Epidemiology

Patients with malignancy have four to seven times greater risk of venous thromboembolism (VTE) than seen in patients without known malignancy^1-4 and use of chemotherapy increases risk by 6.5-fold.⁴

The American College of Chest Physicians, National Comprehensive Cancer Network and American Society of Clinical Oncology all recommend extended anticoagulation in patients with cancer associated thrombosis (CAT).^5-7 Patients typically remain on prolonged anticoagulation, but the decision to continue or discontinue treatment after 3-6 months of anticoagulation should really be based on the risk-benefit profile of the individual, effect of anticancer therapy, VTE recurrence risk, bleeding risk and shared decision making with the patient.^6,8,9

Anticoagulation in Cancer Associated Thrombosis

The landmark CANTHANOX, ONCENOX, CLOT, LITE and CATCH trials showed that low molecular weight heparins (LMWH's) were superior in preventing recurrent VTE in cancer patients with similar or improved bleeding profiles compared to vitamin K antagonists (VKAs).^10-14 As a result, LMWH has remained the standard treatment for cancer-associated VTE. However, with the increased use of direct oral anticoagulants (DOAC's), three recent randomized controlled trials (RCT) have been conducted to compare the safety and efficacy of DOAC's with LMWH.

HOKUSAI VTE Cancer Trial

The HOKUSAI VTE Cancer trial is an open-label, non-inferiority trial that randomized 1050 active cancer patients with acute VTE to either treatment with edoxaban or dalteparin for 6 to 12 months.¹⁵ Basal and squamous-cell skin cancers as well as patients with Eastern Cooperative Oncology Group (ECOG) performance category worse than two were excluded. Overall, approximately 90% of patients had a solid tumor malignancy. Metastatic disease was found in 60% and 57% of patients in the dalteparin arm and edoxaban arm, respectively. Approximately 70% in each arm had received cancer treatment in the four weeks prior to their enrollment.

This trial showed that treatment with edoxaban (initiated with LMWH for 5 days followed by edoxaban 60mg daily) was non-inferior to dalteparin (200 IU/kg daily for 1 month followed by 150 IU/kg daily) with respect to the composite primary outcome of recurrent VTE and major bleeding (hazard ratio (HR) 0.97, 95% CI 0.7–1.36, p = 0.006 for non-inferiority, p = 0.87 for superiority). When these two endpoints were examined individually, it was noted that edoxaban had a non-significant reduction in VTE recurrence (HR 0.71, 95% CI 0.48–1.06, p = 0.09). It also showed a statistically significant increase in major bleeding (HR 1.77, 95% CI 1.03–3.04, p = 0.04) but not clinically relevant non-major bleeding (CRNMB) (HR = 1.38, 95% CI .98-1.94). A post hoc analysis confirmed that the increased risk of major bleeding was due to increased bleeding in patients with resected or unresected gastrointestinal (GI) cancers (HR 4.0, 95% CI 1.5–10.6, p = 0.005).^16,17 Overall, this trial showed that edoxaban had similar efficacy at preventing recurrent VTE when compared to dalteparin but increased the risk of major bleeding, particularly in patients with GI cancers. Death from any cause or related to VTE and bleeding were similar between both groups.

SELECT-D Trial

This prospective, open label randomized multicenter trial randomized 406 patients with active cancer and symptomatic lower extremity deep vein thrombosis (DVT) or symptomatic/incidental pulmonary embolism (PE) to receive rivaroxaban (15mg twice daily for 3 weeks then 20mg once daily) versus. dalteparin (200 IU/kg daily for 1 month followed by 150 IU/kg daily) for 6 months. Patients with basal-cell or squamous-cell skin cancers and ECOG greater than two were not included. Greater than 95% of patients in both arms had solid tumor malignancies, 58% in both arms had metastatic disease and approximately 70% in both arms were currently receiving cancer treatment.¹⁸

This trial showed a statistically significant reduction in the primary outcome of recurrent VTE at 6 months in the rivaroxaban arm compared to dalteparin (4.0% versus 11.0%, respectively, HR 0.43, 95% CI 0.19-0.99). Primary cancers that showed the greatest risk of VTE recurrence were gastric, pancreas, lung, lymphoma, gynecologic and bladder cancers. Major bleeding was higher with rivaroxaban than with dalteparin (6.0% versus 4.0%, respectively), although not statistically significant (HR 1.83, 95% CI 0.68-4.96). CRNMB was significantly higher in the rivaroxaban arm, 13.0%, compared to 4.0% with dalteparin (HR 3.76, 95% CI 1.63-8.69). During the study, the trial's own data and safety monitoring committee noted a nonsignificant increase in major bleeding among 19 patients with esophageal or gastroesophageal cancers. Subsequent enrollment of patients with either of these cancers was halted. The two primary cancer types that had the greatest number of CRNMB in the rivaroxaban arm were bladder and colorectal cancers. Survival during the 6-month treatment period was higher in the rivaroxaban arm, 75% (95% CI 69%-81%) compared to dalteparin, 70% (95% CI 63%-76%).

The SELECT-D trial did show that rivaroxaban was more effective at preventing recurrent VTE in active cancer patients than dalteparin, but it did so at the cost of increased bleeding. The authors suggest two possible reasons for the increased gastrointestinal bleeding: 1) increased antithrombotic effect of rivaroxaban and 2) local and systemic effects of rivaroxaban on the GI system.

ADAM-VTE Trial

The ADAM-VTE trial was also an open-label trial that randomized 300 cancer patients with acute VTE to receive apixaban (10mg twice daily for 7 days then 5mg twice daily) or dalteparin (200 IU/kg daily for 1 month followed by 150 IU/kg daily) for 6 months. Patients with ECOG performance worse than two were excluded. Metastatic disease was present in approximately 66% of patients in both arms and with nearly 74% in each arm receiving concurrent cancer treatment.¹⁹

The trial found lower rates of VTE recurrence with apixaban compared with dalteparin, 0.7% versus 6.3%, respectively (HR=0.099, 95% CI 0.013-0.78, P = .0281). The trial showed low rates of major bleeding in both the apixaban and dalteparin arms, 0% versus 1.4%, respectively (HR not estimable, P = .138). This was much lower than expected in both arms, as the study was designed to detect a 6% major bleed rate in dalteparin with an expected decrease to 1.4% with apixaban. The results were even lower than what was documented for major bleeding with edoxaban (6.9%) and rivaroxaban (4%) in their respective trials.^15,18 Unfortunately, the small sample size and low bleeding rates in both arms of the study did not allow for calculation of a hazard ratio or determination of superiority of apixaban with respect to major bleeding. As might be expected, the secondary safety outcome, which was a composite of major bleeding and CRNMB, was also low in both the apixaban and dalteparin arms, 6.2% versus 6.3%, respectively (P = .8816). VTE recurrence rates in ADAM-VTE with apixaban (0.7%) were lower than edoxaban (7.9%) and rivaroxaban (3.9%) in HOKUSAI VTE Cancer and SELECT-D, respectively. With respect to LMWH and VTE recurrence, ADAM-VTE also showed a much lower incidence of recurrent venous thrombosis (6.3%) when compared to SELECT-D (11%) and HOKUSAI VTE Cancer (11.3%).^15,18

It is possible that the low event rate with regards to recurrent VTE, major bleeding and CRNMB noted in ADAM-VTE could be due to a difference in study design, sample size, patient selection, randomization or management. Additionally, it was noted that the ADAM-VTE trial included far less patients with upper GI cancers (11 total) than either SELECT-D (40 total) or HOKUSAI-VTE (54 total). This is an important difference as major bleeding outcomes in both SELECT-D and HOKUSAI-VTE were driven by these events in patients with upper GI malignancy.

CARAVAGGIO Trial

The CARAVAGGIO trial is the most recent study to examine the use of DOACs for the treatment of cancer associated thrombosis. This larger, open label trial randomized 1170 cancer patients to receive apixaban (10mg twice daily for 7 days then 5mg twice daily) or dalteparin (200 IU/kg daily for 1 month followed by 150 IU/kg daily) for 6 months. As with other studies of DOACs, patients with basal-cell or squamous-cell skin cancers and ECOG status worse than two were excluded. Notable differences were the exclusion of patients with primary brain tumors, known intracerebral metastases, and acute leukemia. Approximately 68% of patients in each arm had recurrent locally advanced or metastatic disease and 60% in each arm were receiving concurrent cancer treatment.²⁰

This trial showed that apixaban was non-inferior to dalteparin with respect to recurrent VTE, 5.6% versus 7.9%, respectively (HR=0.63, 95% CI 0.37-0.1.07, P < 0.001) and was primarily driven by lower rates of recurrent pulmonary embolism. While this was not as dramatic a reduction as in the ADAM-VTE trial, the results from CARAVAGGIO trial are consistent with recurrent VTE rates from both HOKUSAI-VTE Cancer and SELECT-D trials.^15,18,19 For the primary safety outcome of major bleeding, apixaban showed similar event rates when compared to dalteparin, 3.8% versus 4.0%, respectively (HR=0.82, 95% CI 0.40-1.69, P = 0.60). Further examination showed that GI bleeding was the most frequent type of major bleeding but was similar between apixaban and dalteparin 1.9% versus 1.7%, respectively. Major non-GI bleeding rates were also similar between apixaban and dalteparin 1.9% versus 2.2%, respectively. CRNMB was numerically increased with apixaban compared to dalteparin, 9.0% versus 6.0% (HR=1.42, 95% CI 0.88-2.30). The prior HOKUSAI-VTE Cancer and SELECT-D trials showed that bleeding events (MB or CRNMB) most often affected the gastrointestinal and genitourinary (GU) systems, particularly in patients who had GI or GU cancer.^15,18 The CARAVAGGIO trial similarly exhibited an increase in CRNMB driven by GI and GU bleeding, in addition to upper airway bleeding. Death from any cause and event free survival were not significantly different between apixaban and dalteparin arms. The two most prevalent cancers in both arms of the HOKUSAI-VTE Cancer, SELECT-D and CARAVAGGIO trials were colorectal and lung.^15,18

The CARAVAGGIO study confirmed what was already suspected based on results from the ADAM-VTE trial. Apixaban is non-inferior to dalteparin with respect to recurrent VTE and had similar rates of major bleeding. Like the other studies of rivaroxaban and edoxaban, there is increased risk of both major bleeding and CRNMB, particularly in those with GI and GU cancers.

Future Studies

The ongoing CANVAS study aims to compare dalteparin, enoxaparin or fondaparinux alone or with transition to warfarin against all four DOACs for prevention of recurrent cancer associated thrombosis. There is also the MACACOD, a single center observational study that does not exclude cancer patients and examines the real-life incidence of thromboembolic or hemorrhagic complications in patients taking DOACs for atrial fibrillation or venous thrombosis. With respect to long-term management, the multinational API-CAT study is currently enrolling participants to examine if apixaban 2.5mg twice daily is as effective as 5mg twice daily at preventing recurrent VTE in active cancer patients who have already completed at least 6 months of treatment.

Authors' Recommendations

Based on the previous data from studies comparing LMWH to VKA and studies comparing DOAC's to LMWH, clinical guidelines from The International Society on Thrombosis and Haemostasis (ISTH) and The International Initiative on Thrombosis and Cancer (ITAC) recommend that DOACs can be used as first line treatment for CAT in non-GI/GU cancer patients with low bleeding risk. Among those with GI/GU cancer-associated thrombosis, LMWH is preferred. VKA can be considered if patients are not candidates for LMWH or DOAC (e.g. cost), particularly for those with stable disease or in those in remission. The optimal duration of therapy is still unclear, but previous and current guidelines recommend at least 6months of therapy for CAT and longer if the patient has active cancer or is actively receiving antineoplastic therapy. From our experience, we use DOACs as first line therapy for CAT in patients with non-GI/GU cancers and low risk of intracerebral hemorrhage (ICH) who can tolerate oral medications. When considering anticoagulation in a patient with primary brain cancer or brain metastases, it is important to have a discussion with the patient that addresses: risk of ICH which varies based on tumor type, lack of survival benefit, potential quality of life improvement from symptomatic DVT or pulmonary embolism (PE), and use of inferior vena cava (IVC) filters. Factors affecting decision making are highly complex in patients with malignancy and involving the patients themselves in decisions on anticoagulation is always recommended.

Table 1: Trials Comparing Low Molecular Weight Heparins to Vitamin-K Antagonists

Study	Recurrent VTE LMWH n/N (%)	Recurrent VTE VKA n/N (%)	Major Bleeding LMWH n/N (%)	Major Bleeding VKA n/N (%)
CANTHENOX	NA	NA	5/71 (7)	12/75 (16)
CLOT	27/336 (8)	53/336 (16)	19/338 (6)	12/335 (4)
ONCENOX	2/29 (7), 2/32 (6) 1mg/kg, 1.5mg/kg	3/30 (10)	2/31 (7), 4/36 (11) 1mg/kg, 1.5mg/kg	1/34 (3)
LITE	7/100 (7)	16/100 (16)	7/100 (7)	7/100 (7)
CATCH	31/449 (7)	45/451(10)	12/449 (3)	11/451 (2.4)

Table 2: Trials Comparing Direct Oral Anticoagulants with Low Molecular Weight Heparins

	HOKUSAI VTE Cancer		SELECT-D		ADAM-VTE		CARAVAGGIO
	Dalteparin	Edoxaban	Dalteparin	Rivaroxaban	Dalteparin	Apixaban	Dalteparin	Apixaban
VTE Recurrence (N)	11.3%(524)	7.9%(522)	11%(203)	4%(203)	6.3%(142)	.7%(145)	7.9%(579)	5.6%(576)
	Hazard Ratio, 95% CI, p .71, (.48-1.06), p=.09		Hazard Ratio, 95% CI, p .43, (.19-.99), no p		Hazard Ratio, 95% CI, p .099, (.013-.78), p=.0281		Hazard Ratio, 95% CI, p .63, (.37-1.07), p<.001
Major Bleed (N)	4%(524)	6.9%(522)	4%(203)	6%(203)	1.4%(142)	0%(145)	4.0%(579)	3.8%(576)
	Hazard Ratio, 95% CI, p 1.77, (1.03-3.04), p=.04		Hazard Ratio, 95% CI, p 1.83, (.68-4.96), no p		Hazard Ratio, 95% CI, p Not estimable, p=.138		Hazard Ratio, 95% CI, p .82, (.40-1.69), p=.60
CRNMB (N)	11.1%(524)	14.6%(522)	4%(203)	13%(203)	4.2%(142)	6.2%(145)	6.0%(579)	9.0%(576)
	Hazard Ratio, 95% CI, p 1.38, (.98-1.94), no p		Hazard Ratio, 95% CI, p 3.76, (1.63-8.96), no p		Hazard Ratio, 95% CI, p Not provided		Hazard Ratio, 95% CI, p 1.42, (.88-2.30), no p
MB and CRNMB (N)	13.9%(524)	18.6%(522)	6.4%(203)	17.7%(203)	6.3%(142)	6.2%(145)	9.7%(579)	12.2%(576)
	Hazard Ratio, 95% CI, p 1.4, (1.03-1.89), no p		Hazard Ratio, 95% CI, p Not provided		Hazard Ratio, 95% CI, p Not provided, p=.8816		Hazard Ratio, 95% CI, p 1.16, (.77-1.75), no p
Death from any cause (N)	36.6%(524)	39.5%(522)	27.6%(203)	23.6%(203)	11%(142)	16%(145)	26.4%(579)	23.4%(576)
	Hazard Ratio, 95% CI, p 1.4, (1.03-1.89), no p		Hazard Ratio, 95% CI, p Not provided		Hazard Ratio, 95% CI, p Not provided, p=.3078		Hazard Ratio, 95% CI, p .82, (.62-1.09), no p

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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Pulmonary Hypertension and Venous Thromboembolism, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Vascular Medicine

Keywords: Venous Thromboembolism, Fibrinolytic Agents, Prospective Studies, Urinary Bladder Neoplasms, Pyridines, Thiazoles, Warfarin, Enoxaparin, Dalteparin, Heparin, Low-Molecular-Weight, Atrial Fibrillation, Incidence, Sample Size, Vena Cava, Inferior, Patient Selection, Quality of Life, Venous Thrombosis, Vascular Diseases, Aneurysm

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