Apixaban Discontinuation for Invasive Or major Surgical procedures (ADIOS): A prospective cohort study

Background: Apixaban pharmacokinetic properties and some clinical reports suggest cessation 48 hours prior to surgery is safe, but this has not been demonstrated in a naturalistic setting. We sought to measure the residual apixaban exposure in patients who had apixaban held as part of standard of care perioperative management. Methods: This was a prospective, observational study of patients in whom apixaban plasma concentration and anti-Xa activity were measured while at steady state apixaban dosing and again immediately prior to surgery. Clinical management of cessation and resumption of apixaban was at the discretion of the treating physician. Results: Paired blood samples were provided by 111 patients. Ninety-four percent (104/111) of patients had measured apixaban concentrations of ⩽ 30 ng/mL. Only one patient had a value > 50 ng/mL. The median time between the self-reported last dose and presurgery blood sampling was 76 hours (range 32–158) for those who achieved concentrations ⩽ 30 ng/mL and 59 hours (range 49–86) for those > 30 ng/mL. Measured anti-Xa activity correlated well with apixaban exposure. Clinically significant nonmajor bleeding was reported in one patient at 1 week postsurgery. There was one venous thromboembolic event and one stroke in the perioperative period. Conclusion: In a naturalistic setting with a heterogeneous patient population, apixaban discontinuation for at least 48 hours before a procedure resulted in a clinically insignificant degree of anticoagulation prior to a surgical procedure. ClinicalTrials.gov Identifier: NCT02935751

Outcomes of Patients with Extended Anticoagulation Using Low Dose Doacs Compared to Standard Therapeutic Anticoagulation

Background: Reduced or low-dose direct oral anticoagulants (DOACs) have been studied in randomized control trials for the extended prevention of venous thromboembolism (VTE) after 6 months of treatment at the therapeutic doses. The real-world effectiveness as well as utilization of this approach in clinical practice compared to continuing at therapeutic doses is unknown. Aims: Evaluate the efficacy of reduced-dose DOACs compared to standard therapeutic anticoagulation in patients with extended anticoagulation. Methods: Consecutive patients with VTE were identified using the Mayo Clinic VTE Registry from March 1st , 2013 to December 31st, 2020. Patients were followed prospectively for outcomes of VTE recurrence, death, major bleeding and clinically relevant non major bleeding (CRNMB) either in person or by survey. Type of anticoagulation and dose changes were recorded, and progressing to a low dose was treated as an endpoint. In the models relating it to the outcome, it was treated as a time-dependent covariate in the cox models. After completing standard anticoagulation treatment for 3 months with any anticoagulant, patients continuing anticoagulation were divided into two groups: standard therapeutic anticoagulation (any drug) vs those who transitioned to rivaroxaban 10 mg daily or apixaban 2.5mg twice daily any time after 3 months. Patients with recurrent VTE, major or CRNMB during the first 3 months were excluded from further analysis. Results: 219 patients (153 on Apixaban and 66 on Rivaroxaban) were identified in the low dose DOAC and 2521 in the standard anticoagulation group. The mean age was 60.7 years, mean weight was 93.2 Kg and 55.9% were males (Table 1). Patients on low dose DOACs were about the same age and weight compared to standard anticoagulation group. Among all diagnosis categories, patients with active cancer were less likely to be prescribed low dose DOACs (HR 0.56; 95%CI 0.42-0.73; P<0.001), while low dose DOACs prescription was more likely in patients with pulmonary embolism (HR 1.45; 95%CI 1.11-1.89; P=0.007). The median months to start a low dose DOAC after completing the 3 months was 3.1 months with standard deviation of 6.6 months and interquartile range 2.8 months. There was no statistically significant association in the likelihood of going to a low dose group in relation to VTE recurrence (HR 1.36; 95%CI 0.42-4.45; P=0.61) or major bleeding (HR 0.59; 95%CI 0.08-4.37; P=0.61). However, transitioning to low dose DOAC was associated with reduced mortality (HR 0.53; 95%CI 0.35-0.80; P=0.003). Also, patients on low dose DOACs were more likely to have a CRNMB (HR 2.76; 95%CI 1.15-6.62; P=0.02). Conclusion: In this study of patients continuing anticoagulation past 3 months for an initial acute venous thromboembolic event, transitioning to low dose DOACs was not associated with any statistically significant association with VTE recurrence or major bleeding. However, mortality was lower and CRNMB was higher in this unadjusted analysis. Our results show that physicians are not always waiting until 6 months to transition to low doses and low doses are being utilized in cancer patients. Further research is needed to better understand the higher risk for CRNMB identified in this group. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Evaluation of Bivalirudin as the Primary Anticoagulant in Patients Receiving Extracorporeal Membrane Oxygenation for SARS-CoV-2–Associated Acute Respiratory Failure

Background Extracorporeal membrane oxygenation (ECMO) is a potential option for the management of severe acute respiratory failure secondary to COVID-19. Conflicting the use of this therapy is the known coagulopathy within COVID-19, leading to an incidence of venous thrombotic events of 25% to 49%. To date, limited guidance is available on optimal anticoagulation strategies in this population. Objective The purpose of this study was to evaluate the utilization of a pharmacist-driven bivalirudin dosing protocol for anticoagulation in the setting of ECMO for COVID-19–associated respiratory failure. Methods This was a single-center retrospective chart review over a 9-month period of patients receiving bivalirudin while on ECMO. All patients with acute respiratory failure requiring ECMO with a positive SARS-CoV-2 polymerase chain reaction were included. Bivalirudin was dosed via aPTT monitoring after a starting dose of 0.2 or 0.3 mg/kg/h. Results There were 33 patients included in this study, all receiving mechanical ventilation. The most common starting dose of bivalirudin was 0.2 mg/kg/h, with an average time to therapeutic range of 20 hours. Compared to previous reports, rates of bleeding were low at 15.1%, and 6.1% of patients developed a new venous thromboembolic event while on ECMO. ECMO survival was 51.5%, with an ICU mortality rate of 48.5%. Conclusion and Relevance In the first published report of its use within this population, bivalirudin was found to be a viable choice for anticoagulation in those patients on ECMO for severe respiratory failure secondary to COVID-19.

Prevalence of Thromboembolic Complications in COVID-19 Infection: A Systematic Review and Meta-Analysis

Introduction: The coronavirus disease (COVID-19) infection is proved to be involved in the onset of thromboembolism episodes. This study aims to evaluate the prevalence of thromboembolic complications in patients with COVID-19 from March until May 2020. Methods: A literature review was conducted in MEDLINE (via PubMed), Scopus, Embase, Cochrane, and CINHAL without any language and date of publication restriction (Prospero registration number CRD42020186925). The inclusion criteria were as following: 1) patients with diagnosis of COVID-19; 2) occurrence of thromboembolic event, and 3) patients older than 18 years of age. A multi-variable random effects model was computed accounting for correlations among outcomes by considering a heterogeneous compound symmetry covariance matrix. Results: Observational studies included 2,442 participants from 268 to 7,999 participants per study, 1,014 (41.52%) were male and 825 (33.78%) were female. The multi-variable pooled event rate of acute myocardial infarction was rare, estimated to be 0.03 (95% confidence interval [CI]: 0.00–0.07; p=0.23); this is also true for the meta-analytical estimate of disseminated intravascular disease which was 0.04 (95% CI: 0.00–0.08; p=0.03). Conversely, other events were found to be more frequent. Indeed, the pooled proportion of pulmonary embolism was 0.14 (95% CI: 0.08–0.20; p<0.001), while the venous thromboembolic event rate is 0.15 (95% CI: 0.09-0.30; p=0.04). The pooled intrahospital mortality rate was equal to 0.12 (95% CI: 0.08–0.16; p<0.001). Conclusions: Thromboembolic events, particularly venous thromboembolic event rate and pulmonary embolism, are a frequent complication in patients hospitalised with COVID-19. These findings suggest that the threshold for clinical suspicion should be low to trigger prompt diagnostic testing and that evaluation of therapeutic treatment should be considered in patients in intensive care units with COVID-19.

Anticancer drugs associated with venous thromboembolic event: Analysis of the WHO pharmacovigilance database.

3094 Background: Venous thromboembolic event (VTE) is a frequent complication of cancer, as of some classical cancer therapy, like chemotherapy and surgery. The advent of new therapies such as immunotherapy and targeted therapies has meant that new therapies may be associated with VTE. Reliable data concerning the association between ADs and VTE are scarce. Methods: On March 1st, 2020 we utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) to determine the association between the 206 FDA- or EMA-labeled ADs and VTE, defined as deep vein thrombosis and pulmonary embolism. RORs were adjusted (aRORs) on population characteristics including the cancer risk of VTE with the primary tumor site according to Khorana classification and metastatic status. Results: A total of 50,438 VTE cases associated with at least one AD were identified. Thirteen ADs were associated with higher reporting of VTE of which 2 represented new VTE associations not previously confirmed in the summary of product characteristics or literature including sipuleucel-t and megestrol. ADs more reported with VTE were lenalidomide (n:5,796), bevacizumab (n:2,780) and thalidomide (n:1,700). ADs associated-VTE occurred mainly during the first 6 months after AD initiation. Conclusions: Although cancer itself may generate VTE, we identified 13 ADs associated with VTE overreporting. Recognition of AD most likely to cause VTE can help raise practitioner awareness and lead to earlier diagnosis and treatment. Futures studies should include ADs in VTE risk evaluation and evaluate the management of VTE when recurrences occur under AD favoring VTE. ClinicalTrial registration number: NCT04696250.

Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis

BackgroundThe prevalence of venous thromboembolic event (VTE) and arterial thromboembolic event (ATE) thromboembolic events in patients with COVID-19 remains largely unknown.MethodsIn this meta-analysis, we systematically searched for observational studies describing the prevalence of VTE and ATE in COVID-19 up to 30 September 2020.ResultsWe analysed findings from 102 studies (64 503 patients). The frequency of COVID-19-related VTE was 14.7% (95% CI 12.1% to 17.6%, I2=94%; 56 studies; 16 507 patients). The overall prevalence rates of pulmonary embolism (PE) and leg deep vein thrombosis were 7.8% (95% CI 6.2% to 9.4%, I2=94%; 66 studies; 23 117 patients) and 11.2% (95% CI 8.4% to 14.3%, I2=95%; 48 studies; 13 824 patients), respectively. Few were isolated subsegmental PE. The VTE prevalence was significantly higher in intensive care unit (ICU) (23.2%, 95% CI 17.5% to 29.6%, I2=92%, vs 9.0%, 95% CI 6.9% to 11.4%, I2=95%; pinteraction<0.0001) and in series systematically screening patients compared with series testing symptomatic patients (25.2% vs 12.7%, pinteraction=0.04). The frequency rates of overall ATE, acute coronary syndrome, stroke and other ATE were 3.9% (95% CI 2.0% to to 3.0%, I2=96%; 16 studies; 7939 patients), 1.6% (95% CI 1.0% to 2.2%, I2=93%; 27 studies; 40 597 patients) and 0.9% (95% CI 0.5% to 1.5%, I2=84%; 17 studies; 20 139 patients), respectively. Metaregression and subgroup analyses failed to explain heterogeneity of overall ATE. High heterogeneity limited the value of estimates.ConclusionsPatients admitted in the ICU for severe COVID-19 had a high risk of VTE. Conversely, further studies are needed to determine the specific effects of COVID-19 on the risk of ATE or VTE in less severe forms of the disease.

Management of superficial venous thrombosis in unevaluated situations: Cancer, severe renal impairment, pregnancy and post-partum

Background Information is lacking as to the management of patients with superficial venous thrombosis (SVT) whose profile has been excluded from trials, such as patients with active cancer, severe renal impairment, or pregnancy. Objectives To describe the frequency and management of SVT occurring in these situations. Methods We retrospectively analyzed the frequency, management and evolution of all patients with isolated SVT associated with either active cancer, severe renal impairment, or pregnant or postpartum women, diagnosed in 2 university hospital between January 1st, 2015 and December 31st, 2016. Results Of the 594 isolated SVTs individualized from the 7941 reports screened, 149 SVTs (105 in the upper extremity, 44 in the lower extremity) were analyzed: 94 (63%) associated with active cancer, 27 (18%) with severe renal impairment and 30 (20%) pregnant or postpartum women. SVT was treated with anticoagulant in 34 (36%) patients with cancer, 3 (11%) patients with severe renal impairment and 19 (63%) pregnant or postpartum women. At 3-month, 16 patients (10.8%) had a further venous thromboembolic event, 8 (5.4%) major bleeding, and 9 (6.1%) died. Conclusion SVT in patients with active cancer, severe renal impairment and pregnant or postpartum women represents a quarter of isolated SVTs diagnosed. Heterogeneity of treatment patterns mainly affects patients with cancer and severe renal impairment. Poor outcomes, although probably linked to morbidity, call for dedicated research in these specific situations.

COVID-19: Internationale Kooperation für standardisierte Therapieempfehlungen und Forschungsprioritäten

<b>Background:</b> Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. <b>Methods:</b> An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. <b>Results:</b> The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. <b>Conclusions:</b> The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.