Clotting and Bleeding in Oncology Patients: Clinical Scenarios and Challenges

October 15, 2016

Due to the delicate hemostatic balance in cancer patients, an understanding of both the clotting and bleeding risks in this population is crucial to effectively manage hematologic complications.

Introduction

Hematologic complications are routinely encountered in the management of cancer patients. Patients with cancer are up to 7 times more likely to develop a venous thromboembolism (VTE) compared with those without a diagnosis of cancer.[1] Furthermore, VTE is a leading cause of mortality in cancer patients, and contributes to increased morbidity and cost of care.[2-4] The management of cancer-associated thrombosis is especially challenging because of the simultaneous increased risk of bleeding observed in patients who receive anticoagulation.[5-7] Due to the delicate hemostatic balance in cancer patients, an understanding of both the clotting and bleeding risks in this population is crucial to effectively manage hematologic complications.

Clinical Vignette #1

A 70-year-old man with recently diagnosed metastatic pancreatic cancer, currently receiving his second cycle of gemcitabine and nab-paclitaxel, is seen for follow-up. On exam, swelling and tenderness in the left calf is noted, and an emergent lower extremity ultrasound confirms the presence of a deep vein thrombosis (DVT). The patient’s creatinine level is 0.75 mg/dL (estimated glomerular filtration rate > 60 mL/min). The initiation of therapeutic anticoagulation with enoxaparin is recommended; however, the patient is very hesitant to perform daily injections and asks about the new oral anticoagulants he has seen advertised on television.

What is the recommended anticoagulant for cancer patients?

The most recent guidelines from the American Society of Clinical Oncology (ASCO)[8] and the American College of Chest Physicians[9] state that low-molecular-weight heparin (LMWH) remains the standard of care for management of thrombosis in cancer patients without severe renal impairment. This recommendation is based on evidence from the CLOT trial, which demonstrated a decrease in the risk of recurrent VTE (hazard ratio [HR], 0.48; P = .002) in dalteparin-treated patients compared with warfarin-treated patients, with no difference in either major bleeding rates or mortality.[10] Post-hoc analysis of this study revealed a survival benefit in the subgroup of patients without metastatic disease (HR for death at 12 months, 0.50 [95% CI, 0.27–0.95]; P = .03).[11] There have been no randomized studies directly comparing the different LMWH formulations with each other, or with fondaparinux.

Is there a role for DOACs in the treatment of VTE in cancer patients?

Although direct oral anticoagulants (DOACs) are an attractive option for some, they are not currently recommended for routine use in cancer patients, since they have not been directly compared with LMWH in prospective randomized clinical studies. The phase III randomized studies evaluating the safety and efficacy of the DOACs all used a comparator arm of vitamin K antagonists (VKAs), and only included a small proportion of highly selected cancer patients (Tables 1 and 2). A meta-analysis of 2,310 cancer patients from 9 separate randomized trials evaluating LMWH vs VKAs or DOACs vs VKAs found that treatment with LMWH resulted in a significant reduction in recurrent VTE compared with VKAs (relative risk [RR], 0.52 [95% CI, 0.36–0.74]), while treatment with DOACs compared with VKAs did not (RR, 0.66 [95% CI, 0.39–1.11]).[12] In a meta-analysis of the cancer patients enrolled in six of the phase III DOAC trials, the DOAC group had a significantly lower rate of recurrence compared with the VKA group (RR, 0.57 [95% CI, 0.36–0.91]; P = .02), without a significant increase in the rate of major bleeding (RR, 0.77 [95% CI, 0.44–1.33]; P = .35).[13] However, another meta-analysis found no difference in recurrence rates of VTE between the DOAC- and VKA-treated cancer patients (odds ratio, 0.63 [95% CI, 0.37–1.10]).[14] Pooled results of cancer patients enrolled in the phase III studies of dabigatran vs VKAs showed no difference in recurrent VTE or major bleeding rates.[15] Notably, the cancer patients included in these trials likely had a more favorable cancer prognosis (patients with a poor prognosis or those requiring long-term anticoagulation were excluded from these studies), which may have contributed to the observed effects. This is reflected in the overall lower recurrence rates observed in the VKA-treated groups in the DOAC trials (5.9%)[13] compared with the CLOT trial (11%).[10] No randomized controlled studies directly comparing DOACs with LMWH have been published thus far; however, there is an ongoing multicenter randomized study of edoxaban vs dalteparin in cancer patients (ClinicalTrials.gov identifier: NCT02073682).

In summary, LMWH remains the standard of care in cancer patients without significant renal impairment. Although the emerging data on DOACs in cancer patients are encouraging, further prospective studies comparing the efficacy and safety of DOACs with LMWH in this population are warranted before these agents can be routinely recommended. In patients who refuse injections or who are unable to receive LMWH for other reasons, VKAs or DOACs can be considered, with the understanding that data to support their use in this setting are limited. The choice between these oral agents will be dependent on factors including renal function, cost, and patient preference, and should ultimately involve a discussion with the patient on the risks and benefits of each particular option.

Clinical Vignette #2

A 63-year-old heavy smoker is admitted to the hospital with a new diagnosis of metastatic lung adenocarcinoma. On admission he reports new chest pain and is hypoxic. Further workup reveals bilateral pulmonary emboli. His staging brain MRI also reveals multiple nonhemorrhagic metastatic lesions scattered throughout the brain.

What is the risk of intracranial hemorrhage in patients with brain metastases who receive therapeutic anticoagulation? What is the recommended management in this setting?

The management of VTE in cancer patients with intracranial metastasis is challenging because of the tenuous balance between clotting and bleeding, and the limited data to support the safety of anticoagulation in this setting. Studies evaluating the risk of intracranial hemorrhage (ICH) in cancer patients are limited to retrospective analyses. In a study of ICH, 51 cancer patients with central nervous system (CNS) metastasis were followed at a single center between 1980 and 1992; 3 (7%) of 42 patients who received anticoagulation for VTE experienced ICH.[16] In this study, patients were treated with intravenous heparin with transition to warfarin, with two of the three episodes of ICH occurring in the setting of supratherapeutic coagulation parameters and resulting in fatal outcomes.[16] Notably, 4 of the 10 patients who received an inferior vena cava (IVC) filter alone developed a recurrent VTE, and the 2 patients who received no therapy both died of autopsy-proven pulmonary emboli.[16] Another retrospective study of 74 patients with metastatic melanoma reported ICH in 2 of the 57 patients who received therapeutic anticoagulation.[17]

A recent retrospective matched-cohort study compared 104 patients who had intracranial metastasis treated with enoxaparin with a similar cohort of 189 patients who did not receive anticoagulation to evaluate whether treatment with enoxaparin was associated with an increased risk of hemorrhage.[18] While ICH was observed frequently, there was no difference in the 1-year incidence rate of ICH between the two groups (19% in the enoxaparin group vs 21% in the untreated group; HR, 1.02; P = .97). Melanoma and renal cell carcinoma patients had a fourfold increased risk of ICH compared with lung cancer patients, although there was no difference in the rates of ICH in the enoxaparin-treated cohort vs untreated cohort in subgroup analysis (35% vs 34%; P = .80).[18] Although these studies suggest anticoagulation may be safe, these results should be interpreted with caution due to their retrospective nature and the potential inherent bias of clinicians to select patients at lower bleeding risk to receive anticoagulation.

According to current ASCO guidelines, the presence of brain metastases is not an absolute contraindication to anticoagulation.[8] Although data supporting the safety of anticoagulation in the setting of brain metastases are limited, we agree with these recommendations that therapeutic anticoagulation should be initiated in most cancer patients with intracranial metastases who have an acute VTE, with careful analysis of the risks of bleeding vs clotting in each case. In this particular clinical case, given that lung cancer generally carries a lower risk of ICH compared with other tumor types, and there is an absence of active bleeding on imaging, we would recommend treatment with LMWH.

Should placement of an IVC filter be considered in this patient? What are the indications for IVC filter placement in cancer patients?

The role of IVC filters in cancer patients is controversial, as there are limited data to support their efficacy in this population. In the randomized controlled PREPIC study of permanent IVC filter placement plus anticoagulation vs anticoagulation alone, the risk of pulmonary embolism was reduced with IVC filter placement, but the rate of recurrent DVT was increased, with no effect on survival.[19] However, cancer patients only comprised a minority of this study population (16% of patients who received a filter and 12% who did not receive a filter), and both treatment groups received some type of therapeutic anticoagulation.[19] Importantly, the placement of an IVC filter is not without complications in the cancer population, largely due to the hypercoagulable state of malignancy. In one retrospective analysis of 49 cancer patients with CNS metastases and VTE, 12% developed recurrent pulmonary emboli, and 57% developed IVC or filter thrombosis, recurrent DVT, or post-thrombotic syndrome.[20] In general, IVC filter placement should only be considered in cases where anticoagulation is clearly contraindicated. The benefits of IVC filter placement should also be considered in the context of cancer prognosis, as those with advanced disease are less likely to benefit from filter placement.[21,22] If an IVC filter is placed, a retrievable filter should be utilized and removed as soon as safely possible. In this particular clinical scenario, we recommend anticoagulation with LMWH over IVC filter placement.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293:715-22.

2. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632-4.

3. Gussoni G, Frasson S, La Regina M, et al. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res. 2013;131:24-30.

4. Khorana AA, Dalal MR, Lin J, Connolly GC. Health care costs associated with venous thromboembolism in selected high-risk ambulatory patients with solid tumors undergoing chemotherapy in the United States. Clinicoecon Outcomes Res. 2013;5:101-8.

5. 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.

6. Monreal M, Falga C, Valdes M, et al. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry. J Thromb Haemost. 2006;4:1950-6.

7. Hutten BA, Prins MH, Gent M, et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol. 2000;18:3078-83.

8. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2189-204.

9. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52.

10. Lee AY, 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.

11. Lee AY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123-9.

12. Carrier M, Cameron C, Delluc A, et al. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res. 2014;134:1214-9.

13. van Es N, Coppens M, Schulman S, et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124:1968-75.

14. Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest. 2015;147:475-83.

15. 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.

16. Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer. 1994;73:493-8.

17. Alvarado G, Noor R, Bassett R, et al. Risk of intracranial hemorrhage with anticoagulation therapy in melanoma patients with brain metastases. Melanoma Res. 2012;22:310-5.

18. Donato J, Campigotto F, Uhlmann EJ, et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood. 2015;126:494-9.

19. PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005;112:416-22.

20. Levin JM, Schiff D, Loeffler JS, et al. Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology. 1993;43:1111-4.

21. Wallace MJ, Jean JL, Gupta S, et al. Use of inferior vena caval filters and survival in patients with malignancy. Cancer. 2004;101:1902-7.

22. Barginear MF, Lesser M, Akerman ML, et al. Need for inferior vena cava filters in cancer patients: a surrogate marker for poor outcome. Clinical and applied thrombosis/hemostasis. Clin Appl Thromb Hemost. 2009;15:263-9.

23. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21.

24. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost. 2015;13:2187-91.

25. Raskob GE, Buller H, Angchaisuksiri P, et al. Edoxaban for long-term treatment of venous thromboembolism in cancer patients. Blood. 2013;122(suppl 21):abstr 211.