The impact of warfarin on overall survival in cancer patients with VTE

During the 11^th ICTHIC, 2022, Jeffrey Zwicker talked about the impact of warfarin on overall survival (OS) in cancer patients with venous thromboembolism (VTE). Here, we summarize the highlights of his talk.

Warfarin vs low-molecular-weight heparin

For the last 20 years, until recently, low-molecular-weight heparin (LMWH) was preferred to warfarin for secondary prevention of thrombosis [1].

Results from the CATCH study (NCT01130025) indicated that among patients with active cancer and acute symptomatic VTE, LMWH for 6 months, compared with warfarin, did not significantly reduce recurrent VTE and was not associated with reductions in overall mortality or major bleeding [2].

Using the Surveillance, Epidemiology and End Results (SEER) and Medicare-linked database from 2007 through 2016, a study compared the overall survival of 9,706 cancer patients receiving either LMWH or warfarin [3].

The patients were:

• Aged >66 years;
• Diagnosed with primary gastric, colorectal, pancreatic, lung, ovarian or brain cancer;
• Diagnosed with cancer-associated VTE;
• Prescribed LMWH or warfarin within 30 days [3].

Patients were matched 1:1 using exact matching for cancer stage and propensity score matching for cancer diagnosis, age, year of VTE, and time from cancer diagnosis to index VTE [3].

The study investigated the benefits of LMWH over warfarin for the secondary prevention of thrombosis. Results, though, showed an improved OS in patients treated with warfarin compared with LMWH (median OS 9.8 months [95% CI, 9.1–10.4] vs 7.2 months [95% CI, 6.8–7.8]; HR 0.86; 95% CI, 0.83–0.90; p<0.001).

The survival advantage was most pronounced in pancreatic (HR 0.82 [95% CI, 0.74–0.90], p<0.001) and gastric cancers (HR 0.82 [95% CI, 0.68–0.98], p=0.03). Survival benefit of warfarin over LMWH was consistent across subgroups [3].

Other studies also confirmed the improved OS of cancer patients treated with warfarin compared with LMWH [4,5]. However, not only does warfarin correlate with a better OS, but it may also be associated with lower cancer incidence across a broad range of malignant neoplasms.

 

Warfarin anticancer activity

Another study investigated the cumulative probability of a cancer diagnosis during 6 years of follow-up after the first episode of VTE. It seems that 6 months of anticoagulation with warfarin reduced the risk of a cancer diagnosis in the 6 years of follow-up, compared to 6 weeks of treatment [7]. Unfortunately, this difference was not mirrored by a lower death rate due to cancer during 8 years of follow-up [7].

An animal model-based study showed a possible mechanism by which warfarin can achieve its anticancer effects [8]. The activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. The inhibition of Gas6-dependent Axl activation with low-dose warfarin blocks the progression and spread of pancreatic cancer. Warfarin also seems to inhibit Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. It seems that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression. Its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcomes in patients with Axl-expressing tumors [8].

Back in the 1980s, a few studies investigated the potential anticancer activity of warfarin, exploring if chemotherapy + warfarin vs chemotherapy alone was able to give some survival advantage [9].

Warfarin vs direct oral anticoagulants

But what if a patient selection bias causes the benefits shown using warfarin. Do the patients who receive warfarin have a better OS because they are healthier than their counterparts [10]?

Utilizing the SEER-Medicare linked databases from 2012 through 2016, a study analyzed the OS in individuals diagnosed with primary gastric, colorectal, pancreas, lung, ovarian, or brain cancer and VTE who received a prescription of direct oral anticoagulants (DOACs) or warfarin within 30 days of VTE diagnosis.

Patients were matched 1:2 (DOAC:warfarin) through exact matching for cancer stage and propensity score matching for age, cancer site, cancer stage, and time interval from cancer to VTE diagnosis. A total of 4,274 patients received DOACs or warfarin for the treatment of VTE within 30 days of a cancer diagnosis.

Warfarin was associated with a statistically significantly higher OS compared to DOACs (median overall survival 12.0 months [95% CI, 10.9–13.5] versus 9.9 months [95% CI, 8.4–11.2]; HR 0.85; 95% CI: 0.78–0.91; p<0.001).

Observed differences in survival were consistent across subgroups of cancer sites, cancer stages, and type of VTE.

Conclusion

Patients receiving warfarin for cancer-associated thrombosis secondary prevention showed improved survival over patients receiving either LMWH or DOACs. In addition, warfarin is associated with a reduction in cancer incidence. Some preclinical studies showed the possible mechanism by which warfarin could achieve its anticancer ability.

Further randomized studies should investigate the potential survival benefit of warfarin in treating cancer-associated thrombosis.

 

References

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): venous thromboembolic disease. http://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Accessed July 24, 2015.
2. Lee AYY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA. 2015;314(7):677-686. doi: 10.1001/jama.2015.9243.
3. Chiasakul T, Redd R, Patell R, Khan AM, McCarthy EP, Neuberg D, Zwicker JI. Overall survival with warfarin vs. low-molecular-weight heparin in cancer-associated thrombosis. J Thromb Haemost. 2021;19(11):2825-2834. doi: 10.1111/jth.15519.
4. Kinnunen PT, Murto MO, Artama M, Pukkala E, Visvanathan K, Murtola TJ. Anticoagulants and breast cancer survival: a nationwide cohort study. Cancer Epidemiol Biomarkers Prev. 2020;29(1):208-215. doi:10.1158/1055-9965.EPI-19-0147.
5. Kinnunen PTT, Murtola TJ, Talala K, Taari K, Tammela TLJ, Auvinen A. Anticoagulants and cancer mortality in the Finnish randomized study of screening for prostate cancer. Cancer Causes Control. 2019;30(8):877-888. doi:10.1007/s10552-019-01195-x.
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;177(12):1774-1780. doi:10.1001/jamainternmed.2017.5512.
7. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. Duration of Anticoagulation Trial. N Engl J Med. 2000;342(26):1953-1958. doi:10.1056/NEJM200006293422604.
8. Kirane A, Ludwig KF, Sorrelle N, Haaland G, Sandal T, Ranaweera R, Toombs JE, Wang M, Dineen SP, Micklem D, Dellinger MT, Lorens JB, Brekken RA. Warfarin blocks Gas6-mediated Axl activation required for pancreatic cancer epithelial plasticity and metastasis. Cancer Res. 2015;75(18):3699-705. doi: 10.1158/0008-5472.CAN-14-2887-T.
9. Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ Jr, Forcier RJ, Edwards R, Headley E, Kim SH, O’Donnell JR, O’Dell R, Tornyos K, Kwaan HC. Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75. JAMA. 1981;245(8):831-5.
10. Khan AM, Chiasakul T, Redd R, Patell R, McCarthy EP, Neuberg D, Zwicker JI. Survival outcomes with warfarin compared with direct oral anticoagulants in cancer-associated venous thromboembolism in the United States: A population-based cohort study. PLoS Med. 2022;19(5):e1004012. doi: 10.1371/journal.pmed.1004012.