Management of Venous Thromboembolism in Outpatients with Cancer

Abstract

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), constitutes a matter of great concern in cancer patients due to its capacity of increasing morbimortality in such population. It is more common than expected and can occur at any time during the history of cancer, sometimes being the first presenting manifestation of the disease. VTE can complicate chemotherapy treatments, surgeries, and hospitalizations, thus further increasing morbidity and mortality. VTE is the second leading cause of death in cancer patients. An optimal anticoagulation strategy is necessary for patients with cancer associated thrombosis (CAT) with the goals of reducing recurrent thrombosis and minimizing bleeding risk. Although low molecular weight heparins (LMWH) are universally accepted, direct oral anticoagulants (DOACs) have shown to significantly lower recurrent VTE risk and became in the last years an emerging new option for this condition.

1. Introduction

Cancer is a hypercoagulable state with an increased risk of developing venous thromboembolism (VTE). VTE rates in patients with cancer are about 4- to 7-fold higher compared to healthy individuals in part due to the increased survival of the population, thrombogenic chemotherapy treatments, procedures, and surgeries [1]. Of all subjects with VTE, approximately 20% have cancer of different etiologies, and about 20% of unprovoked VTEs are the first sign of an underlying malignancy [2]. Cancer triples VTE risk and doubles the risk of dying from VTE in comparison to individuals without cancer. Cancer patients also develop treatment-related complications that further increase the risk of thrombotic and bleeding rates. The risk of recurrence can be as high as 9-fold, and most of them and about one half of them are incidentally detected [3, 4]. VTE is the second leading cause of death in cancer patients. Furthermore, such patients are exposed to a higher risk of bleeding on anticoagulant therapy. LMWH has been the standard of care for these patients having VTE and cancer. DOAC therapy with apixaban, edoxaban, rivaroxaban, and dabigatran has proved useful in subjects with DVT without cancer disclosing in some cases better outcomes with less bleeding complications, especially major bleeding and intracranial hemorrhage [5, 6, 7, 8]. The CLOT trial randomized 336 VTE cancer patients with an acute episode of proximal DVT or PE to LMWH vs. oral anticoagulation with coumarin to evaluate the efficacy and safety of both treatment arms. Dalteparin was administered at a dose of 200 IU per kilogram of body weight for 1 month and then titrated to 150UI for the following 5 months. In the coumarin arm, dalteparin was given for 5–7 days followed by the antivitamin K agent with a target international normalized ratio of 2.5. This trial showed a lower risk of VTE recurrence (9 vs. 17%) in patients who were treated with dalteparin compared to warfarin or acenocumarol with no significant difference in any bleeding between the two groups. It seemed that from that moment on LMWH became the standard of care in patients with VTE and cancer [9]. Few years later the development of new anticoagulant agents known as DOACs emerged in the market, initially for SPAF (stroke prevention in atrial fibrillation) and then for VTE prevention. Due to their good tolerance, ease of use, few interactions with food and drugs, and good clinical results compared to coumarins, it was decided to test them in subjects with cancer.

2. DOACs trials

Hokusai VTE study included 1050 symptomatic cancer patients with acute or incidental VTE in an open-label fashion to receive any LMWH for 5 days followed by edoxaban 60 mg once daily versus subcutaneous dalteparin 200 IU per kilogram of body weight the first 30 days and then 150 IU until study completion at 12 months. It was a non-inferiority trial. Oral edoxaban proved to be non-inferior to LMWH for the combined endpoint of recurrent VTE or major bleeding (HR 0.97 [95% CI 0.70–1.6], yielding a p value of 0.006 for non-inferiority but higher rates of major bleeding with the novel agent [10].

The SELECT-D trial included 136 patients and randomized them to rivaroxaban 15 mg twice a day for 3 weeks and then 20 mg once daily or dalteparin for 6 months. The primary efficacy outcome was VTE recurrence at 12 months, and the primary safety outcome was major bleeding and clinically nonrelevant bleeding. Rivaroxaban was more effective than dalteparin for the primary outcome (4 vs. 11%; HR: 0.43; 95% CI: 0.19 to 0.99), but it did so at the cost of increased clinically relevant nonmajor bleeding (13 vs. 4%; HR: 3.76; 95% CI: 1.63 to 8.69) and major bleeds 6 vs. 4%, especially in patients with gastric and esophageal malignancies. Fatal bleeding was similar in both treatment arms [11, 12]. Since rivaroxaban and edoxaban use has been shown to increase the risk of bleeding in patients with cancer of gastrointestinal origin and considering the safety profile of apixaban in previous DVT and PE trials in subjects without cancer; a study with apixaban was designed. The ADAM VTE Trial randomized 300 VTE patients to oral apixaban 10 mg twice a day the first week and then half the dose for the rest of the study whereas the comparator dalteparin was administered at the dose of 200UI per kilogram of body weight during the first month following a 150UI/kg dose thereafter until study completion. The Khorana score was used for stratification considering cancer stage and risk factors for VTE. Patients with ECOG performance higher than two were excluded from the study (Figure 1). About 66% of patients had metastatic disease in both arms and nearly 74% of them received specific cancer treatment in both arms. The trial concluded that there were lower rates of VTE recurrence in the apixaban arm compared with dalteparin (HR = 0.099, 95% CI 0.013–0.78, P = 0.0281) with also lower rates of major bleeding 0 vs. 1.4%. The low sample size and low bleeding rates did not allow the investigators to draw consistent conclusions about superiority of apixaban over dalteparin in terms of major bleeding [13].

Figure 1.

Criteria used by the treating physician to assess the progression of the disease according to the ability to perform daily activities.

In the Caravaggio trial (Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer) patients with symptomatic or incidental acute symptomatic proximal DVT or PE (detected on imaging test by chance) were randomized to oral apixaban according to manufacturer’s and guidelines recommendations (10 mg twice daily for the first 7 days and then the standard dose of 5 mg twice daily) for the following 6 months or 200 IU of subcutaneous dalteparin per kilogram of body weight once a day for 1 month followed by 150IUper kilogram of body weight for the rest of the study period. In the apixaban group the primary outcome of VTE recurrence occurred in 5.6% of the apixaban patients and 7.9% in the dalteparin group, meaning a 27% risk reduction in favor of apixaban achieving criteria for non-inferiority. Major bleeding and gastrointestinal major bleeding were similar between groups. Nonmajor bleeding was higher in the apixaban than in the dalteparin group, a finding consistent with previous studies of direct oral anticoagulants. So, this is the first study to show that a DOAC, in this case, apixaban, is non-inferior to subcutaneous dalteparin for the treatment of cancer-associated VTE without an increased risk of major bleeding [14]. A posterior meta-analysis showed that DOACs, as a class, are at least non-inferior to dalteparin in terms of preventing VTE recurrence with nonsignificant risk in major bleeding; however, in patients with gastrointestinal malignancies, they have shown to increase the rates of clinically relevant nonmajor bleeding compared with dalteparin (Figure 2) [15].

Figure 2.

Global evidence shows that DOACs are more effective than LMWH for preventing VTE but are associated with higher bleeding rates.

The OSCAR-US (Observational Studies in Cancer-associated Thrombosis for Rivaroxaban United States Cohort) was a retrospective cohort analysis of 3708 patients with cancer and VTE comparing rivaroxaban to LMWH (in general enoxaparin at a dose of 1 mg/kg twice daily) with outcomes of recurrent VTE, clinically relevant bleeding-related hospitalization, and all-cause mortality. A total of 21% reduction of recurrent VTE events was observed with rivaroxaban compared to enoxaparin at 3 months and 26% at 6 months, respectively. Clinically, relevant bleeding-related hospitalization or all-cause mortality was similar between groups at 3, 6, and 12 months. This present study affirms that rivaroxaban is effective and safe for treating community patients with CAT outside clinical trials in subjects with malignancies not associated with higher rates of bleeding with this anticoagulant agent (esophageal, gastric, unresected colorectal, bladder, and noncerebral central nervous system) [16]. Although doses of anticoagulants are the same as in individuals with VTE without cancer (Table 1), the duration of anticoagulation is not well established in patients with VTE and cancer; while 6 months of treatment is accepted in noncancer patients, an extended duration of anticoagulant therapy has been proposed for them considering their high rates of recurrence, especially in those whose condition remains active [17].

Direct oral anticoagulant dosing for Venous Thromboembolism
Indication	Rivaroxaban	Edoxaban	Apixaban
Standard dose	15 mg BID for 21 days, then 20 mg OD	60 mg daily OD	10 mg BID for 7 days, then 5 mg BID
Reduced dose	15 mg OD	30 mg OD	2.5 mg BID
Criteria for dose reduction	CrCl 15–50 mL/min	CrCl 15–50 mL/min Avoid use if CrCl is above 95 ml/min	Two of the following Body weight ≤ 60 Kg, age ≥ 80 years, serum creatinine ≥1.5 mg/dl

Table 1.

Rivaroxaban, edoxaban, and apixaban are the three agents used for VTE prevention with strong evidence. Indications and dosages are similar to those of patients without cancer.

BID: twice a day; OD: = only dose; and CrCl: creatinine clearence.

A recently published randomized clinical trial comparing DOACs to LMWH, the CANVAS trial, concluded that DOACs are not inferior to LMWH for preventing VTE at 6 months follow up (6.1 vs. 8.8%, difference, −2.7%; 1-sided 95% CI, −100 to 0.7%), bleeding rates and serious adverse events were similar in both groups [18].

3. Thromboprophylaxis in the outpatient setting

Thromboprophylaxis is not routinely recommended for all outpatients with cancer because of lack of benefit improving survival. According to ASCO guidelines, clinicians may offer thromboprophylaxis with apixaban, rivaroxaban, or LMWH to selected high-risk outpatients with cancer [19]. The Khorana score is a tool used to predict the likelihood of developing VTE in subjects with cancer and high risk of venous thrombosis. It ranges from 0 to 6, with higher scores indicating greater risk (Figure 3). It also helps identify those individuals who could benefit more from prophylaxis with anticoagulants [20]. The Cassini trial randomized 841 high-risk ambulatory patients with a Khorana score of 2 or more in 1:1 fashion to receive either rivaroxaban 10 mg daily or placebo for 180 days. The rate of VTE was 6.0% in the rivaroxaban group vs. 8.8% in the placebo group (p = 0.10), so the conclusion was that rivaroxaban was not superior to placebo in preventing VTE in these patients [21]. On the other hand, apixaban 2.5 mg BID resulted in a clinically significant reduction of VTE compared to placebo among ambulatory patients with intermediate to high risk after the initiation of chemotherapy in the AVERT trial. Of note, these patients had higher episodes of major bleeding, and the most common types of cancer in this trial were gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%). The primary efficacy outcome of VTE was observed in 4.2% in the apixaban arm and in 10.2% in the placebo arm (p < 0.001), and the secondary outcome of all-cause mortality was a non-statistically significance difference of 12.2% in the apixaban group and 9.8% in the placebo one. Major bleeding occurred in 2.1% in the apixaban group vs. 1.1% in the placebo group, not statistically significant [22].

Figure 3.

Khorana score identifies subjects at higher risk of developing VTE, including those initiating chemotherapy.

The Khorana risk score did not include multiple myeloma, a high-risk cancer, nor those patients treated with thalidomide-based chemotherapy, a population at very high risk. In such population, LMWH prophylaxis is recommended.

4. Key points to keep in mind when prescribing DOACs

Patients with active cancer are at increased risk of venous thromboembolism (VTE) and bleeding events because of cancer-related impact on the Virchow’s triad (stasis, endothelial injury, and hypercoagulability). Pancreatic, stomach, metastatic, gynecological, lung, brain, hematologic, and genitourinary cancer patients are at higher risk of developing thrombosis. LMWH has been historically the treatment of choice for VTE-associated cancer, but now, this conception is changing in favor of DOACs. The safety of DOACs can be altered by two clinical conditions such as renal impairment and thrombocytopenia, a situation that is very common among active cancer individuals. In this setting, the use of an anticoagulant with less renal depuration would be advisable. When platelet count is less than 50,000–70,000/μL, DOAC therapy is not recommended [23]. The most important drug-drug interactions are those with P-glycoprotein (all DOACs) and CYP3A4 (especially rivaroxaban and apixaban) [24]. Due to the documented increased bleeding risk observed in the Hokusai VTE and the SELECT-D trials, it seems that DOACs are not the best choice for subjects affected by gastrointestinal or genitourinary malignancies; in such clinical situations, LMWH should be used instead. Hospitalized patients with active cancer are at high risk for thrombosis. They should receive thromboprophylaxis balancing the risk of bleeding. DOAC bleeding management requires general measures and a specific antidote treatment that unfortunately is not widely available.

5. Conclusions

Patients with cancer are very complex and usually face a broad range of thromboembolic complications throughout their lives. Cardiovascular diseases constitute the first cause of death among cancer survivors, and VTE is a great issue. Initially, antivitamin K agents and then LMWH were the treatments of choice. The introduction of DOACs is a step forward in the management of patients with VTE now expanded to those having cancer. Its low recurrence and bleeding risk make them a good option for VTE treatment in this high-risk population but should be accepted under appropriate clinical conditions. The choice of the anticoagulant agent must be taken considering efficacy, bleeding, drug-drug interactions, drug-food interactions, cost, and patient preferences and values.

Acknowledgments

To César and Estela, my parents, for instilling in me the value of effort, honesty, and sacrifice; to my kids Lucas, Felipe, Olivia, and Ramiro, source of love and inspiration, and to Ana, my wife, for her unconditional support.

Conflict of interest

The authors declare no conflict of interest.

Additional information

This is a review paper with no discussion section.