Thromb Haemost 2020; 120(10): 1384-1394
DOI: 10.1055/s-0040-1714213
Coagulation and Fibrinolysis

The Association between Oral Anticoagulants and Cancer Incidence among Individuals with Nonvalvular Atrial Fibrillation

Devin Abrahami
1   Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
2   Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
,
Christel Renoux
1   Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
2   Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
3   Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
,
Hui Yin
1   Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
,
Jean-Pascal Fournier
4   Département de Médecine Générale, Université de Nantes, Nantes, France
,
1   Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
2   Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
5   Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
› Institutsangaben
Funding This study was funded by the Canadian Institutes of Health Research, Government of Canada (FDN-143328).

Abstract

Objective Existing evidence on the association between vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) and cancer is limited and contradictory. No observational studies have been conducted to simultaneously address the cancer safety of VKAs and DOACs. The objective of this study was to determine whether use of VKAs and DOACs, separately, when compared with nonuse, is associated with cancer overall and prespecified site-specific incidence.

Methods Using the United Kingdom Clinical Practice Research Datalink, we identified patients newly diagnosed with nonvalvular atrial fibrillation (NVAF) between 2011 and 2017. Using a time-varying exposure definition, each person-day of follow-up was classified as use of (1) VKAs, (2) DOACs, (3) VKAs and DOACs (drug switchers), and (4) nonuse of anticoagulants (reference). We also conducted a head-to-head comparison of new users of DOACs versus VKAs using propensity score fine stratification weighting. Hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer overall and prespecified subtypes were estimated using Cox proportional hazards models.

Results Compared with nonuse, use of VKAs was not associated with cancer overall (HR: 1.05, 95% CI: 0.91–1.22) or cancer subtypes. Similarly, use of DOACs was not associated with cancer overall (HR: 1.13, 95% CI: 0.93–1.37), but an association was observed for colorectal cancer (HR: 1.73, 95% CI: 1.01–2.99), and pancreatic cancer generated an elevated, though nonsignificant HR (HR: 2.15, 95% CI: 0.72–6.44). Results were consistent in the head-to-head comparison.

Conclusion Use of oral anticoagulants is not associated with the incidence of cancer overall among patients with NVAF. Possible associations between DOACs and colorectal and pancreatic cancer warrant further study.

Supplementary Material



Publikationsverlauf

Eingereicht: 07. Mai 2020

Angenommen: 04. Juni 2020

Artikel online veröffentlicht:
27. Juli 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 
  • References

  • 1 Chan NC, Eikelboom JW, Weitz JI. Evolving treatments for arterial and venous thrombosis: role of the direct oral anticoagulants. Circ Res 2016; 118 (09) 1409-1424
  • 2 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146 (12) 857-867
  • 3 Ruff CT, Giugliano RP, Braunwald E. , et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383 (9921): 955-962
  • 4 McCulloch P, George WD. Warfarin inhibition of metastasis: the role of anticoagulation. Br J Surg 1987; 74 (10) 879-883
  • 5 Brown JM. A study of the mechanism by which anticoagulation with warfarin inhibits blood-borne metastases. Cancer Res 1973; 33 (06) 1217-1224
  • 6 Kirane A, Ludwig KF, Sorrelle N. , et al. Warfarin blocks Gas6-mediated axl activation required for pancreatic cancer epithelial plasticity and metastasis. Cancer Res 2015; 75 (18) 3699-3705
  • 7 Haaland GS, Falk RS, Straume O, Lorens JB. Association of warfarin use with lower overall cancer incidence among patients older than 50 years. JAMA Intern Med 2017; 177 (12) 1774-1780
  • 8 Ahern TP, Pedersen L, Sværke C, Rothman KJ, Sørensen HT, Lash TL. The association between vitamin K antagonist therapy and site-specific cancer incidence estimated by using heart valve replacement as an instrumental variable. Am J Epidemiol 2011; 174 (12) 1382-1390
  • 9 Pottegård A, Friis S, Hallas J. Cancer risk in long-term users of vitamin K antagonists: a population-based case-control study. Int J Cancer 2013; 132 (11) 2606-2612
  • 10 Kinnunen PT, Murtola TJ, Talala K, Taari K, Tammela TL, Auvinen A. Warfarin use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer. Scand J Urol 2016; 50 (06) 413-419
  • 11 Pengo V, Noventa F, Denas G. , et al. Long-term use of vitamin K antagonists and incidence of cancer: a population-based study. Blood 2011; 117 (05) 1707-1709
  • 12 Tagalakis V, Tamim H, Blostein M, Collet J-P, Hanley JA, Kahn SR. Use of warfarin and risk of urogenital cancer: a population-based, nested case-control study. Lancet Oncol 2007; 8 (05) 395-402
  • 13 Blumentals WA, Foulis PR, Schwartz SW, Mason TJ. Does warfarin therapy influence the risk of bladder cancer?. Thromb Haemost 2004; 91 (04) 801-805
  • 14 ClinicalTrials.gov. An efficacy and safety study of rivaroxaban with warfarin for the prevention of stroke and non-central nervous system systemic embolism in patients with non-valvular atrial fibrillation. Available at: https://ClinicalTrials.gov/show/NCT00403767 . Accessed June 18, 2020
  • 15 ClinicalTrials.gov. Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) with dabigatran etexilate. Available at: https://ClinicalTrials.gov/show/NCT00262600 . Accessed June 18, 2020
  • 16 ClinicalTrials.gov. Apixaban for the prevention of stroke in subjects with atrial fibrillation (ARISTOTLE). Available at: https://ClinicalTrials.gov/show/NCT00412984 . Accessed June 18, 2020
  • 17 ClinicalTrials.gov. Global study to assess the safety and effectiveness of edoxaban (DU-176b) vs standard practice of dosing with warfarin in patients with atrial fibrillation (EngageAFTIMI48). Available at: https://clinicaltrials.gov/ct2/show/results/NCT00781391 . Accessed June 18, 2020
  • 18 Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJ. Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol 2010; 69 (01) 4-14
  • 19 Margulis AV, Fortuny J, Kaye JA. , et al. Validation of cancer cases using primary care, cancer registry, and hospitalization data in the United Kingdom. Epidemiology 2018; 29 (02) 308-313
  • 20 Boggon R, van Staa TP, Chapman M, Gallagher AM, Hammad TA, Richards MA. Cancer recording and mortality in the General Practice Research Database and linked cancer registries. Pharmacoepidemiol Drug Saf 2013; 22 (02) 168-175
  • 21 Williams R, van Staa T-P, Gallagher AM, Hammad T, Leufkens HGM, de Vries F. Cancer recording in patients with and without type 2 diabetes in the Clinical Practice Research Datalink primary care data and linked hospital admission data: a cohort study. BMJ Open 2018; 8 (05) e020827
  • 22 Dregan A, Moller H, Murray-Thomas T, Gulliford MC. Validity of cancer diagnosis in a primary care database compared with linked cancer registrations in England. Population-based cohort study. Cancer Epidemiol 2012; 36 (05) 425-429
  • 23 Niederle M, Vesterlund L. Explaining the gender gap in math test scores: the role of competition. J Econ Perspect 2010; 24: 129-144
  • 24 Jick SS, Kaye JA, Vasilakis-Scaramozza C. , et al. Validity of the general practice research database. Pharmacotherapy 2003; 23 (05) 686-689
  • 25 Lawrenson R, Williams T, Farmer R. Clinical information for research; the use of general practice databases. J Public Health Med 1999; 21 (03) 299-304
  • 26 European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP) Assessment Report: Pradaxa. 2011
  • 27 Rubin DB. Multiple Imputation for Nonresponse in Surveys (Wiley Series in Probability and Statistics). Hoboken, NJ: John Wiley & Sons, Inc.; 1987
  • 28 Schafer JL. Analysis of Incomplete Multivariate Data. Boca Raton, FL: Chapman and Hall/CRC; 1997
  • 29 Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med 1989; 8 (05) 551-561
  • 30 Cancer Research UK. Cancer incidence for common cancers. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/common-cancers-compared#heading-Zero . Accessed June 18, 2020
  • 31 Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94 (446) 496-509
  • 32 Desai RJ, Rothman KJ, Bateman BT, Hernandez-Diaz S, Huybrechts KF. A propensity-score-based fine stratification approach for confounding adjustment when exposure is infrequent. Epidemiology 2017; 28 (02) 249-257
  • 33 Zacharski LR, Henderson WG, Rickles FR. , et al. Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75. JAMA 1981; 245 (08) 831-835
  • 34 Zacharski LR, Henderson WG, Rickles FR. , et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75. Cancer 1984; 53 (10) 2046-2052
  • 35 Akl EA, Kamath G, Kim SY. , et al. Oral anticoagulation for prolonging survival in patients with cancer. Cochrane Database Syst Rev 2007; (02) CD006466
  • 36 Kahale LA, Hakoum MB, Tsolakian IG. , et al. Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev 2017; 12 (12) CD006466-CD006466
  • 37 Tagalakis V, Tamim H, Blostein M, Hanley JA, Kahn SR. Risk of prostate cancer death in long-term users of warfarin: a population-based case-control study. Cancer Causes Control 2013; 24 (06) 1079-1085
  • 38 Li X, Lund JL, Toh S. Lower cancer incidence-warfarin effect or immortal time bias?. JAMA Intern Med 2018; 178 (04) 584-585
  • 39 Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 2008; 167 (04) 492-499
  • 40 Giugliano RP, Ruff CT, Braunwald E. , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
  • 41 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
  • 42 Granger CB, Alexander JH, McMurray JJV. , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
  • 43 Patel MR, Mahaffey KW, Garg J. , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
  • 44 Najidh S, Versteeg HH, Buijs JT. A systematic review on the effects of direct oral anticoagulants on cancer growth and metastasis in animal models. Thromb Res 2020; 187: 18-27
  • 45 Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 2003; 158 (09) 915-920
  • 46 NICE. Atrial fibrillation: management. Available at: https://www.nice.org.uk/guidance/cg180 . Published 2014. Accessed June 18, 2020