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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.

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.

Introduction Oral anticoagulant (OAC)-related adverse events are high post-hospitalization. We planned to develop and validate a prediction model for OAC-related harm within 30 days of hospitalization. Methods We undertook a population-based study of adults aged ≥66 years who were discharged from hospital on an OAC from September 2010 to March 2015 in Ontario, Canada. The primary outcome was a composite of time to first hospitalization or emergency department visit for a hemorrhagic or thromboembolic event, or mortality within 30 days of hospital discharge. Cox proportional hazards regression was used to build the model. Results We included 120,721 patients of which 5423 experienced the outcome. Most patients were aged ≥75 years (59.5%) and were female (55.6%). Sixty percent of the cohort had a follow-up visit with a healthcare provider within 7 days of discharge. Patients discharged on a direct acting OAC versus warfarin (apixaban: Hazard Ratio [HR] 0.82, 95% confidence interval [CI] 0.71-0.94; dabigatran: HR 0.73, 95% CI 0.63-0.84; rivaroxaban: HR 0.79, 95% CI 0.71-0.88), were prevalent users of the dispensed OAC versus incident users (HR 0.82, 95% CI 0.69-0.96), had a joint replacement in the past 35 days (HR 0.40, 95% CI 0.33-0.50) or major surgery during index hospital stay (HR 0.69, 95% CI 0.60-0.80) had a lower risk for the outcome. The Cox model was stable with acceptable discrimination but poor goodness-of-fit. Conclusions A model for OAC-related harm in the early post-discharge period was developed. External validation studies are required to understand the model's poor calibration.

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.Determine the utility of routinely available coagulation testing at predicting a DOAC concentration of30 ng/ml among patients in the preprocedural setting.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.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 levels30 ng/ml.The PT and APTT perform poorly at safely identifying patients with negligible DOAC levels in the preprocedural setting.

The 2020 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for the Secondary Prevention of Stroke includes current evidence-based recommendations and expert opinions intended for use by clinicians across a broad range of settings. They provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations address triage, diagnostic testing, lifestyle behaviors, vaping, hypertension, hyperlipidemia, diabetes, atrial fibrillation, other cardiac conditions, antiplatelet and anticoagulant therapies, and carotid and vertebral artery disease. This update of the previous 2017 guideline contains several new or revised recommendations. Recommendations regarding triage and initial assessment of acute transient ischemic attack (TIA) and minor stroke have been simplified, and selected aspects of the etiological stroke workup are revised. Updated treatment recommendations based on new evidence have been made for dual antiplatelet therapy for TIA and minor stroke; anticoagulant therapy for atrial fibrillation; embolic strokes of undetermined source; low-density lipoprotein lowering; hypertriglyceridemia; diabetes treatment; and patent foramen ovale management. A new section has been added to provide practical guidance regarding temporary interruption of antithrombotic therapy for surgical procedures. Cancer-associated ischemic stroke is addressed. A section on virtual care delivery of secondary stroke prevention services in included to highlight a shifting paradigm of care delivery made more urgent by the global pandemic. In addition, where appropriate, sex differences as they pertain to treatments have been addressed. The CSBPR include supporting materials such as implementation resources to facilitate the adoption of evidence into practice and performance measures to enable monitoring of uptake and effectiveness of recommendations.

Background Data on resuming oral anticoagulants (OACs) after bleeding are primarily from studies involving patients given warfarin, with few data on direct OACs (DOACs). We aimed to characterize prescribing patterns for OACs after OAC-related bleeding and compare the rates of bleeding, thrombosis and mortality in patients who resumed either type of OAC with those who did not. Methods We conducted a population-based cohort study of adults aged 66 years or older who were admitted to hospital for bleeding while receiving OACs from Apr. 1, 2012, to Mar. 31, 2017, using linked administrative health databases from Ontario. We used competing risk methods to calculate cause-specific adjusted hazard ratios (HRs) for thrombosis, bleeding and mortality with resumption of OACs adjusted as a time-varying covariate. We determined time to OAC resumption using the Kaplan-Meier method. Results We included 6793 patients with gastrointestinal (n = 4297, 63.3%), intracranial (n = 805, 11.9%) or other bleeding (n = 1691, 25.0%). At cohort entry, 3874 patients (57.0%) were prescribed warfarin and 2919 patients (43.0%) were prescribed a DOAC. The most common indication for OAC was atrial fibrillation (n = 5557, 81.8%), followed by venous thromboembolism (n = 1367, 20.1%). Oral anticoagulants were resumed in 4792 patients (70.5%) within 365 days of the index bleed. The median time to resumption was 46 (interquartile range 6-550) days. We found that resuming OAC was associated with reduced rates of thrombosis (adjusted HR 0.60, 95% confidence interval [CI] 0.50-0.72) and mortality (adjusted HR 0.54, 95% CI 0.48-0.60), and an increased rate of rebleeding (adjusted HR 1.88, 95% CI 1.64-2.17). Interpretation We found that resuming OAC is associated with a reduction in thrombosis and mortality but an increase in bleeding. Randomized controlled trials that evaluate the net benefit of strategies for resumption of OAC after a bleeding event are warranted.

Introduction Bariatric surgery patients experience an increased risk of venous thromboembolism (VTE), however, the optimal dose of low-molecular-weight heparin for VTE prophylaxis remains uncertain. Currently, St. Joseph's Healthcare Hamilton utilizes a weight-adjusted tinzaparin dosage (50 to 75 units/kg rounded to nearest pre-filled syringe) for postoperative VTE prophylaxis. Objectives This study analyzed the safety of weight-adjusted tinzaparin for VTE prophylaxis in bariatric surgery patients weighing ≥160 kg. Methods This was a retrospective study involving patients weighing ≥160 kg that underwent bariatric surgery from September 2015 to September 2019. Patients received a single dose of weight-adjusted subcutaneous unfractionated heparin (UFH) [5000 or 7500 IU] immediately prior to surgery, subcutaneous UFH [5000 IU, 7500 IU, or unspecified] immediately postoperatively, and either 10,000 or 14,000 IU of tinzaparin, beginning on the day after surgery, for 10 days. Intra-operative sequential compression devices could be used at the attending surgeon's discretion. Occurrence of VTE and major bleeding within 30 days of surgery were assessed. Results A total of 389 patients were included for analysis, all patients received in-hospital follow-up while 349 patients had also 30-day follow-up. For the primary safety and efficacy analysis of in-hospital events, VTE and major bleeding rates were 0.26% [95% CI 0.01%–1.44%] (1/389) and 0.77% [95% CI 0.21%–2.24%] (3/389) respectively. For patients with 30-day follow-up VTE and major bleeding rates were 0.57% [95% CI 0.1%–2.07%] (2/349) and 1.43% [95% CI 0.61%–3.3%] (5/349) respectively. Conclusions Weight-adjusted tinzaparin was associated with a low risk of bleeding and VTE events, supporting its use for VTE prophylaxis for patients weighing ≥160 kg.

Background The perioperative management of patients taking a direct oral anticoagulant (DOAC) who require a high‐bleed‐risk surgery and/or neuraxial anesthesia is uncertain. We surveyed clinician practices relating to DOAC interruption and related perioperative management in patients having high‐bleed‐risk surgery with neuraxial anesthesia, and assess the suitability of a randomized trial of different perioperative DOAC management strategies. Methods We surveyed members of the American Society of Regional Anesthesia and Pain Medicine, the Canadian Anesthesia Society and Thrombosis Canada. We developed four clinical scenarios involving DOAC‐treated patients who required anticoagulant interruption for elective high‐bleed‐risk surgery. In three scenarios, patients were to receive neuraxial anesthesia, and in one scenario they were to receive general anesthesia. We also asked about the merit of a randomized trial to compare a 2‐day versus longer (3‐ to 5‐day) duration of DOAC interruption. Results There were 399 survey respondents of whom 356 (89%) were anesthetists and 43 (11%) were medical specialists. The responses indicate uncertainty about the DOAC interruption interval for high‐bleed‐risk surgery and/or neuraxial anesthesia; anesthetists favor 3‐ to 5‐day interruption whereas medical specialists favor 2‐day interruption. Anesthetists were unwilling to proceed with neuraxial anesthesia in patients with a 2‐day DOAC interruption interval, preferring to cancel the surgery or switch to general anesthesia. There is general agreement on the need for a randomized trial in this field to compare a 2‐day and a 3‐ to 5‐day DOAC interruption management strategy. Conclusions There is variability in practices relating to the perioperative management of DOAC‐treated patients who require a high‐bleed‐risk surgery with neuraxial anesthesia; this variability relates to the duration of DOAC interruption in such patients.

The management of patients who are receiving chronic oral anticoagulation therapy and require an elective surgery or invasive procedure is a common clinical scenario.What is the best available evidence to support the development of American College of Chest Physicians (ACCP) guideline on the perioperative management of patients who are receiving long-term vitamin K agonist (VKA) or direct oral anticoagulant (DOAC) and require elective surgery/procedures?Literature search including multiple databases from database inception to July 16, 2020, was performed. Meta-analyses were conducted when appropriate.In patients receiving VKA (warfarin) undergoing elective non-cardiac surgery, shorter (5 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 (RR: 9.1 [95% CI, 1.62-51.3]); very low certainty of evidence (COE). Compared with DOACs interruption 1-4 days before surgery, continuing DOACs was not associated with a statistically significant difference in the risk of bleeding; very low COE. Continuing dabigatran was associated with a statistically significant increased risk of thromboembolism (RR: 2.2 [95% CI, 1.3-3.8]); low COE. In patients who needed DOACs interruption, bridging with LMWH was associated a with statistically significant increased risk of minor bleeding compared to no bridging (RR: 1.7 [95% CI, 1.13-2.7]); low COE.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/procedure, or 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 (1-4 days) perioperatively.

POINTS CLES En 2016, au Canada (a l’exclusion du Quebec), 270 204 personnes ont ete admises a l’hopital pour un trouble cardiaque, un accident vasculaire cerebral (AVC) ou un deficit cognitif d’origine vasculaire; de ce nombre, 107 391 etaient des femmes, 162 813 etaient des hommes

Introduction The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) Study assessed a standardized perioperative management strategy in patients with atrial fibrillation who were taking a direct oral anticoagulant (DOAC) and required an elective surgery or procedure. The aim of this substudy is to analyze the safety of this management strategy across different patient subgroups, according to four presurgical variables: (1) DOAC type and dose, (2) surgery/procedure bleed risk, (3) patient renal function, and (4) age. Methods Clinical outcomes analyzed included major bleeding (MB), arterial thromboembolism, any bleeding, and any thromboembolism. We used descriptive statistics to summarize clinical outcomes, where the frequency, proportion, and 95% confidence interval were reported. Fisher's exact tests were used for testing the null hypothesis of independence between the clinical outcome and patient characteristic, where the test p-values were reported. Results There were 3,007 patients with atrial fibrillation requiring perioperative DOAC management. There was no significant difference in bleeding or thromboembolic outcomes according to DOAC type/dose regimen, renal function, or patient age. The rate of MB was significantly higher with high bleed risk procedures than low bleed risk procedures in apixaban-treated patients (2.9 vs. 0.59%; p Conclusion Our results suggest that in DOAC-treated patients who received standardized perioperative management, surgical bleed risk is an important determinant of bleeding but not thromboembolic outcomes, although this finding was not consistent across all DOACs. There were no differences in bleeding and thromboembolism according to DOAC type and dose, renal function, or age.

The novel coronavirus disease of 2019 (COVID‐19) pandemic, as declared by the World Health Organization, is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2). Cardiovascular disease and, in particular, venous thromboembolism (VTE) has emerged as an important consideration in the management of hospitalized patients with COVID‐19. The diagnosis of VTE using standardized objective testing is problematic in these patients, given the risk of infecting non‐COVID‐19 hospitalized patients and hospital personnel, coupled with the usual challenges of performing diagnostic testing in critically‐ill patients. Early reports suggest a high incidence of VTE in hospitalized COVID‐19 patients, particularly those with severe illness, that is similar to the high VTE rates observed in patients with other viral pneumonias, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS‐CoV).

Decisions surrounding periprocedural anticoagulation management must balance thromboembolic and procedural bleed risk. The interruption of both warfarin and DOACs requires consideration of anticoagulant pharmacokinetics, procedural bleed risk and patient characteristics. There is a diminishing role for periprocedural bridging LMWH overall and no role for bridging LMWH for the procedural interruption of DOACs. A clinical approach to perioperative DOAC management based on operative bleeding risk and renal function is safe and effective, and at present, is preferred over preprocedural DOAC levels testing. Clear communication of the anticoagulation interruption plan to both the patient and the patient's care team is essential.

Acute pulmonary embolism (PE) is associated with high in-hospital morbidity and mortality, both via cardiorespiratory decompensation and the bleeding complications of treatment. Thrombolytic therapy can be life-saving in those with high-risk PE, but requires careful patient selection. Patients with PE and systemic arterial hypotension ("massive PE") should receive thrombolytic therapy unless severe contraindications are present. Patients with PE and right ventricular dysfunction/injury, but without hypotension ("submassive PE"), should be considered for thrombolysis on a case-by-case basis, considering bleeding risk, cardiac biomarkers, echocardiography, and most importantly, clinical status.

Background There is limited information on real‐world practice versus current clinical practice guidelines for oral anticoagulant reversal before emergency surgery. Objective To identify current practice/knowledge gaps for oral anticoagulant reversal emergency surgery among anesthesiologists. Methods A 22‐question survey covering aspects of clinical practice relating to oral anticoagulant reversal was sent to American Society of Anesthesiology members with weekly reminders during data collection from October to December 2018. Results Responses were received from 2315 anesthesiologists of which 86% of respondents were United States based. Emergency surgery was defined as occurring within 4 hours of the decision to operate by 60% of respondents. Fresh frozen plasma (FFP) was used by 75% of respondents for vitamin K antagonist (VKA) reversal and by 54% for direct oral anticoagulant (DOAC) reversal in emergency surgery and 67% in major operative bleeding. Only 32% of institutions had emergency anticoagulant reversal protocols, and 54% of respondents selected an international normalized ration (INR) ratio goal for VKA reversal of ≤1.5. Only 13% initially consulted or coordinated management with hematologists, and the final decision regarding coagulation management was made by the respondent in 26% of cases. A coordinated approach with hematologists and cardiologists was reported by 64%, and over half (51%) required approval for prothrombin complex concentrate administration for emergency procedures. Conclusions Despite recommendations to the contrary, FFP is extensively used for emergency VKA and DOAC reversal. There is a clear need for institutions to develop guideline‐informed recommendations/management algorithms based on input from medical professionals routinely involved in management of these patients.

KEY POINTS In 2016, 270 204 people in Canada (excluding Quebec) were admitted to hospital for heart conditions, stroke and vascular cognitive impairment, including 107 391 women and 162 813 men, of whom 91 524 died.[1][1] This equates to 1 out of every 3 deaths in Canada and outpaces other diseases

The perioperative management of patients who are receiving antithrombotic (antiplatelet or anticoagulant) therapy and require urologic surgery is challenging due to the inherent risk for surgical bleeding and the need to minimize thromboembolic risk. The aim of this review is to assess the quality and consistency of clinical practice guidelines (CPGs) and clinical practice recommendations (CPRs) on this topic, and to summarize the evidence and associated strength of recommendations relating to perioperative antithrombotic management. A pragmatic search of electronic databases and guidelines websites was performed to identify relevant CPGs/CPRs. The AGREE II (Appraisal of Guidelines for REsearch and Evaluation) instrument was used to assess the methodological quality and integrity of the CPGs. The CPGs provided by the European Association of Urology (EAU), the American College of Chest Physicians (ACCP) and the European Society of Cardiology/European Society of Anaesthesiology (ESC/ESA), and the CPRs provided by the International Consultation on Urological Disease (ICUD)/American Urologic Association (AUA) were retrieved and reviewed. The 3 CPGs were critically assessed using the AGREE II instrument. Inconsistent recommendations were provided based on the indication for antithrombotic medication, the antiplatelet/anticoagulant agent and the type of urological procedure. Based on the AGREE II tool for CPG assessment, the EAU CPGs scored higher (83.3 points) compared to the ESC/ESA (75 points) and ACCP CPG (66.7 points). The perioperative management of antithrombotic therapy in urological patients is potentially challenging but inconsistent CPG of varying quality may create uncertainty as to best practices to minimize thromboembolic and bleeding risk.

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

Background: We aimed to investigate the potential beneficial effect of immunomodulation therapy on the thromboembolic risk in hospitalized COVID-19 patients. Methods: We searched PubMed and Scopus for randomized trials reporting the outcomes of venous thromboembolism (VTE), ischemic stroke or systemic embolism, myocardial infarction, any thromboembolic event, and all-cause mortality in COVID-19 patients treated with immunomodulatory agents. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using the Mantel–Haenszel random effects method. Results: Among 8499 patients hospitalized with COVID-19, 4638 were treated with an immunomodulatory agent, 3861—with usual care only. Among the patients prescribed immunomodulatory agents, there were 1.77 VTEs per 100 patient-months compared to 2.30 among those treated with usual care (OR: 0.84, 95% CI: 0.61–1.16; I2: 0%). Among the patients who received an interleukin 6 (IL-6) antagonist, VTEs were reported in 12 among the 1075 patients compared to 20 among the 848 receiving the usual care (OR: 0.52, 95% CI: 0.22–1.20; I2: 6%). Immunomodulators as an add-on to usual care did not reduce the risk of stroke or systemic embolism (OR: 1.10, 95% CI: 0.50–2.40; I2: 0%) or of myocardial infarction (OR: 1.06, 95% CI: 0.47–2.39; I2: 0%) and there was a nonsignificant reduction in any thromboembolic event (OR: 0.86, 95% CI: 0.65–1.14; I2: 0%). Conclusions: We did not identify a statistically significant effect of immunomodulation on prevention of thromboembolic events in COVID-19. However, given the large effect estimate for VTE prevention, especially in the patients treated with IL-6 antagonists, we cannot exclude a potential effect of immunomodulation.

Carbamazepine and phenytoin are potent inducers of enzymes that metabolize oral anticoagulants.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).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.Among 85 patients (37% female, median age 68 years) treated with carbamazepine (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.

Background One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis. Management Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic. Current Issues The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments. Perspectives There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) Prevention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA). Conclusion The “PDA strategy” integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide.

Essentials Long-term recurrence risk after a first unprovoked VTE with negative d-dimer levels is uncertain. Anticoagulation was stopped if d-dimer was negative, and was continued if d-dimer was positive. Five years after stopping anticoagulants, recurrent VTE was 30% in men and 17% in women. Negative d-dimers do not justify stopping anticoagulants in most men but appear to in most women. BACKGROUND The long-term risk of recurrence in patients with a first unprovoked venous thromboembolism (VTE) who have negative d-dimer results is uncertain. OBJECTIVES To determine this risk, including in subgroups based on sex. PATIENTS AND METHODS ln a prospective interventional cohort study of 410 patients with a first unprovoked VTE, anticoagulants were stopped if d-dimer was negative on therapy and 1 month after stopping therapy. Other patients remained on anticoagulant therapy. We previously reported findings after a mean of 2.2 years. The current report includes 3 years of additional follow-up in 293 of these patients. RESULTS During a median follow-up of 5.0 years, recurrent VTE after stopping therapy in response to negative d-dimer testing was 5.1% (95% confidence interval [CI], 3.6-6.5) per patient-year overall, 7.5% (95% CI, 5.5-10.0) in men, 3.8% (95% CI, 2.0-6.6) in women with VTE not associated with estrogens, and 0.4% (95% CI, 0.0-2.3) in women with VTE associated with estrogens (P

Pulmonary embolism (PE) is a potentially life-threatening condition, mandating urgent diagnosis and treatment. The symptoms of PE may be non-specific; diagnosis therefore relies on a clinical assessment and objective diagnostic testing. A clinical decision rule can determine the pre-test probability of PE. If PE is "unlikely", refer for a D-dimer test. If the D-dimer result is normal, PE can be excluded. If D-dimer levels are increased, refer for chest imaging. If PE is "likely", refer for chest imaging. Imaging with computed tomography pulmonary angiogram is accurate and preferred for diagnosing PE, but may detect asymptomatic PE of uncertain clinical significance. Imaging with ventilation-perfusion (VQ) scan is associated with lower radiation exposure than computed tomography pulmonary angiogram, and may be preferred in younger patients and pregnancy. A low probability or high probability VQ scan is helpful for ruling out or confirming PE, respectively; however, an intermediate probability VQ scan requires further investigation. The direct oral anticoagulants have expanded the anticoagulation options for PE. These are the preferred anticoagulant for most patients with PE because they are associated with a lower risk of bleeding, and have the practical advantages of fixed dosage, no need for routine monitoring, and fewer drug interactions compared with vitamin K antagonists. Initial parenteral treatment is required before dabigatran and edoxaban.

Diagnosis of deep vein thrombosis (DVT) requires a multifaceted approach that includes clinical assessment, evaluation of pre-test probability, and objective diagnostic testing. Common symptoms and signs of DVT are pain, swelling, erythema and dilated veins in the affected limb. The pre-test probability of DVT can be assessed using a clinical decision rule that stratifies DVT into "unlikely" or "likely". If DVT is "unlikely", refer for D-dimer test. If the D-dimer level is normal, DVT can be excluded; if the D-dimer level is increased, refer for compression ultrasound. If DVT is "likely", refer for compression ultrasound. When DVT is confirmed, anticoagulation is indicated to control symptoms, prevent progression and reduce the risk of post-thrombotic syndrome and pulmonary embolism. Anticoagulation may consist of a parenteral anticoagulant overlapped by warfarin or followed by a direct oral anticoagulant (DOAC) (dabigatran or edoxaban), or of a DOAC (apixaban or rivaroxaban) without initial parenteral therapy. DOACs are the preferred treatment for DVT because they are at least as effective, safer and more convenient than warfarin. DOACs may require dose reduction or avoidance in patients with renal dysfunction, and should be avoided in pregnancy. Recent evidence shows that DVT in patients with cancer may be treated with edoxaban (after discontinuation of 5 days of initial heparin or low molecular weight heparin [LMWH]) or rivaroxaban if patients prefer not to have daily injections of LMWH, but the risk of gastrointestinal bleeding is higher with DOACs than with LMWH in patients with gastrointestinal cancer.

Background Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups. Objective To present current expert insights and evidence on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill. Methodology To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts. Results The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment. Conclusions Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug–drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, low-molecular weight heparins remain the first choice for prophylaxis in critically ill and cancer patients due to their safety and efficacy profile, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins. Herein we present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in patients with cancer and the critically ill.

Orthopedic surgery and surgery for cancer are major risk factors for venous thromboembolism (VTE). Deep vein thrombosis (DVT) can occur in up to 50% of patients after major orthopedic surgery. The rate of VTE after cancer surgery varies according to the type of surgery, with rates as high as those after orthopedic surgery in certain settings. Use of thromboprophylaxis in these high-risk settings is well established and recent studies inform the type and duration of thromboprophylaxis. With major orthopedic surgery, there has been a shift from use of low molecular weight heparins (LMWHs) to direct oral anticoagulants (DOACs) along with renewed interest in aspirin as a thromboprophylaxis agent. Recent studies have also informed optimal thromboprophylaxis strategies after nonmajor orthopedic surgery. Use of thromboprophylaxis after major cancer surgery for cancer is established and recent evidence has focused on the potential benefits of extended-duration thromboprophylaxis. This review will summarize emerging evidence for thromboprophylaxis after orthopedic and cancer surgery with a view to providing clinicians with concise and actionable guidance for best practice.

Background Direct oral anticoagulants (DOACs) are prescribed for over 80% of patients who start anticoagulant therapy for a new diagnosis of atrial fibrillation (AF). Inappropriate DOAC prescriptions are associated with increased mortality. However, limited data exist as to what proportion of primary care physicians (PCPs) initiate anticoagulation in patients with new AF and the extent of their DOAC knowledge. Material and methods We conducted a telephone survey of randomly selected PCPs in Ontario, Canada. Our primary objective was to determine the percentage of PCPs who initiate anticoagulation in new AF patients and the proportion of patients they initiate on DOACs. Our secondary objectives were to assess PCPs' knowledge about DOACs and to identify educational opportunities to address any knowledge gaps. Results Our survey included 50 respondents. After making a new AF diagnosis, 66% of PCPs stated that they usually initiate anticoagulation themselves and 84% prescribed a DOAC at least 75% of the time. Potential DOAC knowledge gaps included: administration considerations, off-label dosing, concomitant use of acetylsalicylic acid (ASA) in stable coronary artery disease (CAD) and use in valvular AF. Conclusion Most PCPs initiate anticoagulants for AF and prescribe DOACs for the vast majority of new patients. PCPs were well versed in certain aspects of DOAC prescribing, however, a number of knowledge gaps were identified. PCPs may benefit from targeted education in these areas to improve patient outcomes in AF.

Venous thromboembolism (VTE), which comprises pulmonary embolus (PE) and deep vein thrombosis (DVT), is a significant cause of postoperative morbidity and mortality. This pilot randomized control trial (RCT) evaluated the feasibility of a full-scale RCT investigating extended thromboprophylaxis in patients undergoing oncological lung resections. Patients undergoing oncological lung resections in 2 tertiary centers received in-hospital, thromboprophylaxis and were randomized to receive post-discharge low-molecular-weight heparin (LMWH) or placebo injections once-daily for 30 days. At 30 days postoperatively, all patients underwent chest computed tomography with PE protocol and bilateral leg venous ultrasound. Primary outcomes included feasibility and safety; VTE incidence and 90-day survival were secondary outcomes. Between December 2015 and June 2018, 619 patients were screened, of whom 62.7% (165/263) of eligible patients consented to participate, and 133 (81%) were randomized. One-hundred and 3 patients, (77.4%), completed the 90-day study follow-up. Reasons for non-participation pre-randomization included patient discomfort and LMWH/placebo administration challenges. Post-randomization withdrawals were due to patient preference, surgeon preference and minor adverse events. Six asymptomatic VTE events (5 PE and 1 DVT) were detected within 30 days (3 in each group), for an overall incidence of 7%. There were 3 minor and no major adverse events. This study is the first to demonstrate the feasibility and safety of a full-scale extended thromboprophylaxis RCT in thoracic surgical oncology. Our results demonstrate that, while recruitment and retention rates were modest, the study design is feasible and with minimal adverse events and no intervention-related mortality.

Background In the PAUSE (Perioperative Anticoagulant Use for Surgery Evaluation) Study, a simple, standardized, perioperative interruption strategy was provided for patients with nonvalvular atrial fibrillation taking direct oral anticoagulants (DOACs). Our objective was to define the factors associated with perioperative bleeding. Methods and Results We analyzed bleeding as the composite of major and clinically relevant nonmajor bleeding. Putative predictors of bleeding, and preoperative DOAC level were prospectively collected during recruitment. We used stratified logistic regression models for analysis. All statistical analyses were performed in R version 3.6.0. There were 3007 patients requiring perioperative DOAC interruption. More than one third of the included patients underwent a high bleeding risk procedure. The 30‐day rates of major and clinically relevant nonmajor bleeding were 3.02% in apixaban (n=1257), 2.84% in dabigatran (n=668), and 4.16% for rivaroxaban (n=1082). Multivariate analysis stratified by region found more bleeding for hypertension (odds ratio [OR], 1.79; 95% CI 1.07‐2.99; P =0.027), and prior bleeding (OR, 1.71; 95% CI, 1.08‐2.71; P =0.021). Surgical bleed risk classification (high‐ versus low‐risk) as a predictor of bleeding was only significant in the univariate analysis. The prediction model for major and clinically relevant nonmajor bleeding had an area under the curve of 0.71, and the preoperative DOAC level did not improve the area under the curve of the model. Conclusions In patients treated with DOACs who required an elective surgery/procedure and were managed with standardized DOAC interruption and resumption, there we did not find reversible risk factors for bleeding, suggesting that adjustment of the PAUSE management protocol to mitigate against bleeding is not needed.

The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study prospectively evaluated a prespecified periprocedural-interruption strategy of direct oral anticoagulants (DOACs) among patients with atrial fibrillation. Logistic regression analyses were performed to identify clinical parameters associated with residual DOAC levels ≥30 ng/mL or ≥50 ng/mL. Patients undergoing low-bleed-risk procedures were more likely to have residual levels of ≥30 ng/mL and ≥50 ng/mL. For low-risk procedures, age ≥75 years, female sex, a creatinine clearance (CrCl)

Essentials The factors influencing anticoagulation management after gastrointestinal bleeding are unclear. Focus groups and a discrete choice experiments survey of health-care providers were conducted. Re-bleeding risk and thrombosis risk were the most important factors influencing decision making. Preference variability exists with a minority most sensitive to the anticoagulation indication. ABSTRACT: Background Oral anticoagulants (OACs) are permanently discontinued in up to 50% of patients after gastrointestinal (GI) bleeding despite evidence of benefit to restarting. Objectives We aimed to identify factors influencing health-care provider decision making regarding resuming OAC after GI bleeding and to identify preference groups. Patients/Methods We conducted focus group discussions (FGDs) with health-care providers. Themes identified and ranked through a dot voting exercise became the attributes for a discrete choice experiment survey of health-care providers developed using Sawtooth (Sawtooth Software, Provo, UT, USA). Hierarchical Bayes analysis was used to estimate preference coefficients (utilities) for each attribute. Preference groups were identified using latent class analysis. Results We conducted four FGDs involving 29 participants. The five most important factors identified in the FGDs were included in the survey. There were 250 survey respondents (mean age 45 years, 53% male). The most important factor was re-bleeding risk followed by thrombosis risk, index bleed severity, indication for OAC, and patient characteristics. Two preference groups were identified, a majority group (87% of respondents) placed the highest utility on re-bleeding risk followed by thrombosis risk, while a minority group (13% of respondents) placed the highest utility on OAC indication. Conclusions Overall, the most important factor influencing provider decision making was re-bleeding risk followed closely by thrombosis risk, although the indication for OAC was most important for a minority of respondents. This highlights variability among providers in an area lacking high-quality data to guide practice. Further research is needed to determine absolute rates of outcomes and patient values and preferences.

Background Oral anticoagulants (OAC) are permanently discontinued in up to 50% of patients after gastrointestinal (GI) bleeding despite ongoing thrombotic risk and evidence of benefit to restarting. The reasons for permanent discontinuation of OAC are unclear, but likely include concerns about re-bleeding and a lack of high-quality evidence. There are no studies evaluating healthcare provider values and preferences following OAC-related GI bleeding and their influence on decision-making about whether and when to resume OACs. Aims We aimed to (i) identify key factors (attributes) that influence healthcare provider decision-making regarding resumption of OAC after GI bleeding, (ii) determine the relative importance of these attributes, and (iii) to identify preference groups. Methods We conducted focus group discussions (FGD) with healthcare providers involved in the care of patients with OAC-related GI bleeding. Participants ranked the relative importance of the attributes identified during the FGD through a dot voting exercise. Transcripts were reviewed and themes (attributes) were identified. Results of the FGD informed a discrete choice experiments survey developed and analyzed using the Sawtooth software platform (Sawtooth Software, USA). The survey was pilot tested and modified by iterative feedback. A sample choice task is shown in Image 1. Hierarchical Bayes analysis was used to estimate preference coefficients (utilities) for each attribute. Latent class analysis was used to identify preference groups. Results There were 4 FGD involving 29 participants. The most important attributes identified and included in the survey were thrombosis risk, indication for OAC, index bleed severity, re-bleeding risk, and patient characteristics. There were 130 survey respondents practicing in hematology (n=68), internal medicine (n=30), gastroenterology (n=7), cardiology (n=4), family medicine (n=3), and others (n=18). The mean age was 45 years (±11) and 51% were male. Thrombosis risk and re-bleeding risk equally had the highest utility followed by index bleed severity, patient characteristics, and indication for OAC. Two preference groups were identified. The dominant preference group (78% of respondents) placed the highest utility on thrombosis risk and re-bleeding risk, while a minority (22% of respondents) placed the highest utility on index bleed severity. Conclusions Thrombosis risk and re-bleeding risk are equally the most important factors influencing OAC resumption following OAC-related GI bleeding. The severity of the index bleed is the most important factor in decision-making for a minority segment of healthcare providers. Further research on the dose, type and timing of OAC resumption is needed to determine the optimal balance between thrombosis and re-bleeding. Funding Agencies Heart and Stroke Foundation

Background In patients who are receiving dabigatran, a direct oral anticoagulant, measuring the anticoagulant effect before surgery may be needed in certain circumstances. Although the dilute thrombin time (dTT) can reliably measure dabigatran levels, it is not consistently available. More commonly used coagulation tests, including the activated partial thromboplastin time (aPTT) and thrombin time (TT) might have clinical utility but their accuracy is uncertain. Methods 103 patients stopped dabigatran 1–4 days before an elective surgery/procedure as part of a standardized dabigatran interruption protocol. With a blood sample taken just before surgery, we assessed the accuracy of five aPTT assays (Actin FS, Stago PTT, C.K. PREST, HemosIL aPTT-SP, SynthASil) and TT to measure the residual anticoagulant effect of dabigatran. We determined the sensitivity, specificity and other accuracy indices of these assays to predict a dabigatran level > 30 ng/mL as determined by a reference standard test, the dTT (Hemoclot). Results Of five aPTT reagents, four assays had excellent (100%) and one assay had good (93%) sensitivity to detect a level of dabigatran > 30 ng/mL, but all had insufficient specificity (50–74%). A TT > 90 s had good sensitivity (93%) and excellent specificity (100%). Conclusion Five aPTT assays had good sensitivity but poor specificity to detect low levels of dabigatran (≤30 ng/mL) after standardized dabigatran interruption before an elective surgery/procedure, thereby limiting the use of aPTT as an alternative to the dTT in preoperative settings.

Essentials The optimal dose and duration of thromboprophylaxis after bariatric surgery are unclear. We evaluated the safety of weight-adjusted tinzaparin prophylaxis in 1212 patients. In-hospital rates of venous thromboembolism and major bleeding were 0.2% and 1.8% respectively. In a sub-set of patients, trough anti-Xa levels did not show excessive anticoagulant activity. Summary Background Patients undergoing bariatric surgery are at moderate to high risk of venous thromboembolism (VTE). The optimal dose and duration of anticoagulant prophylaxis is uncertain. Objective To evaluate the safety of extended-duration weight-adjusted tinzaparin after bariatric surgery. Patients/methods We conducted a single-center retrospective cohort study of consecutive patients undergoing bariatric surgery who received weight-adjusted tinzaparin 4500-14 000 IU daily (75 IU kg-1 rounded to the nearest prefilled syringe) for 10 days after surgery (7-9 days post-hospital discharge). Primary safety outcomes were the frequency of VTE and major bleeding within 30 days of surgery in patients receiving at least one dose of tinzaparin. Results A total of 1279 patients undergoing bariatric surgery between July 2009 and December 2012 were reviewed, of whom 1212 received weight-adjusted tinzaparin. Safety outcomes were collected for 819 patients at 30 days, and for 1212 patients in-hospital only. The median age was 45.0 years, median weight was 130.0 kg and 98.8% of patients underwent gastric bypass or sleeve gastrectomy. In patients completing 30 days of follow-up, VTE occurred in 4/819 (0.5%) and major bleeding occurred in 13/819 patients (1.6%). In-hospital rates of VTE and major bleeding during surgical admission were 3/1212 (0.2%) and 22/1212 (1.8%), respectively. Conclusions Extended thromboprophylaxis with weight-adjusted tinzaparin appears to be a safe strategy after bariatric surgery, with low rates of postoperative VTE and major bleeding.