Does Warfarin Reduce Cancer Risk by 38% in Patients with Atrial Fibrillation?

Editor’s note: As far back as the mid-1970s, some believed that the anticoagulant effect of warfarin reduced the ability of cancer cells to seed (metastasize) to new locations.  At about the same time, interest started to grow in the ability of the body’s immune system to limit and eradicate cancer.  In the article reviewed below by guest authors Drs. Hawkins and Hornsby, the suggestion is put forth that it is the effect of warfarin on the immune system that may explain how warfarin may prevent the development of cancer.  Should this potential anti-cancer effect of warfarin (see table below) be considered when selecting an agent for long-term anticoagulation?

Table:  The Incident Rate Ratio (IRR) of Cancer in Warfarin Users Compared to Non-Users

Cancer Type		All Warfarin Users (n=92,942) IRR (95% Confidence Interval)		Warfarin Users with A. Fib (n=33,313) IRR (95% Confidence Interval)
All Types		0.84 (0.82 – 0.86)		0.62 (0.33 – 0.46)
Lung		0.80 (0.75 – 0.86)		0.39 (0.33 – 0.46)
Prostate		0.69 (0.65 – 0.72)		0.60 (0.55 – 0.66)
Breast (female)		0.90 (0.82 – 1.00)		0.72 (0.59 – 0.87)
Colon		0.99 (0.93 – 1.06)		0.71 (0.63 – 0.81)

Note:  The over-all incidence of cancer was 9.4% in warfarin users vs. 10.6% in warfarin non-users.  The IRR values were adjusted for age and gender.

Review – “Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years”

Zuri Hawkins, PharmD* and Lori Hornsby, PharmD, BCPS**

There is conflicting evidence regarding the antitumor benefits of warfarin and whether there is an association between its use and lower cancer incidence. Several studies have found lower rates of certain cancers such as small cell lung cancer and urogenital cancers while other studies have failed to find an association.^1-5 The exact mechanism by which warfarin may provide antitumor benefits is not completely understood. The authors of a recent cohort trial published in JAMA Internal Medicine cite the inhibition of warfarin on AXL receptor tyrosine kinase-dependent tumorigenesis and enhancement of antitumor immune response as the potential mechanism.⁶ The continued uncertainty of warfarin’s benefit on cancer incidence led the Norwegian researchers to examine this association further in a large, unselected population-based cohort.

Haaland et al. utilized the Norwegian National Registry to identify a study cohort (n = 1,256,725) of individuals born in Norway from January 1, 1924 to December 31, 1954 who were living in Norway during the study period. The Norwegian Prescription Database and the Cancer Registry of Norway, both with a 99% national coverage of cancer diagnoses and prescription use, were utilized to determine cancer diagnoses and warfarin use.  The cohort was divided into 2 groups (warfarin users vs. nonusers).  Warfarin users were defined as individuals who were on warfarin for at least 6 months and at least 2 years before any cancer diagnosis. All others were considered nonusers. The study period lasted 7 years (January 1, 2006 through December 31, 2012). Within the cohort 92,942 (7.4%) were determined to be warfarin users, with a mean duration of use of 4.7 years. There were a total of 132,687 (10.6%) individuals found to have a cancer diagnosis.

Of the warfarin users, 8754 (9.4%) were diagnosed with cancer as compared to 123,933 (10.6%) in the non-users. The incidence ratio rate (IRR) was reduced in favor of warfarin users as compared to non-users for all cancer sites (IRR, 0.84; 95% CI, 0.82-0.86) as well as prevalent organ-specific sites (lung, 0.80 [95% CI, 0.75-0.86]; prostate, 0.69 [95% CI, 0.65-0.72]; and breast, 0.90 [95% CI, 0.82-1.00]). The IRR was not statistically significant for colon cancer (IRR, 0.99; 95% CI, 0.93-1.06). In patients receiving warfarin for stroke prophylaxis in atrial fibrillation or atrial flutter, as opposed to thromboembolic disease which has a known association with cancer, the IRRs were even lower for all cancer sites (IRR, 0.62; 95% CI, 0.59-0.65), as well as prevalent sites (lung, 0.39 [95% CI, 0.33-0.46]; prostate, 0.60 [95% CI, 0.55-0.66]; breast, 0.72 [95% CI, 0.59-0.87]) and significant for colon cancer, 0.71 [95% CI, 0.63-0.81].

Overall, the study concluded warfarin use has potential cancer benefits across a number of cancer sites in patients over 50 years of age. Strengths of the study include the large population size and availability of databases that encompass 99% of the study population. While limiting the potential for misclassification bias, this cannot be ruled out due to the cohort design of the study. The inability to account for potential confounders such as life-style and genetic factors are also potential limitations. Lastly, cancer diagnoses prior to the study period were unavailable resulting in some incidence of cancer diagnosis being reoccurrences.

Data from this trial displays a potential positive association between warfarin use and cancer prevention. While the findings of the study leaves clinicians with additional considerations regarding warfarin use in at risk populations especially those with atrial fibrillation or atrial flutter, over newer oral anticoagulants with benefits such as standardized dosing, clinicians should interpret the results of these findings with caution based the limitations of the trial. Further studies assessing the use of warfarin in cancer prevention are warranted.

References

1. Zacharski L, Henderson W, Rickles F, Forman W, 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;53:2046-52.
2. Akl E, Kamath G, Kim Y, Yosuico V, et al. Oral anticoagulation may prolong survival of a subgroup of patients with cancer: a Cochrane Systematic Review. J Exp Cancer Res 2007;26:175-84.
3. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. NEJM 2000;342:1953-8.
4. Kinnunen PT, Murtola  TJ, Talala K, Taari K, Tammela TLJ, Auvinen A. Warfarin use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer. Scand J Urol. 2016;50(6):413-419.
5. Tagalakis V, Tamim H, Blostein M, Collet J, Hanley JA, Kahn SR. Use of warfarin and risk of urogenital cancer: a population based, nested case-control study. Lancet Oncol. 2007;8: 395–402.
6. 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 Dec 1;177(12):1774-1780.

Author information:

Zuri Hawkins, PharmD is a PGY2 Ambulatory Care Resident at Piedmont Columbus Regional, Midtown Campus in Columbus, Georgia.

Lori Hornsby, PharmD, BCPS is an Associate Clinical Professor with Auburn University Harrison School of Pharmacy in Auburn, Alabama and Ambulatory Pharmacist at Piedmont Columbus Regional, Midtown Campus in Columbus, Georgia.