Minidose warfarin is associated with a high incidence of International Normalized Ratio elevation during chemotherapy with FOLFOX regimen
Authors: M. Magagnoli, G. Masci, C. Carnaghi, P.A. Zucali, L. Castagna, E. Morenghi, A. Santoro
Journal: Annals of Oncology (2003)

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.De Gramont A. Figer A. Seymour M. et al.Leucovorin and fluorouracil with or without oxaliplatin as first line treatment in advanced colorectal cancer.J Clin Oncol. 2000; 18: 2938-2947Crossref PubMed Scopus (3512) Google Scholar, 2.Giacchetti S. Perpoint B. Zidani R. et al.Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil–leucovorin as first-line treatment of metastatic colorectal cancer.J Clin Oncol. 2000; 18: 136-147Crossref PubMed Google Scholar]. In this regimen, 5–FU is administered as a continuous infusion requiring a central venous catheter (CVC) implant with its inherent complications [3.Eastrige B.J. Lefor T.A. Complications of indwelling venous catheter devices in cancer patients.J Clin Oncol. 1995; 13: 233-238Crossref PubMed Google Scholar], 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.Bern M.M. Lokich J.J. Wallach S.R. et al.Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial.Ann Intern Med. 1990; 112: 423-428Crossref PubMed Scopus (791) Google Scholar, 5.Ratcliffe M. Broadfoot C. Davidson M. et al.Thrombosis, markers of thrombotic risk, indwelling central venous catheters and efficiency of antithrombotic prophylaxis using low-dose of warfarin.Br J Haematol. 1998; 101: 79-85Google Scholar]. On the other hand, some reports have described adverse interactions between warfarin and 5-FU [6.Brown M.C. An adverse interaction between warfarin and 5-fluorouracil: a case report and review of the literature.Chemotherapy. 1999; 45: 392-395Crossref PubMed Scopus (45) Google Scholar, 7.Kolesar J.M. Johnson C.L. Freeberg B.L. et al.Warfarin-5-FU interaction—a consecutive case series.Pharmacotherapy. 1999; 19: 1445-1449Crossref PubMed Scopus (53) Google Scholar]. 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.Masci G. Magagnoli M. Zucali P.A. et al.Minidose warfarin prophylaxis for catheter-associated thrombosis in cancer patients: can it be safely associated with fluorouracil-based chemotherapy?.J Clin Oncol. 2003; 21: 736-739Crossref PubMed Scopus (101) Google Scholar]. 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 × 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.Table 1Patient characteristicsCharacteristicNo. of patientsEvaluable patients50Male/female31/19Median age (years)62 (range 36–78)Central venous catheterGroshong35Port-a Cath15Site of primary tumorColon44Rectum6Metastatic disease40Liver metastases39FOLFOX regimenFirst-line39Second or third line11Median number of cycles of FOLFOX6 (range 4–16)FOLFOX, 5-fluorouracil, folinic acid and oxaliplatin. Open table in a new tab 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.AcknowledgementsWe 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: [email protected]) 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.De Gramont A. Figer A. Seymour M. et al.Leucovorin and fluorouracil with or without oxaliplatin as first line treatment in advanced colorectal cancer.J Clin Oncol. 2000; 18: 2938-2947Crossref PubMed Scopus (3512) Google Scholar, 2.Giacchetti S. Perpoint B. Zidani R. et al.Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil–leucovorin as first-line treatment of metastatic colorectal cancer.J Clin Oncol. 2000; 18: 136-147Crossref PubMed Google Scholar]. In this regimen, 5–FU is administered as a continuous infusion requiring a central venous catheter (CVC) implant with its inherent complications [3.Eastrige B.J. Lefor T.A. Complications of indwelling venous catheter devices in cancer patients.J Clin Oncol. 1995; 13: 233-238Crossref PubMed Google Scholar], 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.Bern M.M. Lokich J.J. Wallach S.R. et al.Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial.Ann Intern Med. 1990; 112: 423-428Crossref PubMed Scopus (791) Google Scholar, 5.Ratcliffe M. Broadfoot C. Davidson M. et al.Thrombosis, markers of thrombotic risk, indwelling central venous catheters and efficiency of antithrombotic prophylaxis using low-dose of warfarin.Br J Haematol. 1998; 101: 79-85Google Scholar]. On the other hand, some reports have described adverse interactions between warfarin and 5-FU [6.Brown M.C. An adverse interaction between warfarin and 5-fluorouracil: a case report and review of the literature.Chemotherapy. 1999; 45: 392-395Crossref PubMed Scopus (45) Google Scholar, 7.Kolesar J.M. Johnson C.L. Freeberg B.L. et al.Warfarin-5-FU interaction—a consecutive case series.Pharmacotherapy. 1999; 19: 1445-1449Crossref PubMed Scopus (53) Google Scholar]. 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.Masci G. Magagnoli M. Zucali P.A. et al.Minidose warfarin prophylaxis for catheter-associated thrombosis in cancer patients: can it be safely associated with fluorouracil-based chemotherapy?.J Clin Oncol. 2003; 21: 736-739Crossref PubMed Scopus (101) Google Scholar]. 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 × 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. FOLFOX, 5-fluorouracil, folinic acid and oxaliplatin. 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. AcknowledgementsWe 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: [email protected]) 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: [email protected])