OBJECTIVE: Direct oral anticoagulants (DOAC) are now considered an effective treatment option for cancer associated thrombosis (CAT). There are still controversies in the use of DOACs in CAT associated with gastrointestinal (GI) malignancies.
BACKGROUND: Patients with GI malignancies and CAT present several unique management challenges. Factors such as the risk of bleeding from intact luminal primary, impact on absorption and efficacy of the DOACs due to altered anatomy, chemotherapy-induced nausea and vomiting, the potential drug to drug interactions need to be considered when prescribing DOACs in CAT associated with GI malignancies.
METHODS: The landmark randomised controlled trials (RCTs), systematic reviews and observational studies (OSs) of real-world data comparing DOACs with low molecular weight heparin (LMWH) in treating CAT comprised heterogeneous groups of tumour sites with limited numbers of patients with GI malignancies. This article reviews the available evidence on outcomes of the subset of CAT associated with GI malignancies in recent RCTs.
CONCLUSIONS: Future prospective trials need to evaluate the impact of the factors mentioned above in the efficacy of DOACs in preventing and treating CATs in specific subsets of GI malignancies. Until more evidence is available, LMWH is a more reasonable choice in selected subgroups of CAT in GI malignancies.

Major cardiovascular (CV) events often complicate the natural history of apparently stable atherothrombotic cardiovascular disease (CVD) despite appropriate guideline-based preventive treatment. This finding has been termed residual risk and it has been the focus of recent investigation. New and revisited targets to tackle this so-called residual risk have been proposed, including antithrombotic treatment intensification, further lowering targets of low-density lipoprotein (LDL) cholesterol, novel oral antidiabetic agents with a CV benefit, and drugs to reduce systemic inflammation. In this narrative review, we discuss the evidence, mechanisms and gaps in knowledge concerning the vascular protection derived from low-dose (2.5 mg twice daily) rivaroxaban. On this topic, the main trials (ATLAS ACS 2-TIMI 51, COMPASS and VOYAGER PAD), will be summarized in a comprehensive manner. Indeed, these have shown that a drug developed to prevent thrombus formation (selective Factor Xa inhibition) reduced events that were traditionally platelet-related in concept. Moreover, we propose a simple evidence-based clinically oriented algorithm to thoroughly identify patients at increased risk and who may benefit from this strategy in different clinical scenarios. Low-dose rivaroxaban portrays a novel promising era in atherothrombotic CVD prevention, providing a mechanistic protection beyond traditional strategies in patients overwhelmed by recurrent dismal events.

Background: Venous thromboembolism (VTE) is highly prevalent in cancer patients. Recent guidelines recommend considering direct oral anticoagulants (DOACs) for the treatment of cancer-associated thrombosis (CAT). However, direct head-to-head comparisons among DOACs are lacking, and almost no net clinical benefit (NCB) analysis has been performed in patients with CAT. Methods: We systematically searched PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) reporting on recurrent VTE, major bleeding, or clinically relevant bleeding events in patients with CAT who received DOACs and low-molecular-weight heparins. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated using a random-effect model. Surface under the cumulative ranking curve (SUCRA) values were calculated, and a trade-off analysis was performed to estimate the NCB. Results: Overall, four RCTs involving 2,894 patients were enrolled. DOACs were more effective than dalteparin in reducing the risk of recurrent VTE (RR: 0.62, 95% CI: 0.44-0.87), with a comparative risk of major bleeding (RR: 1.33, 95% CI: 0.84-2.11) and an increased risk of clinically relevant bleeding (RR: 1.45, 95% CI: 1.05-1.99). No significant difference was observed among individual anticoagulants in terms of recurrent VTE and major bleeding. With respect to the ranking of each anticoagulant for the primary outcome, edoxaban (SUCRA: 69.2) was more effective than dalteparin (SUCRA: 60.7), rivaroxaban (SUCRA: 60.7), and apixaban (SUCRA: 25.5) in reducing VTE recurrence. For major bleeding, apixaban (SUCRA: 76.3) had the highest cumulative ranking probability, followed by edoxaban (SUCRA: 66.4), dalteparin (SUCRA: 28.8), and rivaroxaban (SUCRA: 28.5). Similar results were observed for clinically relevant bleeding. In terms of both benefit and safety outcomes, DOACs, especially edoxaban, seemed to confer a better NCB profile than dalteparin. Conclusions: DOACs are a safe and effective alternative therapy to dalteparin in patients with CAT. Among them, edoxaban might provide a good risk-to-benefit balance. However, because of the lack of head-to-head studies, further investigations are needed to confirm our findings.

The off-label use of direct oral anticoagulants (DOACs) for the treatment of left ventricular thrombi has grown over the past several years given the ease of administration, absence of a requirement for international normalized ratio (INR) monitoring, and freedom from dietary restrictions; however, the evidence for their safety and efficacy is contradictory. We systematically searched PubMed and Google Scholar from January 1, 2009, to April 25, 2020, for studies of DOACs for treatment of left ventricular thrombi. Fifty-three articles (of 1,168 patients) met our inclusion criteria. We found that the studies have reached conflicting results; based on our findings, their routine use for the treatment of left ventricular thrombi cannot be recommended. Adequately powered randomized controlled trials are needed to determine the safest and most effective treatment for left ventricular thrombi.

Background: Venous thromboembolism (VTE) is a common complication in patients with cancer. Direct oral anticoagulants (DOACs) have been proved to be effective on anticoagulation therapy in many diseases. However, the efficacy and the safety of DOACs in the secondary prevention of cancer-associated thrombosis (CAT) remain unclear. To assess the value of DOACs in patients with CAT, we performed a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. Methods: Medline, Embase, and the Cochrane Library were searched from their earliest date through to June 2018. Two investigators independently assessed eligibility. Data were extracted by one investigator and verified by the second investigator. The efficacy outcome of this study was recurrent VTE, whereas the safety outcome was major and clinically relevant nonmajor bleeding. Relative risks (RRs) and their corresponding 95% confidence interval (CI) were determined. To pool the results, the Mantel-Haenszel fixed-effects or random-effects models were used. Results: A total of nine articles (six randomized controlled trials and three prospective studies) involving 2,697 patients with CAT who were prescribed DOACs (apixaban, edoxaban, rivaroxaban, or dabigatran) and 2,852 patients who were prescribed traditional anticoagulants [vitamin K antagonists (VKAs), low molecular weight heparin (LMWH), dalteparin, or enoxaparin] were compared. VTE recurrence in the DOAC group was significantly lower than that observed in the traditional anticoagulant group (RR: 0.60; 95%CI: 0.49-0.75; I 2: 0%; p < 0.00001). No significant difference in bleeding risk between both groups was found (RR: 0.95; 95%CI: 0.67-1.36; I 2: 75%; p = 0.79). Conclusions: Our findings showed that anticoagulant therapy with DOACs may be more effective than traditional anticoagulants to prevent recurrent VTE in patients with CAT, while the safety of DOACs may be equal to that of traditional anticoagulants. These findings support the use of DOACs as the first-line therapy for secondary prevention of CAT in most cancer patients.

To conduct a systematic review of real-world (RWD) studies comparing the risk of major bleeding (MB) among patients with non-valvular atrial fibrillation (NVAF) on direct oral anticoagulants (DOACs) or warfarin.
MEDLINE, Embase, NHS-EED, and EconLit were searched for RWD studies published between January 2003 and November 2016 comparing MB risk among DOACs and warfarin. Proceedings of clinical conferences from 2012 to 2016 were reviewed.
A total of 4218 citations were identified, 26 of which met eligibility criteria. Most studies were retrospective analyses of administrative claims databases and patient registries (n = 23 of 26); about half were based in the United States (n = 15). Apixaban showed a significantly lower risk of MB versus warfarin in all eight included studies. MB risk was either significantly lower (n = 9 of 16) or not significantly different (n = 7 of 16) between dabigatran and warfarin; there was no significant difference between rivaroxaban and warfarin in all seven included studies. The risk was significantly lower with apixaban versus rivaroxaban (n = 7 of 7) but not significantly different from dabigatran (n = 6 of 7). MB risk was significantly lower (n = 3 of 4) or not significantly different (n = 1 of 4) with dabigatran versus rivaroxaban. No evidence was identified for edoxaban.
DOACs were associated with similar or lower risks of MB versus warfarin. A lower MB risk was consistently observed for apixaban, but less consistently for dabigatran; MB risk was similar between rivaroxaban and warfarin. Among DOACs, the risk of MB with apixaban was consistently lower than with rivaroxaban, but similar to dabigatran.