Treatment of Venous Thromboembolism in Malignancy
A 62-year-old female with a history of smoking, hypertension, hypothyroidism, and recently diagnosed with non-small cell lung cancer of the right lung presents to your outpatient clinic for evaluation. She is currently undergoing treatment with nivolumab/ipilimumab. Her oncologist noted left lower extremity swelling and pain at a clinic visit 1 week ago and obtained a venous duplex ultrasound of the leg demonstrating a left femoral deep venous thrombosis.
The patient appears comfortable, has an oxygen saturation of 98% on room air, respiratory rate of 20 breaths per minute, blood pressure of 115/72 mmHg, and heart rate of 68 beats per minute. She is afebrile. Her weight is 68 kg. Her current medications include carvedilol and levothyroxine. Her creatinine clearance is 55 mL/min, hemoglobin 12.5 g/dL, and platelet count is 257 thousands/uL.
Which of the following is the most accurate statement regarding the treatment of this patient?
The correct answer is: B. Apixaban 10mg twice daily for 7 days followed by 5mg twice daily thereafter is an acceptable treatment strategy.
Thrombosis in malignancy is a common clinical entity with cancer patients experiencing venous thromboembolism (VTE) up to seven times more frequently than individuals without cancer.1 Vitamin K antagonists had been the cornerstone of treatment for VTE in malignancy until two decades ago. The CLOT trial randomized individuals with cancer and acute, symptomatic deep-vein thrombosis (DVT) or pulmonary embolism (PE) to low-molecular weight heparin (LMWH), dalteparin (subcutaneous injection of 200 IU/kg body weight once daily) for 5-7 days followed by warfarin (INR goal of 2.5) for 6 months versus dalteparin monotherapy (200 IU/kg body weight for 1 month, followed by daily dosing of 150 IU/kg body weight for 5 months). Dalteparin was more effective in reducing the risk of recurrent thrombosis compared with warfarin (hazard ratio [HR]: 0.48, 95% confidence interval [CI]: 0.30-0.77, p = 0.002), without increasing the risk of major bleeding (6% in dalteparin group vs. 4% in warfarin group, p = 0.27).2
Direct oral anticoagulants (DOAC) are more convenient to use compared with warfarin, do not need routine monitoring, and have fewer drug-drug and food-drug interactions. Compared with LMWHs, DOACs are advantageous since DOAC use avoids the requirement for daily injections. DOACs are currently recommended as a first line therapy for VTE (including DVT and PE) in individuals without cancer.
Over the last several years there have been three separate randomized clinical trials evaluating the role of DOACs in malignancy: Hokusai VTE Cancer, SELECT-D, and Caravaggio.
Hokusai VTE Cancer was an open-label, non-inferiority trial that randomly assigned 1,050 patients with cancer and acute symptomatic or incidental VTE either to LMWH (choice of heparin and regimen at discretion of treating provider) for 5 days followed by oral edoxaban (60mg once daily) or subcutaneous dalteparin (200 IU/kg body weight for 30 days followed by 150 IU/kg body weight). Treatment was carried out for a total period of up to 12 months. Oral edoxaban was noninferior to dalteparin for the predetermined composite outcome of recurrent VTE or major bleeding (HR 0.97 [95% CI 0.70-1.6], p = 0.006 for non-inferiority), however, the rate of major bleeding was higher with edoxaban when compared to dalteparin (HR: 1.77, 95% CI: 1.03-3.04, p = 0.04).3
SELECT-D was an open-label, pilot trial randomizing 203 patients with active cancer and PE or symptomatic lower extremity DVT to either dalteparin (200 IU/kg body weight for 30 days followed by 150 IU/kg body weight for the remainder of the study period) or rivaroxaban (15mg twice daily for the first 3 weeks, followed by 20mg daily for the remainder of the study period) for a total treatment period of 6 months. Rivaroxaban had a lower rate of recurrent VTE (HR: 0.43, 95% CI: 0.19-0.99) but higher clinically relevant nonmajor bleeding when compared to dalteparin during the total follow up period (HR: 3.76, 95% CI: 1.63-8.69).4
Caravaggio was an open-label non-inferiority trial randomizing 1,155 patients with cancer and symptomatic or incidental acute proximal DVT or PE to either oral apixaban (10mg twice daily for the first 7 days followed by 5mg twice daily thereafter) or subcutaneous dalteparin (200 IU/kg body weight for 30 days followed by 150 IU/kg body weight for the remainder of the study period) for a total treatment period of 6 months. Oral apixaban was found to be noninferior to dalteparin with regard to recurrent VTE (HR: 0.63, 95% CI: 0.37-1.07, p < 0.001 for non-inferiority). Unlike Hokusai VTE Cancer and SELECT-D, in Caravaggio, the DOAC regimen (apixaban) compared with LMWH was not associated with a significantly increased risk of clinically relevant bleeding (HR: 1.42, 95% CI: 0.88-2.30).5
On the basis of these trials, some clinical guidelines (including the National Clinical Cancer Network and the International Initiative on Thrombosis and Cancer) recommend DOACs as an acceptable first line agent in specific clinical scenarios such as ambulatory cancer patients without a known increased risk of bleeding.6,7 Because of the reported increased risk of bleeding seen in the Hokusai VTE Cancer trial and the SELECT-D trial, DOACs are not routinely recommended for individuals with a luminal gastrointestinal or genitourinary cancer.
- This answer choice is incorrect. The patient is hemodynamically stable and has no other signs or symptoms to suggest she has an acute, symptomatic PE that requires inpatient treatment. Further, warfarin is no longer felt to be the most appropriate first line treatment for cancer associated VTE given an increased rate of recurrent VTE when compared with LMWH.
- This answer choice is incorrect. As discussed, LMWH is an appropriate choice for treatment of cancer associated VTE, however for ambulatory patients without an increased risk of bleeding, DOACs are now also an acceptable treatment option. Apixaban has no known drug-drug interactions with either of the patient's cancer therapies.
- This answer choice is incorrect. Dabigatran was not studied in any of the recent major clinical trials evaluating the use of a DOAC in comparison to LMWH. It is unknown whether this agent is non-inferior to LMWHs for use as an outpatient oral regimen for cancer associated VTE.
- Gervaso L, Dave H, Khorana AA. Venous and arterial thromboembolism in patients with cancer: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2021;3:173-90.
- 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.
- Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;6378:15-24.
- Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018;36:2017-23.
- Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020;382:1599-1607.
- O'Connell C, Escalante CP, Goldhaber SZ, McBane R, Connors JM, Raskob GE. Treatment of cancer-associated venous thromboembolism with low-molecular-weight heparin or direct oral anticoagulants: patient selection, controversies, and caveats. Oncologist 2021;26:e8-e16.
- Farge D, Frere C, Connors JM, et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019;20:e566-e581.