Skip to main content

Advertisement

SpringerLink
Log in

The effect of warfarin therapy on breast, colorectal, lung, and prostate cancer survival: a population-based cohort study using the Clinical Practice Research Datalink

  • Original Paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Purpose

Pre-clinical studies suggest that oral anticoagulant agents, such as warfarin, may inhibit metastases and potentially prolong survival in cancer patients. However, few population-based studies have examined the association between warfarin use and cancer-specific mortality.

Methods

Using prescribing, cause of death, and cancer registration data from the UK Clinical Practice Research Datalink, four population-based cohorts were constructed, comprising breast, colorectal, lung, and prostate cancer patients diagnosed between 1 January 1998, and the 31 December 2010. Comparing pre-diagnostic warfarin users to non-users, multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer-specific mortality.

Results

Overall, 16,525 breast, 12,902 colorectal, 12,296 lung, and 12,772 prostate cancers were included. Pre-diagnostic warfarin use ranged from 2.4 to 4.7 %. There was little evidence of any strong association between warfarin use pre-diagnosis and cancer-specific mortality in prostate (adjusted HR 1.03, 95 % CI 0.84–1.26), lung (adjusted HR 1.06, 95 % CI 0.96–1.16), breast (adjusted HR 0.81, 95 % CI 0.62–1.07), or colorectal (adjusted HR 0.88, 95 % CI 0.77–1.01) cancer patients. Dose–response analyses did not reveal consistent evidence of reductions in users of warfarin defined by the number of prescriptions used and daily defined doses.

Conclusions

There was little evidence of associations between pre-diagnostic use of warfarin and cancer-specific mortality in lung, prostate, breast, or colorectal cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Gil-Bernabé AM, Lucotti S, Muschel RJ (2013) Coagulation and metastasis: what does the experimental literature tell us? Br J Haematol 162:433–441. doi:10.1111/bjh.12381

    Article  PubMed  Google Scholar 

  2. Kakkar AK, Macbeth F (2010) Antithrombotic therapy and survival in patients with malignant disease. Br J Cancer 102(Suppl):S24–S29. doi:10.1038/sj.bjc.6605602

    Article  PubMed Central  PubMed  Google Scholar 

  3. Kuderer NM, Ortel TL, Francis CW (2009) Impact of venous thromboembolism and anticoagulation on cancer and cancer survival. J Clin Oncol 27:4902–4911. doi:10.1200/JCO.2009.22.4584

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Palumbo JS, Kombrinck KW, Drew AF et al (2000) Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 96:3302–3309

    CAS  PubMed  Google Scholar 

  5. Bobek V, Boubelik M, Fiserová A et al (2005) Anticoagulant drugs increase natural killer cell activity in lung cancer. Lung Cancer 47:215–223. doi:10.1016/j.lungcan.2004.06.012

    Article  CAS  PubMed  Google Scholar 

  6. Im JH, Fu W, Wang H et al (2004) Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res 64:8613–8619. doi:10.1158/0008-5472.CAN-04-2078

    Article  CAS  PubMed  Google Scholar 

  7. Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11:123–134. doi:10.1038/nrc3004

    Article  CAS  PubMed  Google Scholar 

  8. Bobek V, Kovarík J (2004) Antitumor and antimetastatic effect of warfarin and heparins. Biomed Pharmacother 58:213–219. doi:10.1016/j.biopha.2003.11.007

    Article  CAS  PubMed  Google Scholar 

  9. Hejna M, Raderer M, Zielinski CC (1999) Inhibition of metastases by anticoagulants. J Natl Cancer Inst 91:22–36

    Article  CAS  PubMed  Google Scholar 

  10. Battinelli EM, Markens BA, Kulenthirarajan RA et al (2014) Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. Blood 123:101–112. doi:10.1182/blood-2013-02-485011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Amirkhosravi A, Mousa SA, Amaya M et al (2010) Assessment of anti-metastatic effects of anticoagulant and antiplatelet agents using animal models of experimental lung metastasis. Methods Mol Biol 663:241–259. doi:10.1007/978-1-60761-803-4_10

    Article  CAS  PubMed  Google Scholar 

  12. Maat B (1980) Selective macrophage inhibition abolishes warfarin-induced reduction of metastasis. Br J Cancer 41:313–316

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Hilgard P, Schulte H, Wetzig G et al (1977) Oral anticoagulation in the treatment of a spontaneously metastasising murine tumour (3LL). Br J Cancer 35:78–86

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Brown JM (1973) A study of the mechanism by which anticoagulation with warfarin inhibits blood-borne metastases. Cancer Res 33:1217–1224

    CAS  PubMed  Google Scholar 

  15. Bobek V, Boubelik M, Kovarík J, Taltynov O (2003) Inhibition of adhesion breast cancer cells by anticoagulant drugs and cimetidine. Neoplasma 50:148–151

    CAS  PubMed  Google Scholar 

  16. McCulloch P, George WD (1989) Warfarin inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumour growth. Br J Cancer 59:179–183

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Akl EA, Vasireddi SR, Gunukula S et al (2011) Oral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev. doi:10.1002/14651858.CD006466.pub3

    Google Scholar 

  18. Chahinian AP, Propert KJ, Ware JH et al (1989) A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol 7:993–1002

    CAS  PubMed  Google Scholar 

  19. Maurer LH, Herndon JE, Hollis DR et al (1997) Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study. J Clin Oncol 15:3378–3387

    CAS  PubMed  Google Scholar 

  20. Zacharski LR, Henderson WG, Rickles FR et al (1984) 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 53:2046–2052

    Article  CAS  PubMed  Google Scholar 

  21. Daly L (1991) The first international urokinase/warfarin trial in colorectal cancer. Clin Exp Metastasis 9:3–11

    Article  CAS  PubMed  Google Scholar 

  22. Levine M, Hirsh J, Gent M et al (1994) Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 343:886–889

    Article  CAS  PubMed  Google Scholar 

  23. Tagalakis V, Tamim H, Blostein M et al (2013) Risk of prostate cancer death in long-term users of warfarin: a population-based case–control study. Cancer Causes Control 24:1079–1085. doi:10.1007/s10552-013-0185-1

    Article  CAS  PubMed  Google Scholar 

  24. Tagalakis V, Tamim H (2010) The effect of warfarin use on clinical stage and histological grade of prostate cancer. Pharmacoepidemiol Drug Saf 19:436–439. doi:10.1002/pds.1943

    CAS  PubMed  Google Scholar 

  25. García Rodríguez LA, Pérez Gutthann S (1998) Use of the UK general practice research database for pharmacoepidemiology. Br J Clin Pharmacol 45:419–425

    Article  PubMed Central  PubMed  Google Scholar 

  26. Dregan A, Moller H, Murray-Thomas T, Gulliford MC (2012) Validity of cancer diagnosis in a primary care database compared with linked cancer registrations in England. Population-based cohort study. Cancer Epidemiol 36:425–429. doi:10.1016/j.canep.2012.05.013

    Article  CAS  PubMed  Google Scholar 

  27. Khan NF, Harrison SE, Rose PW (2010) Validity of diagnostic coding within the general practice research database: a systematic review. Br J Gen Pract 60:e128–e136. doi:10.3399/bjgp10X483562

    Article  PubMed Central  PubMed  Google Scholar 

  28. Khan NF, Perera R, Harper S, Rose PW (2010) Adaptation and validation of the Charlson Index for Read/OXMIS coded databases. BMC Fam Pract 11:1. doi:10.1186/1471-2296-11-1

    Article  PubMed Central  PubMed  Google Scholar 

  29. Hirsh J, Fuster V, Ansell J, Halperin JL (2003) American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 107:1692–1711. doi:10.1161/01.CIR.0000063575.17904.4E

    Article  PubMed  Google Scholar 

  30. Nielsen SF, Nordestgaard BG, Bojesen SE (2012) Statin use and reduced cancer-related mortality. N Engl J Med 367:1792–1802. doi:10.1056/NEJMoa1201735

    Article  CAS  PubMed  Google Scholar 

  31. Lévesque LE, Hanley JA, Kezouh A, Suissa S (2010) Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. BMJ 340:b5087. doi:10.1136/bmj.b5087

    Article  PubMed  Google Scholar 

  32. Chubak J, Boudreau DM, Wirtz HS et al (2013) Threats to validity of nonrandomized studies of postdiagnosis exposures on cancer recurrence and survival. J Natl Cancer Inst 105:1456–1462. doi:10.1093/jnci/djt211

    Article  PubMed Central  PubMed  Google Scholar 

  33. Tagalakis V, Blostein M, Robinson-Cohen C, Kahn SR (2007) The effect of anticoagulants on cancer risk and survival: systematic review. Cancer Treat Rev 33:358–368. doi:10.1016/j.ctrv.2007.02.004

    Article  CAS  PubMed  Google Scholar 

  34. Smorenburg SM, Vink R, Otten HM et al (2001) The effects of vitamin K-antagonists on survival of patients with malignancy: a systematic analysis. Thromb Haemost 86:1586–1587

    CAS  PubMed  Google Scholar 

  35. Stanford CF (1979) Anticoagulants in the treatment of small cell carcinoma of the bronchus. Thorax 34:113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Cunningham MS, Preston RJS, O’Donnell JS (2009) Does antithrombotic therapy improve survival in cancer patients? Blood Rev 23:129–135. doi:10.1016/j.blre.2008.10.002

    Article  CAS  PubMed  Google Scholar 

  37. Ryan JJ, Ketcham AS, Wexler H (1968) Warfarin treatment of mice bearing autochthonous tumors: effect on spontaneous metastases. Science 162:1493–1494

    Article  CAS  PubMed  Google Scholar 

  38. Agostino D, Cliffton EE, Girolami A (1966) Effect of prolonged coumadin treatment on the production of pulmonary metastases in the rat. Cancer 19:284–288

    Article  CAS  PubMed  Google Scholar 

  39. Walker JJ, Johnson JA, Wild SH (2013) Diabetes treatments and cancer risk: the importance of considering aspects of drug exposure. Lancet Diabetes Endocrinol 1:132–139. doi:10.1016/S2213-8587(13)70028-7

    Article  PubMed  Google Scholar 

  40. Sarfati D, Blakely T, Pearce N (2010) Measuring cancer survival in populations: relative survival vs cancer-specific survival. Int J Epidemiol 39:598–610. doi:10.1093/ije/dyp392

    Article  PubMed  Google Scholar 

  41. Lee AYY, Rickles FR, Julian JA et al (2005) Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 23:2123–2129. doi:10.1200/JCO.2005.03.133

    Article  CAS  PubMed  Google Scholar 

  42. Gerotziafas GT, Papageorgiou C, Hatmi M et al (2008) Clinical studies with anticoagulants to improve survival in cancer patients. Pathophysiol Haemost Thromb 36:204–211. doi:10.1159/000175158

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. However, the interpretation and conclusions contained in this study are those of the authors’ alone. C. Cardwell was supported by a Health and Social Care Research and Development, Public Health Agency, Northern Ireland, funded UK NIHR Career Development Fellowship, which also funded access to the CPRD dataset. At the time of writing, M. O’Rorke was also funded as a postdoctoral researcher under this fellowship.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queen’s University Belfast, Institute of Clinical Sciences Block B, Royal Victoria Hospital Site, Grosvenor Road, Belfast, BT12 6BJ, UK

    M. A. O’Rorke, L. J. Murray, M. M. Cantwell & C. R. Cardwell

  2. Clinical and Practice Research Group, School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK

    C. M. Hughes

Authors
  1. M. A. O’Rorke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. J. Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. M. Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. M. Cantwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. R. Cardwell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. A. O’Rorke.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

O’Rorke, M.A., Murray, L.J., Hughes, C.M. et al. The effect of warfarin therapy on breast, colorectal, lung, and prostate cancer survival: a population-based cohort study using the Clinical Practice Research Datalink. Cancer Causes Control 26, 355–366 (2015). https://doi.org/10.1007/s10552-014-0511-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-014-0511-2

Keywords

Search

Navigation