Among the known risk factors for venous thromboembolism (VTE), cancer remains one of the most potent. In a 15-year population study, patients with an active malignancy were 4.1 times more likely to suffer a VTE event than those free from malignancy.¹ This risk increased to 6.5-fold if they were receiving chemotherapy. The risk also varies with the type of malignancy. Solid tumors, such as those involving the pancreas, stomach, or lung, are associated with a two-year VTE incidence ranging from 1.3-3.2%, and the risk increases up to 21.5-fold in the setting of metastatic disease.² Hematologic malignancies are not exempt from these grim statistics. For example, the incidence of VTE in patients with non-Hodgkin's lymphoma ranges from 1.5-6.6%.^2,3

Despite significant advances in cancer therapy, VTE remains a major cause of morbidity and mortality. Patients with cancer have more than double the major bleeding risk while undergoing anticoagulation therapy for VTE,⁴ and bleeding is cited by more than 4% of individuals as a reason for discontinuing anticoagulation.⁵ Recurrent VTE is 2.6-fold more common in those with malignancy, and this increases to 3.6-fold in those undergoing chemotherapy.⁶ Notably, in patients with malignancy, recurrent VTE is more likely to occur in the setting of a therapeutic international normalized ratio (INR) when compared to individuals without malignancy.⁷ VTE also portends a poor prognosis. In a Danish registry, individuals with cancer at the time of VTE diagnosis had a one-year survival rate of 12% compared to 36% among controls (p<0.001).⁸ Given the prevalence and impact of VTE in this population, there is a dire need for clinical trials studying different secondary prevention strategies.

Traditionally, clinicians used unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) followed by at least three months of therapeutic warfarin for secondary VTE prevention in cancer patients;⁹ however, many patients are unable to tolerate oral medications due to chemotherapy-related nausea or due to complications from their disease. Additionally, this patient population frequently requires interruption of anticoagulation for procedures, which can be difficult to manage with vitamin K antagonists (VKAs). As a result, several studies have compared the efficacy of warfarin to therapy with LMWHs.

The earliest secondary prevention trial for patients with malignancy was the CANTHANOX (Secondary Prevention Trial of Venous Thrombosis with Enoxaparin) study.¹⁰ This randomized, multicenter trial studied patients with VTE and either an active malignancy, or disease in remission that required ongoing therapy. Individuals were randomized to receive either enoxaparin 1.5 mg/kg daily or warfarin with an enoxaparin bridge until they reached a target INR of 2.0-3.0. The primary outcome was a composite endpoint of major bleeding or recurrent VTE within three months of treatment. Unfortunately, the trial was terminated early due to poor enrollment, and only 146 patients were included in the analysis. Although the study was not adequately powered, there was a concerning trend toward more recurrent VTE with warfarin (21.1% vs 10.5%, p = 0.09).

The Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients With Venous Thromboembolism (CLOT) trial¹¹ was a multicenter, randomized trial that enrolled a total of 676 patients with active malignancy and acute proximal deep vein thrombosis (DVT), pulmonary embolism (PE), or both. Notable exclusion criteria included an Eastern Cooperative Oncology Group (ECOG) status score of 3 or 4, active or serious bleeding within the previous two weeks, comorbidities associated with a high risk of serious bleeding, and a platelet count less than 75,000 per cubic millimeter. Patients were randomized in a 1:1 manner to either standard VKA therapy or LMWH therapy. Following randomization, patients in the VKA group received the LMWH dalteparin 200 IU/kg once-daily in addition to either warfarin or acenocoumarol. Dalteparin was discontinued after five to seven days once the INR remained greater than 2.0 for two consecutive days, and the VKA was continued for six total months of therapy with a target INR of 2.0-3.0. In the LMWH group, patients received dalteparin 200 IU/kg once-daily for one month, at which point they transitioned to a dose of ~150 IU/kg once-daily for the remaining five months.

The baseline characteristics of the study participants are listed in Table 1.¹¹ Overall, this was an elderly population with a mean age of 62.5 years. The study group was relatively functional with the majority having an ECOG score of 0 or 1 (63%). Of note, a total of 8 patients with an ECOG score of 3 were included before the study protocol was amended to exclude such patients. Although solid malignancies comprised the majority of study participants, nearly 10% of individuals suffered from hematologic malignancies. The majority of patients (67%) had metastatic disease at the time of enrollment. Approximately 78% of patients were undergoing antineoplastic therapy, and nearly 13% had an indwelling central venous catheter.

Table 1: Baseline Characteristics of Patients from the CLOT Trial

Characteristic	Low-Molecular-Weight Heparin (N = 338)	Vitamin K Antagonist (N = 338)
Mean age (years)	62±12	63±13
ECOG score (number of patients)
0	80	63
1	135	150
2	118	122
3	5	3
Hematologic cancer (number of patients)	40	30
Solid tumor (number of patients)
No clinical evidence of disease	36	33
Localized disease	39	43
Metastatic disease	223	232
Antineoplastic treatment (number of patients)	266	259
Central venous catheter (number of patients)	46	40

During the six-month study period, recurrent VTE occurred in 27 of 336 patients in the dalteparin group versus 53 of 336 in the VKA group (hazard ratio [HR] 0.48, p = 0.002).¹¹ This was driven primarily by a difference in the DVT event rate (14 DVTs versus 37, respectively). Of note, all DVTs were in proximal vein segments. There were 13 PEs in the dalteparin group (5 fatal) versus 16 in the VKA group (7 fatal). Twenty of the overall VTE events in the VKA group occurred when the INR was <2.0. There was no significant difference in the rate of major bleeding (6% vs 4%, p = 0.27). Mortality remained high in both groups (39% vs 41%, p = 0.53). Overall, largely based on these findings, LMWH became the standard of care for recurrent VTE prevention in the setting of malignancy.

The more contemporary Comparison of Acute Treatments in Cancer Haemostasis (CATCH) trial served as the second major randomized clinical trial supporting the efficacy of LMWHs.¹² In this study, 900 patients with active malignancy and acute VTE were randomized to either tinzaparin 175 IU/kg once-daily for six months or tinzaparin as a bridge to warfarin with a target INR of 2.0-3.0 for a total of six months. Recurrent VTE occurred in 7.2% of patients in the tinzaparin group versus 10.5% in the warfarin group (HR 0.65, p = 0.07). There were no differences in major bleeding (12 patients vs. 11 patients, p = 0.77), although there was less non-major bleeding in the tinzaparin group (49 patients vs. 69 patients, p = 0.004). There was also no difference in overall mortality (150 patients vs. 138 patients, p = 0.54).

With the more recent development of direct oral anticoagulants (DOACs), there has understandably been interest in prescribing these drugs for patients with cancer. Unfortunately, clinical trial data are limited. Patients with active malignancy requiring extended duration anticoagulation for VTE were excluded from the Apixiban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial of the factor Xa inhibitor apixaban.¹³ Although such patients were not explicitly excluded from the major trials of dabigatran,^14,15 a direct thrombin inhibitor, or the trials of rivaroxaban^16,17 and edoxaban,¹⁸ both factor Xa inhibitors, patients with malignancy made up a small minority of the overall trial populations. The Hokusai-VTE study was a randomized, double-blind trial comparing edoxaban to warfarin for secondary VTE prevention.¹⁸ It enrolled a total of 8,292 patients with acute proximal DVT or PE, and all patients were treated for 3-12 months. Although patients with a history of malignancy were excluded if their physicians recommended extended duration anticoagulation with LMWH, the trial ultimately enrolled a total of 771 patients with either active cancer (208 patients) or a history of cancer (563 patients), and for whom LMWH was not recommended for various reasons.¹⁹ Within this total population, recurrent VTE occurred in 14 patients who received edoxaban (3.7%) versus 28 patients who received warfarin (7.1%) (HR 0.53, 95% confidence interval [CI] 0.28-1.00). Additional outcomes from this trial are detailed in Table 2.

Table 2: Clinical Outcomes in Cancer Patients from Hokusai-VTE

Outcome	Edoxaban	Warfarin	Hazard Ratio with Edoxaban (95% CI)
Primary efficacy outcome: recurrent symptomatic VTE—number/total number (%)
Active cancer	4/109 (3.7)	7/99 (7.1)	0.55 (0.16-1.85)
All cancer patients	14/378 (3.7)	28/393 (7.1)	0.53 (0.28-1.00)
Primary safety outcome: major or clinically relevant non-major bleeding—number (%)
Active cancer	20 (18.3)	25 (25.3)	0.72 (0.40-1.30)
All cancer patients	47 (12.4)	74 (18.8)	0.64 (0.45-0.92)
Major bleeding—number (%)
Active cancer	5 (4.6)	3 (3.0)	Not provided
All cancer patients	10 (2.6)	13 (3.3)	Not provided

The only additional data on DOAC use in cancer patients come from pooled analyses. In one such analysis, investigators identified 514 patients with active cancer who were treated with a DOAC compared to 459 treated with a VKA.²⁰ The pooled incidence rate of recurrent VTE with DOAC therapy was 4.1% compared to 6.1% with VKAs (risk reduction [RR] 0.66, 95% CI 0.38-1.2). The rate of major and clinically-relevant non-major bleeding was similar in both groups (15% vs 16%, RR 0.94, 95% CI 0.7-1.3). A pooled analysis examining only dabigatran therapy found similar results.²¹

In summary, based on the clinical trial data available, LMWH therapy is associated with a lower rate of recurrent VTE and a similar risk of major bleeding when compared to VKAs in patients with cancer. Additionally, there are limited data supporting the use of DOACs in this patient population. Therefore, LMWH should be the standard of care in these patients, which is consistent with the most recent American College of Chest Physicians guidelines;²² however, many questions remain. The optimal duration of therapy, particularly for patients with active malignancy and ongoing therapy, has not been defined. This is particularly relevant given the cost and physical pain often associated with LMWH treatment. As clinicians are increasingly considering extended duration anticoagulation, DOACs may be more appealing to patients in order to avoid frequent lab monitoring or daily injections. The upcoming Hokusai-VTE cancer study, which will compare LMWH to edoxaban in patients with cancer over a 12-month period, will hopefully provide much needed guidance.²³ Until then, it is up to clinicians to use the available data to make evidence-based recommendations while also considering their patients' individual needs and wishes, particularly in this high-risk population.

References

1. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160:809-15.
2. Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458-64.
3. Ottinger H, Belka C, Kozole G, et al. Deep venous thrombosis and pulmonary artery embolism in high-grade non Hodgkin's lymphoma: incidence, causes and prognostic relevance. Eur J Haematol 1995;54:186-94.
4. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-8.
5. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007;92:199-205.
6. Heit JA, Mohr DN, Silverstein MC, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000;160:761-8.
7. Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Büller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normal ratio: a retrospective analysis. J Clin Oncol 2000;18:3078-83.
8. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000;343:1846-50.
9. Linkins L. Management of venous thromboembolism in patients with cancer: role of dalteparin. Vasc Health Risk Manag 2008;4:279-87.
10. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002:162:1729-35.
11. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53.
12. Lee AYY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer: A Randomized Clinical Trial. JAMA 2015;314:677-86.
13. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808.
14. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52.
15. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764-72.
16. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510.
17. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
18. Buller HR, Decousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15.
19. Raskob GE, Buller H, Angchaisuksiri P, et al. Edoxaban for long-term treatment of venous thromboembolism in cancer patients. Blood 2013;122:211.
20. van der Hulle T, Den Exter PL, Kooiman J, van der HOeven JJ, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 2014;12:1116-20.
21. Schulman S, Goldhaber SZ, Kearon C, et al. Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost 2015;114:150-7.
22. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52.
23. van Es N, Di Nisio M, Bleker SM, et al. Edoxaban for treatment of venous thromboembolism in patients with cancer. Rationale and design of the Hokusai VTE-cancer study. Thromb Haemost 2015;114:1268-76.

Keywords: Acenocoumarol, Anticoagulants, Antineoplastic Agents, Central Venous Catheters, Dalteparin, Enoxaparin, Factor Xa, Factor Xa Inhibitors, Hematologic Neoplasms, Hemostasis, Heparin, Heparin, Low-Molecular-Weight, Lymphoma, Non-Hodgkin, Platelet Count, Pulmonary Embolism, Pyrazoles, Pyridines, Pyridones, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Thiazoles, Venous Thromboembolism, Venous Thrombosis, Vitamin K, Warfarin

< Back to Listings