During the 11th ICTHIC, Agnes YY Lee and Marcello Di Nisio debated whether anticoagulation treatment should be continued in patients with cancer-associated thrombosis (CAT) beyond 6 months of therapy. Here, we summarize the evidence suggesting that venous thromboembolism (VTE) treatment should be continued beyond the first 6 months of therapy.
The reasons to discontinue anticoagulation are reported in the article “DEBATE: Should VTE treatment continue beyond six months? Evidence supporting anticoagulation discontinuation.”
No high-level evidence on the optimal duration of anticoagulation in patients with CAT exists. Despite that, Expert Consensus from various guidelines suggests continuing anticoagulant therapy as long as the cancer is active and the patient is maintaining anticoagulant therapy, whereas discontinuing it if the risk of serious bleeding outweighs the risks of recurrent thrombosis [1-3].
When choosing whether or not to continue anticoagulation therapy, the risk of recurrent thrombosis should be weighted versus the risk of major bleeding. However, this is not all; patient-centered outcomes should also be considered. These include the downstream consequences of having a recurrence thrombotic event or bleeding event, such as hospitalization, new or worsening symptoms of events, discontinuation or interruption of their cancer therapy when experiencing a recurrent event, and, most importantly, fatal recurrence as well as fatal bleeding.
It is known that patients make decisions based on the cost of therapy and the overall impact on their quality of life.
Therefore, when deciding whether or not to continue with anticoagulation therapy, the analysis should consider all these outcomes in the context of patient values and preferences and not just the risk numbers of recurrence versus major bleeding.
However, which data are available about the risks of recurrent thrombosis and major bleeding while maintaining anticoagulation beyond 6 months?
Recurrent VTE after 6 months of therapy
Two population database studies showed the risk of symptomatic recurrent thrombosis over 10 years after the index event of CAT [4, 5]. Data indicate that the risk of recurrent thrombosis changes over time, and it is highest during the first six months of therapy, but it continues to grow over the next 5 years during the course of cancer. In fact, the risk of VTE recurrence per 100 persons years in patients with cancer from 6 to 12 months goes from 7.9% to 12.8% [4,5].
Recurrent VTE and bleeding after 6 months of therapy
A retrospective multicenter cohort study looked at the risk of symptomatic recurrent thrombosis and clinically relevant bleeding (major bleeding and clinically relevant nonmajor bleeding) . The risk of recurrent thrombosis resulted in 8% over the 6–12-month period versus only a risk of 4.9% in clinically relevant bleeding. Thus, recurrent thrombosis outweighs the risk of clinically relevant bleeding.
A single-center retrospective study confirmed the data reported above: the risk of recurrent VTE was about 8.2%, whereas the risk of clinically relevant bleedings was 4.1% . However, this study gave us further insights.
Comparing the risk of recurrent VTE in patients who continued anticoagulant therapy vs those that discontinued it (69% of the patients continued anticoagulation beyond 6 months), patients that continued anticoagulation had a recurrent VTE risk of 9.9% vs 4.4% of those that discontinued anticoagulation . These data indicate that a subgroup of patients has an extraordinarily high risk of recurrence despite being on anticoagulation, with a risk of recurrence still of 10% over the 12 months.
Looking at the risk of clinically relevant bleeding, patients that continued anticoagulation had a risk of 5%, while patients that discontinued anticoagulation had a residual risk of 1.8% .
These data indicate that the risk of recurrent thrombosis is at least twofold compared to the risk of clinically relevant bleeding in patients that continue anticoagulation over 6 months.
Data from prospective cohort studies
Two prospective cohort studies (TiCAT and DALTECAN) looked at the extended use of low-molecular-weight heparin (LMWH) in patients with CAT [8-9].
Results indicate that the risk of recurrent VTE is higher in the first 6 months (TiCAT: 4.5% risk within 1–6 months vs 1.1% within 7–12 months; DALTECAN: 8.7% risk within 1–6 months vs 4.1% within 7–12 months) but continues over 12 months [8-10].
However, looking at months 7–12, the risk of bleeding seems to be a little higher or the same as the risk of recurrent VTE [8-10].
Based on these data, one would argue that it is better to stop anticoagulation because the risk of bleeding overrates the risk of recurrent VTE.
Although, when looking at these data, we need to remember that they are based on highly selected patients who may not have had cancer by the time they reach 6 months. So, they are low-risk patients with no longer active cancer and a lower risk of recurrence.
A prospective cohort study from the Cleveland Clinic analyzed 284 patients with CAT after they were treated for 6 months. Approximately 33% discontinued therapy: 13% because of bleeding, 36% because they would have a low risk of recurrence, and 46% for other reasons, including the financial cost .
In the 67% of patients who continue anticoagulant therapy, the risk of recurrence thrombosis was 12%, while the risk of major bleeding was 6.8%. In addition, recurrent VTE was associated with worse overall survival .
Any data about direct oral anticoagulants?
Three randomized control studies (Hokusai, SELECT-D, and DACUS) included patients that continued anticoagulation beyond 6 months.
In the Hokusai study, about 56% of the patients extended their treatment up to 12 months and were randomized for edoxaban or dalteparin .
In the SELECT-D in phase two part of the randomized trial, after 6 months of trial treatment for VTE, patients with active cancer and residual deep vein thrombosis or index pulmonary embolism were eligible for randomization to a further six months of rivaroxaban or placebo .
In the DACUS study, patients with active cancer and a first episode of DVT were treated with LMWH for 6 months. Those with residual vein thrombosis were randomly assigned to continue LMWH for an additional 6 months or to discontinue it .
Looking at the data available from these studies on recurrent thrombosis versus major bleeding and clinically relevant bleeding, it seems that the risk of bleeding outweighs the risk of recurrent VTE during anticoagulation (Table 1).
Table 1: Summary of data for VTE events and bleeding events from Hokusai, SELECT-D, and DACUS study
|Number of patients||294||273||46||46||119||123|
|Bleeding events (major and clinically relevant nonmajor bleeding)||7.2||5.8%||8.6%||0||3.4%||0.8%|
We must consider that these are randomized clinical trials, including patients with a high risk of complications. Most importantly, looking at the risk of recurrence in those patients who stop anticoagulant therapy, the risk of recurrent VTE is approximately 14% versus approximately a risk of bleeding of 8% (considering both major and clinically relevant nonmajor bleeding) when continuing anticoagulant therapy.
This indicates that also randomized control data favor continuing anticoagulation beyond 6 months in most cancer patients since the risk of recurrent thrombosis outweighs the risk of bleeding.
A systematic review pulled all the available evidence from retrospective, prospective and randomized control trials and estimated the risk of recurrent thrombosis and major bleeding over a 6–12-month period .
The risk of recurrent thrombosis goes from 1 to 12% when most of these patients continue anticoagulation, while the risk of major bleeding is only 2–5%.
The author concluded that anticoagulation should be continued beyond 6 months based on the observed VTE recurrence balanced against the risk of bleeding.
There are a few limitations with the data presented:
- The studies presented were not designed to investigate the optimal duration of anticoagulation.
- Some of the historical data may not represent modern oncology practice.
- Some outcomes like quality of life were never covered in these studies.
- Some of the studies, such as SELECT-D and DACUS, selected patients with a high risk of recurrent thrombosis.
- Most randomized control trials excluded high-risk patients.
Incidence vs case fatality rate
Are patients more likely to die from recurrent thrombosis or bleeding events?
While helping patients decide whether it is better to continue or discontinue anticoagulation, weighing all the outcomes, such as recurrent VTE, major bleeding, and fatality rate, is important.
Unfortunately, the fatality rates for recurrent VTE and major bleeding are not available for extended coagulation. However, a meta-analysis looked at these fatality rates in patients with CAT receiving treatment starting from a diagnosis up to 6–12 months of therapy .
The risk of recurrent VTE is higher than the risk of major bleeding (23.7% vs 13.1%), and the case fatality rate of recurrent VTE is 14.8% compared to 8.9% for major bleeding. This means that patients not only experience more recurrent VTE but are also more likely to die of recurrent thrombosis.
Every patient is different, and a number of risk factors (including cancer-related risk factors -stage IV pancreatic cancer, brain cancer, metastatic cancer, lung cancer, progression of cancer – or patient-related risk factors, such as immobility and comorbidity, and other patient-related factors- or therapy-related risk factors) allow us to stratify for risk of recurrent VTE and major bleeding. Unfortunately, many of the recurrent VTE risk factors overlap with the bleeding risk factors, and today we don’t have any risk scores to help us balance the risk of recurrence vs major bleeding.
Considering the data presented (which indicate that the risk of recurrent VTE outnumbers the risk of major bleeding, and the risk of case fatality is higher with recurrent VTE) and that patients have multiple risk factors, anticoagulant therapy should be continued beyond 6 months.
- Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer [published correction appears in Blood Adv. 2021;5(7):1953]. Blood Adv. 2021;5(4):927-974. doi:10.1182/bloodadvances.2020003442
- Streiff MB, Holmstrom B, Angelini D, et al. Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(10):1181-1201. doi:10.6004/jnccn.2021.0047
- Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543-603. doi:10.1093/eurheartj/ehz405
- Chee CE, Ashrani AA, Marks RS, et al. Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. Blood. 2014;123(25):3972-3978. doi:10.1182/blood-2014-01-549733
- Cohen AT, Katholing A, Rietbrock S, Bamber L, Martinez C. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb Haemost. 2017;117(1):57-65. doi:10.1160/TH15-08-0686
- Mahé I, Plaisance L, Chapelle C, Laporte S, Planquette B, Bertoletti L, Couturaud F, Falvo N, Falchero L, Mahé I, Helfer H, Chidiac J, Meyer G. Long-Term Treatment of Cancer-Associated Thrombosis (CAT) Beyond 6 Months in the Medical Practice: USCAT, a 432-Patient Retrospective Non-Interventional Study. Cancers (Basel). 2020;12(8):2256. doi: 10.3390/cancers12082256.
- Schmidt RA, Al Zaki A, Desilet N, et al. Patient characteristics and long-term outcomes beyond the first 6 months after a diagnosis of cancer-associated venous thromboembolism. Thromb Res. 2020;188:106-114. doi:10.1016/j.thromres.2020.02.005
- Jara-Palomares L, Solier-Lopez A, Elias-Hernandez T, et al. Tinzaparin in cancer associated thrombosis beyond 6months: TiCAT study. Thromb Res. 2017;157:90-96. doi:10.1016/j.thromres.2017.07.004
- Francis CW, Kessler CM, Goldhaber SZ, et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015;13(6):1028-1035. doi:10.1111/jth.12923
- Moik F, Colling M, Mahé I, Jara-Palomares L, Pabinger I, Ay C. Extended anticoagulation treatment for cancer-associated thrombosis-Rates of recurrence and bleeding beyond 6 months: A systematic review. J Thromb Haemost. 2022;20(3):619-634. doi:10.1111/jth.15599
- Shyam K Poudel, Chandana A Reddy, Deborah Y Park, Mailey L Wilks, Vicki Pinkava, Meghan O’Brien, Barbara Tripp, Jung-Min Song, Keith R McCrae, Alok A Khorana, Dana E Angelini; Clinical Outcomes of Cancer-Associated Thrombosis Beyond 6 Months of Anticoagulation. Blood2019; 134 (Supplement_1): 3458. doi: https://doi.org/10.1182/blood-2019-127581
- Di Nisio M, van Es N, Carrier M, et al. Extended treatment with edoxaban in cancer patients with venous thromboembolism: A post-hoc analysis of the Hokusai-VTE Cancer study. J Thromb Haemost. 2019;17(11):1866-1874. doi:10.1111/jth.14561
- Marshall A, Levine M, Hill C, et al. Treatment of cancer-associated venous thromboembolism: 12-month outcomes of the placebo versus rivaroxaban randomization of the SELECT-D Trial (SELECT-D: 12m). J Thromb Haemost. 2020;18(4):905-915. doi:10.1111/jth.14752
- Napolitano M, Saccullo G, Malato A, et al. Optimal duration of low molecular weight heparin for the treatment of cancer-related deep vein thrombosis: the Cancer-DACUS Study. J Clin Oncol. 2014;32(32):3607-3612. doi:10.1200/JCO.2013.51.7433
- Abdulla A, Davis WM, Ratnaweera N, Szefer E, Ballantyne Scott B, Lee AYY. A Meta-Analysis of Case Fatality Rates of Recurrent Venous Thromboembolism and Major Bleeding in Patients with Cancer. Thromb Haemost. 2020;120(4):702-713. doi:10.1055/s-0040-1708481