Pathophysiological peculiarities of cancer-associated thrombosis specifying opportunities of therapy with direct oral anticoagulants

Oral Anticoagulants ◽

Individual Treatment ◽

Pharmacological Interactions ◽

Venous Thromboembolic ◽

Long Time ◽

Тромбоз является второй по значимости причиной смертности у онкологических больных. Однако молекулярные механизмы, повышающие предрасположенность онкологических больных к тромбоэмболическим событиям, изучены достаточно плохо. На сегодняшний день рассматривают два основных пути, приводящих к развитию тромбоза. Прямая активация гемокоагуляции и тромбоцитов осуществляется факторами, продуцируемыми или высвобождаемыми из раковых клеток (тканевой фактор, подопланин, тромбоцитарные агонисты, фосфатидилсерин, раковый прокоагулянт и ингибитор активации плазминогена1). В механизме непрямой активации гемокоагуляции участвуют воспалительные цитокины из опухолевых клеток, активирующие тромбоциты, стимуляция нейтрофилов и высвобождение нейтрофильных внеклеточных ловушек. В результате этого происходит выраженная активация тромбоцитов, отложение фибрина и захват эритроцитов, усугубляющие образование сгустков. Наличие нескольких путей тромбообразования у онкологических пациентов снижает эффективность антитромботической терапии. Долгое время для снижения риска венозных тромбоэмболических осложнений (ВТЭО) стандартом дефакто были и пока еще остаются низкомолекулярные гепарины (НМГ). Однако появилось достаточно доказательств из различных рандомизированных клинических исследований в отношении использования пероральных антикоагулянтов прямого действия (ПОАК) для лечения ракассоциированных тромбозов, в том числе с учетом удобства их применения. Рекомендации предлагают применение конкретных ПОАК (ривароксабан и эдоксабан) для онкологических больных с диагнозом ВТЭО, низким риском кровотечений и отсутствием медикаментозных взаимодействий с текущей системной терапией. Наибольшее количество из имеющихся исследований проведено по препарату ривароксабан. Это позволяет составить соответствующий портрет пациента, необходимый для составления индивидуальной схемы лечения ВТЭО ривариксабаном и/или НМГ. Thrombosis is the second leading cause of death in cancer patients. Molecular mechanisms that increase thrombogenicity in cancer patients have been poorly studied. At present two main ways to thrombosis are considered: (1) direct mechanisms through the fact that cancer cells expressed on or released several factors such as tissue factor, podoplanin, platelet agonists, phosphatidylserine, cancer procoagulant and plasminogen activation inhibitor1 (2) indirect mechanism activating hemocoagulation involves inflammatory cytokines from tumor cells, activating platelets, neutrophil stimulation and release neutrophil extracellular traps. As a result there is a pronounced activation of platelets, fibrin deposition and capture of erythrocytes that aggravates clot formation. Acting jointly these two ways lead to reduced effectiveness of antithrombotic therapy in cancer patients. Low molecular weight heparins (LMWH) have been the de facto standard for reducing risk of venous thromboembolic complications (VTE) for a long time and they are still considered that. However a lot of evidence from various randomized clinical trials are appeared about direct oral anticoagulants (DOAC) using for the treatment of cancerassociated thrombosis including topics on the convenience of their administration. Recent guidelines suggest the use of certain DOAC (rivaroxaban and edoxaban) in cancer patients with VTE in cases of low risk of bleeding and the lack of pharmacological interactions with current systemic therapy. Most of the available studies have been conducted with rivaroxaban. That allows to draw sonamed portrait of patient in order to build up individual treatment of VTE with rivaroxaban and/or with LMWH.

Direct Oral Anticoagulants in Cancer Patients. Time for a Change in Paradigm

Cancers ◽

10.3390/cancers12051144 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1144 ◽

Cited By ~ 1

Author(s):

Marek Z. Wojtukiewicz ◽

Piotr Skalij ◽

Piotr Tokajuk ◽

Barbara Politynska ◽

Anna M. Wojtukiewicz ◽

...

Keyword(s):

Cancer Patients ◽

Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Current Evidence ◽

Low Molecular Weight ◽

Treatment And Prevention ◽

Prevention Of Cancer ◽

Selection Of

Thrombosis is a more common occurrence in cancer patients compared to the general population and is one of the main causes of death in these patients. Low molecular weight heparin (LMWH) has been the recognized standard treatment for more than a decade, both in cancer-related thrombosis and in its prevention. Direct oral anticoagulants (DOACs) are a new option for anticoagulation therapy. Recently published results of large randomized clinical trials have confirmed that DOAC may be a reasonable alternative to LMWH in cancer patients. The following review summarizes the current evidence on the safety and efficacy of DOAC in the treatment and prevention of cancer-related thrombosis. It also draws attention to the limitations of this group of drugs, knowledge of which will facilitate the selection of optimal therapy.

Current Recommendations for the Management of Cancer-Associated Venous Thromboembolism

Journal Of Cardiovascular Emergencies ◽

10.2478/jce-2021-0009 ◽

2021 ◽

Vol 7 (2) ◽

pp. 27-38

Author(s):

Katalin Makó

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Cancer Patients ◽

Oral Anticoagulants ◽

Bleeding Risk ◽

Term Treatment ◽

Long Term Treatment ◽

High Bleeding Risk ◽

Abstract Cancer-associated thrombosis (CAT) is a major cause of death in oncological patients. The mechanisms of thrombogenesis in cancer patients are not fully established, and it seems to be multifactorial in origin. Also, several risk factors for venous thromboembolism (VTE) are present in these patients such as tumor site, stage, histology of cancer, chemotherapy, surgery, and immobilization. Anticoagulant treatment in CAT is challenging because of high bleeding risk during treatment and recurrence of VTE. Current major guidelines recommend low molecular weight heparins (LMWHs) for early and long-term treatment of VTE in cancer patients. In the past years, direct oral anticoagulants (DOACs) are recommended as potential treatment option for VTE and have recently been proposed as a new option for treating CAT. This manuscript will give a short overview of risk factors involved in the development of CAT and a summary on the recent recommendations and guidelines for treatment of VTE in patients with malignancies, discussing also some special clinical situations (e.g. renal impairment, catheter-related thrombosis, and thrombocytopenia).

HOW TO TREAT VTEC IN CANCER PATIENTS IN THE ACUTE PERIOD? EXTENDED TREATMENT. THE ROLE OF DIRECT ORAL ANTICOAGULANTS. THE RESULTS OF HOKUSAI VTE CANCER STUDY

Atherothrombosis Journal ◽

10.21518/2307-1109-2018-2-28-35 ◽

2018 ◽

pp. 28-35 ◽

Cited By ~ 1

Author(s):

Yulia A. Fedotkina

Keyword(s):

Cancer Patients ◽

Oral Anticoagulants ◽

Significant Risk ◽

Low Molecular Weight ◽

Efficacy And Safety ◽

Thromboembolic Complications ◽

Cancer Study ◽

Venous Thromboembolic

Cancer is one of the most significant risk factors for venous thromboembolic complications (VTEC). The article discusses the features of the treatment of cancer patients with VTEC. The issues of alternative anticoagulant therapy are considered. The article presents the results of HOKUSAI VTE Cancer study, the first completed study to compare the efficacy and safety of a direct oral anticoagulant endoxaban with a low molecular weight heparin dalterapin for the treatment of VTEC in cancer patients.

Patterns of anticoagulation for atrial fibrillation in cancer patients referred for cardio-oncological evaluation

European Heart Journal ◽

10.1093/ehjci/ehaa946.3269 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Toma ◽

E Rrapaj ◽

S Giovinazzo ◽

M Sarocchi ◽

G Stronati ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cancer Patients ◽

Oral Anticoagulants ◽

Creatinine Concentration ◽

Pharmacological Interactions ◽

Significant Difference ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Background Direct oral anticoagulants (DOAC) are the standard of care for the prophylaxis of non-valvular atrial fibrillation (NVAF)-cardioembolism, but their use in oncological patients has been limited so far. Methods We retrospectively reviewed the records of the patients referred to two cardio-oncology outpatient units between January 2017 and July 2019, and selected those presenting with NVAF, CHA2DS2-VASc ≥1 for men and ≥2 for women, and cancer on active treatment. The following were considered as contraindications to DOAC: severe chronic kidney disease; anti-neoplastic therapy unknown or with potential moderate-to-severe adverse interactions; cirrhosis or liver metastases. Clinical characteristics of patients on DOAC (group 1), on VKA or LMWH with at least 1 contraindication to DOAC (group 2), and on VKA or LMWH despite not having contraindications to DOAC (group 3) were compared by chi-square or ANOVA. Results Of a total of 3,831 patients, 264 (6.9%) met the inclusion criteria (Figure 1). One-hundred fourteen (43.2%) were in group 1, 61 (23.1%) in group 2 (18 on VKA, 43 on LMWH), and 65 (24.6%) in group 3 (27 on VKA, 38 on LMWH). Anticoagulation was omitted in 24 (9.1%) cases for various reasons: spontaneous bleeding (5), anaemia and/or thrombocytopenia (5), frailty (4), CHA2DS2-VASc 1 (3), pharmacological interactions (1), single episode of NVAF (1); and not clearly motivated in 5 subjects. The only significant difference between the 3 groups was serum creatinine concentration (Table 1). Of note, only 10% of subjects in group 1 received an inappropriate DOAC dose, while LMWH was under-dosed for 18% of patients in group 2 and 31% of patients in group 3 (P=0.002). Conclusions In the setting of a dedicated cardio-oncology consultation, DOAC and VKA are most often appropriately prescribed to cancer patients with NVAF. However, there is residual use of LMWH, not infrequently at non-anticoagulant dosage. This is a non-evidence based common practice in clinical oncology that clearly must be abandoned Figure 1 Funding Acknowledgement Type of funding source: None

Efficacy and safety of direct oral anticoagulants for secondary prevention of cancer associated thrombosis: a meta-analysis of randomized controlled trials

Scientific Reports ◽

10.1038/s41598-020-75863-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ruchi Desai ◽

Gautam Krishna Koipallil ◽

Nelson Thomas ◽

Rahul Mhaskar ◽

Nathan Visweshwar ◽

...

Keyword(s):

Major Bleeding ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Efficacy And Safety ◽

Increased Risk ◽

Recurrent Vte ◽

Abstract Direct oral anticoagulants (DOACs) may be good alternatives to low molecular weight heparin (LMWH) or vitamin K antagonists (VKA) for treatment of cancer associated thrombosis (CAT). We conducted a meta-analysis of ten randomized clinical trials to evaluate the efficacy and safety of DOACs in patients with CAT. All had study populations composed in entirety or in part of patients with CAT. The primary outcome (efficacy) was recurrent VTE and the secondary outcomes (safety outcomes) included major bleeding, clinically relevant non-major bleeding (CRNMB), and all bleeding (major bleeding + CRNMB). Participants treated with DOACs had lower risk of recurrent VTE, overall (RR 0.63; 95% CI 0.51–0.79; p < 0.0001), compared to LMWH (RR 0.57; 95% CI 0.40–0.83; p = 0.003), but not compared to VKA (RR 0.69; 95% CI 0.44–1.06; p = 0.09). Compared to LMWH, DOACs showed no difference in major bleeding risk (RR 1.31; 95% CI 0.78–2.18; p = 0.31), though had higher risk of CRNMB (RR 1.60; 95% CI 1.13–2.26; p = 0.008) and all bleeding (RR 1.49; 95% CI 1.10–2.01; p = 0.010). These results indicate that DOACs are more effective than LMWH for prevention of recurrent VTE with CAT though carry an increased risk for non-major bleeding compared to standard of care, LMWH.

Recent Advances in the Management of Cancer-Associated Thrombosis: New Hopes but New Challenges

Cancers ◽

10.3390/cancers11010071 ◽

2019 ◽

Vol 11 (1) ◽

pp. 71 ◽

Cited By ~ 12

Author(s):

Corinne Frere ◽

Ilham Benzidia ◽

Zora Marjanovic ◽

Dominique Farge

Keyword(s):

Cancer Patients ◽

Oral Anticoagulants ◽

Standard Of Care ◽

Primary Prophylaxis ◽

Rapid Onset ◽

Term Therapy ◽

Onset Of Action ◽

Recent Advances ◽

Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients and leads to a significant increase in health care costs. Cancer patients often suffer from multiple co-morbidities and have both a greater risk of VTE recurrence and bleeding compared to non-cancer patients. Anticoagulation is therefore challenging. For many years, long-term therapy with Low-Molecular-Weight Heparin (LMWH) was the standard of care for the management of cancer-associated VTE. Direct oral anticoagulants (DOAC), which offer the convenience of an oral administration and have a rapid onset of action, have recently been proposed as a new option in this setting. Head-to-head comparisons between DOAC and LMWHs for the treatment of established VTE are now available, and data on the efficacy and safety of these drugs for primary prophylaxis of VTE in ambulatory cancer patients receiving systemic anticancer therapy are emerging. This narrative review aims to summarize the main recent advances in the prevention and treatment of cancer-associated VTE, including recent data on the use of individualized factors to stratify the risk of VTE in each individual patient, quality-of-life in patients treated with LMWH, and the place that DOACs will likely take in the cancer-associated VTE management landscape.

Direct oral anticoagulants in patients with cancer

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxz095 ◽

2019 ◽

Vol 76 (14) ◽

pp. 1019-1027

Author(s):

John B Bossaer ◽

Kelly L Covert

Keyword(s):

Atrial Fibrillation ◽

Cancer Patients ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Safety Data ◽

Standard Of Care ◽

Patients With Cancer ◽

Thrombotic Complications

AbstractPurposeThis review summarizes the available evidence concerning direct oral anticoagulant (DOAC) use to treat venous thromboembolism (VTE) in patients with cancer as well as pertinent safety data on the use of DOACs in patients with both cancer and atrial fibrillation.SummaryThe introduction of DOACs into clinical practice changed the way thrombotic complications are managed and prevented in diverse patient populations, including VTE and atrial fibrillation. Low-molecular-weight heparins have been the standard of care for treating VTE in cancer patients due to superiority over vitamin K antagonists in preventing recurrent VTE. Therefore, widespread DOAC use for VTE in patients with active cancer has not been adopted.ConclusionRecent randomized clinical trials (SELECT-D, Hokusai VTE Cancer) have provided evidence that DOACs may have a role in treating VTE in cancer patients.

Primary prophylaxis of venous thromboembolic disease with direct oral anticoagulants in patients with severe inherited thrombophilia

Research and Practice in Thrombosis and Haemostasis ◽

10.1002/rth2.12479 ◽

2021 ◽

Vol 5 (2) ◽

pp. 261-264

Author(s):

Evelien Krumb ◽

Cedric Hermans

Keyword(s):

Oral Anticoagulants ◽

Primary Prophylaxis ◽

Thromboembolic Disease ◽

Venous Thromboembolic Disease ◽

Inherited Thrombophilia ◽

Venous Thromboembolic

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 ◽

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.

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 ◽

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.