ranged from 2% to 14%.Conclusion: Although it appears that coronary angiography with or without PCI can be safely performed without interrupting VKA, the low methodologic quality of existing studies precludes any definitive conclusions. Randomized trials assessing different anticoagulation strategies are needed to establish evidence-based practice guidelines in this setting. [ABSTRACT FROM AUTHOR]

Context: In patients with suspected lower extremity deep vein thrombosis (DVT), compression ultrasound (CUS) is typically the initial test to confirm or exclude DVT. Patients with an initial negative CUS result often require repeat CUS after 5 to 7 days. Whole-leg CUS may exclude proximal and distal DVT in a single evaluation.Objective: To determine the risk of venous thromboembolism after withholding anticoagulation in patients with suspected lower extremity DVT following a single negative whole-leg CUS result.Data Sources: MEDLINE, EMBASE, CINAHL, LILACS, Cochrane, and Health Technology Assessments databases were searched for articles published from January 1970 through November 2009. Supplemental searches were performed of Internet resources, reference lists, and by contacting content experts.Study Selection: Included studies were randomized controlled trials and prospective cohort studies of patients with suspected DVT and a negative whole-leg CUS result who did not receive anticoagulant therapy, and were followed up at least 90 days for venous thromboembolism events.Data Extraction: Two authors independently reviewed and extracted data regarding a single positive or negative whole-leg CUS result, occurrence of venous thromboembolism during follow-up, and study quality.Results: Seven studies were included totaling 4731 patients with negative whole-leg CUS examinations who did not receive anticoagulation. Of these, up to 647 patients (13.7%) had active cancer and up to 725 patients (15.3%) recently underwent a major surgery. Most participants were identified from an ambulatory setting. Venous thromboembolism or suspected venous thromboembolism-related death occurred in 34 patients (0.7%), including 11 patients with distal DVT (32.4%); 7 patients with proximal DVT (20.6%); 7 patients with nonfatal pulmonary emboli (20.6%); and 9 patients (26.5%) who died, possibly related to venous thromboembolism. Using a random-effects model with inverse variance weighting, the combined venous thromboembolism event rate at 3 months was 0.57% (95% confidence interval, 0.25%-0.89%).Conclusion: Withholding anticoagulation following a single negative whole-leg CUS result was associated with a low risk of venous thromboembolism during 3-month follow-up. [ABSTRACT FROM AUTHOR]

Background: Clinicians should consider the clinical impact of anticoagulant-related bleeding when deciding on the duration of anticoagulant therapy in patients with venous thromboembolism.Purpose: To provide reliable estimates of the clinical impact of anticoagulant-related bleeding, defined as the case-fatality rate of major bleeding and the risk for intracranial bleeding.Data Sources: MEDLINE (January 1989 to May 2003), Cochrane Controlled Trial Registry, thromboembolism experts, and reference lists; English-language literature only.Study Selection: Randomized, controlled trials and prospective cohort studies that investigated patients with venous thromboembolism who received oral anticoagulant therapy (target international normalized ratio, 2.0 to 3.0) for at least 3 months and that reported major bleeding and death as primary study outcomes.Data Extraction: Two reviewers independently extracted data on the number of anticoagulant-related major and intracranial bleeding episodes and on whether these events were fatal or nonfatal.Data Synthesis: The authors analyzed 33 studies involving 4374 patient-years of oral anticoagulant therapy. For all patients, the case-fatality rate of major bleeding was 13.4% (95% CI, 9.4% to 17.4%) and the rate of intracranial bleeding was 1.15 per 100 patient-years (CI, 1.14 to 1.16 per 100 patient-years). For patients who received anticoagulant therapy for more than 3 months, the case-fatality rate of major bleeding was 9.1% (CI, 2.5% to 21.7%), and the rate of intracranial bleeding was 0.65 per 100 patient-years (CI, 0.63 to 0.68 per 100 patient-years) after the initial 3 months of anticoagulation.Conclusion: The clinical impact of anticoagulant-related major bleeding in patients with venous thromboembolism is considerable, and clinicians should take this into account when deciding whether to continue long-term oral anticoagulant therapy in an individual patient. [ABSTRACT FROM AUTHOR]

Background: Excessive anticoagulation due to warfarin use is associated with hemorrhage. Subcutaneously administered vitamin K has not been evaluated for the treatment of warfarin-associated coagulopathy, yet it is widely used.Objective: To show that oral vitamin K is more effective than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy.Design: Randomized, controlled trial.Setting: Two teaching hospitals.Patients: Patients with an international normalized ratio (INR) between 4.5 and 10.0.Intervention: Warfarin therapy was withheld, and 1 mg of vitamin K was given orally or subcutaneously.Measurements: The primary outcome measure was the INR on the day after administration of vitamin K. Secondary outcome measures were hemorrhage and thrombosis during a 1-month follow-up period.Results: 15 of 26 patients receiving oral vitamin K and 6 of 25 patients receiving subcutaneous vitamin K had therapeutic INRs on the day after study drug administration (P = 0.015; odds ratio, 4.32 [95% CI, 1.13 to 17.44]).Conclusion: Oral vitamin K lowers INR more rapidly than subcutaneous vitamin K in asymptomatic patients who have supratherapeutic INR values while receiving warfarin. [ABSTRACT FROM AUTHOR]

Study Objectives: (1) To determine physician preferences in the management of warfarin-induced excessive anticoagulation (AC); and (2) to assess compliance with the American College of Chest Physicians (ACCP) guidelines for the reversal of excessive AC.Design: Cross-sectional physician survey.Participants: Members of the Canadian Society of Internal Medicine practicing in Ontario, Canada.Measurements and Results: Physicians were asked to provide management preferences in six clinical scenarios describing warfarin-induced excessive AC. The scenarios represent various combinations of international normalized ratio (INR) value, treatment setting, and presence and severity of bleeding. In scenarios with INRs < 5.2 without bleeding, conservative approaches complying with the ACCP guidelines, such as withholding warfarin or reducing its dose, were most common. In scenarios with high INRs (ie, > 7.1) and/or bleeding, the selection of vitamin K in any form ranged between 71% and 82%. However, compliance with the ACCP-recommended doses and the routes of vitamin K administration ranged from 1 to 10%. In five of the six scenarios, subcutaneous injection, a route not recommended by the ACCP, was the most common method of vitamin K delivery.Conclusions: Physician preferences for the reversal of warfarin-induced excessive AC were highly variable and, in most cases, did not follow the recommendations of the ACCP consensus guidelines. Furthermore, the widespread reported use of subcutaneous vitamin K is concerning because this route of vitamin K administration has been demonstrated to be less effective than IV administration of vitamin K. These findings highlight the need for randomized controlled trials to compare the efficacy of different routes of administration of vitamin K for warfarin-associated coagulopathy. [ABSTRACT FROM AUTHOR]

Background: This guideline addresses the management of patients who are receiving anticoagulant or antiplatelet therapy and require an elective surgery or procedure.Methods: The methods herein follow those discussed in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement.Results: In patients requiring vitamin K antagonist (VKA) interruption before surgery, we recommend stopping VKAs 5 days before surgery instead of a shorter time before surgery (Grade 1B). In patients with a mechanical heart valve, atrial fibrillation, or VTE at high risk for thromboembolism, we suggest bridging anticoagulation instead of no bridging during VKA interruption (Grade 2C); in patients at low risk, we suggest no bridging instead of bridging (Grade 2C). In patients who require a dental procedure, we suggest continuing VKAs with an oral prohemostatic agent or stopping VKAs 2 to 3 days before the procedure instead of alternative strategies (Grade 2C). In moderate- to high-risk patients who are receiving acetylsalicylic acid (ASA) and require noncardiac surgery, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C). In patients with a coronary stent who require surgery, we recommend deferring surgery > 6 weeks after bare-metal stent placement and > 6 months after drug-eluting stent placement instead of undertaking surgery within these time periods (Grade 1C); in patients requiring surgery within 6 weeks of bare-metal stent placement or within 6 months of drug-eluting stent placement, we suggest continuing antiplatelet therapy perioperatively instead of stopping therapy 7 to 10 days before surgery (Grade 2C).Conclusions: Perioperative antithrombotic management is based on risk assessment for thromboembolism and bleeding, and recommended approaches aim to simplify patient management and minimize adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Importance: Direct oral anticoagulants (DOACs), comprising apixaban, rivaroxaban, edoxaban, and dabigatran, are commonly used medications to treat patients with atrial fibrillation and venous thromboembolism. Decisions about how to manage DOACs in patients undergoing a surgical or nonsurgical procedure are important to decrease the risks of bleeding and thromboembolism., Observations: For elective surgical or nonsurgical procedures, a standardized approach to perioperative DOAC management involves classifying the risk of procedure-related bleeding as minimal (eg, minor dental or skin procedures), low to moderate (eg, cholecystectomy, inguinal hernia repair), or high risk (eg, major cancer or joint replacement procedures). For patients undergoing minimal bleeding risk procedures, DOACs may be continued, or if there is concern about excessive bleeding, DOACs may be discontinued on the day of the procedure. Patients undergoing a low to moderate bleeding risk procedure should typically discontinue DOACs 1 day before the operation and restart DOACs 1 day after. Patients undergoing a high bleeding risk procedure should stop DOACs 2 days prior to the operation and restart DOACs 2 days after. With this perioperative DOAC management strategy, rates of thromboembolism (0.2%-0.4%) and major bleeding (1%-2%) are low and delays or cancellations of surgical and nonsurgical procedures are infrequent. Patients taking DOACs who need emergent (<6 hours after presentation) or urgent surgical procedures (6-24 hours after presentation) experience bleeding rates up to 23% and thromboembolism as high as 11%. Laboratory testing to measure preoperative DOAC levels may be useful to determine whether patients should receive a DOAC reversal agent (eg, prothrombin complex concentrates, idarucizumab, or andexanet-α) prior to an emergent or urgent procedure., Conclusions and Relevance: When patients who are taking a DOAC require an elective surgical or nonsurgical procedure, standardized management protocols can be applied that do not require testing DOAC levels or heparin bridging. When patients taking a DOAC require an emergent, urgent, or semiurgent surgical procedure, anticoagulant reversal agents may be appropriate when DOAC levels are elevated or not available.

Introduction: Patients with atrial fibrillation (AF) undergoing elective procedures are at risk for Major Adverse Cardiovascular Events (MACE) and symptomatic bleeding. We aimed to identify risk factors to guide perioperative risk stratification., Methods: We conducted a post-hoc analysis of the "Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery" randomized trial. The primary outcomes were MACE and symptomatic bleeding. Our statistical approach encompassed standard univariate analysis, logistic stepwise regression, and Cox regression models. Additional interaction analyses evaluated the interplay between low-molecular-weight heparin bridge therapy and other identified risk factors., Results: Among a total of 1,813 participants (mean age 71.6 ± 8.8, 73.3 % male), MACE occurred in 25 (1.4 %) individuals, with pre-procedure clopidogrel use (adjusted hazard ratio [aHR] 7.73, 95 % CI 2.63-22.72, p < 0.001) and CHA 2 DS 2 -VASc score ≥ 5 (aHR 2.89, 95 % CI 1.26-6.63, p = 0.012) identified as risk factors. Symptomatic bleeding occurred in 57 (3.1 %) individuals, with bridge therapy (aHR 1.84, 95 % CI 1.07-3.19, p = 0.029), renal disease (aHR 2.50, 95 % CI 1.34-4.67, p = 0.004), post-procedure aspirin use (aHR 2.86, 95 % CI 1.66-4.91, p < 0.001), post-procedure nonsteroidal anti-inflammatory drug use excluding aspirin (aHR 3.40, 95 % CI 1.22-9.43, p = 0.019), and major surgery (aHR 3.94, 95 % CI 2.26-6.85, p < 0.001) identified as risk factors. The interactions between risk factors and bridging therapy on MACE and symptomatic bleeding outcomes were not significant (p > 0.05)., Conclusion: We identified predictors for MACE and symptomatic bleeding in AF patients undergoing elective procedures. These insights may help guide perioperative decisions to reduce the risk of adverse outcomes., Competing Interests: Declaration of competing interest All authors have completed and submitted the appropriate disclosure forms. Further details regarding potential conflicts of interest can be found in the submitted forms., (Copyright © 2024. Published by Elsevier Inc.)

Background: Clinically important perioperative atrial fibrillation (POAF) is a common cardiac complication after noncardiac surgery. Little is known about how patients with POAF are managed acutely and whether practices have changed over time., Methods: We conducted an observational substudy of patients who had POAF, were at elevated cardiovascular risk, and were enrolled in the PeriOperative Ischemic Evaluation (POISE)-1, 2 and 3 trials between 2002 and 2021. POAF was defined as new, clinically important atrial fibrillation occurring within 30 days after surgery. We assessed the use of rhythm-control and anticoagulation treatment in response to POAF, at hospital discharge and at 30 days after surgery. We assessed for temporal trends using multivariable logistic regression., Results: Of the 27,896 patients included, 545 (1.9%) developed clinically important POAF. Patients received rhythm-control treatment in 48.6% of cases. The level of use of rhythm-control treatment increased over the course of the trials (POISE-1 vs POISE-2 vs POISE-3; 40.9% vs 49.5% vs 59.1%). A later randomization date was associated independently with use of rhythm-control treatment (odds ratio, 1.05 per year; 95% confidence interval, 1.01-1.09). Anticoagulation treatment was prescribed in 21% of POAF cases. The level of anticoagulation treatement use was higher in POISE-3, compared to that in the 2 previous trials (POISE-1 vs POISE-2 vs POISE-3-16.4% vs 16.5% vs 33.6%). A later randomization date was associated independently with use of anticoagulation treatment (odds ratio, 1.06 per year; 95% confidence interval, 1.02-1.11)., Conclusions: Despite the absence of randomized controlled trials, the level of use of rhythm-control and anticoagulation treatment for POAF is rising. High-quality trials are needed urgently to determine whether these interventions are safe and effective in this population., (© 2024 The Authors.)

Background: No study has investigated the perioperative management and clinical outcomes in patients who are receiving rivaroxaban 2.5 mg twice a day and acetylsalicylic acid (ASA) 81 to 100 mg daily., Objective: To assess perioperative management and outcomes in patients who are receiving low-dose rivaroxaban, 2.5 mg twice-daily, and low-dose ASA, 81 to 100 mg daily. To assess perioperative management and outcomes in patients who are receiving low-dose rivaroxaban, 2.5 mg twice-daily, and low-dose ASA, 81 to 100 mg daily., Methods: Subanalysis of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was performed to assess perioperative management and clinical outcomes in patients with stable coronary or peripheral artery disease who were randomized to receive rivaroxaban 2.5 mg twice a day plus ASA 100 mg daily, rivaroxaban 5 mg twice a day, or ASA 100 mg daily. Patients studied required a surgery/procedure during the trial. The study outcomes, which included myocardial infarction, angina, stroke, acute limb ischemia, bleeding, and death, were assessed according to treatment allocation., Results: There were 2632 patients studied (mean age, 68 years; 80% male) who had a surgery/procedure, comprising percutaneous coronary interventions (∼43%), carotid or other arterial angioplasty (∼15%), pacemaker or internal cardiac defibrillator implantation (∼9%), and coronary artery bypass graft surgery (∼7%). Perioperative study drug management varied, with about one-third of patients not interrupting study drug and the remainder interrupting it between 1 and ≥10 days preprocedure. The incidences of adverse outcomes across treatment groups were 12.7% to 15.3% for myocardial ischemia, 0.8% to 1.2% for stroke, 0.1% to 0.2% for venous thromboembolism, and 3.1% to 4.2% for any bleeding. There was no statistically significant difference in outcome rates across treatment groups., Conclusion: In patients in the COMPASS trial who required a surgery/procedure, there was no significant difference in perioperative adverse outcomes whether patients were receiving rivaroxaban 2.5 mg twice a day and ASA 100 mg daily, rivaroxaban 5 mg twice a day, or ASA alone., Competing Interests: Declaration of competing interests There was no funding provided for the development and for any other aspect of the work in this manuscript. J.D.D. reports consulting and lecture honoraria from Servier Canada, Leo Pharma, Pfizer, and Fresinius Kabi. Q.L. reports no disclosures. D.L.B. reports advisory for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys and research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio. E.M. reports being employed as a global clinical lead by Bayer AG, Germany. M.K.W. reports no disclosures. S.C. reports grants from Bayer AG and personal fees from BMS, Pfizer, Portola, Boehringer Ingelheim, Servier, Daiichi Sankyo, and Medtronic. S.Y. reports grants and personal fees from Bayer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, and Cadila. A.P.M. reports receiving personal fees from Bayer, AstraZeneca, and Novartis. J.W.E. reports grants and/or personal fees from Anthos, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Idorsia, Janssen, Astra Zeneca, Eli Lilly, GlaxoSmithKlein, and Sanofi Aventis., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Cancer and atrial fibrillation (AF) are common concurrent disorders. Direct oral anticoagulants (DOACs) are prescribed to prevent stroke in patients with AF. Patients with cancer often undergo invasive procedures for diagnostic or therapeutic purposes, necessitating interruption of anticoagulation. There are limited data to guide best periprocedural anticoagulation management practices in the setting of active cancer., Objectives: To describe patient characteristics, periprocedural management, and clinical outcomes in DOAC-treated patients with AF according to active cancer status., Methods: We conducted descriptive and comparative analyses using data from the PAUSE study. Multivariable logistic regression was used to determine whether active cancer status was an independent risk factor for bleeding outcomes. Covariates were selected a priori based on biological rationale and preexisting knowledge., Results: Patients with active cancer were older (P < .001), more likely to be thrombocytopenic (P = .026), have moderate renal dysfunction (P = .005), and more likely to receive low-dose DOAC therapy (P < .001). A greater proportion of patients with active cancer underwent a high-bleed-risk procedure (P < .001), with longer periprocedural DOAC-interruption intervals (P <.001) and lower preprocedural residual DOAC levels (P = .002). Active cancer was an independent predictor for surgical major bleeding (OR = 2.45; 95% CI, 1.08-5.14) after adjusting for study center, procedure category and bleed risk, thrombocytopenia, hypertension, and the use of a P2Y12 inhibitor., Conclusions: Active cancer status is associated with an increased risk of surgical major bleeding among DOAC-treated patients with AF undergoing interruption of anticoagulation for elective invasive procedures., Competing Interests: Declaration of competing interests J.R. Shaw has received in-kind laboratory support from Diagnostica Stago. T-F. Wang reports research funding from Leo Pharma and advisory honoraria from Valeo Pharma. Dr. Spyropoulos has received research support from Boehringer Ingelheim and Janssen, and consulting fees from Janssen, Bristol-Meyer Squibb/Pfizer Alliance, Sanofi, Alexion, Boehringer Ingelheim, Bayer, Roche Diagnostics. M. Carrier has received research funding from Leo Pharma and Pfizer, in addition to honoraria from BMS, Valeo Pharma, Leo Pharma, Sanofi, and Servier. J. Douketis has conducted consultancy/advisory board work for AstraZeneca, Cytosorb, PhaseBio, Servier, Leo Pharma and Pfizer. N. Li, J. Abdulrehman, S. Frosi Stella, M. St John, J. Nixon and S. Schulman declare no relevant conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Source Citation: Villiger R, Juillard P, Darbellay Farhoumand P, et al. Prediction of in-hospital bleeding in acutely ill medical patients: external validation of the IMPROVE bleeding risk score. Thromb Res. 2023;230:37-44. 37634309., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J23-0104.

Background: In patients with acute deep vein thrombosis (DVT) treated with catheter-based thrombolysis and venous stenting, poststenting anticoagulant management is uncertain., Objectives: To determine the type and duration of antithrombotic therapy used in patients who have received venous stents for treatment of acute lower extremity DVT., Methods: We created an international registry of patients with leg DVT from 2005 to 2019 who received venous stents as part of their acute management. We collected data on baseline clinical characteristics and pre-venous and post-venous stent antithrombotic therapy., Results: We studied 173 patients with venous stents: 101 (58%) were aged ≤50 years, 105 (61%) were female, and 128 (74%) had risk factors for thrombotic disease. DVT was iliofemoral in 150 (87%) patients, and catheter-based treatment was given within 7 days of diagnosis in 92 (53%) patients. After venous stenting, 109 (63%) patients received anticoagulant-only therapy with a direct oral anticoagulant (29%), warfarin (22%), or low-molecular-weight heparin (10%), and 59 (34%) received anticoagulant-antiplatelet therapy. In patients taking anticoagulant-only therapy, 29% received indefinite treatment; in patients on anticoagulant-antiplatelet therapy, 19% received indefinite treatment. Factors associated with combined anticoagulant-antiplatelet therapy vs anticoagulant-only therapy were use of thrombolytic, thrombectomy, and aspiration interventions (odds ratio [OR], 5.11; 95% CI, 1.45-18.05); use of balloon angioplasty (OR, 2.62; 95% CI, 1.20-5.76); and immediate stent restenosis (OR, 7.2; 95% CI, 1.45-5.89)., Conclusion: Anticoagulant therapy without concomitant antiplatelet therapy appears to be the most common antithrombotic strategy in patients with DVT and venous stenting. More research is needed to determine outcomes of venous stenting in relation to antithrombotic therapy., Competing Interests: Declaration of competing interests J.D.D. reports personal fees from Pfizer, Servier, Fresinius-Kabi, and Leo Pharma; and grants from Canadian Institutes of Health Research outside the submitted work. The remaining authors report no conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Anticoagulant and Antiplatelet Drug ManagementManagement of patients on an anticoagulant or antiplatelet drug who require surgery or an invasive procedure is a common clinical problem. Douketis and Spyropoulos provide an evidence-based but practical approach to managing anticoagulants and antiplatelet drugs in the perioperative setting.

Background: The management of patients who are receiving chronic oral anticoagulation therapy and require an elective surgery or an invasive procedure is a common clinical scenario., Research Question: What is the best available evidence to support the development of American College of Chest Physicians guidelines on the perioperative management of patients who are receiving long-term vitamin K agonist (VKA) or direct oral anticoagulant (DOAC) and require elective surgery or procedures?, Study Design and Methods: A literature search including multiple databases from database inception through July 16, 2020, was performed. Meta-analyses were conducted when appropriate., Results: In patients receiving VKA (warfarin) undergoing elective noncardiac surgery, shorter (< 3 days) VKA interruption is associated with an increased risk of major bleeding. In patients who required VKA interruption, heparin bridging (mostly with low-molecular-weight heparin [LMWH]) was associated with a statistically significant increased risk of major bleed, representing a very low certainty of evidence (COE). Compared with DOAC interruption 1 to 4 days before surgery, continuing DOACs may be associated with higher risk of bleeding demonstrated in some, but not all studies. In patients who needed DOAC interruption, bridging with LMWH may be associated with a statistically significant increased risk of bleeding, representing a low COE., Interpretation: The certainty in the evidence supporting the perioperative management of anticoagulants remains limited. No high-quality evidence exists to support the practice of heparin bridging during the interruption of VKA or DOAC therapy for an elective surgery or procedure, or for the practice of interrupting VKA therapy for minor procedures, including cardiac device implantation, or continuation of a DOAC vs short-term interruption of a DOAC in the perioperative period., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Direct oral anticoagulants (DOACs) are widely used in patients with atrial fibrillation and venous thromboembolism. However, DOACs have important potential drug-drug interactions (DDIs) with several classes of drugs. In particular, antiepileptic (AE) drugs may induce cytochrome P450 3A4 or P-glycoprotein. Co-administration of DOACs and AE drugs may result in lower DOAC drug levels and reduced DOAC efficacy. However, the clinical significance of such DDIs is uncertain., Objectives: The aim of this systematic review was to generate an updated review of these DDIs and their clinical relevance, given the rapidly evolving knowledge relating to DOAC and AE DDIs., Methods: We searched the MEDLINE and Embase databases for studies reporting clinical adverse outcomes (thrombotic events, bleeding events, and all-cause mortality) in patients concomitantly taking DOACs and AE drugs., Results: We retrieved 874 studies of which 15 were deemed eligible for this review, including 4 congress abstracts, 3 case reports, 2 letters to the editor, 5 retrospective cohorts, and 1 prospective cohort study. No randomized clinical trials were found. Most of the included studies reported thrombotic events, 3 studies reported major bleeding, and one study reported all-cause mortality associated with DOAC and AE drug administration. Substantial differences in the study designs did not allow for a meta-analysis to be performed., Conclusion: The current literature assessing these adverse clinical outcomes from DOAC and AE drug co-administration is limited. Although the available data point to a possible increased risk of thrombotic events, they are insufficient to draw definitive conclusions. Well-designed clinical studies are of utmost importance., (© 2023 The Authors. Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Background: The Perioperative Anticoagulation Use for Surgery Evaluation study prospectively evaluated a prespecified periprocedural interruption strategy of direct oral anticoagulants (DOACs) among patients with atrial fibrillation. Coagulation testing is widely available and frequently requested prior to invasive procedures. Coagulation assays display poor sensitivity to clinically relevant DOAC concentrations., Objectives: Determine the utility of routinely available coagulation testing at predicting a DOAC concentration of <30 ng/ml among patients in the preprocedural setting., Methods: We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratio (LR+ and LR-) of a normal coagulation assay result for identifying patients with a preprocedural DOAC level < 30 ng/ml., Results: We identified weak or very weak correlations between coagulation assay results and DOAC levels in the preprocedural setting, except for a moderate correlation between the thrombin time (TT) and dabigatran concentrations (ρ = 0.68; p < .001). The prothrombin time (PT) and activated partial thromboplastin time (APTT) demonstrated modest sensitivity (78.9% to 88.2%) and PPVs (76.4% to 93.1%) but poor specificity (13.2% to 53.3%) and NPVs (16.3% to 30.2%) across all three DOACs. A normal TT was associated with 100% specificity and PPV values for a dabigatran level < 30 ng/ml. A normal APTT among patients on dabigatran was associated with an LR+ of 1.671 (95% confidence interval [CI] 1.297, 2.154) and an LR- of 0.395 (95% CI 0.207, 0.751) for levels <30 ng/ml., Conclusions: The PT and APTT perform poorly at safely identifying patients with negligible DOAC levels in the preprocedural setting., (© 2022 International Society on Thrombosis and Haemostasis.)

Background: The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug., Methods: Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines., Results: A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures., Conclusions: Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management questions., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug., Methods: Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines., Results: A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures., Conclusions: Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management questions., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: To summarize the available evidence about the perioperative management of patients who are receiving long-term antiplatelet therapy and require elective surgery/procedures., Methods: This systematic review supports the development of the American College of Chest Physicians guideline on the perioperative management of antiplatelet therapy. A literature search of MEDLINE, EMBASE, Scopus and Cochrane databases was conducted from each database's inception to July 16, 2020. Meta-analyses were conducted when possible., Results: In patients receiving long-term antiplatelet therapy and undergoing elective noncardiac surgery, the available evidence did not show a significant difference in major bleeding between a shorter vs longer antiplatelet interruption, with low certainty of evidence (COE). Compared with patients who received placebo perioperatively, aspirin continuation was associated with increased risk of major bleeding (relative risk [RR], 1.31; 95% CI, 1.15-1.50; high COE) and lower risk of major thromboembolism (RR, 0.74; 95% CI, 0.58-0.94; moderate COE). During antiplatelet interruption, bridging with low-molecular-weight heparin was associated with increased risk of major bleeding compared with no bridging (RR, 1.86; 95% CI, 1.24-2.79; very low COE). Continuation of antiplatelets during minor dental and ophthalmologic procedures was not associated with a statistically significant difference in the risk of major bleeding (very low COE)., Conclusion: This systematic review summarizes the current evidence about the perioperative management of antiplatelet therapy and highlights the urgent need for further research, particularly with the increasing prevalence of patients taking 1 or more antiplatelet agents., (© 2022 The Authors.)

Despite the emergence of high quality randomized trial data with the use of antithrombotic agents to reduce the risk of thromboembolism, end-organ failure, and possibly mortality in patients with coronavirus disease 2019 (COVID-19), questions still remain as to optimal patient selection for these strategies, the use of antithrombotics in outpatient settings and in-hospital settings (including critical care units), thromboprophylaxis in special patient populations, and the management of acute thrombosis in hospitalized COVID-19 patients. In October 2021, the International Society on Thrombosis and Haemostasis (ISTH) formed a multidisciplinary and international panel of content experts, two patient representatives, and a methodologist to develop recommendations on treatment with anticoagulants and antiplatelet agents for COVID-19 patients. The ISTH Guideline panel discussed additional topics to be well suited to a non-Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for Good Practice Statements (GPS) to support good clinical care in the antithrombotic management of COVID-19 patients in various clinical settings. The GPS panel agreed on 17 GPS: 3 in the outpatient (pre-hospital) setting, 12 in the hospital setting both in non-critical care (ward) as well as intensive care unit settings, and 2 in the immediate post-hospital discharge setting based on limited evidence or expert opinion that supports net clinical benefit in enacting the statements provided. The antithrombotic therapies discussed in these GPS should be available in low- and middle-income countries., (© 2022 International Society on Thrombosis and Haemostasis.)

Apixaban is frequently used off-label in transplant recipients. However, a potential drug interaction exists with the calcineurin inhibitors. We conducted an open-label drug-drug interaction study to determine the pharmacokinetics of apixaban in lung and kidney transplant recipients who were taking a calcineurin inhibitor. A single dose of apixaban 10 mg was administered orally to kidney and lung transplant recipients maintained on either tacrolimus or cyclosporine, and pharmacokinetic parameters were compared to a reference cohort of 12 healthy subjects who used the same apixaban dose and pharmacokinetic blood sampling. Fourteen participants were enrolled (n = 6 kidney, n = 8 lung), with 10 maintained on tacrolimus and four on cyclosporine. Data from 13 participants was usable. Participants were taking triple therapy immunosuppression and had a mean (SD) of 12 (3) medications. Participants receiving tacrolimus and cyclosporine had area under the plasma concentration-time curve from time zero to infinity (AUC 0-inf ) geometric least square means (90% confidence interval [CI]) of 4312 (95% CI 3682, 5049) and 5388 (95% CI 3277, 8858), respectively. Compared to healthy subjects, the associated geometric mean ratios (GMRs) for apixaban maximum plasma concentration (C max ), AUC from time zero to the last quantifiable concentration (AUC 0-tlast ) and AUC 0-inf were 197% (95% CI 153, 295), 244% (95% CI 184, 323), and 224% (95% CI 170, 295) for transplant recipients on tacrolimus. The GMR (90% CI) C max , AUC 0-tlast , and AUC 0-inf of apixaban for patients on cyclosporine were 256% (95% CI 184, 358), 287% (95% CI 198, 415), and 280% (95% CI 195, 401). Kidney and lung transplant recipients receiving tacrolimus had higher apixaban exposure. A similar trend was noted for patients receiving cyclosporine, but additional patients are needed to confirm this interaction. Future studies are needed before apixaban can be safely recommended in this population, and the impact of dose staggering should be investigated. This study highlights the importance of pharmacokinetic studies in actual patient populations., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Carbamazepine and phenytoin are potent inducers of enzymes that metabolize oral anticoagulants., Objectives: To determine the clinical impact of drug-drug interactions between these anticonvulsants and oral anticoagulants, and whether they affect the treatment with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs)., Material and Methods: Data on patients cotreated with carbamazepine or phenytoin and an oral anticoagulant were retrospectively retrieved from medical records from 2011 to 2020. Outcomes were time in therapeutic range (TTR), DOAC levels, thromboembolic events, major bleeding, and all-cause mortality., Results: Among 85 patients (37% female, median age 68 years) treated with carbamazepine ( n  = 43 [51%]) or phenytoin ( n  = 42 [49%]), 53 (62%) were initially treated with VKAs and 32 (38%) with DOACs. TTR in VKA patients was 63%, which improved in year 2. Four of seven trough and five of 12 peak DOAC plasma levels were lower than expected. The incidence rate (95% confidence interval) per 100 person-years for thromboembolism was 3.6 (3.1-4.2) for VKA patients and 4.4 (3.5-5.6) for DOAC patients; for major bleeding 1.8 (1.5-2.1) and 1.5 (1.2-1.9), and for all-cause mortality 3.6 (3.1-4.2) and 1.5 (1.2-1.9), respectively. Incidence rates between VKAs and DOACs and between carbamazepine and phenytoin were similar., Conclusion: There was a high incidence of thromboembolism in patients cotreated with anticoagulants and carbamazepine or phenytoin. The incidence rates of thrombotic and bleeding events were similar between VKA and DOAC patients. DOAC levels were lower than expected in 47% of cases tested, without correlation with clinical outcomes., Competing Interests: Drs. Candeloro and Chan have no conflict of interest to declare. Dr. Schulman has received research funding from Boehringer Ingelheim and Octapharma and honoraria from Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Daiichi‐Sankyo, Pfizer, and Sanofi. Dr. Bhagirath has received honoraria from Bayer and Pfizer, and an unrestricted educational grant from Pfizer. Dr. Eikelboom has received consulting/honoraria from Astra‐Zeneca, Bayer, Boehringer‐Ingelheim, Bristol‐Myer‐Squibb, Daiichi‐Sankyo, Eli‐Lilly, Glaxo‐Smith‐Kline, Pfizer, Janssen, and Sanofi‐Aventis and Servier grants and/or in‐kind support from Astra‐Zeneca, Bayer, Boehringer‐Ingelheim, Bristol‐Myer‐Squibb, Glaxo‐Smith‐Kline, Pfizer, Janssen, and Sanofi‐Aventis. Dr. Douketis has received consulting fees and/or honoraria from Bayer, BMS, Janssen, Leo Pharma, Pfizer, and Servier., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

The periprocedural management of patients who are receiving vitamin K antagonists, direct oral anticoagulants and antiplatelet therapy is a common and challenging clinical scenario as the decision to interrupt or continue these medications is anchored on patient and procedure-related risks for bleeding and thrombosis. Adding to the complexity of clinical management is the fact that anticoagulants have varied pharmacokinetic and pharmacodynamic properties and indications for clinical use. In many minimal-bleed-risk procedures, anticoagulants can be safely continued, without interruption, whereas in cases where anticoagulants cannot be safely continued, the timing of interruption and resumption, as well as the need for heparin bridging requires consideration. Perioperative antithrombotic management scenarios occur most often in patients with atrial fibrillation, mechanical heart valves, coronary stents, and cerebrovascular disease as such patients are likely to be prescribed anticoagulant and/or antiplatelet therapy. The objective of this case-based narrative review is to provide a practical evidence-based approach to the perioperative management of patients on anticoagulation and antiplatelet therapy. Four clinical scenarios will be provided: (1) managing patients in whom anticoagulants can be continued; (2) perioperative management of direct oral anticoagulants; (3) management of patients on dual antiplatelet therapy; and (4) anticoagulant management for emergency or urgent surgery., (© 2021. Società Italiana di Medicina Interna (SIMI).)