Authors: Marissa Chow, Pharm.D. Candidate Class of 2021 and
Emily Shor, Pharm. D.
Patients with malignancies have a 20% to 30% increased risk for venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE), due to their hypercoagulable state.1-3 Additionally, a VTE at the time of or within one year of cancer diagnosis is correlated with more advanced stages of cancer and increased risk of death.4 The 2019 NCCN and 2016 CHEST guidelines recommend that patients with a cancer associated VTE be anticoagulated for at least three months or indefinitely while cancer is active, patient is undergoing treatment, or risk factors remain present.2-3,5 However, the NCCN guidelines do not provide recommendations regarding routine VTE prophylaxis in ambulatory cancer patients unless they have certain risk factors, such as certain cancer types and/or chemotherapy agents. 2 Managing cancer-associated thrombosis (CAT) must balance both a patient’s increased risk of recurrent VTE patients alongside risks of bleeding.
The CLOT trial established low-molecular-weight heparin (LMWH) as first line therapy for chronic anticoagulation therapy in patients with metastatic disease with acute VTE.6 Despite frequent self-injections, which can affect patient adherence, LMWHs have a faster onset and reaches steady state more quickly than vitamin K antagonists.7 Moreover, dalteparin significantly decreased risk of recurrent VTE compared to oral anticoagulants.6 While warfarin offers an oral alternative, it can be difficult to maintain a therapeutic INR due to frequent follow-up, drug-drug interactions with chemotherapy agents, malnutrition, and possible liver dysfunction.
Since their development, utilization of direct oral anticoagulants (DOACs) has greatly increased as their efficacy and safety were established in the setting of VTE treatment within the general population in various landmark trials. DOACs do not require frequent lab monitoring and have few drug-food interactions. However, until recently, the role of DOACs in CAT has been unclear due to limited evidence from subgroup analyses of cancer patients in each DOAC’s landmark trials. Although DOACs offer more convenient administration, further investigation of the role of DOACs as effective and safe agents in the prophylaxis and treatment of VTE in cancer patients is needed. This article will review the recently published literature regarding the use of DOACs in cancer patients.
VTE Treatment in Cancer Patients
The studies assessing the efficacy and safety of DOACs for VTE treatment in the general population had limited enrollment of cancer patients, ranging from 3% to 9%.8-11 Subgroup analyses of these patients show promising results, but the enrolled cancer patients likely had a lower risk profile. Randomized trials have recently assessed the role of apixaban, rivaroxaban, and edoxaban in CAT treatment as compared to the efficacy and safety of utilizing therapeutic dosing of a LMWH, dalteparin.
Apixaban: ADAM VTE12
The ADAM VTE Trial, a multicenter, open-label trial, randomized patients with cancer-associated acute VTE to receive dalteparin or apixaban (10 mg twice daily for seven days followed by 5 mg twice daily). The most frequent types of cancer were colorectal, lung, pancreas, and breast cancers, and 65.5% of patients had metastatic disease. In the apixaban group (n=145), no major bleeding events occurred within six months compared to three major bleeding events (2.1%) in the dalteparin group (n=142) (p=0.9956). Recurrent VTE occurred in five patients (3.4%) in the apixaban group and 20 patients (14.1%) in the dalteparin group (HR [hazard ratio]: 1.36; 95% CI [confidence interval]: 0.79-2.35). Monthly quality of life surveys regarding concern for excess bruising, stress, irritation, burden of delivery, and overall satisfaction (p<0.05) also favored apixaban. Thus, data from this trial supports oral apixaban therapy as it was associated with low rates of bleeding and significantly lower VTE recurrence rates. However, full results of this study have not been published yet.
The SELECT-D Trial was a multicenter, open-label pilot study that assessed the safety and efficacy of rivaroxaban for treatment of active VTE in patients with cancer. Patients with an active VTE were randomized to receive dalteparin or rivaroxaban (15 mg BID for three weeks, followed by 20 mg daily for a total of six months). The most prevalent primary tumors included colorectal cancer and lung cancer. The primary efficacy endpoint (VTE recurrence at 6 months) occurred in 18 (8.9%) of 203 dalteparin patients and eight (3.9%) of 203 rivaroxaban patients, resulting in a cumulate VTE recurrence rate at six months of 11% for patients receiving dalteparin and 4% for those receiving rivaroxaban (HR: 0.43; 95% CI: 0.19-0.99). The primary safety endpoint of major bleeding occurred in six patients (3.0%) receiving dalteparin and 11 patients (5.4%) receiving rivaroxaban, resulting in a cumulative major bleeding rate of 4% for the dalteparin group and 6% for rivaroxaban group (HR: 1.83; 95% CI: 0.68-4.96). Major bleeding events most commonly occurred within the gastrointestinal tract, and there were no identified CNS bleeds. Clinically relevant non-major bleeding (CRNMB) during the six-month period occurred in 4% of dalteparin patients and 13% of rivaroxaban patients (HR: 3.76; 95% CI: 1.63-8.69), indicating that although rivaroxaban and dalteparin have similar rates of major bleeding, patients receiving rivaroxaban experienced higher rates of CRNMB. Most CRNMB occurred within gastrointestinal or urologic systems. Overall, patients with esophageal/gastroesophageal cancer experienced more bleeding compared to other cancer types, which may be related to the site of action of rivaroxaban. Ultimately, this trial suggests that rivaroxaban may be a viable alternate VTE treatment option to LMWH in cancer patients. However, results of this trial cannot be translated to longer treatment due to the short follow up period.
Edoxaban: Hokusai VTE Cancer 14
The Hokusai VTE Cancer trial was an open-label, noninferiority trial that assessed the role of edoxaban for CAT treatment. Adult patients with active cancer and VTE were randomized and stratified to receive either dalteparin or edoxaban 60 mg daily after receiving a LMWH for five days. The edoxaban dose was adjusted based on renal function (CrCl 30-50 mL/min), body weight (< 60 kg), or use of concomitant potent P-glycoprotein inhibitors. Colorectal, lung, genitourinary, and breast cancer were the most common cancer types included. Patients were treated for six to 12 months as determined by the treating physician. The primary outcome (composite of recurrent VTE or major bleeding after 12 months) occurred in 67 of 522 edoxaban patients (12.8%) and 71 of 524 dalteparin patients (13.5%) (HR: 0.97; 95% CI: 0.70-1.36; p=0.006 for noninferiority; p=0.87 superiority). Separately, recurrent VTE occurred in 41 patients (7.9%) in the edoxaban group and 59 patients (11.3%) in the dalteparin group (HR: 0.71; 95% CI: 0.48-1.06; p = 0.09) while major bleeding occurred in 36 (6.9%) and 21 (4.0%) in the edoxaban and dalteparin group, respectively (HR: 1.77; 95% CI: 1.03-3.04; P = 0.04). Most major bleeding events in the edoxaban arm occurred as gastrointestinal bleeding in the setting of gastrointestinal cancer. Ultimately, edoxaban was found to be noninferior to dalteparin in regard to the primary composite outcome, but it is important to consider the patient’s risk for bleeding, particularly based on cancer type. However, the study was underpowered to determine a difference in major bleeding based on cancer site in order to determine if solely patients with gastrointestinal cancer had an increased risk of bleeding compared to other cancer types. Additionally, similar to the ADAM VTE and SELECT-D studies, the ideal duration of anticoagulation treatment remains unclear as patients received anticoagulation for up to 12 months.
Based on the available literature, rivaroxaban, edoxaban, and apixaban appear to be well-tolerated and efficacious in the treatment of CAT. However, a patient-specific approach that takes into consideration a patient’s type of cancer, renal function, hepatic function, and adherence should be utilized. A recent consensus statement from the International Society of Thrombosis and Haemostasis Scientific and Standardization Committee recommends DOACs as first-line options in cancer patients if they have a low bleeding risk, and there are no drug-drug interactions.15 Remaining patients should continue to receive LMWH, especially if they have a high risk of bleeding. In particular, DOACs appear to consistently be associated with increased bleeding risk in patients with gastrointestinal or genitourinary cancers, so DOACs should be avoided in these populations. In accordance, the NCCN guidelines caution the use of DOACs in patients with cancer and urinary or GI tract lesions, pathology, or instrumentation as noted in the SELECT-D and Hokusai VTE Cancer studies.3,13-14 At this time, it is difficult to make direct comparisons between DOACs in regard to their efficacy and safety due to the trial designs only comparing each DOAC to LMWH, but, most notably, rivaroxaban and edoxaban were found to have a statistically significant increased risk of CRNMB and major bleeding, respectively. Thus, patient specific factors, such as renal function, hepatic function, cancer type, and bleeding risk, should be considered when selection anticoagulation therapy.
VTE Prophylaxis in Ambulatory Cancer Patients
A cancer patient’s risk of CAT is strongly associated with the type of cancer. Currently, thromboprophylaxis in ambulatory cancer patients is not routinely recommended but has been considered in high risk patients, such as those with a high Khorana Risk Score (> 3 points indicates high risk). The Khorana score assess the patient’s cancer diagnosis, body mass index, and CBC. DOACs offer a convenient alternative for VTE prophylaxis to LMWH.16 Recently, apixaban and rivaroxaban have been assessed in trials to be utilized in this setting.
Apixaban: AVERT Trial17
The AVERT Trial was a placebo-controlled, double-blind trial that assessed the role of apixaban compared to placebo for thromboprophylaxis in intermediate-to-high risk (Khorana score >2) ambulatory patients with cancer and initiating chemotherapy. Patients were randomized to initiate apixaban 2.5 mg twice daily or placebo within 24 hours of chemotherapy initiation for a treatment period of 180 days. The most common types of primary cancer included gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%) cancers. The primary efficacy outcome (first episode of objectively documented major VTE (proximal DVT or PE) within 180 days) occurred in 12 of 288 patients (4.2%) in the apixaban group and 28 of 275 patients (10.2%) in the placebo group (HR: 0.41; 95% CI: 0.26-0.65; p<0.001), indicating a significantly lower risk of VTE in patients treated with apixaban, which was primarily driven by a lower rate of PE in the apixaban group. However, a statistically significant increase in major bleeding episodes was found in the apixaban group. Major bleeding events occurred in 10 of 288 patients (3.5%) in the apixaban group and five of 275 patients (1.8%) in the placebo group (HR: 2.0; 95% CI: 1.01-3.95; p=0.046). The major bleeding events were primarily associated with gastrointestinal bleeding, hematuria, and gynecologic bleeding with apixaban, and major bleeding most commonly occurred in patients with cancer of gastrointestinal or gynecologic nature. Overall, this trial displayed that there was no difference in survival between the apixaban and placebo groups; however, most of the patients in the trial had advanced stages of cancer. The study consisted of limited types of cancers, so it is difficult to make conclusions regarding apixaban’s safety and efficacy in other cancer types; however, most commonly, included patients had cancers that significantly increased their risk for thrombosis events. Additionally, this study had a limited population with reduced renal function, a population at an increased risk of bleeding.
Rivaroxaban: CASSINI Trial18
The CASSINI Trial was a double-blind, multi-centered, placebo-controlled trial. This study randomized patients with a solid tumor or lymphoma initiating a new cancer regimen and a Khorana score of at least two to receive rivaroxaban 10 mg or placebo daily for up to 180 days. Patients were screened every eight weeks for the development of the efficacy and safety endpoints. The most common types of primary cancer included pancreatic cancer (32.6%) and gastric/gastroesophageal junctional cancer (20.9%). Of patients with a solid tumor, 54.5% had metastatic disease. Of note, more patients with a history of VTE were randomly assigned to the rivaroxaban group compared to the placebo group (2.6% v. 0.5%). Additionally, 43.7% of patients in the rivaroxaban group and 50.2% of patients in the placebo group discontinued therapy prematurely. The mean intervention period (time period from the first dose of either drug through the last dose plus two days) was 4.3 months. The primary efficacy endpoint (development of DVT or PE) occurred in 11 (2.6%) of 420 rivaroxaban patients compared to 27 (6.4%) of 421 placebo patients during the intervention period (HR: 0.40; 95% CI: 0.20-0.80). However, during the period up to day 180, the primary efficacy composite endpoint occurred in 25 (6.0%) of the rivaroxaban patients compared to 37 (8.8%) of the 421 placebo patients (HR: 0.66; 95% CI: 0.40-1.09). The primary safety endpoint (major bleeding) occurred in 8 (2.0%) of the 405 rivaroxaban patients and 4 (1.0%) patients in the placebo arm (HR: 1.96; 95% CI: 0.59-6.49; p=0.26). Ultimately, in this population, low-dose rivaroxaban did not result in a statistically significant reduction in VTE at 180 days when compared to placebo, but, in the pre-specified intervention period, there was a 3.6% absolute reduction in thromboembolism with rivaroxaban, which may be hypothesis generating as this time period could be subject to bias. These findings are consistent with results of previous trials assessing rivaroxaban for thromboprophylaxis in cancer patients, such as the PROTECHT and SAVE-ONCO trials. However, the CASSINI trial included a higher-risk population. Additionally, an overall discontinuation rate of approximately 47% may be a limitation due to the inability to fully depict the bleeding and VTE occurrence. Overall, the role of rivaroxaban as thromboprophylaxis in this patient population remains promising.
Apixaban and rivaroxaban have both been shown to be noninferior to current standard therapy placebo. Current recommendation for anticoagulation therapy for ambulating cancer patients suggest that no further anticoagulation is needed. However, these studies show that DOACs may be used as primary prophylaxis in high-risk patients. Most notably, both studies showed an increased risk of bleeding, which must be considered and evaluated for each patient. Further research is needed in order to determine optimal anticoagulation in ambulating cancer patients with less advanced stages of cancer. Additionally, the optimal timing and duration of thromboprophylaxis as well as the impact of thromboprophylaxis on cancer prognosis remain unclear.