Management of VTE beyond 12 months in patients with cancer-associated thrombosis

During the ICTHIC webinar, “Long-term treatment & DDI implications in the management of CAT,” Dr. Luis Jara-Palomares gave a lecture on the management of venous thromboembolism (VTE) beyond 12 months in patients with cancer-associated thrombosis (CAT). Here, we summarize the key messages of his speech. You can also watch Jara-Palomares’s lecture in the video below and the full webinar recording here.

What guidelines say

Almost 20% of the patient with VTE have cancer [1]. Guidelines exist on the short-term treatment of VTE within 6 months from diagnosis [2]. Direct evidence indicates long-term treatment beyond 6 months (e.g., TiCAT study or CARAVAGGIO study) and during end-of-life care [3, 4]. But no recommendations and insufficient data exist about VTE treatment beyond 12 months.

The European Society of Cardiology guidelines in 2019 suggested that, for patients with pulmonary embolism and cancer, anticoagulant treatment should be considered beyond 6 months for an indefinite period or until the cancer is cured [2].

The International Initiative on Thrombosis and Cancer (ITAC) guidelines in 2019 suggested using an anticoagulant treatment for a minimum of 6 months in people with cancer and VTE [5]. An update published in 2022 suggests that the final decision about extending anticoagulation after 6 months should be based on an individual evaluation, benefit-risk ratio, tolerability, drug availability, patient preference, and cancer activity [6].

In other words, the ITAC guidelines leave the decision to prolong anticoagulation to the clinician because no definite information is available for VTE treatment in cancer patients beyond 12 months.

The American Society of Hematology (ASH) guidelines suggest continuing anticoagulation beyond 6 months even though a low-level certainty of evidence exists in this context, and the risk of major bleeding needs to be taken into account [7].

Major bleeding risk scores

Unfortunately, no risk score exists at the moment to predict the risk of bleeding in cancer patients.

It is known that the risk factors associated with major bleeding in patients with CAT receiving anticoagulant therapy are diverse, heterogenous, and largely unknown.

In clinical trials, the incidence of major bleeding is around 3.9%, while in the real-world population is nearly 20%. In addition, the case fatality rate in clinical trials is 6.2%, while it is around 30% in the RIETE registry [8-12].

Also, differences in the analyzed populations should be taken into consideration. For example, the risk of major bleeding might differ in ambulatory patients with VTE compared with patients in the intensive care unit or on catheter-directed therapy. All these different populations and scenarios require different approaches.

Several bleeding risk models have been proposed, but a recent study comparing HEMORR₂HAGES, HAS-BLED, and VTE-BLEED models suggests a poor prediction ability, with a c-statistic around 0.56 [13].

Even more, analyzing the Hokusai-VTE Cancer patients with different risk scores shows a different output for each risk score. For example, the ACCP-VTE scores would classify all the patients as high-risk of bleeding, while the HAS-BLED score would categorize most of them as low-risk (data not published yet).

For this reason, it has been suggested to build a new prediction model, the CAT-BLEED score, that considers the cancer site and the treatment [14]. External validation is needed for this score, and more data on its performance in predicting the risk of bleeding in real life or other courts are needed.

Most recommendations to continue anticoagulation indefinitely are based on the assumption that what happens in the short term is equal to what happens in the long term.

For example, it assumes that a risk of 6% of major bleeding at 6 months will be doubled (12%) at 12 months. But this is not the case.

The TiCAT study showed that the relationship between the risk of major bleeding and time is not linear, and the rate of clinically relevant major bleeding can change, resulting in 5.4% at 6 months and 3.6% at 12 months [3].

A study compared the rate of clinically relevant bleeding in the first period from 1 to 12 months versus the second period of 12 to 24 months in almost 600 patients with CAT. Results show that the rate of clinically relevant bleeding in the second period is lower than in the first period [15].

The ASH guidelines also state that anticoagulation can be discontinued in patients with no longer a high risk of recurrent VTE [7].

But how can we identify if patients are at high or low risk of recurrent VTE?

Several scores were developed to identify the risk of VTE, but most of these calculate the risk for the first event and not recurrent VTE after stopping anticoagulant treatment.

The rate of recurrent VTE is generally higher in the first 6 months but continues to be important in the first years and then declines [16]. However, it is important to understand what happens to patients with CAT who have stopped anticoagulant treatment.

A study not yet published tried to investigate this last point and showed a 6% incidence of recurrent VTE at 6 months. If replicated in other courts, these results should be considered and lead to the need to identify the patients in whom anticoagulant treatment can be safely stopped.

Conclusions

In conclusion, guidelines suggest a long-term anticoagulant treatment in patients with CAT, but new evidence suggests that the risk of recurrent VTE decreases over time.

Also, the risk of recurrent VTE after stopping anticoagulant treatment is high (6% in 6 months).

Watch Luis Jara-Palomares’s speech:

References

1. Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer. 2011;117(7):1334-1349. doi:10.1002/cncr.25714
2. 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
3. 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
4. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
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6. Farge D, Frere C, Connors JM, et al. 2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19. Lancet Oncol. 2022;23(7):e334-e347. doi:10.1016/S1470-2045(22)00160-7
7. 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 Apr 13;5(7):1953]. Blood Adv. 2021;5(4):927-974. doi:10.1182/bloodadvances.2020003442
8. 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(20):2017-2023. doi:10.1200/JCO.2018.78.8034
9. Kraaijpoel N, Di Nisio M, Mulder FI, et al. Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study. Thromb Haemost. 2018;118(8):1439-1449. doi:10.1055/s-0038-1667001
10. Agnelli G, Becattini C, Meyer G, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020;382(17):1599-1607. doi:10.1056/NEJMoa1915103
11. Palareti G, Antonucci E, Mastroiacovo D, et al. The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism. J Thromb Haemost. 2018;16(10):1994-2002. doi:10.1111/jth.14253
12. Klok FA, Hösel V, Clemens A, et al. Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. Eur Respir J. 2016;48(5):1369-1376. doi:10.1183/13993003.00280-2016
13. Sanfilippo K, Luo S, Khorana A, GageB, Three Available Risk Scores Modestly Predict Hemorrhage in Patients with Cancer-associated Thrombosis (CAT). ISTH poster available here: https://abstracts.isth.org/abstract/three-available-risk-scores-modestly-predict-hemorrhage-in-patients-with-cancer-associated-thrombosis-cat/
14. de Winter MA, Dorresteijn JAN, Ageno W, et al. Estimating Bleeding Risk in Patients with Cancer-Associated Thrombosis: Evaluation of Existing Risk Scores and Development of a New Risk Score. Thromb Haemost. 2022;122(5):818-829. doi:10.1055/s-0041-1735251
15. Lopez-Ruz S, Barca-Hernando M, Marin-Romero S, Elias-Hernandez T, Otero-Candelera R, Jara-Palomares L. Low-molecular-weight heparin beyond 12 months in patients with cancer-associated thrombosis [published online ahead of print, 2022 Oct 14]. Br J Cancer. 2022;10.1038/s41416-022-02007-x. doi:10.1038/s41416-022-02007-x
16. 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