Minidose warfarin is associated with a high incidence of International Normalized Ratio elevation during chemotherapy with FOLFOX regimen

M. Magagnoli, G. Masci, C. Carnaghi, P. A. Zucali, L. Castagna, E. Morenghi and A. Santoro

Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Milan, Italy

*E-mail: massimo.magagnoli@humanitas.it

Randomized trials have demonstrated that the combination of 5-fluorouracil (5-FU) and folinic acid (FA) with oxaliplatin, the FOLFOX regimen, is highly active in metastatic colorectal cancer [1, 2]. In this regimen, 5–FU is administered as a continuous infusion requiring a central venous catheter (CVC) implant with its inherent complications [3], such as venous thromboembolism (VTE). Prophylaxis with low-dose heparin or oral anticoagulants is recommended.

Two studies have shown that warfarin 1 mg/day (minidose) reduces catheter-related thrombosis without altering coagulative parameters or causing bleeding [4, 5]. On the other hand, some reports have described adverse interactions between warfarin and 5-FU [6, 7]. However, no data on CVC-VTE prophylaxis in patients receiving continuous infusion 5-FU in combination with oxaliplatin have so far been reported. Preliminary data on a small cohort of patients showed a high incidence of elevation of International Normalized Ratio (INR) during treatment with FOLFOX [8]. To confirm whether such an interaction exists, we decided to perform an analysis of the incidence of INR elevation in 72 patients receiving a FOLFOX regimen with concomitant prophylactic minidose warfarin, treated in our institution from April 2000 to August 2002.

Twenty-two patients were excluded from the analysis for the following reasons: lack of INR evaluation at baseline, seven patients; less than three determinations of INR during the treatment program, six patients; use of therapeutic warfarin (>1 mg/day), three patients; other reasons (platelet count <100 x 109/l, use of antiplatelet agents, refusal to start treatment), seven patients. All fifty evaluable patients had normal INR levels at the time of CVC insertion, received minidose warfarin (1 mg/day) and were treated with the FOLFOX-4 regimen (oxaliplatin 85 mg/m2 as a 2-h i.v. infusion on day 1, FA 100 mg/m2 as a 2-h i.v. infusion on days 1 and 2, 5-FU 400 mg/m2 as a short infusion on days 1 and 2; 5-FU 600 mg/m2 as a 22-h i.v. continuous infusion on days 1 and 2). Thirty-five patients had an external device such as Groshong CVC (Bard Access System, Salt Lake City, UT) and 15 patients had a completely internalized device such as Port-a Cath (BardPort; Bard Access System). Patient characteristics are listed in Table 1.


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Table 1. Patient characteristics
 
Prothrombin time and INR were measured at baseline and subsequently at least four times during the chemotherapy program along with the routine biochemistry performed every two chemotherapy cycles. Blood chemistry also included liver and renal function, and electrolytes assessment. The prothrombin time was measured using Hemoliance Recombiplastin (Instrumentation Laboratory Inc., Lexington, KY). The normal value of INR was 0.90–1.18, with an INR >1.5 being regarded as significantly elevated. Among the 50 evaluable patients, the median INR value at baseline was 1.07. Altogether, 273 INR determinations were performed. The median number of INR determinations per patient was 5.5 (range 4–12). INR elevation was observed in 25/50 patients (50%), ranging from 1.55 to 9.4 (mean 3.22). Of these, four patients (8%) had an INR between 3.0 and 6.0 and four (8%) had an INR ≥6.0. The median time to INR elevation was 69 days (range 14–160) from the start of chemotherapy. Two patients developed hematuria requiring hospitalization, with INR levels at that time of 7.0 and 7.38. One patient developed epistaxis with an INR level of 1.48. The statistical analysis showed no relationship between liver metastases, hepatic function, chemotherapy toxicity or other parameters, and INR elevation.

Warfarin administration was discontinued if INR >2.0 and prothrombin time prolongation resolved within 48 h in all patients. Chemotherapy was continued thereafter without oral anticoagulant prophylaxis and none of these patients had any further prothrombin time alteration. In conclusion, these data confirm an adverse interaction between FOLFOX and warfarin and represent a relevant complication of minidose warfarin prophylaxis; the oncologist should be aware of this interaction and should regularly monitor the INR level in these patients.

Acknowledgements

We are indebted to Nordiana Marina Baruzzi for editing this letter.

M. Magagnoli*, G. Masci, C. Carnaghi, P. A. Zucali, L. Castagna, E. Morenghi & A. SantoroDepartment of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Milan, Italy (*E-mail: massimo.magagnoli@humanitas.it)

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