Use of Direct Oral Anticoagulants in Patients with Cancer: Practical Considerations for the Management of Patients with Nausea or Vomiting

The consensus recommendations outlined in this review provide a useful reference for health care professionals and will help to improve the management of anticoagulation in patients with venous thromboembolism, atrial fibrillation, and cancer who are at risk of nausea and vomiting.

Abstract

Direct oral anticoagulants (DOACs) have proven efficacy and safety and are approved for use in the prevention and treatment of thromboembolic events in patients with venous thromboembolism (VTE) and those with atrial fibrillation (AF). There is no clear guidance on the use of DOACs in the significant proportion of these patients who have or will develop concomitant cancer. The occurrence of nausea and vomiting in these patients, despite implementation of guideline‐recommended antiemetic strategies, is a particular concern because it may affect oral drug intake and consequently outcomes with anticoagulation therapy.

Here, we review recent data on the incidence and management of cancer‐associated nausea and vomiting and the current evidence and guidance relating to the use of DOACs in patients with cancer. On the basis of this evidence, an international working group of experts in the fields of cancer‐associated thrombosis/hemostasis, hematology, and oncology discussed key issues related to the use of DOACs in patients with VTE or AF and cancer who are at risk of nausea and vomiting and developed some consensus recommendations. We present these consensus recommendations, which outline strategies for the use and management of anticoagulants, including DOACs, in patients with VTE or AF and cancer for whom oral drug intake may pose challenges. Guidance is provided on managing patients with gastrointestinal obstruction or nausea and vomiting that is caused by cancer treatments or other cancer‐related factors.

The recommendations outlined in this review provide a useful reference for health care professionals and will help to improve the management of anticoagulation in patients with VTE or AF and cancer.

Implications for Practice.

Direct oral anticoagulants (DOACs) offer several advantages over traditional anticoagulants, including ease of administration and the lack of need for routine monitoring. However, the management of patients with an indication for anticoagulation and concomitant cancer, who are at high risk of thromboembolic events, presents several challenges for administering oral therapies, particularly with regard to the risk of nausea and vomiting. In the absence of robust data from randomized trials and specific guidelines, consensus recommendations were developed for healthcare professionals regarding the use of DOACs in patients with cancer, with a focus on the management of patients who are at risk of nausea and vomiting.

Introduction

Direct Oral Anticoagulants

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, have been shown to be as effective as the vitamin K antagonist (VKA) warfarin for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF) and for the treatment and secondary prevention of venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. The balance between thrombosis prevention and the risk of bleeding is also a key consideration in anticoagulation therapy. DOACs are associated with fewer bleeding events than VKAs [1], [2], [3], [4], [5], [6], [7], [8], [9], [10] and have a rapid onset of action as well as predictable and stable pharmacokinetics and pharmacodynamics, with no need for routine dose monitoring [11]. These favorable attributes, combined with the positive results from large‐scale clinical trials, have led to DOACs being recommended in major guidelines for patients with AF and individuals with VTE [12], [13], [14], [15].

Epidemiology of Concomitant Cancer and VTE/AF

Incidences of AF, VTE, and cancer all increase with age, meaning that a significant proportion of patients with VTE or AF, many of whom will be receiving DOACs, have or develop cancer [16], [17], [18], [19], [20], [21]. In patients with idiopathic or unprovoked VTE, the reported incidence of cancer ranges from 3.1% to 9.4% over a period of 1 to 2.5 years [16], [17], [18], [19], [20], [21]. Although the incidence of cancer is less well documented in patients with AF than in patients with VTE, a recent cohort study reported a 1‐year cancer incidence of 4% in Danish patients with new‐onset AF [22].

There is also evidence for an increased risk of VTE and AF in patients with cancer, probably as a result of the cancer inducing a hypercoagulable state [23], [24], [25]; indeed, approximately 20% of all VTE cases occur in patients with cancer, and thromboembolism is the second leading cause of death in patients with malignancy [26], [27], [28]. The reported overall incidence of VTE in patients with different types of cancer is 4% to 8%, with exact incidences depending on disease‐, treatment‐, and patient‐specific factors [29], [30], [31], [32]. AF has also been found to occur with increased frequency in patients with malignancies compared with individuals who do not have cancer [33], and the most frequent form of cancer‐related AF occurs postoperatively [25], [34], [35].

Anticoagulation Strategies in Patients with Concomitant Cancer and VTE or AF

The current standard of care for patients with cancer and VTE is low‐molecular‐weight heparins (LMWHs) [36], [37], [38]. However, LMWHs have several associated disadvantages, including high cost and daily subcutaneous injections, which adversely impact patients’ quality of life [39].

DOACs could be a favorable alternative to LMWHs in cancer‐associated VTE because of their relative ease of administration, and first evidence indicates that DOACs are already being used in patients with cancer and VTE [40], [41], [42], [43], [44]. There is no established guidance for anticoagulation management of AF specific to patients with active cancer. For these patients, there is no evidence‐based alternative to oral anticoagulants. DOACs may be a reasonable anticoagulant choice in patients with cancer, given that they do not need frequent laboratory monitoring and are much less sensitive to dietary changes or drug interactions than VKAs, and less costly and burdensome than LMWHs. However, the reliance of DOACs on oral intake and gastrointestinal absorption means that their efficacy may be affected by both the symptoms of cancer and any associated treatments [45]. Nausea and vomiting, frequent side effects of cancer and cancer treatments [46], are a particular concern because they may affect the administration and/or absorption of DOACs, thereby increasing the risk of thromboembolic events. Currently, an individualized approach to the treatment of patients receiving anticoagulation therapy for VTE or AF and with concomitant cancer is recommended [25]. Therefore, it is essential that physicians are equipped with knowledge and guidance on how to manage patients in this challenging clinical group.

DOACs may be a reasonable anticoagulant choice in patients with cancer, given that they do not need frequent laboratory monitoring and are much less sensitive to dietary changes or drug interactions than VKAs and less costly and burdensome than LMWHs. However, the reliance of DOACs on oral intake and gastrointestinal absorption means that their efficacy may be affected by both the symptoms of cancer and any associated treatments.

This review is intended to: assess available evidence on the magnitude of the problem of nausea and vomiting in patients with cancer and the effectiveness of current treatments for nausea and vomiting in these patients; review data, recent guidelines, and current prescribing practices regarding the use of DOACs in patients with VTE or AF and cancer; and develop consensus recommendations for the use and management of DOACs in patients with cancer who are at risk of, or experiencing, nausea and vomiting.

Materials and Methods

Literature Searches

In developing this nonsystematic review article, searches of MEDLINE and Embase were performed in Ovid to identify recent relevant articles published between January 2010 and January 2017. Searches used various combinations of terms for cancer, nausea and vomiting, AF, VTE, and anticoagulants. Searches of PubMed and specialist society websites were also performed to retrieve current guidelines relating to the use of DOACs in patients with VTE or AF, articles describing current prescribing practices for DOACs, and articles reporting pharmacokinetic or pharmacodynamic data on DOACs. Key reviews were also checked to identify any additional relevant articles. In addition, a search of ClinicalTrials.gov was conducted to identify ongoing clinical trials of DOACs in populations of patients with concomitant VTE or AF and cancer.

Development of Recommendations

An international working group that included physicians, nurses, and scientists with expertise in the fields of cancer‐associated thrombosis/hemostasis, hematology, and oncology was assembled. This multidisciplinary group reviewed all of the evidence and identified and discussed key issues relevant to the management of patients with VTE or AF and cancer being treated with DOACs. To reduce bias, finalized questions were circulated to individual group members, and each member provided independent written responses. These responses were then collated, and consensus recommendations were developed, refined, and finalized after discussions between group members.

Nausea and Vomiting in Patients with Cancer—Incidence and Current Management Strategies

Nausea and vomiting are common symptoms in patients with cancer [47], [48]. The overall incidence of nausea and vomiting in patients with cancer is difficult to estimate because a large number of treatment‐, disease‐, and patient‐related factors affect the risks of these events [49], [50], [51], [52], [53], [54], [55].

Cancer‐associated nausea and vomiting can be broadly classified into cases that are treatment‐related and those that occur as a result of the cancer itself (Table 1) [56]. Treatment‐related nausea and vomiting can be caused by chemotherapy, radiotherapy, and other treatments, such as opioids and anesthesia during surgery [49], [57], [58], and causes of cancer‐related nausea and vomiting include physical obstruction caused by tumors or functional obstruction due to reduced gastrointestinal motility [59], [60], [61].

Table 1. Categories of cancer‐associated nausea and vomiting.

Abbreviations: —, Not applicable; CINV, chemotherapy‐induced nausea and vomiting; GI, gastrointestinal; N/V, nausea and vomiting; RINV, radiotherapy‐induced nausea and vomiting.

The reported incidence of chemotherapy‐ and radiotherapy‐induced nausea and vomiting is highly variable, as it is influenced by the specific chemotherapeutic agents, dosing regimen of the agents, schedule and route of administration of the agents, and target of the radiation therapy, in addition to patient‐related factors [62]. According to the National Cancer Institute, chemotherapies can be classified as high risk (emesis occurs in >90% of patients), moderate risk (emesis in 30%–90% of patients), and low risk (10%–30% of patients) [63]. In patients undergoing conventional external radiotherapy regimens, the overall incidence of nausea and vomiting is estimated to be 50% to 80% in the absence of prophylactic antiemetic therapy [64].

Supplemental online Table 1 provides a summary of primary studies that have evaluated the incidence of nausea and vomiting associated with chemotherapy and radiotherapy, as well as that reported for pain medication, following surgery, and related to cancer itself.

Antiemetic Therapies

There have been substantial advances in antiemetic strategies in the last 2 decades because of the elucidation of new therapeutic targets and licensing of agents targeting different pathways involved in emesis.

The principal classes of antiemetic agents globally now include neurokinin‐1 (NK₁) receptor antagonists [65], 5‐hydroxytryptamine type 3 (5‐HT₃) inhibitors [66], steroids (usually dexamethasone) [67], and dopamine receptor antagonists (metoclopramide and prochlorperazine) [68]. Recent advances in the management of nausea and vomiting include the development of second‐generation 5‐HT₃ inhibitors, which appear to be more effective than first‐generation agents [69], [70] and triple‐combination therapy [71], [72].

Recent guidelines for the prevention and treatment of nausea and vomiting in patients with cancer show broad agreement between cancer societies on key principles [62], [73], [74] (supplemental online Table 2). There are evidence‐based guidelines that advise on antiemetic therapies for the control of chemotherapy‐induced nausea and vomiting (supplemental online Table 3) and radiation‐induced nausea and vomiting (supplemental online Table 4) and for the treatment of nausea and vomiting in patients with advanced cancer or in those taking opioids (supplemental online Table 5). Studies have shown that conformity to guideline‐recommended therapies can decrease the risk of nausea and vomiting in susceptible individuals [75], [76], [77]; however, availability of therapies can vary among countries, and adherence to antiemetic therapies is frequently suboptimal [78], [79]. Interventions such as the use of computer‐based prescribing, increased physician awareness of antiemetic guidelines, and improved patient‐physician communication may help to improve adherence rates in the future [78], [80], [81].

The advances in therapies and the availability of comprehensive, evidence‐based guidelines have allowed for significant improvements in the management of nausea and vomiting in patients with cancer. Nevertheless, there remain considerable unmet needs, particularly for chemotherapy‐induced nausea [82], [83]; this has implications not only for patient compliance with and willingness to undergo chemotherapy [83], but also for the potential for reduced absorption (and therefore efficacy) of orally administered drugs, an effect that is particularly pertinent for short‐acting drugs that must be given frequently to maintain therapeutic levels.

DOACS in Patients with VTE or AF and Cancer

Efficacy and Safety of DOACs in Patients with Cancer

There are limited data from large‐scale randomized studies on the efficacy and safety of DOACs in patients with VTE or AF and concomitant cancer. In the pivotal phase III trials of DOACs versus standard of care in patients with VTE, the proportion of patients with active cancer was low, ranging from 1.7% to 9.4% (supplemental online Table 6) [5], [6], [7], [8], [9], [10], [84], [85], [86], [87]. It is also worth noting that the patients with cancer in these randomized controlled trials (RCTs) were those with stable cancer who did not have characteristics typical of many individuals with cancer, such as frequent hospitalizations, low platelet counts, and mucositis. In the pivotal phase III trials of DOACs versus warfarin in patients with AF, patients with cancer were excluded (supplemental online Table 6) [1], [2], [3], [4], [88], [89], [90].

Two observational studies and a subanalysis of RCT data have specifically investigated the effect of cancer on the efficacy and safety of DOACs, with findings suggesting similar safety and efficacy of these therapies in patients with and without cancer (Table 2) [40], [41], [91]. In a 12‐week phase II pilot trial in patients with metastatic cancer undergoing chemotherapy, treatment with apixaban for primary prevention of VTE was well tolerated, with an incidence of major bleeding similar to that observed with placebo [42].

Table 2. Efficacy and safety of DOACs in patients with cancer.

Abbreviations: AMPLIFY, Apixaban for the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis as First‐Line Therapy; CI, confidence interval; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; EINSTEIN‐DVT, Oral, Direct Factor Xa Inhibitor Rivaroxaban in Patients with Acute Symptomatic Deep Vein Thrombosis; EINSTEIN‐PE, Oral, Direct Factor Xa Inhibitor Rivaroxaban in Patients with Acute Symptomatic Pulmonary Embolism; HR, hazard ratio; LMWH, low‐molecular‐weight heparin; OR, odds ratio; PE, pulmonary embolism; RCT, randomized controlled trial; RR, relative risk; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Several subanalyses and meta‐analyses of data from RCTs have found similar efficacy and safety outcomes with DOACs and VKAs or standard therapy in patients with cancer [44], [92], [93], [94], [95], [96], [97], [98], [99] (Table 2). In a large‐scale meta‐analysis, Brunetti et al. compared the efficacy and safety of DOACs with those of conventional treatment with either a VKA (seven trials) or LMWH (two trials) in 1,952 patients with VTE and cancer [97]. The results showed similar efficacy and safety of DOACs compared with conventional therapy, with a nonsignificant reduction of 20% in the incidence of recurrent VTE in patients taking DOACs. When DOACs were compared with VKAs and LMWHs separately, DOACs were associated with higher rates of bleeding than LMWHs but were found to be as effective as and to have a similar safety profile to VKAs [97]. Data from retrospective or observational studies in patients with cancer and VTE seem to indicate that DOACs have a similar efficacy and tolerability profile (including the risk of major bleeding) to LMWHs (Table 2) [99], [100], [101], [102], [103]. The vast majority of these clinical data was collected when specific reversal agents for the DOACs were not available. For dabigatran, a specific antibody for reversal (idarucizumab) is now available, and for the factor Xa inhibitors, a reversal agent (andexanet alfa) is undergoing clinical evaluation [104]. The availability of effective DOAC reversal agents with favorable safety profiles may further improve outcomes in patients with cancer who develop bleeding while receiving DOACs.

Robust data from RCTs comparing DOACs with LMWH in patients with VTE and cancer are expected to be published in the near future. Trials comparing the efficacy and safety of apixaban (ClinicalTrials.gov identifier NCT02585713) and rivaroxaban (ClinicalTrials.gov identifier NCT02583191) with those of a LMWH in cancer‐associated VTE are ongoing, with completion of the studies expected in 2018. First study results for edoxaban in patients with cancer and VTE (Hokusei VTE‐Cancer; ClinicalTrials.gov identifier NCT02073682; n = 1,050) were presented at the 2017 American Society of Hematology Annual Meeting and demonstrated noninferiority of edoxaban compared with the LMWH dalteparin for the composite primary endpoint of first recurrent VTE and major bleeding [105]. The results of a pilot trial with rivaroxaban (Select‐d; n = 406) were presented at the same meeting. Select‐d is part of the CALLISTO program, which was initiated in 2015 and consists of a total of nine studies evaluating rivaroxaban for the prevention and treatment of VTE in patients with cancer [106], [107]. In Select‐d, patients receiving rivaroxaban had numerically lower rates of recurrent VTE (4% vs. 11%) and similar (numerically higher) rates of major bleeding (4% vs. 3%) compared with patients receiving dalteparin [108]. Valuable data are also expected from the CANVAS study (ClinicalTrials.gov identifier NCT02744092), which is currently recruiting and is a pragmatic randomized effectiveness trial designed to compare all licensed DOACs with LMWHs (alone or with warfarin) in terms of benefits (based on VTE recurrence), harms (based on bleeding rates), and burdens (based on patient‐reported outcomes and mortality data).

There is a paucity of data for patients with AF and cancer from studies of DOACs, because patients with cancer were excluded from the pivotal phase III trials [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [84], [85], [86], [87], [88], [89], [90]. A recent small observational study addressed the safety and efficacy of rivaroxaban in patients with active cancer and AF. The estimated cumulative incidence of ischemic stroke, major bleeding, and clinically relevant nonmajor bleeding was 1.4% (95% confidence interval [CI], 0%–3.4%) and 1.2% (95% CI, 0%–2.9%) in the acute (first 90 days of anticoagulation) and subsequent chronic phases of anticoagulation, respectively [109]. Although the authors noted that these safety and efficacy findings were similar to those from the ROCKET‐AF study, further large prospective studies are needed to comprehensively address the question of whether DOACs are suitable for use in patients with AF and concomitant cancer.

Additional Considerations for the Use of DOACs in Patients with Cancer

Drug‐Drug Interactions Involving DOACs in Patients with Cancer.

It is well established that in contrast to LMWH, the DOACs undergo complex metabolism and elimination pathways (supplemental online Table 7) [110], [111], [112], [113], [114], and cancer therapies may influence these pathways. All DOACs are substrates of the adenosine triphosphate‐binding cassette transporters (mainly P‐glycoprotein). Factor Xa inhibitors (but not dabigatran) are also metabolized in the liver via cytochrome P450 (CYP) enzymes, with about 32%, 25%, and <10% of the absorbed dosage undergoing metabolic degradation via CYP‐dependent pathways (mainly CYP3A4/5) for rivaroxaban [115], apixaban [112], and edoxaban [113], respectively. Therefore, strong inducers and inhibitors of CYP3A4 and/or P‐glycoprotein can affect plasma concentrations of DOACs and alter the anticoagulant effects, although the effect on clinical outcomes, if any, is still unknown [116]. In general, it is therefore advised that DOACs should be avoided in patients with cancer who are taking strong CYP3A4 and P‐glycoprotein inhibitors [116]. There is evidence of some antiemetic therapies, including dexamethasone and the 5‐HT₃ receptor antagonist ondansetron, interacting with both CYP3A4 and P‐glycoprotein [116]. In addition, the NK₁ receptor antagonists aprepitant and fosaprepitant may cause either moderate inhibition or moderate induction of CYP3A4 depending on the duration of their use [116]; however, data on interactions between antiemetic therapies and DOACs remain limited.

Effects of Renal Impairment on DOAC Use in Patients with Cancer.

An additional complication is that patients with cancer are prone to renal impairment, which may be a consequence either of the cancer itself or of its treatment, as well as being a result of advancing age. Moreover, prolonged vomiting may acutely exaggerate this renal impairment. The four commonly used DOACs undergo varying degrees of renal elimination (from 25% to >80%; supplemental online Table 7); consequently, renal impairment can lead to increased drug exposure, with a concomitant increase in bleeding risk in this patient group. Accordingly, current guidelines and product labels recommend the consideration of renal function for treating patients with DOACs. Doses of edoxaban and dabigatran should be adjusted in patients with moderate‐to‐severe renal impairment [111], [113]; for apixaban and rivaroxaban, dose modifications are recommended in patients with severe renal insufficiency [110], [112].

Patients with Gastrointestinal Cancer.

The risk of VTE is particularly high in patients with gastrointestinal cancer (e.g., gastric cancer or pancreatic cancer), and gastrointestinal cancer may also be complicated by splanchnic vein thrombosis, portal hypertension, hepatopathy‐associated coagulation defects and thrombocytopenia [45]. However, clinical data on VTE prevention and treatment specifically in this patient population are scarce. Standard prophylactic dosages of LMWH may not be sufficient for those at highest risk (e.g., patients with pancreatic cancer), and half‐therapeutic dosages of LMWH have been suggested for patients with advanced pancreatic cancer during the first 3 months of chemotherapy. For patients with gastrointestinal cancer and VTE, anticoagulation therapy with LMWH has been recommended for at least 3 to 6 months [45].

Standard prophylactic dosages of LMWH may not be sufficient for those at highest risk (e.g., patients with pancreatic cancer), and half‐therapeutic dosages of LMWH have been suggested for patients with advanced pancreatic cancer during the first 3 months of chemotherapy. For patients with gastrointestinal cancer and VTE, anticoagulation therapy with LMWH has been recommended for at least 3 to 6 months.

Current Guidelines

In patients with cancer and thrombosis, current guidelines advise the use of anticoagulants for a minimum of 6 months (Table 3). The recommended treatment option is subcutaneous administration of a LMWH, based on evidence showing LMWHs to be effective and well‐tolerated anticoagulants in this patient group [37], [38]. For the first time, the most recent international guidelines on the treatment of cancer‐associated VTE also now mention DOACs as a treatment option [14]. Longer‐term anticoagulant treatment, beyond the initial 6 months of anticoagulant therapy, is recommended in patients who still have malignancy or are undergoing cancer treatment, but no guidance is provided as to which types of therapies are most appropriate. Expert guidance statements report that LMWHs are still the preferred treatment for this patient group, on the basis of familiarity and concerns that vomiting episodes may affect the overall risk‐benefit balance of oral treatment [117], [118], [119]. The LONGHEVA (ClinicalTrials.gov identifier NCT01164046) and ALICAT (ClinicalTrials.gov identifier NCT01817257) studies were intended to provide further information on the effectiveness of LMWHs in the long‐term prevention of recurrent VTE (compared with VKAs or discontinuation of treatment) in patients with cancer, but these trials were terminated early because of very slow recruitment.

Table 3. Guidelines on the use of DOACs in patients with cancer.

Abbreviations: —, Not applicable; ACC, American College of Cardiology; ACCP, American College of Chest Physicians; AF, atrial fibrillation; AHA, American Heart Association; ASCO, American Society of Clinical Oncology; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; EHRA, European Heart Rhythm Association; ESC, European Society of Cardiology; ESMO, European Society for Medical Oncology; HRS, Heart Rhythm Society; INR, international normalized ratio; LMWH, low‐molecular‐weight heparin; NCCN, National Comprehensive Cancer Network; NICE, National Institute for Health and Care Excellence; NOAC, novel oral anticoagulant; PE, pulmonary embolism; TIA, transient ischemic attack; VKA, vitamin K antagonist; VTE, venous thromboembolism.

For patients with AF, most current treatment guidelines do not advise a differential use of anticoagulants for patients with cancer compared with individuals without cancer; however, a recent publication from the European Heart Rhythm Association provides some practical guidance on the use of DOACs in patients with AF and malignancies (Table 3) [118].

There are guidelines on the management of switching to or from DOAC treatment to another type of anticoagulant and missed doses of DOACs (supplemental online Table 8). However, there are no current data or guidelines on pausing and then resuming DOAC therapy specifically in patients with cancer and thrombosis.

Current Prescribing Practices

In line with current treatment guidelines, there are reports that physicians prefer prescribing LMWHs over VKAs in patients with VTE and cancer [102]. Indeed, in a multinational survey of physicians, LMWHs were indicated as the first‐choice anticoagulant class for long‐term VTE treatment in patients with concomitant cancer [120]. A study of data from RIETE, a computerized registry of patients with VTE, reported that 91% of women with active cancer and VTE had received initial therapy with an LMWH [121]. However, there is also evidence that some physicians do routinely prescribe DOACs or other oral anticoagulants to patients with VTE and cancer. In a study of 309 patients with active cancer, similar numbers of patients were prescribed LMWH therapy as were prescribed non‐LMWH therapy (including warfarin, dabigatran, apixaban, rivaroxaban, or fondaparinux) after a VTE event [122]. Furthermore, in a retrospective analysis of U.S. patients with VTE and newly diagnosed cancer, warfarin was the most‐used anticoagulant for cancer‐associated VTE, and more patients remained on oral versus injectable agents over a 6‐month period [123]. In a multinational survey of physicians, LMWH was reported to be the first choice for initial treatment of cancer‐associated VTE by 82% of physicians. However, when continuing anticoagulant treatment after the initial 3 to 12 months of treatment, only 44% of respondents preferred LMWHs, with 10% preferring VKAs and 45% choosing an anticoagulation strategy on a patient‐specific basis [120]. In another study, although LMWHs were the dominant class of anticoagulant used during the first 6 months postevent in patients with active cancer, 21% of patients were switched to rivaroxaban therapy during the first 6 months after VTE diagnosis [102]. Perhaps because of a lack of clear guidelines, patients with cancer and VTE who eventually receive DOACs do not always receive doses of these drugs that are in line with those recommended by the product labels [100].

Adherence to anticoagulant therapy for VTE has been associated with a significant reduction in VTE recurrence in patients with VTE and concomitant cancer [124]; however, available evidence shows less than optimal adherence to anticoagulation strategies in this patient group. For example, preliminary results of EXTEND, a retrospective study that followed up with patients with cancer‐associated VTE who had been taking a LMWH or warfarin for 6 months, reported an overall anticoagulant discontinuation rate of 25% [125]. In addition, a recent cohort study found that 51% of patients with VTE and cancer discontinued LMWH therapy within 6 months of treatment initiation, of whom 21% reported side effects of treatment as their reason for discontinuation [126]. Use of DOACs in these patients may increase adherence to treatment; indeed, patient surveys have indicated increased willingness to use oral thromboprophylaxis strategies compared with injectable agents [127].

Expert Recommendations for the Use of DOACS in Patients with Cancer

The use of anticoagulant drugs in patients with cancer requires careful management by physicians, because patients with cancer and acute VTE have high risks of life‐threatening VTE recurrence and major bleeding [26], [27], [28]. In patients with cancer, it is particularly important to be able to decrease the intensity of anticoagulation quickly when additional risk factors for hemorrhage (such as cancer‐ or treatment‐related thrombocytopenia) occur and to avoid prolonged anticoagulant‐free periods due to operations or interventions. In regard to these points, LMWHs clearly have a better pharmacological profile than VKAs, but LMWHs also have specific shortcomings (such as subcutaneous application, cost, and animal source). Regarding pharmacological properties such as time to peak concentration and half‐life, DOACs are very similar to LMWH, and the two can easily be switched in either direction [118]. However, it must be realized that the oral route of application—preferred by most patients—opens new fields of concern for DOACs compared with LMWHs. Interdisciplinary discussion of these concerns resulted in consensus recommendations for the management of patients with VTE or AF and cancer receiving DOACs, with a focus on those at risk of nausea and vomiting (Fig. 1; Table 4).

Figure 1.

Summary of general recommendations for managing nausea and vomiting and GI obstruction in patients with cancer and VTE or AF (A) and patients undergoing cancer treatment (B). Guidance is evidence‐based for patients with VTE. For patients with AF, physicians should consider individual patient factors specified by the European Heart Rhythm Association [118] before making treatment decisions.

Abbreviations: AC, anticoagulant; AF, atrial fibrillation; AN, anticipatory nausea and vomiting; DOAC, direct oral anticoagulant; GI, gastrointestinal; LMWH, low‐molecular‐weight heparin; N/V, nausea and vomiting; OAC, oral anticoagulant; VTE, venous thromboembolism.

Table 4. Expert recommendations for the use of DOACs in patients with cancer.

^aAssessing thromboembolic risk in patients: the risk of thromboembolic events depends primarily on the indication for anticoagulation and individual patient factors, which can include concomitant medications (e.g., steroids).

• AF: depends on CHA₂DS₂‐VASc score. Patients with a score of at least 2, particularly those with recent stroke, are considered to be at high risk of thromboembolic events [138].

• VTE: depends on the risk of VTE recurrence [139]. The type of VTE (DVT or PE), its location (e.g., distal or proximal DVT), and the time since the index VTE event must also be considered, with the 3 to 4 weeks after the index event considered to be high risk [140].

^bAn LMWH is preferable to an unfractionated heparin (UFH) because of its more predictable pharmacokinetic profile and ease of use [141].

^cIn patients with severely impaired renal function, an UFH is preferable to other parenteral therapies because of the risks of bioaccumulation associated with LMWH therapy in these individuals [142].

Abbreviations: AF, atrial fibrillation; CINV, chemotherapy‐induced nausea and vomiting; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; EHRA, European Heart Rhythm Association; GI, gastrointestinal; LMWH, low‐molecular‐weight heparin; N/V, nausea and vomiting; PE, pulmonary embolism; PEG, percutaneous endoscopic gastrostomy; RINV, radiotherapy‐induced nausea and vomiting; SPC, summary of product characteristics; VTE, venous thromboembolism.

Patient safety was the leading argument in building these recommendations. This means that physicians treating patients with cancer should be alert to symptoms of gastrointestinal obstructions and the risk of cancer‐ or treatment‐related nausea and vomiting, both before initiation and during application of DOACs. All patients are to be advised of the risk of nausea and vomiting and the consequences of missed anticoagulant doses. They should be advised to follow the recommendations for antiemetic prophylaxis and therapy and instructed how to manage anticoagulation when nausea or vomiting occur. Whenever oral DOAC uptake is hindered, a primarily preventive switch to LMWH should be considered. In low‐risk situations of nausea or vomiting, availability of a “just in case” package of one or two doses of LMWH is recommended.

Conclusion

Nausea and vomiting affect a significant proportion of patients with cancer (up to 100% and 50%, respectively), and this is a particular concern in patients with concomitant VTE or AF receiving treatment with oral anticoagulants. However, current preventive and rescue treatment with antiemetic therapies can now prevent vomiting, and to a lesser extent nausea, in the majority of patients with cancer, and future studies are likely to yield further improvements in the management of cancer‐associated nausea and vomiting.

Initial data suggest similar efficacy and safety of DOACs in patients with and without cancer and comparable efficacy and safety profiles of DOACs and conventional treatment (VKAs or LMWHs) in patients with VTE and cancer. Furthermore, studies reviewing clinical practice in the treatment of patients with VTE and cancer have shown that up to approximately 50% of patients with VTE are switched from LMWHs to oral anticoagulants, with an increasing proportion of individuals receiving DOACs, particularly in the long term. Data on patients with AF and concomitant cancer are currently lacking, and the study of the use of DOACs in this patient group remains an important research priority. In the absence of robust data from RCTs and specific evidence‐based guidelines, consensus recommendations on the management of DOACs in patients with VTE or AF and cancer were developed based on the available evidence to date and expert discussions (Fig. 1). It is considered that DOACs may be suitable for use in patients with concomitant VTE or AF and cancer who are at risk of nausea, vomiting, or oral obstruction but that caution and careful consideration of all relevant patient‐specific characteristics are required. In particular, physicians should consider the risk of thromboembolic and bleeding events, cancer treatment regimen, and renal function.

See http://www.TheOncologist.com for supplemental material available online.

Author Contributions

Conception/design: Hanno Riess, Cihan Ay, Rupert Bauersachs, Cecilia Becattini, Jan Beyer‐Westendorf, Francis Cajfinger, Ian Chau, Alexander T. Cohen, Alok A. Khorana, Anthony Maraveyas, Marcos Renni, Annie M. Young

Provision of study material or patients: Hanno Riess, Cihan Ay, Rupert Bauersachs, Cecilia Becattini, Jan Beyer‐Westendorf, Francis Cajfinger, Ian Chau, Alexander T. Cohen, Alok A. Khorana, Anthony Maraveyas, Marcos Renni, Annie M. Young

Collection and/or assembly of data: Hanno Riess, Cihan Ay, Rupert Bauersachs, Cecilia Becattini, Jan Beyer‐Westendorf, Francis Cajfinger, Ian Chau, Alexander T. Cohen, Alok A. Khorana, Anthony Maraveyas, Marcos Renni, Annie M. Young

Data analysis and interpretation: Hanno Riess, Cihan Ay, Rupert Bauersachs, Cecilia Becattini, Jan Beyer‐Westendorf, Francis Cajfinger, Ian Chau, Alexander T. Cohen, Alok A. Khorana, Anthony Maraveyas, Marcos Renni, Annie M. Young

Manuscript writing: Hanno Riess, Cihan Ay, Rupert Bauersachs, Cecilia Becattini, Jan Beyer‐Westendorf, Francis Cajfinger, Ian Chau, Alexander T. Cohen, Alok A. Khorana, Anthony Maraveyas, Marcos Renni, Annie M. Young

Final approval of manuscript: Hanno Riess, Cihan Ay, Rupert Bauersachs, Cecilia Becattini, Jan Beyer‐Westendorf, Francis Cajfinger, Ian Chau, Alexander T. Cohen, Alok A. Khorana, Anthony Maraveyas, Marcos Renni, Annie M. Young

Disclosures

Hanno Riess: Aspen, Bayer, Bristol‐Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Leo Pharma, Merck, Novartis, Pfizer, Roche, Sanofi‐Aventis, Shire (C/A, SAB); Cihan Ay: Pfizer, Bristol‐Myers Squibb, Daiichi Sankyo, Boehringer Ingelheim, Bayer (H); Rupert Bauersachs: Aspen, Bayer, Boehringer, Bristol‐Myers Squibb, Pfizer, Daiichi‐Sankyo (C/A), Bayer, Bristol‐Myers Squibb, Pfizer, Daiichi‐Sankyo (SAB); Cecilia Becattini: Bayer HealthCare, Bristol‐Myers Squibb, Pfizer, Daiichi Sankyo (H), Bayer, Boehringer, Pfizer, Daiichi Sankyo (RF); Jan Beyer‐Westendorf: Bayer, Boehringer, Pfizer, LEO, Portola, Daiichi Sankyo (H); Francis Cajfinger: Bayer (C/A, SAB), Leo Pharma, Pfizer, Sanofi (other—expert testimony); Ian Chau: Sanofi Oncology, Eli Lilly & Co., Bristol‐Myers Squibb, Merck Sharp & Dohme, Bayer, Roche, Five Prime Therapeutics (SAB), Eli Lilly & Co., Janssen‐Cilag, Sanofi Oncology, Merck‐Serono, Novartis (H), Taiho, Pfizer, Amgen, Eli Lilly & Co. (RF); Alexander T. Cohen: Aspen, Bayer, Boehringer‐Ingelheim, Bristol‐Myers Squibb, CSL Behring, Daiichi‐Sankyo, GlaxoSmithKline, GLG, Guidepoint Global, Johnson and Johnson, Leo Pharma, Medscape, McKinsey, Navigant, ONO, Pfizer, Portola, Sanofi, Takeda, Temasek Capital, TRN, XO1 (C/A), Aspen, Bayer, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Daiichi, GlaxoSmithKline, Johnson and Johnson, Medscape, Pfizer, Portola (H); Alok A. Khorana: Leo Pharma, Janssen, Pfizer, Sanofi, Halozyme, AngioDynamics (C/A, H); Anthony Maraveyas: Bayer (C/A, SAB); Annie M. Young: Bayer AG (RF), Helsinn, Bayer AG. Leo Pharma (H), Bayer AG (SAB). Marcos Renni indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board