Annals of Oncology Advance Access originally published online on August 12, 2005
Annals of Oncology 2006 17(1):174-176; doi:10.1093/annonc/mdj002
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© 2005 European Society for Medical Oncology
letter to the editor |
High incidence of INR alteration in gastrointestinal cancer patients treated with mini-dose warfarin and 5-fluorouracil-based regimens
Several studies have been performed to evaluate pharmacological prophylaxis with warfarin in cancer patients with central venous catheters (CVCs), but the analysis of these studies does not allow firm conclusions to be drawn. Some studies have showed that mini-doses of warfarin (1 mg/day) reduced catheter-related thrombosis [1
, 2], whereas other studies did not support this practice [3, 4]. However, in all these studies this prophylaxis was considered safe, because it generally does not alter coagulative parameters.
On the other hand, in the first retrospective study of 95 consecutive cancer patients, we observed that the combination of mini-dose warfarin and continuous infusion 5-fluorouracil (5-FU)-based regimens resulted in an international normalized ratio (INR) elevation in 33% of cases [5]. To confirm whether such an interaction exists, we performed a prospective analysis on the incidence of INR elevation in 247 gastrointestinal cancer patients receiving 5-FU-based regimens with concomitant prophylactic mini-dose warfarin to prevent CVC thrombosis (Table 1). All patients had normal INR levels at the time of CVC insertion. Median age was 60 years (range 28–78). All patients received prophylactic oral warfarin at the fixed dose of 1 mg/day starting on the day of CVC insertion. Prothrombin time and INR were measured at baseline (CVC insertion) and during the chemotherapy program along with routine biochemistry. Prothrombin time was measured using ‘Hemoliance Recombiplastin’ (Instrumentation Laboratory, Inc., Lexington, MA, USA); the normal value of INR was 0.90–1.18 with an INR of >1.5 being regarded as significantly elevated, even in the case of a single abnormal assessment. Clinical adverse events were graded according to the National Cancer Institute of Canada common toxicity criteria grading system.
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We observed six thrombotic events, directly related to catheter in five cases. The median number of days between line insertion and thrombosis was 163 days (range 28–216). A total of 1141 INR determinations were performed. The median number of INR determinations per patient was six (range four to 10). INR elevation was observed in 103 of 247 patients (42%), ranging from 1.5 to 9.4 (mean 2.94). The median time to INR elevation was 95 days (range 14–298) from the start of chemotherapy. Bleeding was observed in eight patients; in all but one of these the INR was abnormal. In these patients, INR alteration ranged between 1.34 and 9.4. With regard to chemotherapy regimens, the INR became elevated in 40 of 83 (48%) patients treated with the FOLFOX regimen, 33 of 91 (36%) patients treated with the de Gramont regimen and 23 of 45 (51%) patients treated with the FOLFIRI regimen. The statistical analysis did not show a significant association between INR elevation and any chemotherapy. We could not identify other prognostic factors associated with INR elevation. Warfarin administration was discontinued at the first sign of INR elevation; in all patients INR normalized within 48 h. Chemotherapy was then continued without warfarin prophylaxis. None of these patients showed any further INR elevation, but two patients developed a catheter-related venous thrombosis after warfarin administration was stopped.
This prospective analysis definitively showed the relationship between mini-dose warfarin and INR elevation when given concurrently with 5-FU-containing regimens. It has been postulated that 5-FU may impair vitamin K absorption or may interfere with warfarin during its absorption, vascular transport, degradation or excretion. Prolonged 5-FU half-life and increased INR have been reported, and are thought to be due to an interference with the synthesis of hepatic cytochrome 450 and impaired metabolism of warfarin and 5-FU [6].
With respect to our previous observations, in the present series we were not able to identify any prognostic factor related to INR elevation, even FOLFOX, which has been reported previously [7]. The reasons for such discrepancy mostly reside in the higher incidences of INR elevation in patients receiving de Gramont (36% versus 27%) or FOLFIRI (51% versus 26%) regimens, compared with the previous series. However, the overall incidence of INR elevation (42%) remains an issue of major concern. According to this observation, oncologists should be aware of this interaction and should regularly monitor INR levels in these patients. Furthermore, we think that oncologists should also be aware of the INR level in all patients with previous episodes of thromboembolism concomitantly treated with 5-fluorouracil-based regimen and warfarin at therapeutic doses.
Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Milan, Italy
* E-mail: massimo.magagnoli{at}humanitas.it
References
1. Bern MM, Lokich JJ, Wallach SR et al. Very low doses of warfarin can prevent thrombosis in central venous catheters. Ann Intern Med 1990; 112: 423–428.
2. Boraks P, Seale J, Price J et al. Prevention of central venous catheter associated thrombosis using minidose warfarin in patients with haematological malignancies. Br J Haematol 1998; 101: 483–486.[CrossRef][Web of Science][Medline]
3. Couban S, Goodyear M, Burnell M et al. Randomized placebo-controlled study of low-dose warfarin for the prevention of CVC-associated thrombosis in patients with cancer. J Clin Oncol 2005; 23: 4063–4069.
4. Heaton DC, Han DY, Inder A. Minidose (1 mg) warfarin as prophylaxis for central vein catheter thrombosis. Intern Med J 2002; 32: 84–88.[CrossRef][Web of Science][Medline]
5. Masci G, Magagnoli M, Zucali PA et al. Minidose warfarin prophylaxis for catheter-associated thrombosis in cancer patients. Can it be safely associated with 5-fluorouracil-based chemotherapy? J Clin Oncol 2003; 21: 736–739.
6. Afsar A, Lee C, Riddick DS. Modulation of the expression on constitutive rat epatic cytocrome p450 isozymes by 5-fluorouracil. Can J Physiol Pharmacol 1996; 74: 150–156.[CrossRef][Medline]
7. Magagnoli M, Masci G, Carnaghi C et al. Minidose warfarin is associated with high incidence of International Normalized Ratio elevation during chemotherapy with FOLFOX regimen. Ann Oncol 2003; 14: 959–960.
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