Abstract
Thrombosis is a leading cause of mortality in cancer patients. Cancer patients are at an increased risk of developing atrial fibrillation, and venous thromboembolism is a leading cause of mortality, especially in patients undergoing chemotherapy. The anticoagulant strategy to be administered in these cases is particularly difficult to choose due to an altered state of coagulation that makes the balance between hypercoagulation and bleeding risk in anticoagulated cancer patients fragile. Historically, warfarin and even more low molecular weight heparins are the preferred anticoagulant drugs in this population as direct acting anticoagulants, with a more favorable drug profile, have collected less evidence in cancer patients with atrial fibrillation and venous thromboembolism. Recent evidences from retrospective studies and meta-analyses in the literature suggest that direct acting oral anticoagulants may be as effective as vitamin K antagonists and low molecular weight heparins for the prevention of stroke and systemic embolism in patients with atrial fibrillation and cancer, and more interestingly, some randomized clinical trials are already available to compare direct oral anticoagulants and heparins for the treatment of VTE in the cancer population. Due to the clinical interest of the field, this chapter review aims to collect and summarize the most important findings related to the use of direct oral anticoagulants in cancer patients with atrial fibrillation and venous thromboembolism.
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Introduction
Thrombosis is the second leading cause of mortality in cancer patients (Prandoni et al. 2005; Noble and Noble 2006). Venous thromboembolism (VTE) , arterial thromboembolism, and disseminated intravascular coagulation are all possible manifestations of cancer-mediated thrombosis (Levi 2014; Eichinger 2016). Atrial fibrillation (AF) and VTE are two common thromboembolic cardiovascular disease (CVD) largely represented in cancer patients. Several studies showed an increased risk of AF after cancer first diagnosis (O’Neal et al. 2015; Hu et al. 2013; Guzzetti et al. 2002) and VTE is estimated to occur in approximately 20% of cases (Blom et al. 2005; Khorana and Francis 2018; Walker et al. 2013) being one of the leading causes of death in cancer patients receiving chemotherapy (Khorana et al. 2007). Anticoagulation is the main prophylactic and treatment regimen in patients suffering thromboembolic events. A number of risk factors (Mandala et al. 2011) and pathogenetic mechanisms (Falanga et al. 2015) are involved in cancer-mediated thrombosis. Anticoagulation exposes cancer patients to an increased risk of bleeding, especially when compared to anticoagulated non-cancer patients (Hull et al. 2006; Hutten et al. 2000; Meyer et al. 2002; Schulman et al. 2013; Prandoni et al. 2002; Palareti et al. 2000). Therefore, the prophylaxis and treatment management of thromboembolic events is challenging in this subset of patients. In general population direct acting oral anticoagulants (DOACs) are preferred over Vitamin K antagonists (VKAs) for treatment of VTE and stroke prevention in AF (Hindricks et al. 2020; Konstantinides et al. 2020). Little is still known about use of DOACs in cancer patients with AF with evidences only available from retrospective, observational and subgroup analysis of randomized clinical trial (RCTs) and no available specific guidelines (Russo et al. 2019a; Deng et al. 2019; Yang et al. 2020). More data are available for treatment with DOACs in VTE cancer patients. However, major guidelines still recommend low molecular weight heparin (LMWH) for VTE treatment in this subgroup of patients (Farge et al. 2016; Kearon et al. 2016; Lyman et al. 2015) with the exception of rivaroxaban and edoxaban who were directly compared with LMWH (Khorana et al. 2018). Due to the more favorable pharmacological profile of DOACs over VKAs and LMWH, deepening the knowledge in this field is mandatory. For this reason, we aim to review the available data on the use of DOACs in AF cancer patients for stroke prevention and for treatment of cancer-mediated thrombosis.
Use of DOACs in AF Cancer Patients
Literature data for the use of DOACs in AF cancer patients are generally lacking. The main RCTs of DOACs have included a small number of patients with cancer due to reduced life expectancy or an excessively high risk of bleeding in patients with malignancies (Connolly et al. 2009; Granger et al. 2011; Patel et al. 2011; Giugliano et al. 2013).
Recently several studies have explored the role of DOACs in this subgroup of patients (Russo et al. 2019a; Deng et al. 2019; Yang et al. 2020).
From the observational and metanalytical results obtained, it was possible to conclude that DOACs could be a valid alternative to VKAs for stroke prevention in AF cancer patients (Russo et al. 2019a; Deng et al. 2019; Yang et al. 2020).
From the systematic review including six studies by Russo (Russo et al. 2019a) and colleagues emerged that efficacy and safety profile of DOACs in AF cancer patients are maintained when compared to that of general population. Specifically, some interesting results emerge from this descriptive analysis: (a) the annual incidence of bleedings, ischemic stroke, and thromboembolic events in AF cancer patients on DOAC therapy is generally small compared with VKAs (range for bleedings:1.2–4.4% (Melloni et al. 2017; Laube et al. 2017); range for ischemic stroke and thromboembolic events: 0–4.9% (Ording et al. 2017; Russo et al. 2018)); (b) the risk of thromboembolic and bleeding events in AF cancer patients is similar to that of non-cancer patients, irrespective of the treatment they are prescribed (DOACs vs VKAs) (Ording et al. 2017); (c) in DOACs patients, the risk of stroke, thromboembolic, and bleeding complications is similar between cancer and non-cancer patients (Melloni et al. 2017; Ording et al. 2017); and (d) when gastrointestinal bleedings occur, clinical characteristics are similar between those occurring on dabigatran and those on warfarin (hospitalization rate, mean nights in hospital, intensive care unit requirement, transfusion requirement, the need for endoscopic, and surgical intervention) (Russo et al. 2019a; Flack et al. 2017). Details of the studies included in Russo et al. analysis are available in Table 10.1.
Deng and Yang’s working groups separately conducted a meta-analysis of five studies (Deng et al. 2019; Yang et al. 2020) [three post hoc analyses from three RCTs (Melloni et al. 2017; Fanola et al. 2018; Chen et al. 2019), one retrospective propensity score-matched study (Shah et al. 2018), and one retrospective population-based observational data study (Kim et al. 2018)].
The pooled analysis from the three post hoc analyses of the Apixaban Versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial (Melloni et al. 2017), Rivaroxaban Versus Warfarin in Non-valvular Atrial Fibrillation (ROCKET-AF) trial (Chen et al. 2019), and the Edoxaban Versus Warfarin in Patients with Atrial Fibrillation (ENGAGE-TIMI 48) trial (Fanola et al. 2018) in Deng’s metanalysis showed that cancer and non-cancer patients have similar efficacy and safety outcome (all P > 0.05) (Deng et al. 2019). Moreover, results from the analysis of all studies included showed that cancer patients on DOACs had significantly lower risk of stroke/systemic embolism (S/SE) (P = 0.04) and VTE (P < 0.0001) with a trend toward a lower rate of ischemic stroke (P = 0.05). No significant differences were found in risk of myocardial infarction (P = 0.26), all-cause death (P = 0.39), and CV death (P = 0.13). About safety outcomes, use of DOACs was associated with a decreased risk of intracranial or gastrointestinal bleeding (P = 0.04) and a tendency toward statistical significance for a reduced risk of major bleeding (MB) compared with warfarin (RR = 0.73; 95% CI: 0.53–1.00; P = 0.05). Risks of major or clinically relevant nonmajor bleeding (CRNMB) and any bleeding were similar between treatment groups (P = 0.96 and P = 0.39, respectively) (Deng et al. 2019).
Yang et al. conducted a network meta-analysis (NMA) on the same five studies (Yang et al. 2020; Laube et al. 2017; Fanola et al. 2018; Chen et al. 2019; Shah et al. 2018; Kim et al. 2018) to evaluate and rank anticoagulant strategies in AF cancer patients. The rank score used was the surface under the cumulative ranking area (SUCRA) probabilities: the larger the value, the higher the probability of the endpoint event. The NMA showed no significant differences between DOACs regarding outcome (primary efficacy outcome: S/SE; secondary efficacy outcome: all-cause death; incidental VTE was described too), with all DOACs achieving a better efficacy profile compared with warfarin. Rivaroxaban followed by apixaban ranked the first and second best in lowering risk of S/SE followed by dabigatran and edoxaban and finally warfarin (SUCRAs: 25.2%, 29.3%, 52.3%, 55.8%, 87.4%, respectively) (Yang et al. 2020). In addition, apixaban and dabigatran were associated with the lower probability and the better ranking for VTE occurrence (Yang et al. 2020). Regarding safety outcomes (MB according to the International Society on Hemostasis and Thrombosis (ISTH) criteria (Schulman et al. 2010)), no statistically significant differences were found between treatment groups with the exception of apixaban which was found safer than warfarin (OR 0.39, 95% CI: 0.18–0.79, SUCRA:4.9%) (Yang et al. 2020) .
Table 10.2 shows principal characteristics and results of the five studies included in the abovementioned metanalyses while Table 10.3 summarizes results of Deng and Yang’s studies.
VTE in Cancer Patients: Are the DOACs Always the Best Choice?
VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication of cancer, and its prevention and treatment is a challenge because of the drug interactions and varieties of coexisting comorbidities (Khorana 2010). According to a large observational cohort study, the incidence of VTE in active cancer patients is 5.8 per 100 person-years (Cohen et al. 2017). Cancer patients are usually in a state of hypercoagulability that results from various factors, including the type of malignancy, extent of disease, patient age, antitumor treatment, and the presence of coexisting diseases (Zwicker et al. 2007). The highest rate of VTE was observed among patients receiving systemic cancer therapy for tumors of the pancreas, stomach, or lung (Khorana et al. 2007; Blom et al. 2006; Chew et al. 2006; Lyman et al. 2013). VTE is an important cause of death in cancer patients as it is second only to tumor progression (Khorana et al. 2007). VTE can lead to a series of comorbidities, such as longer hospitalization, higher risk of bleeding, and delay or discontinuation of chemotherapy, which may affect patients’ quality of life and prognosis (Carrier and Lee 2014). For these reasons, the choice of the best anticoagulation therapy is mandatory for this group of patients.
Primary Prevention of VTE in Cancer Patients
Pharmacological prophylaxis can reduce VTE incidence, but it may also increase the risk of bleeding (Agnelli et al. 2009; Khorana et al. 2017). According to existing research, the most commonly used anticoagulant drugs are LWMH and warfarin. Many large RCTs have demonstrated the efficacy and safety of anticoagulants to reduce the incidence of VTE events in ambulatory cancer patients. The PROTECHT study, involving 1150 patients, has shown that nadroparin reduces the incidence of VTE events without significantly increasing bleeding risks (Agnelli et al. 2009). The SAVE ONCO study involving 3212 patients has shown similar results using the ultra-LMWH semuloparin (Agnelli et al. 2012). However, current guidelines do not recommend the routine thromboprophylaxis in patients receiving chemotherapy (Lyman et al. 2015; https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf) . A systematic review published in the Cochrane Library has indicated some positive results for thromboprophylaxis, but routine thromboprophylaxis is not indicated in ambulatory cancer patients, and the evaluation of the risks and benefits is necessary before its prescription in high-risk patients (Di Nisio et al. 2016). The risk differs among cancer patients, and the Khorana risk score allows for identification of patients with cancer at increased risk for VTE (Khorana et al. 2008).
In recent years, DOACs have played an increasingly important role in clinical practice (Russo et al. 2015, 2019a, b; Russo et al. 2020a, b, c, d). DOACs have been shown to be safe, effective, and well tolerated for VTE among non-cancer patients (Agnelli et al. 2013; Prins et al. 2013). RCTs comparing DOACs with placebo have been performed for primary prophylaxis in cancer patients with inconstant results for the incidence of VTE events and bleeding complications (Khorana et al. 2019; Carrier et al. 2019). Studies of thromboprophylaxis with LMWH in ambulatory patients with cancer have demonstrated that anticoagulation is associated with a significant relative risk reduction in VTE, but current clinical guidelines do not recommend routine outpatient VTE prophylaxis (except for multiple myeloma and select high-risk solid tumors), because the overall benefit-to-risk profile in an unselected patient population is uncertain (Khorana et al. 2019; Carrier et al. 2019). CASSINI trial (Khorana et al. 2020) is a randomized clinical study that compares the efficacy and safety of rivaroxaban with placebo in the prevention of VTE in high-risk ambulatory patients with cancer receiving systemic cancer therapy, as determined by the validated Khorana risk score. This study confirms the benefit of rivaroxaban in thromboprophylaxis, but only after determining the risk/benefit of anticoagulation in high-risk patients with cancer (Khorana et al. 2020).
Also, apixaban was tested in this setting in the AVERT trial (Carrier et al. 2019). Apixaban therapy resulted in a significantly lower rate of VTE than placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of MB episodes was higher with apixaban than with placebo (Carrier et al. 2019).
High-risk outpatients with cancer (Khorana score of 2 or higher prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or LMWH provided there are no significant risk factors for bleeding and no drug interactions (Lyman et al. 2015). Consideration of such therapy should be accompanied by a discussion with the patient about the relative benefits and harms (Lyman et al. 2015).
At present, no anticoagulant is approved for routinely primary thromboprophylaxis in outpatients with cancer.
Treatment of VTE in Cancer Patients
In the general population, the efficacy and safety of DOACs in the long-term therapy of VTE were demonstrated in six large randomized trials (RECOVER I-II; EINSTEIN-TVP, EINSTEIN-TEP; AMPLIPHY; HOKUSAI TEV). Post hoc analysis and meta-analysis suggested efficacy and safety of DOACs in patients with cancer, but these patients were underrepresented, not well identified for the type of oncological diagnosis and treatment, and finally the definition of “active cancer” varied greatly from one study to another.
Recent randomized trials have investigated the efficacy of DOACs among cancer patients with VTE (Agnelli et al. 2020; Raskob et al. 2018; Young et al. 2018; McBane et al. 2020). These trials have some limitations: one was a pilot trial (Young et al. 2018), whereas another small trial was prematurely terminated (McBane et al. 2020). Moreover, the two large studies were noninferiority trials and not powered to evaluate the safety of DOACs in this setting (Agnelli et al. 2020; Raskob et al. 2018). The Table 10.4 summarizes the most important characteristics of these studies.
Furthermore, a sub-analysis of the HOKUSAI-VTE cancer study has evaluated the occurrence of the composite outcome, recurrent VTE, or MB in subgroups based on adjudicated cancer diagnoses, including those with gastrointestinal, lung, urogenital, breast, hematological, and gynecological cancer. In the gastrointestinal cancer group, the benefit–risk trade-off requires careful evaluation because edoxaban was associated with an absolute 9.2% increase in MB compared with dalteparin. The absolute risk of recurrent VTE was 3.9% numerically lower with edoxaban. Oral edoxaban is an attractive alternative to subcutaneous dalteparin for the treatment of the majority of patients with cancer-associated VTE, including those with urogenital, lung, breast, hematological, and gynecological cancer (Mulder et al. 2020).
Based on the currently available evidence, the guidelines of European Society of Cardiology and of American Society of Clinical Oncology (Konstantinides et al. 2020; Lyman et al. 2015) recommend that patients with VTE and cancer, particularly those with gastrointestinal cancer, should be encouraged to continue LMWH for 3–6 months. This also applies to patients in whom oral treatment is unfeasible due to problems of intake or absorption, and to those with severe renal disease. In all other cases, the choice between LMWH and edoxaban or rivaroxaban (the publication of the CARAVAGGIO trial on apixaban in this setting is subsequent to the guidelines) is left to the discretion of the physician and the patient’s preference. Owing to the high risk for recurrence, patients with cancer should receive indefinite anticoagulation after a first episode of VTE. Renal function and drug–drug interaction should be checked prior to using a DOAC.
Discussion
Compared to warfarin , DOACs have a more predictable anticoagulant effect with a more favorable pharmacological profile, so that they are the first-line anticoagulant treatment proposed in the general population affected by AF and VTE (Hindricks et al. 2020; Konstantinides et al. 2020). Cancer patients are a subgroup of patients with a delicate balance between hemorrhagic and thrombotic risk, so it is essential to choose the right anticoagulation and the time to start it; on the other hand, particular attention is needed for the greater risk of bleeding of the cancer patients during anticoagulant treatment compared to the general population (Hull et al. 2006; Hutten et al. 2000; Meyer et al. 2002; Schulman et al. 2013; Prandoni et al. 2002; Palareti et al. 2000; Hindricks et al. 2020). Especially for AF cancer patients, evidences are rare and sparse. There are no RCTs available that directly compare DOACs to warfarin in this subgroup of patients and results emerge only from retrospective analysis of RCTs (Melloni et al. 2017; Flack et al. 2017; Fanola et al. 2018; Chen et al. 2019) and from very small studies (Russo et al. 2018, 2019a; Deng et al. 2019; Yang et al. 2020; Laube et al. 2017; Shah et al. 2018; Kim et al. 2018; Ianotto et al. 2017). However, in August 2019, the ISTH guidelines recommended the use of DOAC over VKAs and LMWH in cancer patients receiving chemotherapy with newly diagnosed NVAF (Delluc et al. 2019) with the exception of patients with gastrointestinal cancer or the presence of gastrointestinal abnormalities that can lead to gastrointestinal bleeding events. More evidence is currently available on the use of DOACs in VTE cancer patients. Rivaroxaban, edoxaban, and recently apixaban were compared directly with LMWH for the treatment of VTE in cancer patients, demonstrating noninferiority in lowering the rate of VTE recurrence but with some concern for bleeding events (Khorana et al. 2019; Carrier et al. 2019; Raskob et al. 2018). Indeed, a higher risk of CRNMB mainly driven by gastrointestinal bleeding events was evidenced with DOAC in cancer patients and VTE, but such events were almost entirely referable to gastrointestinal cancer patients, which is why guidelines still suggest the use of LMWH in patients with gastrointestinal tumors or gastrointestinal abnormalities that may increase the risk of bleeding events.
Conclusion
DOACs are a revolutionary anticoagulation treatment. Several preliminary evidences suggest their effectiveness and safety in AF cancer patients but RCTs should improve these findings. Currently it is better defined their role in VTE cancer patients even if some concern still remains for their safety profile especially in gastrointestinal malignancies and above all for thromboprophylaxis for which no defined recommendations are available due to the paucity of targeted evidences.
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Bottino, R. et al. (2021). Direct Oral Anticoagulation in Cancer Patients. In: Proietti, R., AlTurki, A., Ferri, N., Russo, V., Bunch, T.J. (eds) Direct Oral Anticoagulants. Springer, Cham. https://doi.org/10.1007/978-3-030-74462-5_10
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