Direct Oral Anticoagulant Drugs: On the Treatment of Cancer-Related Venous Thromboembolism and their Potential Anti-Neoplastic Effect

Cancer patients develop a hypercoagulable state with a four- to seven-fold higher thromboembolic risk compared to non-cancer patients. Thromboembolic events can precede the diagnosis of cancer, but they more often occur at diagnosis or during treatment. After malignancy itself, they represent the second cause of death. Low molecular weight heparins are the backbone of the treatment of cancer-associated thromboembolism. This treatment paradigm is possibly changing, as direct oral anticoagulants (DOACs) may prove to be an alternative therapeutic option. The currently available DOACs were approved during the first and second decades of the 21st century for various clinical indications. Three molecules (apixaban, edoxaban and rivaroxaban) are targeting the activated factor X and one (dabigatran) is directed against the activated factor II, thrombin. The major trials analyzed the effect of these agents in the general population, with only a small proportion of cancer patients. Two published and several ongoing studies are specifically investigating the use of DOACs in cancer-associated thromboembolism. This article will review the current available literature on the use of DOACs in cancer patients. Furthermore, we will discuss published data suggesting potential anti-cancer actions exerted by non-anticoagulant effects of DOACs. As soon as more prospective data becomes available, DOACs are likely to be considered as a potential new therapeutic option in the armamentarium for patients suffering of cancer-associated thromboembolism.

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The Role of Direct Oral Anticoagulants in Treatment of Cancer-Associated Thrombosis

Cancers ◽

10.3390/cancers10080271 ◽

2018 ◽

Vol 10 (8) ◽

pp. 271 ◽

Cited By ~ 20

Author(s):

Hanny Al-Samkari ◽

Jean Connors

Keyword(s):

Cancer Patient ◽

Cancer Patients ◽

Patient Population ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Population Data ◽

Standard Of Care ◽

Published Data ◽

Onset Of Action ◽

Recurrent Vte

Venous thromboembolism (VTE) complicates the clinical course of approximately 5–10% of all cancer patients. Anticoagulation of the cancer patient often presents unique challenges as these patients have both a higher risk of recurrent VTE and a higher risk of bleeding than patients without cancer. Although low molecular weight heparins (LMWH) are the standard of care for the management of cancer-associated VTE, their use requires once or twice daily subcutaneous injections, which can be a significant burden for many cancer patients who often require a long duration of anticoagulation. The direct oral anticoagulants (DOACs) are attractive options for patients with malignancy. DOACs offer immediate onset of action and short half-lives, properties similar to LMWH, but the oral route of administration is a significant advantage. Given the higher risks of recurrent VTE and bleeding, there has been concern about the efficacy and safety of DOACs in this patient population. Data are now emerging for the use of DOACs in the cancer patient population from dedicated clinical trials. While recently published data suggest that DOACs hold promise for the treatment of cancer associated VTE, additional studies are needed to establish DOACs as the standard-of-care treatment. Many such studies are currently underway. The available data for the use of DOACs in the treatment of cancer-associated VTE will be reviewed, focusing on efficacy, safety, and other considerations relevant to the cancer patient.

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https://www.cardiologiaambulatoriale.eu/osimertinib-induced-venous-thromboembolism-in-lung-cancer-a-challenging-clinical-case/

CARDIOLOGIA AMBULATORIALE ◽

10.17473/1971-6818-2020-4-7 ◽

2020 ◽

pp. 276-280

Author(s):

Tiziana Leopizzi ◽

Agnese Maria Fioretti

Keyword(s):

Lung Cancer ◽

Deep Vein Thrombosis ◽

Venous Thromboembolism ◽

Cancer Patients ◽

Therapeutic Option ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

T790m Mutation ◽

Vein Thrombosis ◽

Deep Vein

Venous thromboembolism is the second leading cause of mortality among cancer patients, with a 20% incidence, after the progression of cancer itself. In the last two years clinical trials have studied direct oral anticoagulants also in the oncological clinical setting with prom-ising results in efficacy and safety. Osimertinib has been approved for the treatment of EGFR T790M mutation-positive non small cell lung cancer resistant to first- and second-generation EGFR tirosin kinase inhibitors. However, little is known about venous thromboem-bolism induced by osimertinib. Here, we report the case of a woman with lung cancer treated by osimertinib who developed deep vein thrombosis of the common femoral right vein, successfully treated wih edoxaban. In conclusion, on one side deep vein thrombosis is a possible side effect of osimertinib, on the other side edoxaban is a new practical, effective and safe therapeutic option also in active cancer patients.

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Current and Emerging Direct Oral Anticoagulants: State-of-the-Art

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0039-1692703 ◽

2019 ◽

Vol 45 (05) ◽

pp. 490-501 ◽

Cited By ~ 14

Author(s):

Giuseppe Lippi ◽

Robert Gosselin ◽

Emmanuel J. Favaloro

Keyword(s):

State Of The Art ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Disease Patient ◽

Factor X ◽

Anticoagulant Drugs ◽

History Of ◽

Heparin Derivatives ◽

New Generation ◽

New Onset

AbstractAnticoagulant drugs comprise a specific subcategory of antithrombotic agents that act to inhibit blood coagulation at various stages, reducing clot development and ultimately lowering the risk of developing new-onset or recurrent thrombosis. Although the long history of anticoagulant drugs has been characteristically shaped by coumarin and heparin derivatives, a new generation of direct oral anticoagulants (DOACs), which specifically inhibit thrombin or activated factor X, combine many advantages of their progenitor drugs, and hence are prepotently revolutionizing the landscape of antithrombotic therapy. Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766], rivaroxaban [BAY 59–7939]) have already received widespread approval by national or supranational medicinal agencies. This narrative article provides a state-of-the-art for these and for several other DOACs at different stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, nokxaban), and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717, odiparcil, otamixaban, TTP889, and ximelagatran). What clearly emerges from our analysis is that DOACs sharing very similar mechanisms of action are still characterized by different efficacy and safety profiles. This not only depends on biochemical, biological, and pharmacokinetic characteristics, but also on lack of standardization between different clinical trials in terms of targeted disease, patient recruitment, sample size, duration and endpoints, as well as lack of harmonization around procedures used for drug licensing. These factors contribute to challenging the minds of physicians, who may find difficulty navigating their way through multiple indications, different pharmacological profiles, various side effects, and specific drug-to-drug interactions. Such considerations also burden laboratory professionals, who may face organizational and economic challenges in developing and/or implementing multiple assays to assess the pharmacodynamics (effect on coagulation) or pharmacokinetics (drug levels) of DOACs.

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Unplanned pregnancy on a direct oral anticoagulant (Rivaroxaban): A warning

Obstetric Medicine ◽

10.1177/1753495x15621814 ◽

2015 ◽

Vol 9 (1) ◽

pp. 40-42 ◽

Cited By ~ 16

Author(s):

B Myers ◽

R Neal ◽

O Myers ◽

M Ruparelia

Keyword(s):

Inhibitory Action ◽

Unplanned Pregnancy ◽

Case Reports ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor X ◽

Childbearing Age ◽

Factor Ii ◽

Pregnancy And Delivery ◽

In Pregnancy

Direct oral anticoagulants (DOACs or NOACs -non-vitamin K oral anticoagulants), as the name suggests, are oral anticoagulants with a direct inhibitory action either against factor X or factor II (thrombin). Pregnant women were excluded from participating in all the large trials of the DOACs and they are considered contra-indicated in pregnancy and breast feeding. We present a case of inadvertent exposure to rivaroxaban in a woman who presented at 25 weeks' gestation. The management of her pregnancy and delivery is described, and the previous published case reports are reviewed with a discussion about the use of DOACs in woman of childbearing age.

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Treatment Patterns and Clinical Outcomes in Korean Cancer Patients With Venous Thromboembolism: A Retrospective Cohort Study

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029620979575 ◽

2021 ◽

Vol 27 ◽

pp. 107602962097957

Author(s):

Soo-Mee Bang ◽

Jin-Hyoung Kang ◽

Min Hee Hong ◽

Jin-Seok Ahn ◽

So Yeon Oh ◽

...

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Clinical Outcomes ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Events ◽

Factors Associated ◽

Vein Thrombosis ◽

Medical Chart Review ◽

Deep Vein

This study assessed epidemiologic data and clinical outcomes, including venous thromboembolism (VTE) recurrence and bleeding events, in patients with cancer-associated VTE, and assessed factors associated with clinical outcomes. Data were extracted from retrospective medical-chart review of adult patients diagnosed with cancer-associated deep vein thrombosis or pulmonary embolism who received anticoagulation treatment for ≥3 months. Patients were classified by: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and other anticoagulants. First VTE recurrence and bleeding events, and factors associated with their occurrence, were assessed during the initial 6 months of treatment. Overall, 623 patients (age: 63.7 ± 11.3 years, 49.3% male) were included (119, 132, and 372 patients in LMWH, DOACs and other anticoagulants groups, respectively). The cumulative 6-month incidence of VTE recurrence was 16.6% (total), 8.3% (LMWH), 16.7% (DOACs), and 20.7% (other); respective bleeding events were 22.5%, 11.0%, 12.3%, and 30.7%). VTE recurrence and bleeding rates differed only between LMWH and other anticoagulants (HR 2.4, 95% CI: 1.2-5.0 and 3.6, 1.9-6.8, respectively). These results highlight the importance of initial VTE treatment choice for preventing VTE recurrence and bleeding events. LMWH or DOACs for ≥3 months can be considered for effective VTE management in cancer patients.

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ANTICOAGULANT THERAPY IN CANCER PATIENTS WITH ATRIAL FIBRILLATION. CONSIDERING AGE FACTOR

Успехи геронтологии ◽

10.34922/ae.2020.33.1.013 ◽

2020 ◽

pp. 99-106

Author(s):

В. И. Потиевская ◽

А. А. Ахобеков ◽

М. Ф. Баллюзек

Keyword(s):

Atrial Fibrillation ◽

Cancer Patients ◽

Anticoagulant Therapy ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Current Data ◽

Related Factors ◽

Age Related ◽

Liver And Kidney ◽

After Cancer

Рассматривается современное состояние вопроса выбора антикоагулянтной терапии при фибрилляции предсердий (ФП) у онкологических больных. Отмечается, что сложность выбора антикоагулянта при злокачественных новообразованиях (ЗНО) определяется такими факторами, как коморбидные сердечно-сосудистые заболевания, нарушения функции печени и почек, метаболические дисфункции, свойственные, прежде всего, пациентам старшей возрастной группы. Приводятся актуальные данные по оценке риска геморрагических и тромбоэмболических осложнений ФП при ЗНО в аспекте возраста. Обсуждаются возможные причины увеличения риска развития ФП во время и после лечения ЗНО, в том числе и в связи с возраст-ассоциированностью этих патологий. Рассмотрены вопросы выбора антикоагулянтов у пациентов, находящихся на активной противоопухолевой терапии, особенно на препаратах из группы прямых оральных антикоагулянтов (ПОАК). Согласно данным обсервационных исследований, именно ПОАК являются перспективным, относительно безопасным и эффективным выбором для онкологических пациентов с ФП, в связи с чем их применение должно активно изучаться в рандомизированных клинических исследованиях с учетом фактора возраста. Подчеркивается, что подбор схемы антикоагулянтной терапии у пациентов с ФП и ЗНО требует междисциплинарного участия кардиологов и онкологов, а часто и гериатров, чтобы индивидуализировать лечение и предложить наиболее эффективную терапию. The current issue of the choice of anticoagulant therapy of atrial ﬁbrillation (AF) in cancer patients is considered. It is noted that the difﬁculty of choosing an anticoagulant in malignancies is largely determined by age-related factors, such as comorbid cardiovascular diseases, liver and kidney dysfunction, metabolic disorders common for in elderly patients. Current data on the risk assessment of hemorrhagic and thromboembolic complications of AF in cancer patients in the aspect of age presented. During and after cancer treatment, the risk of developing AF can increase, also in connection with the age-associated pathology. Possible reasons of it are discussed. The choice of different anticoagulants groups in patients treated with anticancer therapy, including direct oral anticoagulants (DOAC) is considered. According to available data from observational studies, it is the DOAC that is a promising, relatively safe and effective choice for cancer patients with AF, and therefore their use should be actively studied in randomized trials, considering the factor of age. It is particularly noted that solving this problem requires the interdisciplinary involvement of cardiologists, oncologists, and sometimes, geriatrics, to individualize treatment for each case and to offer the most effective therapy.

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Abstract P146: Comparative Effectiveness Of Direct Oral Anticoagulants Versus Warfarin Among Medicare Beneficiaries With Atrial Fibrillation

Circulation ◽

10.1161/circ.143.suppl_1.p146 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Shirin Ardeshirrouhanifard ◽

Huijun An ◽

Ravi Goyal ◽

Mukaila Raji ◽

Caleb Alexander ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Cancer Patients ◽

Risk Model ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Competing Risk ◽

Secondary Outcome ◽

Systemic Embolism ◽

Competing Risk Model

Objective: Post-hoc analysis of three pivotal clinical trials suggests no difference in risk of ischemic stroke or systemic embolism among cancer patients with atrial fibrillation treated with direct oral anticoagulants (DOACs) vs. warfarin. However, these studies were underpowered and also do not reflect the context of real-world use. We compared the effectiveness of DOACs versus warfarin for the risk of stroke or systemic embolism and all-cause death in patients with NVAF. Methods: We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2009 to 2016 and included patients aged ≥66 years diagnosed with cancer (breast, bladder, colorectal, esophagus, lung, ovary, kidney, pancreas, prostate, stomach or uterus) and NVAF. We limited the cohort to patients who newly initiated warfarin or DOACs (from 2010 to 2016) with no history of ischemic stroke or systemic embolism. The primary outcome was hospitalization due to ischemic stroke or systemic embolism and the secondary outcome was all-cause death. We used Fine and Gray’s competing risk model, while treating death as a competing risk, to determine the association of oral anticoagulants with the incidence of stroke or systemic embolism. We also adjusted the analysis using inverse probability of treatment weighted (IPTW). Additionally, an IPTW-adjusted Cox proportional hazards regression model was constructed for all-cause death. Results: Of 1,028,784 patients with cancer, 158,744 (15.4%) were diagnosed with atrial fibrillation. After applying all inclusion criteria, the final study cohort included 7,334 cancer patients diagnosed with incident NVAF who newly initiated warfarin or DOACs, of which 3,194 (43.6%) used warfarin and 4,140 (56.4%) used DOACs. The unadjusted rate of stroke or systemic embolism was similar among warfarin and DOACs users (1.20 vs. 1.32 cases per 100 person-years, p=0.27). In the IPTW weighted competing risk model, the use of DOACs was not associated with an increased risk of stroke or systemic embolism compared with warfarin users (Hazard Ratio [HR] 1.41, 95% confidence intervals [CI] 0.90-2.20). However, DOACs users had a significantly lower risk of all-cause death compared with warfarin users (HR 0.82, CI 0.74-0.91). Conclusion: Among cancer patients diagnosed with NVAF, DOACs had a similar risk for stroke or systemic embolism compared to warfarin, although DOAC use was associated with reduced risk of all-cause mortality.

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Underdosed Direct Oral Anticoagulants in Atrial Fibrillation Patients Reduce Stroke Severity and Improve Outcome

Cerebrovascular Diseases ◽

10.1159/000520857 ◽

2021 ◽

pp. 1-8

Author(s):

Masaki Naganuma ◽

Yuichiro Inatomi ◽

Toshiro Yonehara ◽

Makoto Nakajima ◽

Mitsuharu Ueda

Keyword(s):

Atrial Fibrillation ◽

Functional Outcomes ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

National Institutes Of Health ◽

Stroke Severity ◽

Anticoagulant Drugs ◽

Scale Scores ◽

Anticoagulant Drug ◽

Ischemic Attack

Background and Purpose: Anticoagulant drugs, including vitamin K antagonist (VKA) and direct oral anticoagulants (DOACs), can reduce stroke severity and are associated with good functional outcomes. Some patients are prescribed lower-than-recommended doses of DOACs; whether these have similar effects has not been clarified. Methods: We retrospectively evaluated 1,139 consecutive ischemic stroke and transient ischemic attack patients with atrial fibrillation. Patients were divided into 5 groups according to their preceding anticoagulant drug therapies: no anticoagulant therapy (ACn), undercontrolling VKA doses (VKAuc), recommended, controlling VKA doses (VKArec), prescribed underdoses of DOAC (DOACud), and recommended doses of DOAC (DOACrec). We investigated the associations between these anticoagulant drug therapies and patients’ initial stroke severity and 3-month outcomes. Results: Median National Institutes of Health Stroke Scale scores at admission were as follows: ACn: 16, VKAuc: 15, VKArec: 9, DOACud: 5, and DOACrec: 7. When the ACn group was used as a reference, regression analysis showed that VKArec (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.01–2.21), DOACud (OR 2.84, 95% CI: 1.47–5.66), and DOACrec (OR 1.83, 95% CI: 1.23–2.74) were associated with milder stroke severity, while VKAuc was not. Median 3-month modified Rankin Scale scores were 2 in the DOACud and DOACrec groups and 4 in all other groups. After adjusting for confounding factors, DOACud (OR 3.14, 95% CI: 1.50–6.57) and DOACrec (OR 1.67, 95% CI: 1.05–2.64) were associated with good 3-month outcomes while VKAuc and VKArec were not. Conclusions: In patients with atrial fibrillation, recommended doses and underdoses of DOACs reduced stroke severity on admission and were associated with good 3-month outcomes.

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Effect of Antithrombotic Therapy on Secondary Bleeding After Proctological Surgery

10.21203/rs.3.rs-27989/v1 ◽

2020 ◽

Author(s):

Ryo Maemoto ◽

Shingo Tsujinaka ◽

Yasuyuki Miyakura ◽

Erika Machida ◽

Nao Kakizawa ◽

...

Keyword(s):

Antithrombotic Therapy ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Individual Risk ◽

Bleeding Rate ◽

Secondary Bleeding ◽

Number Of Patients ◽

Anticoagulant Drugs ◽

The Individual ◽

Median Interval

Abstract Background: The purpose of this study was to identify the incidence and severity of secondary bleeding after proctological surgery for patients with or without antithrombotic therapy.Methods: We retrospectively identified 113 patients who underwent proctological surgery in our hospital from March 2009 to February 2019. In general, antiplatelet drugs were continued and anticoagulant drugs were either substituted or withdrawn prior to the surgery. The severity of secondary bleeding was classified as mild, moderate, severe.Results: Eighteen patients underwent antiplatelet therapy (A group) and 95 patients did not undergo antithrombotic therapy (N group). Secondary bleeding was observed in nine patients (8.0%) and patients in the A group exhibited significantly higher rate of secondary bleeding rate than patients in the N group (39% vs. 2.4%, P < 0.01). The median interval from surgery to the onset of secondary bleeding was 5 (range: 0-11days). The severity of bleeding was the highest in patients administered direct oral anticoagulants (DOAC) and was the lowest in those administered aspirin. There was no mortality or cardiovascular event.Conclusions: Antithrombotic therapy is associated with high risk of secondary bleeding after proctological surgery, particularly in patients who undergo anticoagulant therapy. Delaying of postoperative resumption of anticoagulants may be considered in balancing the individual risk of postoperative thromboembolic complications against the risk of secondary bleeding. Future prospective studies with larger number of patients are needed to determine the appropriate timing of resuming antithrombotic therapy.

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