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Treatment of cancer-associated venous thromboembolism

Venous thromboembolism (VTE) is one of the major causes of morbidity and mortality in cancer patients, who may also be at increased risk of bleeding. We review current knowledge and recommendations about the treatment of cancer-associated VTE.

Cardio-Oncology


Keywords

cancer, treatment, venous thromboembolism

 

Abbreviation list

DOAC: direct oral anticoagulants

DVT: deep venous thrombosis

LMWH: low-molecular-weight heparins

GI: gastrointestinal

GU: genitourinary

PE: pulmonary embolism

VTE: venous thromboembolism

Take-home message:

Introduction

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep venous thrombosis (DVT), is one of the major causes of morbidity and mortality in cancer patients. We aim to review the current knowledge and recommendations for treatment of cancer-associated VTE

Epidemiology

The risk of VTE is 4-to-7-fold higher in cancer patients, according to the type of cancer (the highest risk is for stomach and pancreatic cancer), as well as the stage of cancer (metastatic >locally advanced>primary site). In addition, VTE is the second cause of death after cancer itself (>60% within the first year following the VTE diagnosis). Cancer patients also have a high risk of VTE recurrence (up to 20% within 12 months after the stop of anticoagulant therapy) with a case fatality rate of 14.8% (95% confidence interval [CI]: 6.6-30.1) [1].

Even the risk of bleeding is increased in cancer patients with a 12 month cumulative incidence rate of major bleeding of 12.4% (95% CI: 6.5-18.2) and a case fatality rate of 8.9% (95% CI: 3.5-21.1) [1]. The risk is highest for colorectal and prostate cancer [2].

Anticoagulant options

Over the last two decades, low-molecular-weight heparin (LMWH) has been the first-line therapy for VTE. The CLOT study showed that LMWH (i.e., dalteparin) was more effective than vitamin K antagonists (VKA) in reducing the risk of VTE recurrence in cancer patients (risk ratio [RR] 0.51, 95% CI: 0.33–0.79] without significant differences in major bleeding events [3]. Several meta-analyses confirmed the superiority of LMWH (including dalteparin, tinzaparin, enoxaparin, nadroparin) over VKA [4-5]. Long-term treatment with LMWH can be problematic due to both the burden of daily injections (leading patients to prematurely stop the anticoagulant therapy) as well as the risk of haematoma at site of injection, osteoporosis, and heparin-induced thrombocytopenia.

The direct oral anticoagulants (DOAC) represent an alternative to LMWH. The three anti-Xa inhibitors: edoxaban, rivaroxaban, and apixaban, have been evaluated for the treatment of cancer-associated VTE (Table 1).

 

Table 1. Randomised clinical trial with DOAC.

Clinical trials Patients

Primary endpoint
(DOAC vs LMWH)

Secondary endpoint
(DOAC vs LMWH)

HOKUSAI-VTE study [6]
edoxaban vs dalteparin

1046
  • VTE recurrence or MB at 12 months 12.8% vs 13.5%
     HR 0.97 (0.70-1.36)
  • VTE recurrence
    7.9% vs 11.3%
    HR 0.71 (0.48-1.06)
  • MB
    6.9% vs 4.0%
    HR 1.77 (1.03-3.04) P=0.04
  • CRNMB
    14.6% vs. 11.1%
    HR 1.38 (0.98-1.94)

SELECT-D pilot study [7]
rivaroxaban vs dalteparin

406
  • VTE recurrence at 6 months
    4% vs 11%
    HR 0.43 (0.19-0.99)
  • MB
    6% vs 4%
    HR 1.83 (0.68-4.96)
  • CRNMB
    13% vs 4%
    HR 3.76 (1.63-8.69)

CARAVAGGIO study [8]
apixaban vs dalteparin

1,155
  • VTE recurrence at 6 months
    5.6% vs 7.9%
    HR 0.63 (0.37-1.07)
  • MB
    3.8% vs 4.0%
    HR 0.82 (0.40-1.69) P=0.60
  • CRNMB
    9.0% vs 6.0%
    HR 1.42 (0.88-2.30)

CRNMB: clinically relevant non-major bleeding; DOAC: direct oral anticoagulants; HR: hazard ratio; LMWH: low-molecular-weight heparin; MB: major bleeding; VTE: venous thromboembolism

 

Compared to LMWH (dalteparin), both edoxaban [6] and rivaroxaban [7] showed a non-inferiority for VTE recurrence. However, the incidence of bleeding (major bleeding and clinically relevant non-major bleeding) was significantly higher for both DOACs (Table 1) although primarily confined to patients with gastrointestinal cancer [6, 7]. In the Caravaggio study, apixaban showed non-inferiority compared to dalteparin for VTE recurrence at 6 months (Table 1) [8]. However, and conversely to previous studies, the incidence of major bleeding and clinically relevant non-major bleeding events was similar in both treatment groups [8]. In a further sub-analysis, the incidence of bleeding remained similar in both groups, irrespective of cancer localisation (Table 2) [9]. The highest incidence of bleeding was observed in patients with gastrointestinal (GI) and genitourinary (GU) cancer, primarily if the cancer was not resected [9]. It should be noted that patients with primary or metastatic cerebral cancers and acute leukaemia were excluded from the Caravaggio study.


 Table 2. Bleeding events in Caravaggio study according to cancer site [9].


Apixaban (188)Dalteparin (187)Risk difference (95% CI)Apixaban (66)Dalteparin (73)Risk difference (95% CI)

     
  Gastrointestinal cancer (n=375)
 Genitourinary cancer (n=139)
Major bleeding 4.8% (9)* 4.8% (9)* ‒0.0003 (0.1009- 0.1009) 6.1% (4)* 8.2% (6)* ‒0.0216 (‒0.1866- 0.1450)
CRNMB 10.1% (19) 3.7%(7) 0.0636 (‒0.0372- 0.1642) 7.6% (5) 11% (8) ‒0.0338 (‒0.1982- 0.1330)
  Lung cancer (n=200) Breast cancer (n=155)
  Apixaban (105) Dalteparin (95) Risk difference (95% CI) Apixaban (79) Dalteparin (76) Risk difference (95% CI)
Major bleeding 3.8% (4) 3.2% (3) 0.0065 (‒0.1319- 0.1447) 3.8% (3) 3.9% (3) ‒0.0010 (‒0.1574- 0.1572)
CRNMB 12.4% (13) 7.4% (7) 0.0501 (‒0.0891- 0.1880) 6.3% (5) 2.6% (2) 0.0370 (‒0.1193-0.1949)
  Gynaecological cancer (n=119) Haematological cancer (n=85
  Apixaban (60) Dalteparin (59) Risk difference (95% CI) Apixaban (33) Dalteparin (52) Risk difference (95% CI)
Major bleeding 3.3% (2) 3.4% (2) ‒0.0006 (‒0.1781- 0.1781) 0 0  
CRNMB 5.0% (3) 13.6% (8) ‒0.0856 (‒0.2594- 0.0954) 9.1% (3) 3.8% (2) 0.0524 (‒0.1655- 0.2660)

*Unresected cancer.

CI: confidence interval, CRNMB: clinically relevant non-major bleeding

 

How to choose the best anticoagulant for my patient

The algorithm in Figure 1 is intended as a guide on how to choose the best anticoagulant according to the cancer’s characteristics and treatment as well as patient’s characteristics and preferences. Several guidelines and consensus documents have been published in the last three years about the treatment of VTE in cancer patients, all with similar recommendations [10-13]. Edoxaban and rivaroxaban should be considered as an alternative to LMWH in patients without gastrointestinal or genitourinary cancer and, in general, for those patients with low risk of bleeding. Caution should be made for any potential drug interaction with anti-cancer therapy.

 

Figure 1. Algorithm for the treatment of cancer-associated venous thromboembolism.

323_Mazzolai_Figure 1.jpg

DOAC: direct oral anticoagulants; GI: gastrointestinal; GU: genitourinary; LMWH: low-molecular-weight heparin; VTE: venous thromboembolism

 

Apixaban should be considered as an alternative to LMWH for initial and long-term treatment in patients without primary or metastatic brain cancer or acute leukaemia. Caution should be made for any potential drug interaction with anti-cancer therapy and in patients with unresected cancer.

LMWH is preferred over DOACs in cancer patients with unstable clinical situations including low platelet count, nausea and vomiting, risk of expected drug-drug interaction, patients undergoing surgery involving the upper gastrointestinal tract or with unresected GI or GU cancers.

Two elements should always be considered in the choice of an anticoagulant: the patient’s bleeding risk and any drug interactions with cancer therapy. Concerning bleeding risk, several bleeding scores have been evaluated but none have shown sufficient predictive accuracy to be recommended in routine clinical practice. In addition, bleeding scores specifically developed for the cancer population are lacking. In the evaluation of bleeding risk in cancer patients several elements should be considered:

  • GI or GU cancer
  • Brain cancer
  • Recent surgery or life-threatening bleeding
  • Concomitant cancer therapy associated with high risk of bleeding (i.e., bevacizumab, agents provoking GI mucosal-toxicity)
  • Severe thrombocytopenia (<50,000)
  • Renal or hepatic failure
  • Concomitant antiplatelet therapy

Concerning drug-drug interactions, apixaban, edoxaban, and rivaroxaban are all substrates for P-glycoprotein (P-gp). Therefore, interactions with strong P-gp inducers or inhibitors may lead to a decrease or an increase in DOAC concentrations, respectively. In addition, apixaban and rivaroxaban are also dependent on cytochrome CYP3A4 for part of their metabolism. So, strong CYP3A4 inducers and inhibitors will also potentially alter their efficacy or safety.

There are different ways to evaluate a drug-drug interaction. First of all, this can be discussed with the local pharmacist or found in product monographs or package inserts of drugs. There are also different databases which are constantly updated, notably the Lexicomp Drug Interaction tool and the drug interactions checker at the University of Liverpool (https://cancer-druginteractions.org/). This last-one is free of charge.

Incidental VTE

Up to 50% of VTE diagnosed in oncology centres are incidentally detected during imaging performed for cancer staging, evaluation of treatment response and routine follow-up. Although VTE diagnosis in unsuspected in these patients, approximately one-half of patients report symptoms of PE (or DVT). However, as these symptoms are non-specific, they are often attributed to cancer or the side effects of treatment.

Recent studies showed that incidental PE (as well as subsegmental PE) carries the same risk of VTE recurrence and mortality as symptomatic PE [14, 15]. Therefore, patients with active cancer and incidental PE should always receive anticoagulant treatment. Before starting treatment, it is recommended to carefully review the images with an experienced radiologist, especially in cases of isolated subsegmental PE. In addition, compression ultrasonography of the lower limbs to detect concomitant incidental DVT is also suggested. In the same way, in patients with incidental iliofemoral DVT on computed tomography of the abdomen and pelvis are recommended to have a a venous ultrasonography of the pelvis and lower limbs.

Duration of anticoagulant treatment

The duration of anticoagulant therapy is typically 3-6 months and usually for as long as the cancer is active. According to clinical trials, cancer is considered active if metastatic or if cancer treatment (either chemotherapy and/or radiotherapy) is ongoing. Conversely, cancer is considered non-active if it has been in remission for more than 6 months.

Two recent studies showed that if anticoagulation is stopped too early, when cancer is still active, the risk of recurrence is significantly higher (up to 6-fold) [16, 17]. A safer alternative to stop anticoagulation could be to reduce the dose. To this end, a large randomised clinical trial, comparing the efficacy and safety of a reduced dose of apixaban (2.5 mg bid) vs a standard dose (5 mg bid) for the prevention of recurrent VTE in cancer patients who have completed at least 6 months of anticoagulant therapy, is currently ongoing [18].

In addition, it is important to periodically assess the risk of recurrence and bleeding as well as the cancer status and patient’s preferences.

Conclusions

Treatment of cancer-associated VTE remains a challenge. In these patients, anticoagulant therapies should be individualised, based on the type and stage of cancer, cancer treatment and potential drug-drug interactions, bleeding risk, and the patient’s preference.

Patients should be treated for three-six months and for as long as the cancer is active.

Incidental VTE should be treated as a symptomatic form because of the risk of recurrence.

References


  1. 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;120:702-13. 
  2. Mahe I, Chidiac J, Bertoletti L, Font C, Trujillo-Santos J, Peris M, Perez Ductor C, Nieto S, Grandone E, Monreal M; RIETE investigators. The Clinical Course of Venous Thromboembolism May Differ According to Cancer Site. Am J Med. 2017;130:337-47. 
  3. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-53.
  4. Kahale LA, Hakoum MB, Tsolakian IG, Matar CF, Terrenato I, Sperati F, Barba M, Yosuico VE, Schünemann H, Akl EA. Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer. Cochrane Database Syst Rev. 2018;6:Cd006650. 
  5. Kirkilesis GI, Kakkos SK, Tsolakis IA. Editor's Choice - A Systematic Review and Meta-Analysis of the Efficacy and Safety of Anticoagulation in the Treatment of Venous Thromboembolism in Patients with Cancer. Eur J Vasc Endovasc Surg. 2019;57:685-701. 
  6. Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Buller HR; Hokusai VTE Cancer Investigators. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018;378:615-24. 
  7. Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. 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;36:2017-23. 
  8. Agnelli G, Becattini C, Meyer G, Munoz A, Huisman MV, Connors JM, Cohen A, Bauersachs R, Brenner B, Torbicki A, Sueiro MR, Lambert C, Gussoni G, Campanini M, Fontanella A, Vescovo G, Verso M; Caravaggio Investigators. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020;382:1599-1607. 
  9. Agnelli G, Muñoz A, Franco L, Mahé I, Brenner B, Connors JM, Gussoni G, Hamulyak EN, Lambert C, Suero MR, Bauersachs R, Torbicki A, Becattini C. Apixaban and Dalteparin for the Treatment of Venous Thromboembolism in Patients with Different Sites of Cancer. Thromb Haemost. 2022;122:796-807. 
  10. Mazzolai L, Ageno W, Alatri A, Bauersachs R, Becattini C, Brodmann M, Emmerich J, Konstantinides S, Meyer G, Middeldorp S, Monreal M, Righini M, Aboyans V. Second consensus document on diagnosis and management of acute deep vein thrombosis: updated document elaborated by the ESC Working Group on aorta and peripheral vascular diseases and the ESC Working Group on pulmonary circulation and right ventricular function. Eur J Prev Cardiol. 2022;29:1248-63. 
  11. Lyman GH, Carrier M, Ay C, Di Nisio M, Hicks LK, Khorana AA, Leavitt AD, Lee AYY, Macbeth F, Morgan RL, Noble S, Sexton EA, Stenehjem D, Wiercioch W, Kahale LA, Alonso-Coello P. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021;5:927-74. 
  12. Carrier M, Blais N, Crowther M, Kavan P, Le Gal G, Moodley O, Shivakumar S, Suryanarayan D, Tagalakis V, Wu C, Lee AYY. Treatment Algorithm in Cancer-Associated Thrombosis: Updated Canadian Expert Consensus. Curr Oncol. 2021;28:5434-51. 
  13. Key NS, Khorana AA, Kuderer NM, Bohlke K, Lee AYY, Arcelus JI, Wong SL, Balaban EP, Flowers CR, Gates LE, Kakkar AK, Tempero MA, Gupta S, Lyman GH, Falanga A. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Guideline Update. J Clin Oncol. 2023:JCO2300294. 
  14. den Exter PL, Hooijer J, Dekkers OM, Huisman MV. Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. J Clin Oncol. 2011;29:2405-9. 
  15. Kraaijpoel N, Bleker SM, Meyer G, Mahé I, Muñoz A, Bertoletti L, Bartels-Rutten A, Beyer-Westendorf J, Porreca E, Boulon C, van Es N, Iosub DI, Couturaud F, Biosca M, Lerede T, Lacroix P, Maraveyas A, Aggarwal A, Girard P, Büller HR, Di Nisio M; UPE investigators. Treatment and Long-Term Clinical Outcomes of Incidental Pulmonary Embolism in Patients With Cancer: An International Prospective Cohort Study. J Clin Oncol. 2019;37:1713-20. 
  16. van der Hulle T, den Exter PL, van den Hoven P, van der Hoeven JJ, van der Meer FJ, Eikenboom J, Huisman MV, Klok FA. Cohort Study on the Management of Cancer-Associated Venous Thromboembolism Aimed at the Safety of Stopping Anticoagulant Therapy in Patients Cured of Cancer. Chest. 2016;149:1245-51. 
  17. Barca-Hernando M, Lopez-Ruz S, Marin-Romero S, Garcia-Garcia V, Elias-Hernandez T, Otero-Candelera R, Carrier M, Jara-Palomares L. Risk of recurrent cancer-associated thrombosis after discontinuation of anticoagulant therapy. Res Pract Thromb Haemost. 2023;7:100115. 
  18. Mahé I, Agnelli G, Ay C, Bamias A, Becattini C, Carrier M, Chapelle C, Cohen AT, Girard P, Huisman MV, Klok FA, López-Núñez JJ, Maraveyas A, Mayeur D, Mir O, Monreal M, Righini M, Samama CM, Syrigos K, Szmit S, Torbicki A, Verhamme P, Vicaut E, Wang TF, Meyer G, Laporte S. Extended Anticoagulant Treatment with Full- or Reduced-Dose Apixaban in Patients with Cancer-Associated Venous Thromboembolism: Rationale and Design of the API-CAT Study. Thromb Haemost. 2022;122:646-56. 

Notes to editor


Authors:

Lucia Mazzolai, MD, PhD; Adriano Alatri, MD

Division of Angiology, Heart and Vessel Department, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

 

Address for correspondence:

Dr Adriano Alatri, Service d’Angiologie, Département Coeur et vaisseaux, Chemin de Mont-Paisible 18, CH-1011 Lausanne, Switzerland

E-mail: adriano.alatri@chuv.ch

Twitter handle: @adriano_alatri

 

Author disclosures:

L. Mazzolai has received grants or contracts from Novartis and Sanofi and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Daiichi Sankyo and Sigvaris. A. Alatri has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS.

 

 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.