Warfarin Regimen Research Articles

Influence of Warfarin Regimen Type on Clinical and Monitoring Outcomes in Stable Patients in an Anticoagulation Management Service

Options for dosing warfarin include same daily dosing, such as 7 mg/day, and alternate-day dosing, such as 5 mg Monday and Thursday, and 7.5 mg all other days. Some practitioners favor same daily dosing because it is simple, whereas others prefer alternate-day dosing because it requires a single tablet size. Computerized records of patients followed by an anticoagulation management service were reviewed retrospectively to identify those whose anticoagulation was stable with one of these two dosing methods. Clinical and monitoring outcomes were compared between groups. Rates of hemorrhagic and thromboembolic complications were similar in the two groups, as were monitoring outcomes, including clinic visits/year, warfarin dosage adjustments/year, and percentage of international normalized ratios within range. Patients receiving the same daily dose reported lower rates of confusion (0% vs 7%) and dosing errors (3.3% vs 14%) that those receiving alternate-day dosing, and expressed a stronger preference for their regimen (40% vs 1.5%). When selecting a regimen, consideration must be given to patient-specific risk of confusion and dosing errors, associated costs, practicality and precision of dosing adjustments, and patient preference.

ATRIAL FIBRILLATION, THROMBOEMBOLISM AND ANTITHROMBOTIC THERAPY

SUMMARYAtrial fibrillation is the commonest sustained disorder of cardiac rhythm and is associated with increased risk of stroke and thromboembolic events. Warfarin (dose‐adjusted to a target INR of 2.0‐3.0) has been well established to reduce this risk of stroke by 68% (95% CI 50‐79%), while aspirin provides a risk reduction of 21% (95% CI 0‐38%). Nevertheless, warfarin confers a risk of bleeding and the inconvenience of regular monitoring checks, while aspirin seems effective only for certain low‐risk subgroups. Thus there have been strenuous efforts to improve thromboprophylaxis in atrial fibrillation, by using low‐intensity anticoagulation regimens, combination antiplatelet therapy and refinement of risk stratification strategies. Attempts at using a low‐intensity, fixed‐dose warfarin regimen have, however, been disappointing. For now, a strategy of risk stratification should be adopted to identify highest risk patients with atrial fibrillation who would benefit from anticoagulation.

Initiating and Maintaining Patients on Warfarin Anticoagulation: The Importance of Monitoring.

BACKGROUND: The VA Stroke Prevention in Nonrheumatic Atrial Fibrillation study was a prospective, randomized, double-blind study comparing low-dose warfarin with placebo in patients with nonrheumatic atrial fibrillation. The trial showed a 79% reduction in stroke rate in warfarin randomized patients without an increase in bleeding complications. We examined the need for frequent prothrombin time monitoring (international normalized ratios [INR] were not measured directly) in patients receiving warfarin.</P METHODS AND RESULTS: Patients were initiated on 4.0 mg/d warfarin with a goal of maintaining the prothrombin time ratio (PTR) within the range of 1.2-1.5 (estimated INR: 1.4-2.8). PTR monitoring was performed weekly during a 12-week induction period and monthly thereafter for a total follow-up of 3 years. Two hundred sixty patients were randomized to receive warfarin. During the induction period, the proportion of patients whose PTRs were in the desired range increased from 28% at 1 week postrandomization to 65% at 12 weeks postrandomization; the proportion of patients requiring a dose adjustment decreased from 52% to 16% during the same period. During the maintenance period, the mean proportion of patients whose PTRs were within 1.2-1.5 was 60.5% +/- 6.2%. CONCLUSIONS: Low-dose anticoagulation with warfarin in outpatients should be initiated at the anticipated maintainance dose. This approach reduces the chance of being out of range on the high side. Weekly INR estimation during this phase seems optimal. Considerable dose adjusting was required during the maintenance phase to keep patients within range; monthly INRs are required. Because of the need for dose adjustments, fixed-dose warfarin regimens are unlikely to keep patients in the desired narrow therapeutic range.

Probable Nafcillin—Warfarin Interaction

Objective: To report a case of probable nafcillin—warfarin interaction and to discuss the occurrence of this event. Case Summary: A 74-year-old white woman with stage IV ovarian cancer was given warfarin and nafcillin concurrently for a subclavian venous thrombus and an infected subclavian mediport. After 10 days of therapy, the patient's prothrombin time remained within the range of 11.6–13.8 seconds (control range 10.4–12.8). Her international normalized ratio (INR) ranged from 1.0 to 1.45 and her activated partial thromboplastin time ranged from 49 to 80 seconds (22–34). Nafcillin was discontinued. Continuous intravenous heparin was continued, and the patient was given warfarin 10 mg po for four days. A maintenance regimen of warfarin 5 mg po daily was then initiated. Within seven days of discontinuing nafcillin, the INR increased from 1.08 to 2.10. Discussion: Several cases of nafcillin—warfarin interaction have been reported in the literature. The case reported here is similar to a previously reported one in which a lower dose of nafcillin (6 g/d) was used for a short time (10 d). Therapeutic warfarin doses were started simultaneously with nafcillin. The interaction usually occurs within three to 10 days and abates within one to eight weeks. The postulated mechanism of interaction is induction of hepatic microsomal enzymes by nafcillin, leading to warfarin resistance. Conclusions: When nafcillin is prescribed concomitantly with warfarin, high doses of warfarin are usually required and close monitoring is necessary to keep the patient's INR within a designated range. Clinicians should be aware of a potential nafcillin—warfarin interaction because warfarin has a narrow therapeutic window that may readily lead to therapeutic failure or toxicity. Frequent review of clinical signs and symptoms of bleeding or thromboembolism and warfarin dosage adjustment are necessary if both drugs are used concurrently, and also when nafcillin is discontinued.

Low dose oral anticoagulation therapy in Chinese children with congenital heart disease.

This study aims to evaluate the efficacy of a low dose warfarin regimen for Chinese children requiring anticoagulation therapy and its safety when monitored on an outpatient basis. Current recommendations are based on extrapolations from the adult experience and a high target international normalised ratio (INR) is adopted amongst the Western countries. This is a 10-year retrospective study from January 1986 to June 1996. Effectiveness of warfarin therapy was monitored by the prothrombin time, standardised and expressed as the INR. A target INR of 1.5-2.5 was adopted for children with cardiac diseases requiring anticoagulation therapy for primary and secondary prophylaxis against thromboembolism. From the clinical records, demographic data, induction warfarin dosage, changes of dosages and related events on follow-up, frequency of outpatient visits, complications and serial INR results were reviewed. Thirty-five patients (23 boys, 12 girls) were included with a mean age at initiation of warfarin therapy of 8.4+/-5.8 years. Amongst these, 66% (n = 23) were after isolated valvar replacement, 28% (n = 10) after Fontan operation with or without valvar replacement and 6% (n = 2) after deep vein thrombosis. Regression estimate of the induction dose was 0.05-0.13 mg x kg(-1) in order to achieve the target INR range after 2 days of warfarin therapy. The daily maintenance warfarin dose was correlated with the bodyweight [dose (mg x day(-1))= 0.04 x bodyweight (kg) + 0.87, r = 0.63, P<0.0001]. Young children required significantly higher daily warfarin maintenance dose when adjusted for bodyweight [dose (mg x kg day(-1)) = antilog(10)¿-0.02 x age (years)- 0.80¿, r = -0.74, P<0.0001]. The mean maintenance warfarin dosage was significantly lower in patients after the Fontan operation, with or without valvar replacement, in the absence of apparent liver dysfunction. The total period of followup was 159 patient-years. No serious bleeding complications or embolic phenomena were documented. One patient died of thrombosis of the mitral valve prosthesis. The overall incidence of thrombosis was 0.6 per 100 patient-years. A low dose warfarin regimen to maintain a target INR of 1.5-2.5 provides adequate protection in Chinese children against thromboembolism whilst allowing safe outpatient monitoring of the anticoagulation status.

Diagnosing coronary arterial stent thrombosis and arterial closure

This single-center review of a consecutive series of patients requiring reexamination by angiography within 1 week of a coronary stent placement due to chest pain reveals that patients treated with a poststent anticoagulation regimen of warfarin and aspirin, and those with lower poststent deployment dilation pressures, have an increased risk of subacute stent thrombosis. Repeat cardiac catheterization within the first week after coronary artery stent implantation should be reserved for patients with significant electrocardiographic changes.

Gemfibrozil-Warfarin Drug Interaction Resulting in Profound Hypoprothrombinemia

The following describes a patient on a stable regimen of warfarin who developed severe hypoprothrombinemia and bleeding 4 weeks after starting gemfibrozil. Despite a warning by the manufacturer, only one report of this interaction has been published in the literature. This interaction may be overlooked by clinicians, which may result in a serious bleeding risk for patients on warfarin.

A pharmacoeconomic assessment of enoxaparin and warfarin as prophylaxis for deep vein thrombosis in patients undergoing knee replacement surgery

This paper examines the relative cost-effectiveness of enoxaparin and warfarin as prophylactic therapy for the prevention of deep vein thrombosis (DVT) in patients undergoing knee replacement surgery in a managed care setting. Although enoxaparin is more expensive than warfarin, it is also more effective in the prevention of DVT after knee replacement surgery. To date there has been no comprehensive assessment of the cost-effectiveness of the alternative agents used for this purpose. This evaluation is undertaken using a decision model that contrasts enoxaparin and warfarin regimens. The model takes explicit account of the incidence of proximal DVT, distal DVT, pulmonary embolism (PE), and major bleeds. The probabilities of clinical events are taken from data from a published randomized, controlled, clinical trial. Key assumptions are that PEs derive only from asymptomatic proximal DVTs and that a false-positive diagnosis of DVT is made in 10% of cases. Unit resource cost data are taken from pharmacoeconomic studies of DVT prophylaxis in hip replacement surgery. The analysis focuses on the actual or expected cost of prophylactic treatment using enoxaparin as opposed to warfarin and, as appropriate measures of cost-effectiveness, the cost per DVT event avoided and the cost per incidence of PE avoided. The expected cost of warfarin prophylaxis is $105 less per patient than that of enoxaparin. In terms of expected cost per DVT event avoided, enoxaparin prophylaxis is $2525 less than for warfarin; in terms of expected cost per PE avoided, it is $87,201 less. Enoxaparin is more cost-effective than warfarin in terms of both DVT events and PEs avoided in patients who have undergone knee replacement surgery.

The evolution of antithrombotic therapy in coronary stenting

A rare but important side effect associated with the use of coronary stents is the development of subacute thrombotic occlusion within the first week after implantation. Recent studies have indicated that the incidence of subacute thrombosis can be reduced with a combination regimen consisting of aspirin and ticlopidine instead of the standard regimen of aspirin and warfarin. The evolution in our understanding of the factors causing subacute stent thrombosis, coupled with the development of new implantation procedures, has permitted the development of a new treatment strategy with less aggressive anticoagulation therapy, fewer side effects, and, it is hoped, lower costs. (Am Heart J 1997;134:S78-S80)

The evolution of antithrombotic therapy in coronary stenting

A rare but important side effect associated with the use of coronary stents is the development of subacute thrombotic occlusion within the first week after implantation. Recent studies have indicated that the incidence of subacute thrombosis can be reduced with a combination regimen consisting of aspirin and ticlopidine instead of the standard regimen of aspirin and warfarin. The evolution in our understanding of the factors causing subacute stent thrombosis, coupled with the development of new implantation procedures, has permitted the development of a new treatment strategy with less aggressive anticoagulation therapy, fewer side effects, and, it is hoped, lower costs. (Am Heart J 1997;134:S78-S80)

Rationale for low–molecular weight heparin in coronary stenting

Stents have been as revolutionary for the practice of coronary revascularization in recent years as was the coronary angioplasty balloon 15 years ago, but they have also been associated with a high rate of stent thrombosis. The Enoxaparin and Ticlopidine After Elective Stenting (ENTICES) trial is designed to determine the impact of a reduced anticoagulation regimen on clinical outcomes after stent deployment. Patients are randomly assigned 2:1 to enoxaparin-ticlopidine-aspirin versus the conventional warfarin regimen, and surrogate markers of platelet activation and thrombin activity are measured after 3 days. Three factors underpin ENTICES: (1) a desire to eliminate stent thrombosis, (2) a desire to reduce length of stay after stent placement by avoiding the prolonged hospitalization required with the five-drug regimen of heparin, aspirin, dipyridamole, dextran, and warfarin, and (3) a desire to reduce the bleeding complications associated with the intense anticoagulation typically used in patients receiving stents. Patients are enrolled at seven sites in the United States and include patients with recent infarctions, restenotic lesions, and lesions as large as 30 mm in length. Other trials have also addressed issues concerning anticoagulation in patients undergoing stenting. The Stent Antithrombotic Regimen Study (STARS) trial compared aspirin, aspirin plus ticlopidine, and aspirin plus warfarin in 1650 patients receiving stents. The Aspirin/Ticlopidine vs Low-Molecular Weight Heparin/Aspirin/Ticlopidine High-Risk Stent Trial (ATLAST) is comparing aspirin plus ticlopidine with enoxaparin, aspirin, and ticlopidine in a group of patients at high risk undergoing stenting. The Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial, a trial of ticlopidine, aspirin, and 12 hours of postprocedural heparin versus phenocoumaron on and aspirin after stenting in 517 patients, found a significantly lower incidence of the combined end point of death, myocardial infarction, bypass surgery, or repeated percutaneous transluminal angioplasty in the patients who received antiplatelet therapy, but the patients enrolled were not representative of the usual population undergoing stenting. New trials of stents and their sequelae should include low–molecular weight heparins and should gather cost and outcome data to satisfy capitated systems and managed care. Innovative stent designs may also permit changes in antithrombotic regimens. (Am Heart J 1997;134:S81-S87)

Rationale for low-molecular weight heparin in coronary stenting

Stents have been as revolutionary for the practice of coronary revascularization in recent years as was the coronary angioplasty balloon 15 years ago, but they have also been associated with a high rate of stent thrombosis. The Enoxaparin and Ticlopidine After Elective Stenting (ENTICES) trial is designed to determine the impact of a reduced anticoagulation regimen on clinical outcomes after stent deployment. Patients are randomly assigned 2:1 to enoxaparin-ticlopidine-aspirin versus the conventional warfarin regimen, and surrogate markers of platelet activation and thrombin activity are measured after 3 days. Three factors underpin ENTICES: (1) a desire to eliminate stent thrombosis, (2) a desire to reduce length of stay after stent placement by avoiding the prolonged hospitalization required with the five-drug regimen of heparin, aspirin, dipyridamole, dextran, and warfarin, and (3) a desire to reduce the bleeding complications associated with the intense anticoagulation typically used in patients receiving stents. Patients are enrolled at seven sites in the United States and include patients with recent infarctions, restenotic lesions, and lesions as large as 30 mm in length. Other trials have also addressed issues concerning anticoagulation in patients undergoing stenting. The Stent Antithrombotic Regimen Study (STARS) trial compared aspirin, aspirin plus ticlopidine, and aspirin plus warfarin in 1650 patients receiving stents. The Aspirin/Ticlopidine vs Low-Molecular Weight Heparin/Aspirin/Ticlopidine High-Risk Stent Trial (ATLAST) is comparing aspirin plus ticlopidine with enoxaparin, aspirin, and ticlopidine in a group of patients at high risk undergoing stenting. The Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial, a trial of ticlopidine, aspirin, and 12 hours of postprocedural heparin versus phenocoumaron on and aspirin after stenting in 517 patients, found a significantly lower incidence of the combined end point of death, myocardial infarction, bypass surgery, or repeated percutaneous transluminal angioplasty in the patients who received antiplatelet therapy, but the patients enrolled were not representative of the usual population undergoing stenting. New trials of stents and their sequelae should include low–molecular weight heparins and should gather cost and outcome data to satisfy capitated systems and managed care. Innovative stent designs may also permit changes in antithrombotic regimens. (Am Heart J 1997;134:S81-S87)

Effect of Fixed Minidose Warfarin, Conventional Dose Warfarin and Aspirin on INR and Prothrombin Fragment 1 + 2 in Patients with Atrial Fibrillation

The efficacy of conventional dose adjusted oral anticoagulation for stroke prevention in patients with non-valvular atrial fibrillation is well-documented but not considered ideal as primary antithrombotic treatment in elderly patients. The antithrombotic effect of fixed minidose warfarin 1.25 mg/day alone or in combination with aspirin 300 mg/day, of conventional dose adjusted warfarin (INR 2.0-3.0), and of aspirin 300 mg/day have been investigated in outpatients with chronic nonvalvular atrial fibrillation in the second Copenhagen Atrial Fibrillation, Aspirin and Anticoagulant Therapy Study (AFASAK 2). In order to investigate the effect on the coagulation system of the treatments, the International Normalized Ratio of the prothrombin time (INR) and prothrombin fragment 1 + 2 (F1 + 2) were monitored at baseline and after three months of treatment in 100 patients consecutively included in the trial. At baseline no differences in INR and F1 + 2 between the four treatment groups were present. After three months of therapy the level of INR increased significantly from baseline in patients receiving warfarin in any dose and the level of F1 + 2 decreased significantly by combined minidose warfarin-aspirin and by dose adjusted warfarin. When comparing the changes over time in F1 + 2 (three-month value minus baseline value) during therapy with fixed minidose warfarin, combined minidose warfarin-aspirin and aspirin alone no significant difference between the groups was found. In conclusion, INR was changed by all three warfarin regimens but only dose adjusted warfarin (INR 2.0-3.0) had a marked effect on F1 + 2.

Status of Antithrombotic Therapy for Patients With Atrial Fibrillation in University Hospitals

The risk of stroke in patients with atrial fibrillation can be significantly reduced with antithrombotic therapy. Despite this, many physicians remain hesitant to prescribe warfarin sodium or aspirin therapy for patients with atrial fibrillation. To assess the use of antithrombotic therapy in patients with atrial fibrillation at 6 academic hospitals in the United States. Records were reviewed from consecutive hospital admissions of 309 patients with atrial fibrillation at 6 members of the University Health System Consortium, Oak Brook, III, which is a member driven alliance of 70 academic health centers in the United States. Risk factors for stroke, contraindications to anticoagulant therapy, and use of antithrombotic therapy at admission and discharge were recorded. The mean age of patients was 71.6 years, 54% had chronic, 22% paroxysmal, and 24% new-onset atrial fibrillation. Eighty-two percent of the patients had cardiovascular risk factors that have been associated with increased risk of stroke. At least 1 relative contraindication to anticoagulant therapy was present in 44%. At the time of admission. 32% of the patients with previously diagnosed atrial fibrillation (n = 235) were receiving warfarin (or warfarin plus aspirin), 31% were receiving aspirin alone, and 36% were receiving no antithrombotic therapy. At discharge (n = 230), 41% of these patients were taking warfarin (or warfarin plus aspirin) and 36% were taking aspirin. Forty-four percent of the patients with risk factors for stroke and no contraindications to anticoagulation (n = 134) were discharged on a regimen of warfarin (or warfarin plus aspirin), 34% were discharged on a regimen of aspirin, and 22% received no antithrombotic therapy. About half of the patients with atrial fibrillation admitted to these academic hospitals had clinical risk factors that are associated with increased risk of stroke and no contraindications to anticoagulation. Antithrombotic therapy was underused in these patients.

Six-Year Experience with CarboMedics Prosthetic Heart Valves

Between July 1989 and July 1995, 89 CarboMedics prosthetic heart valves were implanted in 70 patients (38 males, 32 females) ranging in age from 13 to 54 years (mean 33 years). Forty-one of these patients underwent mitral valve replacement, 10 had aortic valve replacement, and 19 had double aortic and mitral valve replacement. Early mortality was 4.9%, 0%, and 15.8% respectively in these groups. Mean follow-up time was 3.4 years and was 95.4% complete (3 lost). There were 5 late deaths (7.7%); 1 in the mitral group, 1 in the aortic group, and 3 who had double valve replacements. Three of these late deaths were considered valve-related. The 5-year actuarial survival rates, hospital mortality excluded, were 97% for mitral, 88% for aortic, and 88% for double valve replacement. Preoperatively, 80% of the patients were in New York Heart Association functional class III or IV, whereas postoperatively, 99.5% of the patients were in class I or II. No structural failures were observed. There was 1 case of systemic embolism and 1 case of valve thrombosis, neither of these patients were taking anticoagulants. Hemorrhage was the most frequent complication; 1 of 4 events was fatal. A less intensive warfarin regimen and improvement in hepatic function may reduce hemorrhagic risk while maintaining thromboembolic protection. On the basis of this experience, the CarboMedics prosthetic heart valve appears to be an excellent mechanical prosthesis for cardiac valve replacement, in terms of hemodynamic performance and low thrombogenicity, in patients receiving anticoagulants.

Comparison of Two Warfarin Regimens in the Prevention of Venous Thrombosis following Total Knee Replacement

A prospective, randomized trial was conducted to compare the effectiveness and safety of warfarin given in two regimens in prevention of venous thrombosis after total knee replacement. Adult patients scheduled for primary or revision total knee replacement were randomly assigned to receive either a "two-step" warfarin regimen beginning 10-14 days pre-operatively or, alternatively, to begin warfarin the night before surgery. Post-operatively, the dose was adjusted in both groups to achieve a target International Normalized Ratio (INR) of 2.2 and prophylaxis was continued until venography on post-operative days five through nine. Bleeding was assessed by surgical blood loss, transfusion requirements, changes in hematocrit, and clinically identified bleeding complications. The occurrence of deep vein thrombosis was nearly the same in the two treatment groups, 39% in patients randomized to the two-step regimen as compared to 38% in those beginning the night before surgery. The occurrence of proximal vein thrombosis was also similar, 5% versus 7% (p = NS). Patients in the two-step group received 1.33 +/- 1.26 transfusions compared to 0.95 +/- 1.22 in the night before group (p < 0.05) and also had a lower nadir post-operative hematocrit of 26.7 +/- 3.1 as compared to 28.5 +/- 3.2 (p < 0.0001). Major bleeding complications were associated with excessively prolonged INRs and occurred in five patients in the two-step group and two in the night before group. Patients in both groups who developed thrombosis had a significantly lower INR on post-operative days two and three compared to those without thrombosis. We conclude that a prophylactic warfarin regimen for prevention of deep vein thrombosis after total knee replacement beginning the night before surgery is more convenient and may be associated with less bleeding than a regimen beginning warfarin 10-14 days pre-operatively. Careful control of anticoagulant intensity is needed to achieve maximum effectiveness and avoidance of bleeding complications.

Minidose Warfarin and Failure to Prevent Deep Vein Thrombosis After Joint Replacement Surgery Despite Inhibiting the Postoperative Rise in Plasminogen Activator Inhibitor Activity

In a prospective randomised study in patients undergoing elective total hip or knee replacement surgery, the antithrombotic efficacy of fixed-minidose warfarin (1 mg daily commenced 7 days before surgery) was compared with that of subcutaneous calcium heparin (Calciparine, 5,000 IU t.d.s. commenced 2 h before surgery). Both regimens were continued until venography of the operated limb was performed 9-14 days postsurgery. Venographically detected deep vein thromboses (DVTs) occurred in 15 of the 31 patients (48.4%) in the minidose warfarin group and in eight of the 37 patients (21.6%) receiving heparin. The absolute difference in the incidence of DVT was 26.8% in favour of heparin (95%l confidence interval [CI] -4.&amp;--48.8%; p = 0.039). Proximal DVTs were detected in three patients receiving minidose warfarin and in none of those on heparin (p = 0.09). Minidose warfarin appeared to prevent the postoperative rise in the activity of plasminogen activator inhibitor (PAI) that occurred with heparin, although preoperative PAI activity was greater in the warfarin group. The prothrombin time (PT) and activated partial thromboplastin time (APTT) were within the normal range on the day of surgery in both treatment groups. Postsurgery, the minidose warfarin regimen produced a small, but significant prolongation of the PT compared with the group receiving heparin, In contrast to heparin, 1 mg warfarin daily failed to prevent postoperative acceleration of the APTT. There was no significant difference between the two regimens in bleeding complications. In conclusion, the fixed-minidose warfarin regimen cannot be recommended for prevention of DVT after hip or knee replacement surgery. Inhibition of the postoperative rise in PAI activity appears not to protect against DVT after major joint replacement surgery. Key Words: Warfarin—Heparin—Deep vein thrombosis prophylaxis—Coagulation—Fibrinolysis— Plasminogen activator inhibitor.

Thrombotic obstruction of bileaflet valves: Surgical management and fiberoptic thrombectomy

Three patients underwent emergency operation for thrombotic obstruction of a bileaflet mechanical prosthesis (two St. Jude and one Duromedics) in the mitral position. The three valves were successfully thrombaectomized with return to normal function. In 2 patients removal of the thrombus at the valve hinges was assisted by the use of a flexible fiberoptic choledochoscope. All 3 patients remain well 2 years after the procedure, maintained on a regimen of warfarin and dipyridamole.

Possible Drug Interaction between Warfarin and Combination of Levamisole and Fluorouracil

To report a possible drug interaction between the combination of fluorouracil (5-FU), levamisole, and warfarin. An elderly patient with chronic atrial fibrillation and prosthetic valve replacements had been taking warfarin 22.5 mg/wk. Following the diagnosis of colon cancer (Duke's classification D), a chemotherapy regimen of 5-FU and levamisole was started. Within four weeks after initiation of chemotherapy, the International Normalization Ratio (INR) increased from 3.04 to 39.56. Warfarin was discontinued and restarted at 7.5 mg/wk. Discontinuation of levamisole and 5-FU for a five-week period resulted in the INR falling to a subtherapeutic level. Reinstitution of the chemotherapeutic regimen once again led to an increase in INR. A literature search showed no reports of an interaction between warfarin and levamisole. However, prolongation of 5-FU half-life and an increase in INR have been reported with the concurrent use of 5-FU and warfarin. Inhibition of the hepatic metabolism of warfarin by 5-FU and levamisole is the postulated mechanism of this drug interaction. This case describes the clinically significant increase of INR in an elderly patient after adding a chemotherapy regimen of levamisole and 5-FU to a previous regimen of warfarin alone. The increasing incidence of both atrial fibrillation and colon cancer with age could potentially require the concomitant use of 5-FU, levamisole, and warfarin. Because of the potential severity of this interaction, close monitoring of INR and warfarin dosage adjustment is recommended in patients receiving warfarin along with levamisole and 5-FU.

Prophylaxis against deep venous thrombosis following total hip replacement by combined regimen of low-dose warfarin and intermittent pneumatic compression stockings: Terrance C. Devlin, MD, Albuquerque, NM; Richard E. White, Jr., MD, Albuquerque, NM; Kenneth E. Teter, MD, La Jolla, CA

Prophylaxis against deep venous thrombosis following total hip replacement by combined regimen of low-dose warfarin and intermittent pneumatic compression stockings: Terrance C. Devlin, MD, Albuquerque, NM; Richard E. White, Jr., MD, Albuquerque, NM; Kenneth E. Teter, MD, La Jolla, CA