During the ICTHIC webinar “Clinical insights in CAT to include COVID‐19“, Prof. Florian Langer gave a talk on cancer-associated thrombosis (CAT) treatment algorithms. Here, we report the highlights of his presentation.
You can find Prof. Langer’s presentation and the full webinar here.
In patients with venous thromboembolism (VTE) and active cancer, it is important to carefully balance between oral anticoagulation with direct oral anticoagulants (DOACs) and parenteral anticoagulation with low-molecular-weight heparin (LMWH).
The same is true for patients with a history of cancer in whom a diagnosis of VTE leads to the diagnosis of progressive or recurrent malignancy and for those with seemingly unprovoked VTE diagnosed with hidden cancer during anticoagulant therapy.
A case report
A 74-year-old male was diagnosed with locally advanced metastatic pancreatic cancer and offered aggressive combination chemotherapy (liposomal irinotecan/5-FU/folinic acid with alternate oxaliplatin/5-FU/folinic acid every 2 weeks).
The patient also had nonspecific hemorrhagic lesions inside the colon, extensive liver metastasis, concrement in the left distal ureter, and a lateral centrally located pulmonary embolism.
It is known that pancreatic cancer is the most thrombogenic tumor. Generally, the risk of VTE is increased ninefold compared to the general population within the first year after cancer diagnosis [1].
In particular, patients with cancer receiving systemic anticancer therapies (such as chemotherapy or targeted therapy) have a 23-fold higher risk of developing VTE compared to the general population. In addition, the VTE risk in cancer patients dramatically increased in the last two decades, increasing cumulative VTE incidence threefold for cancer patients and sixfold for patients receiving chemotherapy and targeted therapy [1].
Based on this, it is necessary to carefully balance efficacy and safety in systemic anticoagulation in the case under discussion.
The balance between efficacy and safety
Oral vs parenteral anticoagulation
A meta-analysis indicated that anticoagulation with DOACs is associated with a significantly reduced risk of recurrent VTE compared to parenteral anticoagulation with LMWH or dalteparin [2].
Instead, the risk of major bleeding is numerically increased, and there is a significantly increased risk of clinically relevant non-major bleeding during oral anticoagulation with the DOACs [2].
In the HOKUSAI VTE cancer trial (NCT02073682), patients with gastrointestinal (GI) cancer (including pancreatic and hepatic biliary cancer) had a fourfold increased risk of major bleeding when treated with edoxaban compared with dalteparin [3,4].
In general, the rate of major bleeding was significantly higher with edoxaban than with dalteparin (6.9% and 4.0%, respectively), which was mainly due to the higher rate of upper GI bleeding with edoxaban [4].
However, recurrent VTE events in the dalteparin arm after the first 3 months of anticoagulation were higher than in the edoxaban arm (11.3% and 7.9%, respectively) [4].
Treatment persistence beyond the first 3 months was significantly better in the edoxaban than the dalteparin [4].
A retrospective study confirmed that the treatment persistence is usually better during oral anticoagulation with the DOACs than parental anticoagulation with LMWH (median 116 days vs 34 days, respectively). However, medication adherence was very high and not different between the two treatment groups [5].
In the complex shared decision-making process, the patient needs to be informed about parenteral or oral anticoagulation’s potential benefits and risks. Treatment persistence, lack of interference with the specific anticancer therapy and the lower risk of major bleeding are key features in the decision-making process.
A study assessed what features are most important to CAT patients regarding their choice of anticoagulant. A total of 70% of the patients were treated with LMWH and 30% with oral medications. The results show that patients prefer an anticoagulant that does not interfere with their cancer treatment, suggesting the importance of the cancer disease over VTE in these patients. Patients also favor efficacy and safety over the convenience of the route of administration [6].
The risk of bleeding
In the SELECT-D trial (NCT02583191), safety analysis after the first 220 patients indicated an increased risk of major bleeding in patients with upper GI cancer receiving rivaroxaban. These patients were excluded from further study enrollment as a precautionary measure. Despite this measure, the clinically relevant bleeding risk was approximately three times more frequent in the rivaroxaban than in the dalteparin arm [7].
The CARAVAGGIO trial (NCT03045406) compared apixaban with dalteparin in patients with cancer-associated VTE and GI cancer (including pancreatic cancer and hepatobiliary tumors). The risk of major bleeding was similar between the two treatment groups. Still, clinically relevant non-major bleeding events were approximately three times more frequent in the apixaban compared to the dalteparin arm [8, 9].
In addition, patients in the apixaban group had an increased risk of developing mucosal bleeding at other sites, such as genitourinary, hematuria and vaginal bleeding or bleeding from the upper airways [8, 9].
Patients with GI cancer are a very vulnerable patient population, which is confirmed by a recent single-center retrospective study investigating major bleeding events in cancer patients with VTE treated with apixaban [10]
Patients with GI cancer, compared to patients with non-GI cancer, had an increased risk of major bleeding during treatment with apixaban, particularly patients with luminal GI cancer [10].
Although not from a randomized control trial, the data indicate that patients with luminal GI cancer have an increased risk of major bleeding when treated with apixaban compared to treatment with enoxaparin.
Patients with non-resected primary tumors have a significantly increased risk for bleeding during anticoagulant therapy for VTE, which can be explained by the fact that they receive particularly aggressive multidisciplinary therapy [11]
The CATCH trial (NCT01130025) compared tinzaparin to warfarin in patients with cancer-associated VTE for 6 months [12, 13]
Clinically relevant efficacy endpoints, such as VTE recurrence or symptomatic deep vein thrombosis, were lower in the tinzaparin arm than the warfarin arm. In contrast, the clinically relevant bleeding risk was significantly reduced during parenteral anticoagulation with LMWH [12, 13].
Differences between available LMWH
It is very important to point out that the commercially available LMWH are not the same.
The risk of accumulation during renal insufficiency is dependent on the average molecular weight. Tinzaparin and dalteparin are the only LMWH formally approved for the treatment and secondary prevention of CAT. They have a comparably high average molecular weight and are less likely to accumulate during kidney insufficiency.
This is supported by a study indicating a lack of accumulation of activity levels in patients with VTE and severe renal insufficiency, receiving therapeutic dosages of tinzaparin for up to 10 days [14].
Drug-drug interaction
A case report
A 51-year-old female with a malignant brain tumor has received a combination of radiotherapy and chemotherapy, and the patient required quite high doses of dexamethasone because of the significant brain edema.
In April 2020, the patient presented to a different hospital because of a pulmonary embolism. She was treated with a DOAC because of the availability of a specific antidote in case of significant intracranial hemorrhage.
In August 2020, the patient presented to Professor Langer’s hospital with highly symptomatic recurrent VTE; she had a bilateral pulmonary embolism and a highly symptomatic proximal right-sided iliac vein thrombosis.
At hospital admission, the patient was taking dexamethasone several times a day. Dexamethasone is a moderate inducer of CYP3A4, and it may possibly have interacted with the anticoagulation medication, reducing DOAC’s plasma levels in the patient.
The numbers and indications for anticancer agents are constantly increasing, and it is very difficult in clinical practice to judge potential drug-drug interactions.
Many anticancer agents also have GI toxicities (such as vomiting, diarrhea, stomatitis, and colitis), which are highly relevant in oral anticoagulation because the DOACs are absorbed in the upper GI tract [15].
CAT treatment algorithm
Tumor-, patient- and therapy-related factors must be considered when balancing oral vs parenteral anticoagulation effects. So, how do we approach a patient with acute cancer-associated VTE in clinical practice?
Several treatment algorithms exist. In one of these, patients with active cancer and newly diagnosed symptomatic or incidental VTE are generally treated with DOACs if they:
- are not at an increased risk of bleeding from the GI or genito-urinary tract
- are not currently or suspected soon to be treated with medication that strongly interacts with DOAC.
As an alternative, LMWH is recommended [17].
A very similar treatment algorithm has recently been published, and it is also based on risk factors for bleeding, cancer type, potential drug-drug interactions, and GI toxicities. Based on this algorithm, patients with advanced malignancy receiving very aggressive multidisciplinary therapy are good candidates for long-term treatment with LMWH [18].
Finally, according to Prof. Langer’s experience patients with gastrointestinal, genitourinary, and gynecological cancer have a significantly increased risk of major bleeding. Therefore, for people with these cancers, LMWH is the recommended choice.
References
1. Mulder FI, Horváth-Puhó E, van Es N, et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood. 2021;137(14):1959-1969.
2. Moik F, Posch F, Zielinski C, Pabinger I, Ay C. Direct oral anticoagulants compared to low-molecular-weight heparin for the treatment of cancer-associated thrombosis: Updated systematic review and meta-analysis of randomized controlled trials. Res Pract Thromb Haemost. 2020;4(4):550-561. Published 2020 May 21.
3. 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.
4. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018;378(7):615-624.
5. Schaefer JK, Li M, Wu Z, et al. Anticoagulant medication adherence for cancer-associated thrombosis: A comparison of LMWH to DOACs. J Thromb Haemost. 2021;19(1):212-220.
6. Noble S, Matzdorff A, Maraveyas A, Holm MV, Pisa G. Assessing patients’ anticoagulation preferences for the treatment of cancer-associated thrombosis using conjoint methodology. Haematologica. 2015;100(11):1486-1492.
7. 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.
8. 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.
9. Ageno W, Vedovati MC, Cohen A, et al. Bleeding with Apixaban and Dalteparin in Patients with Cancer-Associated Venous Thromboembolism: Results from the Caravaggio Study. Thromb Haemost. 2021;121(5):616-624.
10. Houghton DE, Vlazny DT, Casanegra AI, et al. Bleeding in Patients With Gastrointestinal Cancer Compared With Nongastrointestinal Cancer Treated With Apixaban, Rivaroxaban, or Enoxaparin for Acute Venous Thromboembolism [published online ahead of print, 2021 Aug 20]. Mayo Clin Proc. 2021;S0025-6196(21)00435-3.
11. Carmona-Bayonas A, Gómez D, Martínez de Castro E, et al. A snapshot of cancer-associated thromboembolic disease in 2018-2019: First data from the TESEO prospective registry. Eur J Intern Med. 2020;78:41-49.
12. Kamphuisen PW, Lee AYY, Meyer G, et al. Clinically relevant bleeding in cancer patients treated for venous thromboembolism from the CATCH study. J Thromb Haemost. 2018;16(6):1069-1077.
13. Lee AYY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer: A Randomized Clinical Trial [published correction appears in JAMA. 2017 Nov 28;318(20):2048]. JAMA. 2015;314(7):677-686.
14. Siguret V, Pautas E, Février M, et al. Elderly patients treated with tinzaparin (Innohep) administered once daily (175 anti-Xa IU/kg): anti-Xa and anti-IIa activities over 10 days. Thromb Haemost. 2000;84(5):800-804.
15. Martin KA, Lee CR, Farrell TM, Moll S. Oral Anticoagulant Use After Bariatric Surgery: A Literature Review and Clinical Guidance. Am J Med. 2017;130(5):517-524.
16. 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(10):e566-e581.
17. Moik F, Pabinger I, Ay C. How I treat cancer-associated thrombosis. ESMO Open. 2020;5(1):e000610.
18. Pernod G, Joly M, Sonnet B. Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for the treatment of cancer-associated thrombosis (which agent for which patient). J Med Vasc. 2020;45(6S):6S17-6S23.