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© 2003 American Society for Clinical Oncology Minidose Warfarin Prophylaxis for Catheter-Associated Thrombosis in Cancer Patients: Can It Be Safely Associated With Fluorouracil-Based Chemotherapy?From the Departments of Medical Oncology and Hematology and Interventional Radiology, Istituto Clinico Humanitas, Rozzano, Milan, Italy. Address reprint requests to Giovanna Masci, MD, Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Via Manzoni 56, 20089, Rozzano, Milano, Italy; email: giovanna.masci{at}humanitas.it.
Purpose: The use of prophylactic low-dose oral warfarin in cancer patients with a central venous catheter (CVC) in place has an established role in the prevention of thrombotic complications and is associated with a low hemorrhagic risk. Despite the literature indicating an adverse interaction between warfarin and fluorouracil (FU), the frequency of this interaction and whether it occurs when minidose warfarin is used is unknown. We analyzed the incidence of alterations in the International Normalized Ratio (INR) and bleeding in cancer patients given minidose warfarin during treatment with continuous-infusion FU-based regimens. Patients and Methods: Between July 1999 and August 2001, 95 cancer patients were evaluated. Forty-one patients (43%) had liver metastases. Seventy-nine patients (83%) had a Groshong CVC (Bard Access System, Salt Lake City, UT), and 16 (17%) had a Port-a-Cath device (Bard Access System). All patients received oral warfarin at a dose of 1 mg/daily as prophylaxis beginning the day after the catheter was positioned. An INR of more than 1.5 was considered significantly elevated. Results: INR elevation occurred in 31 patients (33%), with 18 patients (19%) having an INR more than 3.0. Twelve (39%) of the 31 patients had liver metastases. Bleeding was observed in eight patients (8%); seven of these patients had elevated INR levels. We observed INR elevations in 12 of 21 patients treated with a FU, folinic acid, and oxaliplatin (FOLFOX) regimen, 11 of 40 treated with a de Gramont regimen (FU and folinic acid), and five of 19 treated with a FU, folinic acid, and irinotecan (FOLFIRI) regimen. Conclusion: A high incidence of INR abnormalities was observed in our cohort of patients, especially those treated with FOLFOX regimen. Clinicians should be aware of this interaction and should regularly monitor the prothrombin time in patients receiving warfarin and FU.
THE PATHOGENESIS of venous thromboembolism (VTE), which is frequently observed during the management of cancer patients, is multifactorial. Stasis, secondary to immobilization or vascular compression by tumor masses, and the production of procoagulant factors from monocytes and tumor cells both contribute to the hypercoagulable state.1,2 Moreover, endocrine therapy and chemotherapy, as well as the insertion of central venous catheters (CVCs) further increase the incidence of VTE.3–6 CVCs are used in cancer patients who require chemotherapy, such as continuous-infusion fluorouracil (FU), multiple days of infusion of cytotoxic agents, antibiotic administration, or just supportive care, that cannot be easily administered through a peripheral vein. The causes of catheter-related thrombosis are also multifactorial. Insertion of the CVC may cause a degree of vessel-wall trauma.7 Moreover, the sclerosing nature of certain chemotherapeutic agents can damage the vessel walls.8 It is also possible that abrasion of the endothelial wall may occur because of the movement of the catheter within the vein.9 Because CVC-related thrombosis worsens patients’ well-being and is associated with pulmonary emboli in 10% to 15% of cases,10 the opportunity to use pharmacologic prophylaxis has been evaluated. Several studies have shown that 1 mg/d (minidose) of warfarin reduces catheter-related thrombosis without inducing alterations in prothrombin time (PT) or activated partial thromboplastin time or causing bleeding.11,12 However, literature reports have described cases of adverse interaction between warfarin and chemotherapeutic agents, particularly FU.13 In this study, we retrospectively analyzed adverse interactions and the incidence of INR alterations or bleeding in a large cohort of patients treated with continuous-infusion FU-based chemotherapy and minidose warfarin. Furthermore, we evaluated a number of potential predictive factors to determine their effect on the International Normalized Ratio (INR) alteration in these patients.
Patients Ninety-five consecutive cancer patients (53 males and 42 females) treated with continuous-infusion FU-based chemotherapy between July 1999 and August 2001 were evaluated. Median age was 59 years (range, 34 to 78 years). All patients had a performance status of 0 to 1, and all had normal INR levels at the time of CVC insertion. Seventy-nine patients (83%) were affected by colon cancer, 10 by gastric cancer, three by pancreatic cancer, two by gallbladder carcinoma, and one patient by esophageal cancer. Sixty-four patients (67%) had stage IV disease, 23 had stage III, and eight patients had stage II disease. Forty-one patients (43%) had liver metastases. Most of the patients had been pretreated with a median of one chemotherapeutic regimen (range, one to four regimens). Patient characteristics are listed in Table 1  .
CVC Positioning After informed consent was obtained, following specific mention of CVC complications, including thrombosis, sepsis, pneumothorax, and hemorrhage, all patients had a CVC positioned under local anesthesia in the outpatient angiographic room by a radiologist. All CVCs were placed on the right side. The puncture of the subclavian vein was always performed under ultrasound guidance to avoid the risk of pneumothorax. Guidewire and catheter position were evaluated by intraoperative fluoroscopy. Two types of CVC were used throughout the study period. Seventy-nine patients (83%) had an external device such as Groshong Catheter (Bard Access System, Salt Lake City, UT), and 16 patients had a device completely internalized such as Port-a-Cath (titanium port with attachable radiopaque silicone 6.6-Fr open-ended single-lumen venous catheter; 76 cm in length, 1.0 mm lumen; BardPort, Bard Access System). The Port-a-Cath insertion technique involved puncturing the subclavian vein and tunneling the puncture site with a subcutaneous pouch.14 The pouch was prepared with an electric scalpel, and the reservoir was fixed to the pectoral muscle fascia. Groshong catheters were inserted and tunneled approximately 4 cm under the skin before entrance into the subclavian vein and then fixed to the skin with a stitch.15
Treatment Plan and Evaluation
All patients received prophylactic oral warfarin at the fixed dose of 1 mg/d starting on the day of CVC insertion. PT and INR were measured at baseline (CVC insertion) and at least four more times during the chemotherapy program along with the routine biochemistry performed every three or four chemotherapy cycles. Blood chemistry also included liver function (AST, ALT, bilirubin, gamma-glutamyl transferase, total serum lactate dehydrogenase, and alkaline phosphatase), renal function (serum creatinine and blood urea nitrogen), and electrolyte assessment. The only patients excluded from this analysis were those who had PT and INR measured fewer than four times or who were not measured at baseline. PT was measured using Hemoliance Recombiplastin (Instrumentation Laboratory Inc, Lexington, MA); the normal value of INR was 0.90 to 1.18, with an INR of more than 1.5 being regarded as significantly elevated even in the case of a single abnormal assessment. Major bleeding was defined as soft tissue bleeding requiring blood transfusion, hematemesis, hemoptysis, melena, macrohematuria, vaginal bleeding apart from that of normal menses, epistaxis for more than 1 hour with gross blood loss, or retinal hemorrhages with vision impairment. Clinical adverse events were graded according to the National Cancer Institute of Canada common toxicity criteria grading system.
Statistical Analysis
No operative complications related to CVC positioning, such as pneumothorax and hemothorax, were observed. There were no cases of sepsis, and only one patient had internal saphenous vein thrombosis. Altogether, 488 INR determinations were performed, 50 of which (10%) showed an INR of more than 1.5. The median number of INR determinations per patient was five (range, four to 12 determinations). Of 95 cancer patients, a significant elevation in INR levels was observed in 31 patients (33%). Of these, six patients had an INR of more than 2.0 to 2.9, 18 patients had an INR of more than 3.0 to 4.9, and seven patients had an INR of more than 5.0. Twenty-eight patients (29%) had minimal INR elevation (between 1.18 and 1.5). Bleeding was observed in eight patients; in all but one of these patients, the INR was abnormal. In these patients, INR alteration ranged between 1.34 and 8.8. Epistaxis with no gross blood loss was observed in six patients, and hematuria was observed in two patients. Bleeding was not correlated with risk of death. Hospitalization was required for two patients with hematuria not requiring RBC transfusion. We did not observe grade 3 to 4 hematologic or nonhematologic toxicity in these patients. Liver metastases were present in 12 (39%) of 31 patients.
Table 1
Regimens based on the continuous infusion of FU are the mainstay of chemotherapy for several malignancies, particularly gastrointestinal cancer. Continuous infusion of FU needs to be administered via a CVC, although this does pose some problems, such as VTE and infection. Previously published reports indicated an incidence of symptomatic thrombosis in 5% to 10% of patients with implanted catheters.19 VTE, however, is mostly asymptomatic, although it occurs in approximately 30% to 70% of patients.20 Levine et al21 demonstrated that very low dose warfarin decreases the incidence of VTE in patients with metastatic breast cancer treated with chemotherapy. On the basis of these data, prophylaxis with low-dose heparin or oral anticoagulant has been recommended. In fact, the daily use of minidose warfarin (1 mg)22,23 or low–molecular weight heparin (reviparin sodium, Clivarin; Knoll, Ludwigshafen, Germany)24 were protective in terms of catheter-related VTE and are considered safe because they generally do not alter coagulative parameters.25–27 The antithrombotic mechanism of minidose warfarin is not known but is presumed to be the result of a reduced potential for thrombin generation.28 The appropriate duration of minidose warfarin therapy is undefined, but it is usually continued from the day of catheter insertion until the day of its removal. An adverse interaction between FU and warfarin has been reported, and the routine use of warfarin during continuous infusion of FU is theoretically hampered by a potential interaction between these two drugs. It has been postulated that FU may impair vitamin K absorption or may interfere with warfarin during its absorption, vascular transport, degradation, or excretion.29–31 Prolonged FU half-life and increased INR have been reported and are thought to be a result of an interference with the synthesis of hepatic cytochrome 450 and impaired metabolism of warfarin and FU.32,33 The frequency of this interaction is not known, and only case reports have been published on the subject. In previously reported cases34–38 indicating an interaction between FU and warfarin, all except one patient had liver metastases (six patients from colorectal cancer, one patient from breast cancer, and one patient from small-cell lung cancer), and most patients were receiving warfarin for a malignancy-related deep vein thrombosis. Only the patient suffering from small-cell lung cancer took minidose warfarin as prophylaxis against catheter-associated thrombosis, and this patient developed both a prolonged PT (INR 8.4) and a markedly elevated bilirubin of 16.0 mg/dL (predominantly conjugated).39 Our study showed that the combination of warfarin and FU resulted in an INR elevation in 33% of patients and that of the eight patients who developed bleeding problems, seven had an elevated INR. No relationship was observed between liver metastases, hepatic function, age, performance status, number of previous chemotherapy regimens administered, or chemotherapy toxicity and INR alteration or bleeding. In patients treated with the FOLFOX regimen, we observed a significantly higher incidence of INR elevation (P = .041). In this regard, oxaliplatin seems to synergize the anticoagulant effect of FU, but to the best of our knowledge, this is the first report to point out this phenomenon. Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation, and it is not subjected to CYP450-mediated metabolism. In vitro studies have proven that oxaliplatin does not inhibit CYP450 isoenzymes.40 These data could exclude an inhibition of warfarin metabolism. Furthermore, oxaliplatin is largely bound to plasma proteins and especially to albumin (85%); therefore, displacement of warfarin from plasma proteins could be the most immediate mechanism to explain the prolongation of INR in our patients. However, the exact mechanism of interaction between warfarin and oxaliplatin should be extensively studied. In conclusion, this large retrospective study revealed a high incidence of INR elevation when minidose warfarin was given along with a FU infusion. Because warfarin is recommended as prophylaxis against catheter-associated thrombosis, clinicians should be aware of this interaction and should regularly monitor the PT of patients receiving warfarin and FU-based chemotherapy.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Analysis was repeated for selected baseline characteristics. 
