A 65-Year-Old Man With Cancer and a New Acute DVT
Vineela Kasireddy, MD; James Martin, MD, and Ronald N. Rubin, MD—Series Editor
Kasireddy V, Martin J, Rubin RN. A 65-year-old man with cancer and a new acute DVT. Consultant. 2018;58(7):182-184.
A 65-year-old man with a history of hypertension, type 2 diabetes, chronic kidney disease, and metastatic pancreatic adenocarcinoma presents to the emergency department with acute left lower-extremity swelling and pain. He has been receiving frontline systemic chemotherapy with fluorouracil, leucovorin, irinotecan and oxaliplatin.
Venous Doppler ultrasonography examination demonstrates an acute deep-vein thrombosis (DVT) extending from the popliteal vein to the common femoral vein. Notably, he has been having significant nausea and vomiting associated with the chemotherapy. Overall, his appetite is poor, and he has chronic epigastric pain that is worse with food intake. He has lost 6.35 kg in past few months, and his current weight is 55.3 kg.
Laboratory test results are notable for a serum creatinine level of 2.1 mg/dL, which is near his baseline level (estimated creatinine clearance was 27.22 mL/min). His platelet count, prothrombin time, and activated partial thromboplastin time are within normal limits. He has grade 1 transaminitis, but his total bilirubin level is within normal limits.
He knows that he will require some type of therapy to prevent further DVT or pulmonary embolism (PE), but he reports being quite fatigued with his intensive and frequent medical needs, so he prefers the most convenient yet effective means of prevention.
Answer: C, apixaban, 5 mg twice daily (after an initial loading dose of 10 mg twice daily for 7 days) is the most appropriate choice.
It is estimated that approximately 20% to 30% of all first venous thromboembolism (VTE) events are related to cancer.1 Persons with cancer have approximately a 4-fold to 7-fold increased risk of VTE compared with persons without cancer, with an incidence rate of approximately 8% to 10%, although the reported rate varies greatly among studies.1,2 The incidence rate of VTE also varies by cancer type, with pancreatic adenocarcinomas having among the highest rates of detected VTE.2,3
Several risk-assessment scores have been developed in an attempt to identify cancer patients who are at high risk of VTE. These risk-assessment systems incorporate variables such as the site of cancer, the presence of leukocytosis or thrombocytosis, the type of chemotherapeutic agents received, and biomarkers such as D-dimer and soluble P-selectin. The ability of these scores to accurately predict VTE has been poor, and they are generally not used in clinical practice.4 The data supporting prophylactic anticoagulation for patients with cancer who are at high risk of VTE also remains controversial.5 Thus, anticoagulation is not given until VTE events occur.
The proposed pathways of VTE in cancer are numerous and diverse.6 Candidate mechanisms include increased tissue factor expression by monocytes7 or adenocarcinoma cells themselves,8 as well as interleukin 6–induced thrombocytosis.9 Further studies are needed to further elucidate the complex pathophysiology of cancer-associated thrombosis.
NEXT: Management of Cancer-Associated VTE
MANAGEMENT OF CANCER-ASSOCIATED VTE
The standard of care for the treatment of VTE in patients with cancer has evolved from oral vitamin K antagonists (VKAs), such as warfarin, to the use of a low-molecular-weight heparin (LMWH) after a large randomized, multicenter, phase-3 trial demonstrated that dalteparin is more effective than coumarin-derivatives.10 The risk of recurrent VTE in the study was 9% versus 17%, respectively (hazard ratio [HR], 0.48; 95% CI, 0.30-0.77; P = .002). Dalteparin was also associated with a lower risk of bleeding, although the finding was not statistically significant (14% vs 19%; P = .09). LMWH seems to overcome the challenges associated with the use of oral VKAs in patients with cancer, such as unpredictable absorption due to liver dysfunction and malnutrition. Thus, Answer A, warfarin, is not optimal here. However, the need for subcutaneous administration and the potentially high cost make LMWH unappealing for many patients with cancer, such as the patient in our case, who already feels burdened by the invasive and difficult diagnostic and therapeutic interventions directed at his cancer diagnosis.
The direct thrombin inhibitors and direct factor Xa inhibitors, colloquially termed as direct oral anticoagulants (DOACs), have revolutionized the management of systemic anticoagulation for both atrial fibrillation and VTE in the past decade. The data on efficacy and safety of these agents as treatment in cancer-associated VTE until recently had been quite limited, because only about 5% of participants had active cancer in the landmark trials that led to these agents being approved for VTE.11 A meta-analysis looking at 10 randomized trials that compared DOACs to VKAs in patients with cancer-associated VTE suggested that these agents are likely equivalent in terms of safety and efficacy.12 In practice, many oncologists have already been using DOACs, without published prospective data, for cancer-associated VTE in patients who refuse or have a contraindication for LMWH. A single-arm study of 124 cases of cancer-associated VTE treated with rivaroxaban demonstrated recurrence rates and bleeding similar to historical LMWH data.13
Recently, 2 large randomized studies have presented potentially exciting and definitive data on the use of DOACs for cancer-associated VTE. A large multinational phase-3 trial randomly assigned 1050 cancer patients with acute symptomatic or incidental VTE to receive either oral edoxaban or subcutaneous dalteparin for up to 12 months.14 The primary outcome was a composite of both recurrent VTE and major bleeding during the 12 months after randomization. Major bleeding was defined as the current standard by the International Society on Thrombosis and Haemostasis: hemoglobin decrease of greater than 2 g/dL, requiring transfusion of 2 or more units of blood, occurring in a critical site (intracranial, intraocular, retroperitoneal, intraarticular, or pericardial bleeding), or bleeding that had contributed to death. The study met its primary outcome of noninferiority between the 2 arms (HR, 0.97; 95% CI, 0.70-1.36; P = .0056 for noninferiority). The rate of recurrent VTE was similar between the 2 arms, with 7.9% of edoxaban patients and 11.3% of dalteparin patients experiencing recurrent thrombosis (HR, 0.71; 95% CI, 0.48-1.06; P = .06). However, there was a slight but statistically significant increased risk of major bleeding in the edoxaban group, 6.9% vs 4% (HR, 1.77; 95% CI, 1.03-3.04; P = .04), which the authors attributed to a higher number of gastrointestinal tract malignancies within this cohort.
NEXT: Management (Continued)
Another large, randomized, phase-2 trial from the United Kingdom explored rivaroxaban compared with dalteparin in 406 patients with cancer-associated thrombosis.15 The primary outcome in this study was VTE recurrence. Patients in the rivaroxaban arm had a VTE recurrence rate of 4%, vs 11% in the dalteparin arm. Major bleeding was similar across both arms (3% vs 4%, respectively), although clinically significant nonmajor bleeding was higher in the rivaroxaban arm (13% vs 2%). A large phase-3 trial is reportedly being planned. Thus, a sound and growing body of data suggests DOACs, such as the regimen suggested in Answer C, seem optimal in most cancer-associated VTE cases in regard to efficacy, safety, and convenience, and appear to be the best option in this case.
In the above patient’s case, potential anticoagulation options would be a LMWH such as enoxaparin, 1 mg/kg twice daily, or apixaban, 5 mg twice daily (following an initial 7-day loading dose of 10 mg twice daily). Both of these agents are safe for use in patients with mild chronic kidney disease, and there are dose reductions available if our patient’s creatinine clearance worsens. Both patient preference and cost of medication can be considered in the decision.
We recommend against the use of warfarin (Answer A) in this patient’s case, since his erratic eating habits and overall anorexia make proper dosing and adjustment of this medication difficult. And, as discussed, warfarin has been shown to be inferior to LMWH in large trials.10 An inferior vena cava filter (Answer D) is not recommended, since nothing in the patient’s history suggests that he cannot safely receive systemic anticoagulation.
NEXT: Patient Follow-Up
In the patient’s case presented earlier, apixaban therapy was initiated with plans to continue systemic anticoagulation for 3 to 6 months, although it can be argued that since this patient has an irreversible risk factor for VTE (ie, active metastatic malignancy), indefinite anticoagulation should be pursued if tolerated.
His acute DVT symptomatically resolved after 6 weeks, and he remains on apixaban.
Vineela Kasireddy, MD, is a fellow in hematology-oncology at Fox Chase Cancer Center at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania.
James Martin, MD, is a fellow in hematology-oncology at Fox Chase Cancer Center at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania.
Ronald N. Rubin, MD, is a professor of medicine at the Lewis Katz School of Medicine at Temple University and is chief of clinical hematology in the Department of Medicine at Temple University Hospital in Philadelphia, Pennsylvania.
- Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122(10):1712-1723.
- Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med. 2012;9(7):e1001275.
- Alcalay A, Wun T, Khatri V, et al. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol. 2006;24(7):1112-1118.
- van Es N, Di Nisio M, Cesarman G, et al. Comparison of risk prediction scores for venous thromboembolism in cancer patients: a prospective cohort study. Haematologica. 2017;102(9):1494-1501.
- Hogg K, Carrier M. Prevention and treatment of venous thromboembolism in patients with cancer. Ther Adv Hematol. 2012;3(1):45-58.
- Hisada Y, Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood. 2017;130(13):1499-1506.
- von Brühl M-L, Stark K, Steinhart A, et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209(4):819-835.
- Khorana AA, Francis CW, Menzies KE, et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost. 2008;6(11):1983-1985.
- Stone RL, Nick AM, McNeish IA, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med. 2012;366(7):610-618.
- Lee AYY, Levine MN, Baker RI, et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153.
- van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124(12):1968-1975.
- 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(2):475-483.
- Yhim H-Y, Choi W-I, Kim S-H, et al. Long-term rivaroxaban for the treatment of acute venous thromboembolism in patients with active cancer in a prospective multicenter trial [published online May 23, 2018]. Korean J Intern Med. doi:10.3904/kjim.2018.097.
- Raskob GE, van Es N, Verhamme P, et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615-624.
- Young A, Phillips J, Hancocks H, et al. OC-11—Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism. Thromb Res. 2016;140(suppl 1):S172-S173.
- Streiff MB. Are direct acting oral anticoagulants ready for prime-time use in cancer-related thrombosis? Clin Adv Hematol Oncol. 2018;16(3):180-184.