Dual anticoagulation with fondaparinux and dabigatran for treatment of cancer‐associated hypercoagulability
Authors: Hanny Al‐Samkari, Jean M. Connors
Journal: American Journal of Hematology (2018)

Venous thromboembolism (VTE) occurs in approximately 5%-10% of cancer patients, traditionally treated with low-molecular-weight heparin (LMWH) anticoagulants,1 although data for the use of direct oral anticoagulants in this setting are emerging.2 Recurrence is common despite standard intensity anticoagulation; it is managed with dose escalation of parenteral anticoagulants despite limited supporting data. A 38-year-old man with a three-month history of fatigue, low back pain, and unintentional weight loss was ultimately diagnosed with metastatic EML4-ALK rearranged lung adenocarcinoma. Four days after starting crizotinib, he presented with right-sided hemiparesis and lower extremity swelling. Imaging revealed an acute middle cerebral artery stroke and bilateral lower extremity deep venous thromboses (DVT) and superficial venous thromboses (SVT). Transthoracic echocardiogram and cardiac MRI revealed marantic endocarditis. Heparin-platelet factor 4 ELISA was negative; further hypercoagulability testing was not performed as it was determined to be unlikely to influence management of this patient with active cancer and multiple thrombotic events. Enoxaparin 1 mg/kg every 12 hours was started; the patient's weight was 65.3 kg. Over the following six weeks, the patient had four episodes of recurrent radiographically confirmed events, including cerebral venous sinus thrombosis, new strokes, and DVT. In each case, a new, distinct intraluminal defect was seen on imaging, confirming true thrombosis recurrence. He was managed with successive dose escalation of parenteral agents and then addition of aspirin antiplatelet therapy. He was stable for three weeks without recurrent events on fondaparinux 12.5 mg once daily (well above standard weight-based dosing) and aspirin 81 mg once daily until he developed symptomatic bilateral pulmonary emboli (PE). Dabigatran 75 mg twice daily was added and aspirin was discontinued. The patient had no further thrombotic events and developed no bleeding complications. He died six months later from progressive lung cancer. Autopsy revealed chronic pulmonary embolus without evidence of acute thromboembolism. Figure 1 illustrates the patient's clinical course, noting each specific thrombotic event and the corresponding anticoagulation modification, as well as the patient's cancer therapy and response to therapy. The timeline demonstrates two notable findings, namely (1) that the thrombotic events ceased only with combination fondaparinux and dabigatran therapy and (2) disease control status did not correlate well with thrombotic events. Timeline illustrating thrombotic events, anticoagulation, malignancy treatment, and response to treatment [by Response Evaluation Criteria in Solid Tumors (RECIST)]. DVT, deep venous thrombosis; SVT, superficial venous thrombosis; PE, pulmonary embolus; CVST, cerebral venous sinus thrombosis; QD, once daily; BID, twice daily; SD, stable disease; PR, partial response; PD, progressive disease. *Was maintained on IV unfractionated heparin infusion as an inpatient for the duration between this DVT and the subsequent cerebral venous sinus thrombosis. [Color figure can be viewed at wileyonlinelibrary.com] Recent data suggests ALK-rearranged lung cancer may impart a higher thrombotic risk than other types of lung cancer. While approximately 8%-15% of all patients with non-small cell lung cancer (NSCLC) develop VTE over the course of their disease, one retrospective analysis of 98 patients with ALK-rearranged NSCLC found a 36% incidence of VTE.3 In this study, patients developing VTE tended to be younger and had a shorter overall survival. The thrombotic diathesis associated with ALK-rearranged NSCLC may be particularly severe, as two recently published reports describe cases of fulminant disseminated intravascular coagulation upon presentation of newly-diagnosed ALK-rearranged NSCLC.4, 5 Management of recurrent cancer-associated thrombosis is challenging. Although the CLOT trial established LMWH as the standard-of-care for cancer-associated VTE,1 data for the management of recurrent VTE on standard intensity anticoagulation are limited. Small retrospective studies assessed the results of the use of 120%-125% of standard dose LMWH, with variable success.6-8 When our patient developed symptomatic PE, dabigatran etexilate was added to the supra-therapeutic dose of fondaparinux as it directly inhibits thrombin, while fondaparinux indirectly inhibits activated factor X after binding to antithrombin. This combination of anticoagulants was specifically chosen for the different coagulation factor targets of each. The availability of idarucizumab, the dabigatran reversal agent, was also a consideration in case bleeding occurred. Only two other publications, both case reports, describe a dual anticoagulant approach. Both were successful, describing dalteparin plus warfarin for multiple recurrences of cancer-associated VTE9 and rivaroxaban plus warfarin for multiple recurrences of idiopathic VTE.10 Our patient appears to have had a more severe thrombotic course than either of these previously described cases. In patients with severe cancer-associated hypercoagulability with recurrent thrombosis despite multiple dose escalations of LMWH or fondaparinux, a dual-anticoagulant strategy adding dabigatran, an agent with a distinct mechanism of action and available reversal agent, may be an effective and safe option. Al-Samkari, H: Agios Pharmaceuticals (Consultancy); Connors, JM: Boehringer Ingelheim (Scientific Advisory Board); Bristol-Myers Squibb (Scientific Advisory Board, Consultant, Independent Review Committee); Unum Therapeutics (Data Safety Monitoring Board) H. Al-Samkari designed the report, collected the data, analyzed the data, wrote/revised the manuscript, and created the figure; J.M. Connors designed the report and critically revised the manuscript.