Evaluating the Need for Anticoagulation Beyond 6 Months for Patients with Cancer-Associated Venous Thromboembolism: A Retrospect of Real Life (EXTEND Study)
Authors: Louzada Martha L , Kovacs Michael J. , Al-ani Fatimah , Siqueira Lenicio , Lazo-Langner Alejandro 
Published: October 2019

Abstract
Background: The association between cancer and venous thromboembolism (VTE) has been well documented. In patients with cancer, the risk for a first cancer- associated thrombosis is 5 to 28-fold higher than in non-cancer patients. Current oncology clinical practice guidelines recommend that patients with cancer- associated thrombosis be treated for a minimum of 6 months with low molecular weight heparin (LMWH) provided they do not have any contraindications to anticoagulant therapy. The length of anticoagulation beyond the initial 6 months is controversial due to the absence of clinical trials data. Panel consensus from the ASCO 2013 clinical practice guidelines recommends continuing anticoagulation if malignancy remains active or patient is still on active anticancer treatment. There is clear equipoise in which type of anticoagulation approach, if any, is the best beyond 6 months of anticoagulation for these patients. In this retrospective analysis we sought to evaluate what has been the extended anticoagulation therapy of choice in our thrombosis clinic over the past 5 years and its efficacy in preventing late recurrent venous thromboembolism.
Methods: We conducted a single- centre retrospective cohort study (London, Canada) to collect data from adult patients with cancer -associated VTE who received anticoagulation with therapeutic LMWH for at least 6 months. We collected data from January 2008 to December 2013. We included patients 18 years old or older; with any type of active cancer (except basal cell and squamous cell carcinoma of the skin) or stage. Follow up period started at 6 months of anticoagulation and finished at 12 months (total of 6 months of study follow-up), or at time of a recurrent VTE, or death or last follow up in clinic, whichever came first. We used SAS 9.2 to perform the data analysis.
Results: In total 417 patients were potentially eligible but 149 fulfilled our inclusion criteria. 78 (52%) were males, median age was 65 (range 25-86). 123 (82.4%) patients had solid tumors and 26 (17.6%) hematological malignancy. Of the patients with solid tumors, 98 (80.3%) had stage III or IV disease. The most frequent primary tumor sites were colorectal (n= 36; 34%), lung (n=29;20%) and pancreas (n= 17; 11%) among others (n= 41). After the first 6 months of anticoagulation, 20 (13%) patients were considered to be in complete remission of their cancer. In total, 45 of 149 (31%) patients discontinued anticoagulant therapy. 64 (43%) remained on full weight-adjusted dose LMWH, 10 (6%) on prophylactic dose, 29 (19%) were switched to warfarin and 1 (1%) to rivaroxaban. Of the 45 patients that discontinued anticoagulation, 7 were considered to be in complete remission.
Overall, there were 21 (14%) VTE recurrences after the first 6 months of anticoagulation. 12 (57%) occurred in patients using full dose LMWH. Patients in complete remission had a lower risk for VTE recurrence (OR= 0.31; 95%CI: 0.102 - 0.920; p= 0.0349). Although not statistically significant, there is a trend of high VTE recurrence risk in patients with lung or colon cancer, or stage III/IV and for patients on full doseLMWH (Table). A post-hoc power calculation of our study demonstrated 84% power with a 2-sided alpha of 0.05.
Conclusion: Our study demonstrated a significant increased risk for recurrent VTE (14%) in after the firs 6 months of anticoagulation in patients with cancer-associated VTE irrespective of anticoagulation approach. Being in complete remission is significantly associated with a low risk for recurrence. Having lung or colon cancer or advanced stage may increase recurrence risk. Interestingly, patients on full LMWH also showed trend to high VTE recurrence risk. This may reflect a sicker subset of patients with an inherent higher VTE risk. Further prospective trials are warranted to better study the best anticoagulation approach for patients with cancer-associated VTE beyond the first 6 months of anticoagulation.
Table. Univariate analysis for the association of VTE recurrence and tunor and patients characteristics Variables OR (95%CI)# P -value Female 0.58 (0.2 - 1.7) 0.321 Warfarin 0.97 (0.3 - 3.1) 0.958 Prophylactic LMWH^ 0.75 (0.09 - 6.3) 0.791 Full LMWH^ 1.56 (0.62 - 3.9) 0.348 Colorectal* 1.69 (0.4 - 6.4) 0.443 Lung* 1.76 (0.4 - 7.0) 0.422 Pancreas* 0.90 (0.15 - 5.5) 0.909 stageIII or IV 1.93 (0.67 - 5.5) 0.223
#odds ratio ( 95% confidence interval)
^ reference: no anticoagulation
* reference: hematological cancer

Disclosures
No relevant conflicts of interest to declare.