In a randomized trial, 1050 patients with cancer who had acute venous thromboembolism were assigned to receive either dalteparin or edoxaban for 6 to 12 months. Edoxaban was noninferior to dalteparin ...with respect to the outcome of recurrent venous thromboembolism or major bleeding.
Abstract
Background
Coronavirus disease 2019 (COVID-19) increases thrombosis in hospitalized patients prompting adoption of different thromboprophylaxis strategies. Safety and efficacy of ...escalated-dose pharmacologic thromboprophylaxis are not established.
Objectives
To determine the pooled incidence of thrombosis/bleeding in hospitalized patients with COVID-19 for standard-dose, intermediate-dose, therapeutic anticoagulation, and no pharmacologic thromboprophylaxis.
Methods
MEDLINE, EMBASE, and Cochrane CENTRAL were searched up to August 29, 2020 for studies reporting pharmacologic thromboprophylaxis and thrombosis or bleeding. Pooled event rates were calculated using a random-effects model.
Results
Thirty-five observational studies were included. The pooled incidence rates of total venous thromboembolism (
N
= 4,685) were: no prophylaxis 41.9% (95% confidence interval CI: 28.1–57.2,
I
2
= 76%), standard-dose prophylaxis 19.8% (95% CI: 13.2–28.6,
I
2
= 95%), intermediate-dose prophylaxis 11.9% (95% CI: 4.3–28.6,
I
2
= 91%), and therapeutic-dose anticoagulants 10.5% (95% CI: 4.2–23.8,
I
2
= 82%,
p
= 0.003). The pooled incidence rates of arterial thrombosis (
N
= 1,464) were: no prophylaxis 11.3% (95% CI: 5.2–23.0,
I
2
= 0%), standard-dose prophylaxis 2.5% (95% CI: 1.4–4.3,
I
2
= 45%), intermediate-dose prophylaxis 2.1% (95% CI: 0.5–7.7,
I
2
= 45%), and therapeutic-dose anticoagulants 1.3% (95% CI: 0.2–8.8,
I
2
= 0,
p
= 0.009). The pooled bleeding event rates (
N
= 6,393) were nonsignificantly higher in therapeutic-dose anticoagulants compared with standard-dose prophylaxis, (6.3 vs. 1.7%,
p
= 0.083).
Conclusion
Thrombosis rates were lower in hospitalized COVID-19 patients who received pharmacologic thromboprophylaxis. Thrombosis and bleeding rates for patients receiving intermediate-dose thromboprophylaxis or therapeutic anticoagulation were similar to those who received standard-dose pharmacologic thromboprophylaxis.
Abstract
In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with ...cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1–4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.
In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit–risk weighting.
Coronavirus disease 2019 (COVID-19) is associated with a prothrombotic state with a high incidence of thrombotic events during hospitalization; however, data examining rates of thrombosis after ...discharge are limited. We conducted a retrospective observational cohort study of discharged patients with confirmed COVID-19 not receiving anticoagulation. The cohort included 163 patients with median time from discharge to last recorded follow-up of 30 days (interquartile range IQR, 17-46 days). The median duration of index hospitalization was 6 days (IQR, 3-12 days) and 26% required intensive care. The cumulative incidence of thrombosis (including arterial and venous events) at day 30 following discharge was 2.5% (95% confidence interval CI, 0.8-7.6); the cumulative incidence of venous thromboembolism alone at day 30 postdischarge was 0.6% (95% CI, 0.1-4.6). The 30-day cumulative incidence of major hemorrhage was 0.7% (95% CI, 0.1-5.1) and of clinically relevant nonmajor bleeds was 2.9% (95% CI, 1.0-9.1). We conclude that the rates of thrombosis and hemorrhage appear to be similar following hospital discharge for COVID-19, emphasizing the need for randomized data to inform recommendations for universal postdischarge thromboprophylaxis.
•Cumulative incidence of overall thrombosis was 2.5% and of bleeding was 3.7% at day 30 after discharge for hospitalization for COVID-19.•These data highlight the importance of a data-driven risk-benefit ratio assessment for postdischarge extended thromboprophylaxis.
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Venous thromboembolism (VTE) is a common complication in patients with cancer. Warfarin has largely been replaced by low-molecular-weight heparin (LMWHs) and direct oral anticoagulants (DOACs) as the ...standard of care in cancer-associated VTE. The survival benefit of these anticoagulants over warfarin in the cancer population has not been demonstrated in clinical trials. There are emerging population-based studies suggesting that warfarin may be associated with improved overall survival in cancers. Warfarin has anti-neoplastic activity mediated through both coagulation pathway -dependent and -independent mechanisms, the latter of which includes inhibition of the Gas6-AXL signaling pathway. Further research is warranted to understand the clinical and laboratory predictors of survival benefit with warfarin. In this review article, we summarize and update the current evidence regarding the potential impact of warfarin on the overall survival of cancer patients and incidence of cancer, as well as review the potential mechanism of such effect and future perspectives.
•Emerging population-based evidence suggests an association of warfarin with improved overall survival in cancer patients.•Anti-neoplastic mechanisms of warfarin include inhibition of thrombin and Gas6 signaling.•Implications for future research include identifying subgroups with improved outcomes.
The study of thrombus formation has increasingly applied in vivo tools such as genetically modified mice and intravital microscopy to the evaluation of molecular and cellular mechanisms of ...thrombosis. Among several unexpected findings of this approach was the discovery that protein disulfide isomerase serves an essential role in thrombus formation at sites of vascular injury. The observation that the commonly ingested quercetin flavonoid, quercetin-3-rutinoside, inhibits protein disulfide isomerase and blocks thrombus formation in preclinical studies has set the stage for clinical trials using protein disulfide isomerase antagonists as antithrombotics. Although the mechanisms by which protein disulfide isomerase facilitates platelet activation and fibrin formation have yet to be elucidated, protein disulfide isomerase antagonists are currently being developed as antithrombotics. This review will consider what is known about the role of protein disulfide isomerase in platelet accumulation and fibrin generation with a focus on pharmacological strategies for blocking protein disulfide isomerase activity in the context of thrombus formation. Potential indications and clinical trial design for testing the efficacy of protein disulfide isomerase inhibition to reduce the incidence of thrombosis will be considered.
Background
Despite the frequency of venous thromboembolism (VTE) in pancreatic cancer, it is inconsistently reported as an adverse event in clinical trials. We hypothesized that reported rates of VTE ...in pancreatic cancer clinical trials are influenced by the objectives of the trial, with higher rates reported in thromboprophylaxis compared with chemotherapeutic trials. We performed a systematic review and meta‐analysis of randomized, controlled trials (RCT) in pancreatic cancer to quantify differences in reported rates of VTE in thromboprophylaxis and chemotherapeutic trials.
Methods
We systematically searched MEDLINE, EMBASE, and Clinicaltrials.gov. Eligible thromboprophylaxis RCTs were required to report rates of thrombosis in non‐anticoagulant pancreatic cancer cohorts. Eligible chemotherapy studies were RCTs evaluating chemotherapy regimens in advanced pancreatic cancer and reported thrombosis as adverse events. Pooled event rates of VTE and arterial thrombosis were calculated using a random‐effects model.
Results
The pooled VTE rate in 13 chemotherapy studies (5694 patients) was 5.9% (95% confidence interval CI, 3.9‐9.0%) compared with 16.5% (95% CI, 11.7%‐23.3%; P < .001) in 9 thromboprophylaxis studies (631 patients). The pooled symptomatic VTE rate from chemotherapy studies was 5.4% (95% CI, 3.5%‐8.3%), which was significantly lower than the pooled rate from thromboprophylaxis studies of 10.5% (95% CI, 7.3%‐14.9%; P = .02).
Conclusion
The VTE incidence reported in chemotherapy RCTs in pancreatic cancer is significantly lower than reported in thromboprophylaxis studies. This finding highlights the underrecognition of VTE in chemotherapeutic trials and emphasizes the need to standardize approaches towards monitoring and reporting of VTE in clinical trials.
Most patients diagnosed with venous thromboembolism (VTE) are currently treated with direct oral anticoagulants (DOACs). Before an invasive procedure or surgery, clinicians face the challenging ...decision of how to best manage DOACs. Should the DOAC be held, for how long, and are there instances where bridging with other anticoagulants should be considered? Although clinical trials indicate that most patients taking DOACs for atrial fibrillation do not require bridging anticoagulation, the optimal strategy for patients with a history of VTE is undefined. In this review, we present a case-based discussion for DOAC interruption perioperatively in patients receiving anticoagulation for management of VTE.
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