warfarin and Carcinoma--Transitional-Cell

A case of supratherapeutic International Normalized Ratio (INR) values and hematomas subsequent to concomitant administration of warfarin and intravesical gemcitabine is reported.. A 90-year-old man with bladder cancer refractory to bacillius Calmette-Guérin was diagnosed with deep vein thrombosis (DVT) and started on warfarin one month before starting treatment with intravesical gemcitabine 2 g (one dose per week for six weeks). Before intravesical gemcitabine was started, the patient reached consecutive therapeutic INR values. During the first five cycles of intravesical gemcitabine, the patient began to experience critically elevated INRs, which resulted in hospitalization and led to the discovery of hematomas. At hospital discharge, the decision was made to discontinue warfarin permanently given the patient's history of critically elevated INRs. Instead, enoxaparin was initiated due to the patient's history of DVT and active malignancy. Enoxaparin was started at a therapeutic, renally adjusted dosage of 60 mg subcutaneously once daily after the patient's hematomas resolved and hemoglobin level stabilized. The patient was cleared for discharge to his home after 17 days of hospitalization. He was scheduled to follow up with both urology and hematology departments regarding any further treatment for bladder cancer. A week after discharge, the patient's family decided that he would not receive the last (sixth) cycle of intravesical gemcitabine. To our knowledge, this is the first reported case of an interaction between intravesical gemcitabine and warfarin.. A 90-year-old man on a stable dose of warfarin experienced an increase in INR values after receiving intravesical gemcitabine for the treatment of bladder cancer.

Topics: Administration, Intravesical; Aged, 80 and over; Anticoagulants; Antimetabolites, Antineoplastic; BCG Vaccine; Carcinoma, Transitional Cell; Deoxycytidine; Drug Interactions; Enoxaparin; Gemcitabine; Humans; International Normalized Ratio; Male; Urinary Bladder Neoplasms; Venous Thrombosis; Warfarin

Studies suggest that the antitumor effect of bacillus Calmette-Guerin depends on bacillus Calmette-Guerin attachment to fibronectin at fibrin clot formation sites and medications that impact fibrin clot formation may modify bacillus activity. We evaluated the impact of fibrin clot inhibitors on the clinical efficacy of bacillus Calmette-Guerin.. We reviewed the records of 907 consecutive patients treated with bacillus Calmette-Guerin between 1990 and 2006. Time to disease recurrence and progression to surgery were compared in patients who did and did not receive fibrin clot inhibitors by Kaplan-Meier methods and multivariate Cox regression models.. Overall 221 patients (24%) received at least 1 fibrin clot inhibitor, including 170, 34 and 52 on aspirin, clopidogrel and warfarin, respectively. Patients on warfarin had shorter time to progression than patients not on warfarin (median 2.1 vs 9.0 years, p <0.005). Patients on aspirin had a significantly improved 5-year probability of freedom from surgery (66% vs 56%, p = 0.029). On multivariate analysis warfarin was associated with an increased risk of progression to surgery (HR 1.89, 95% CI 1.31, 2.74, p = 0.0007), while aspirin was associated with a decreased risk (HR 0.71, 95% CI 0.52, 0.96, p = 0.024). Warfarin alone was associated with an increased risk of tumor recurrence (HR 1.39, 95% CI 1.00, 1.94, p = 0.047).. These data suggest that the risks of recurrence and progression to surgery after bacillus Calmette-Guerin are higher in patients on warfarin, while the risk of progression is lower in patients on aspirin. These findings may have important treatment implications in patients in whom bacillus Calmette-Guerin is contemplated.

Topics: Adjuvants, Immunologic; Aged; Anticoagulants; Aspirin; BCG Vaccine; Carcinoma, Transitional Cell; Clopidogrel; Drug Interactions; Female; Fibrinolytic Agents; Humans; Male; Platelet Aggregation Inhibitors; Retrospective Studies; Ticlopidine; Urinary Bladder Neoplasms; Warfarin

Topics: Adjuvants, Immunologic; Anticoagulants; Aspirin; BCG Vaccine; Carcinoma, Transitional Cell; Clopidogrel; Drug Interactions; Female; Fibrinolytic Agents; Humans; Male; Platelet Aggregation Inhibitors; Ticlopidine; Urinary Bladder Neoplasms; Warfarin

A 63-year-old Caucasian man had a painless episode of dark-colored urine while taking warfarin 62.5 mg/week for lone atrial fibrillation in the presence of documented stable anticoagulation. Urinalysis revealed microscopic hematuria. Three weeks later, he had an episode of gross, painless hematuria. Thorough evaluation of the upper and lower urinary tract with renal ultrasound, intravenous pyelography, and cystoscopy revealed poorly differentiated, early-stage, transitional cell carcinoma of the bladder. The patient was not aware of any exposure to carcinogens known to predispose to bladder cancer, nor was he a tobacco user. Early identification of the malignancy allowed for aggressive surgical intervention. Although this patient was considered low risk for the development of bladder cancer and was taking anticoagulants, the presence of hematuria was indicative of underlying pathology. Timely and thorough evaluation of hematuria in patients taking anticoagulants is necessary to identify and treat clinically important pathology.

Topics: Anticoagulants; Carcinoma, Transitional Cell; Hematuria; Humans; Male; Middle Aged; Urinary Bladder Neoplasms; Warfarin

After transurethral resection (TUR) of superficial bladder tumors, intravesical instillations with BCG are successfully used to lower the recurrence rate. The mechanism of the antitumor activity of BCG is not completely understood. After TUR, a fibrin clot is formed on the damaged urothelium. Fibronectin (FN) is part of the clot. It has been demonstrated that binding of BCG to the bladder wall is mediated by FN, and therefore FN seems necessary for the antitumor activity of BCG. This binding can be inhibited by fibrin clot inhibitors, like aspirin and coumarin. A reduced efficacy of BCG in patients with superficial bladder cancer using these drugs has been described. We studied 183 patients with superficial bladder cancer, treated with one or two 6-week courses of intravesical BCG instillations. Of the 42 patients that used fibrin clot inhibitors, 13 (31%) experienced a recurrent tumor, as compared to 56 (40%) of 141 patients who did not use these drugs (p = 0.28). The mean time to recurrence was the same in both groups. These results did not depend on the BCG strain used (Tice or RIVM, p = 0.92) and were not influenced by the use of antibiotics against urinary tract infections. We conclude that in our study fibrin clot inhibitors have no adverse effect on the efficacy of BCG therapy for superficial bladder cancer.

Topics: Administration, Intravesical; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; BCG Vaccine; Carcinoma in Situ; Carcinoma, Transitional Cell; Coumarins; Dipyridamole; Fibrin; Humans; Male; Random Allocation; Urinary Bladder Neoplasms; Warfarin

Although intravesical bacillus Calmette-Guerin therapy has proved to be efficacious in the treatment and prophylaxis against tumor recurrence of superficial bladder tumors, its mechanism of action has not been fully elucidated. Previous work has suggested that bacillus Calmette-Guerin organisms attach to the matrix protein, fibronectin, during fibrin clot formation at sites of urothelial disruption and that this attachment was required for the antitumor effect of bacillus Calmette-Guerin to be expressed. Furthermore, drugs inhibiting clot formation were found to abrogate the antitumor effect of intravesical bacillus Calmette-Guerin therapy in a murine bladder tumor model. To examine the effect of inhibitors of fibrin clot formation on the results of intravesical bacillus Calmette-Guerin therapy, a retrospective analysis of 149 evaluable patients receiving intravesical bacillus Calmette-Guerin for superficial bladder tumors was performed. The over-all response rate free of tumor for 29 patients who concomitantly received inhibitors of fibrin clot formation with bacillus Calmette-Guerin therapy was 48%, as compared with 67% for 120 patients who were not receiving these medications (p = 0.0655, chi-square). The most striking difference was noted for patients who failed with recurrent superficial disease. Of the patients who received fibrin clot inhibitors during intravesical bacillus Calmette-Guerin therapy 35% had recurrent superficial tumors compared to only 8% of those who did not receive these drugs during a mean followup of 29.8 plus or minus 11 months (p = 0.005, chi-square). Our study suggests that inhibitors of fibrin clot formation may have an adverse influence on the results of intravesical bacillus Calmette-Guerin therapy for superficial bladder tumors.

Topics: Administration, Intravesical; BCG Vaccine; Carcinoma in Situ; Carcinoma, Transitional Cell; Fibrin; Fibronectins; Humans; Neoplasm Recurrence, Local; Platelet Aggregation Inhibitors; Retrospective Studies; Urinary Bladder Neoplasms; Warfarin