CC BY-NC-ND 4.0 · Thromb Haemost 2021; 121(03): 383-395
DOI: 10.1055/s-0040-1718728
Stroke, Systemic or Venous Thromboembolism

Effectiveness and Safety of Apixaban, Low-Molecular-Weight Heparin, and Warfarin among Venous Thromboembolism Patients with Active Cancer: A U.S. Claims Data Analysis

Alexander Cohen
1   Department of Hematological Medicine, Guy's & St Thomas' NHS Foundation Trust, King's College London, Westminster Bridge Road, London, United Kingdom
,
Allison Keshishian
2   SIMR, LLC, Ann Arbor, Michigan, United States
,
Theodore Lee
3   Pfizer Inc., New York, New York, United States
,
Gail Wygant
4   Bristol-Myers Squibb Company, Lawrenceville, New Jersey, United States
,
Lisa Rosenblatt
4   Bristol-Myers Squibb Company, Lawrenceville, New Jersey, United States
,
Patrick Hlavacek
3   Pfizer Inc., New York, New York, United States
,
Jack Mardekian
3   Pfizer Inc., New York, New York, United States
,
Daniel Wiederkehr
3   Pfizer Inc., New York, New York, United States
,
Janvi Sah
2   SIMR, LLC, Ann Arbor, Michigan, United States
,
Xuemei Luo
5   Pfizer Inc., Groton, Connecticut, United States
› Author Affiliations
Funding This research was funded by Pfizer Inc. and Bristol-Myers Squibb Company.

Abstract

Background This study primarily evaluates the risk of recurrent venous thromboembolism (VTE) and major bleeding (MB) among patients with VTE and active cancer prescribed apixaban, low-molecular-weight heparin (LMWH), or warfarin, with claims data.

Methods Four U.S. commercial insurance claims databases were used to identify patients with VTE and active cancer who initiated apixaban, LMWH, or warfarin within 30 days following the first VTE event. Stabilized inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Cox proportional hazard models were used to evaluate risk of recurrent VTE and MB.

Results All eligibility criteria were fulfilled by 3,393 apixaban, 6,108 LMWH, and 4,585 warfarin patients. After IPTW, all patient characteristics were balanced. When the follow-up was censored at 6 months, apixaban patients had a lower risk of recurrent VTE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.47–0.81) and MB (HR: 0.63; 95% CI: 0.47–0.86) versus LMWH. Apixaban patients had a lower risk of recurrent VTE (HR: 0.68; 95% CI: 0.52–0.90) and similar risk of MB (HR: 0.73; 95% CI: 0.53–1.00) versus warfarin. Warfarin patients had a similar risk of recurrent VTE (HR: 0.91; 95% CI: 0.72–1.15) and MB (HR: 0.87; 95% CI: 0.68–1.12) versus LMWH. The trends were similar for the entire follow-up; however, apixaban patients had a lower risk of MB versus warfarin patients.

Conclusion Patients with VTE and active cancer who initiated apixaban had a lower risk of recurrent VTE and MB compared with LMWH patients. Apixaban patients also had a lower risk of recurrent VTE compared with warfarin patients.

Supplementary Material



Publication History

Received: 04 May 2020

Accepted: 02 September 2020

Article published online:
10 November 2020

© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res 2010; 125 (06) 490-493
  • 2 Heit JA, O'Fallon WM, Petterson TM. et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162 (11) 1245-1248
  • 3 Gussoni G, Frasson S, La Regina M, Di Micco P, Monreal M. RIETE Investigators. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res 2013; 131 (01) 24-30
  • 4 Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol 2006; 24 (03) 484-490
  • 5 Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166 (04) 458-464
  • 6 Holm T, Singnomklao T, Rutqvist LE, Cedermark B. Adjuvant preoperative radiotherapy in patients with rectal carcinoma. Adverse effects during long term follow-up of two randomized trials. Cancer 1996; 78 (05) 968-976
  • 7 Trinh VQ, Karakiewicz PI, Sammon J. et al. Venous thromboembolism after major cancer surgery: temporal trends and patterns of care. JAMA Surg 2014; 149 (01) 43-49
  • 8 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 (01) 57-65
  • 9 Elting LS, Escalante CP, Cooksley C. et al. Outcomes and cost of deep venous thrombosis among patients with cancer. Arch Intern Med 2004; 164 (15) 1653-1661
  • 10 Prandoni P, Lensing AW, Piccioli A. et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100 (10) 3484-3488
  • 11 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
  • 12 Konstantinides SV, Meyer G, Becattini C. et al. The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J 2019; 54 (03) 1-61
  • 13 Farge D, Bounameaux H, Brenner B. et al. International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2016; 17 (10) e452-e466
  • 14 Streiff MB, Holmstrom B, Angelini D. et al. NCCN guidelines insights: cancer-associated venous thromboembolic disease, version 2.2018. J Natl Compr Canc Netw 2018; 16 (11) 1289-1303
  • 15 Lee AYY, Peterson EA. Treatment of cancer-associated thrombosis. Blood 2013; 122 (14) 2310-2317
  • 16 Key NS, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020; 38 (05) 496-520
  • 17 Khorana AA, Yannicelli D, McCrae KR. et al. Evaluation of US prescription patterns: are treatment guidelines for cancer-associated venous thromboembolism being followed?. Thromb Res 2016; 145: 51-53
  • 18 Raskob GE, van Es N, Verhamme P. et al. Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
  • 19 Win KZ, Wilson N, Stenehjem DD, Tanner N, Rodgers GM, Gilreath J. Effectiveness and safety of rivaroxaban in treatment of venous thromboembolism in cancer patients. Blood 2015; 126: 2319
  • 20 Khorana AA, Noble S, Lee AYY. et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1891-1894
  • 21 Agnelli G, Becattini C, Meyer G. et al. Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382 (17) 1599-1607
  • 22 McBane II RD, Wysokinski WE, Le-Rademacher JG. et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial. J Thromb Haemost 2020; 18 (02) 411-421
  • 23 Pan X, Kachroo S, Liu X. et al. Real world discontinuation among early users of apixaban, dabigatran, rivaroxaban or warfarin among atrial fibrillation patients newly initiated on anticoagulation therapy: Tell of first 200 days [abstract]. Eur Heart J [serial online] 2014; 35 (Abstract Supplement): 897
  • 24 Teutsch C, Huisman MV, Lip GY. et al. Persistence with dabigatran therapy for stroke prevention in patients with non-valvular atrial fibrillation: the Gloria-AF Registry. Blood 2016; 128: 2616
  • 25 Tamariz L, Harkins T, Nair V. Mini-sentinel systematic evaluation of health outcome of interest definitions for studies using administrative data venous thromboembolism report. Mini-Sentinel. 2011 . Available at: https://www.sentinelinitiative.org/sites/default/files/surveillance-tools/validations-literature/Mini-Sentinel-HOI-Evidence-Review-Venous-Thromboembolism-Report.pdf . Accessed August 20, 2020
  • 26 Fang MC, Fan D, Sung SH. et al. Validity of using inpatient and outpatient administrative codes to identify acute venous thromboembolism: the CVRN VTE study. Med Care 2017; 55 (12) e137-e143
  • 27 Khorana AA, McCrae KR. Risk stratification strategies for cancer-associated thrombosis: an update. Thromb Res 2014; 133 (Suppl. 02) S35-S38
  • 28 Austin PC. Variance estimation when using inverse probability of treatment weighting (IPTW) with survival analysis. Stat Med 2016; 35 (30) 5642-5655
  • 29 Comorbidity Index Overview NCI. Healthcaredelivery.cancer.gov [online]. Available at: https://healthcaredelivery.cancer.gov/seermedicare/considerations/comorbidity.html . Accessed March 19, 2020
  • 30 Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med 2015; 34 (28) 3661-3679
  • 31 Thoemmes F, Ong AD. A primer on inverse probability of treatment weighting and marginal structural models. Emerg Adulthood 2016; 4 (01) 40-59
  • 32 Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health 2010; 13 (02) 273-277
  • 33 Mahé I, Chidiac J, Helfer H, Noble S. Factors influencing adherence to clinical guidelines in the management of cancer-associated thrombosis. J Thromb Haemost 2016; 14 (11) 2107-2113
  • 34 Wittkowsky AK. Barriers to the long-term use of low-molecular weight heparins for treatment of cancer-associated thrombosis. J Thromb Haemost 2006; 4 (09) 2090-2091
  • 35 Bauer KA. Pros and cons of new oral anticoagulants. Hematology (Am Soc Hematol Educ Program) 2013; 2013: 464-470
  • 36 Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 2015; 11: 967-977
  • 37 Hull RD, Pineo GF, Brant RF. et al. LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119 (12) 1062-1072
  • 38 Lee AYY, Kamphuisen PW, Meyer G. et al. CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015; 314 (07) 677-686
  • 39 Lee AY, Levine MN, Baker RI. et al. 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 (02) 146-153
  • 40 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
  • 41 Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest 2015; 147 (02) 475-483
  • 42 Li A, Garcia DA, Lyman GH, Carrier M. Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis. Thromb Res 2019; 173: 158-163
  • 43 Ross JA, Miller MM, Rojas Hernandez CM. Comparative effectiveness and safety of direct oral anticoagulants (DOACs) versus conventional anticoagulation for the treatment of cancer-related venous thromboembolism: a retrospective analysis. Thromb Res 2017; 150: 86-89
  • 44 Wysokinski WE, Houghton DE, Casanegra AI. et al. Comparison of apixaban to rivaroxaban and enoxaparin in acute cancer-associated venous thromboembolism. Am J Hematol 2019; 94 (11) 1185-1192
  • 45 Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 2009; 27 (29) 4839-4847
  • 46 Ay C, Dunkler D, Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116 (24) 5377-5382
  • 47 Broder MS, Neary MP, Chang E, Cherepanov D, Katznelson L. Treatments, complications, and healthcare utilization associated with acromegaly: a study in two large United States databases. Pituitary 2014; 17 (04) 333-341
  • 48 Cunningham A, Stein CM, Chung CP, Daugherty JR, Smalley WE, Ray WA. An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiol Drug Saf 2011; 20 (06) 560-566
  • 49 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126