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Background: Oral anticoagulation with warfarin can lead to life-threatening events as a result of either over-anticoagulation or undertreatment. One of the main contributors to an undesirable warfarin effect is the need to adjust its daily dose for a specific patient. The dose is adjusted empirically based on the experience of the clinician, a method that is often imprecise. There is currently no other well-accepted method for predicting the maintenance dose of warfarin., Objective: To describe the application of an artificial neural network to the problem of warfarin maintenance dose prediction., Methods: We designed a neural network that predicts the maintenance dose of warfarin. Data on 148 patients attending a large anticoagulant clinic were collected by file review. Using correlational analysis of the patients' data we selected the best input variables. The network was trained by using the back-propagation algorithm on a subset of our data and the results were validated against the rest of the data. We used a multivariate linear regression to create a comparable model., Results: The neural network generated reasonable predictions of the maintenance dose (r = 0.823). The results of the linear regression model were similar (r = 0.800)., Conclusion: Neural networks can be applied successfully for warfarin maintenance dose prediction. The results are promising, but further investigation is needed.

Many patients with cardiac arrhythmias require concomitant therapy with warfarin and amiodarone. Beyond the predictable pharmacokinetic drug-drug interaction requiring a significant warfarin dose reduction, the iodine-rich amiodarone affects the thyroid gland, causing overt hypothyroidism or thyrotoxicosis in 14%-18% of cases. In turn, thyroid disorders may affect warfarin sensitivity, with hypothyroidism and thyrotoxicosis resulting in increased or decreased warfarin requirements, respectively. We describe 3 patients on concomitant amiodarone and warfarin who developed amiodarone-induced thyrotoxicosis heralded by a significant decrease in warfarin requirements. We review the literature on the mechanisms of the complex drug-drug and drug-disease interactions within the thyroid gland, warfarin, and amiodarone triad. Given that significant thyroid disorders may be only mildly symptomatic and thus may escape clinical detection, we suggest that thyroid function should be tested in any patient with otherwise unexplained changes in warfarin dose requirements, particularly if concomitantly treated with amiodarone.

Portable prothrombin time (PT) monitors facilitate the control of warfarin therapy. Few studies have compared the influence of using different monitors on dosage decisions. We determined the comparability of data generated by two portable PT monitors, Coaguchek S, (Roche Diagnostics Boehringer-Mannheim) and Hemochron Jr (International Technidyne Corporation Ltd.), with that of a reference laboratory. Simultaneous International Normalized Ratio (INR) measurements (portable monitor and laboratory) were performed in 193 consecutive patients receiving warfarin for at least 3 months. Agreement of measurements was assessed by both regression analysis and influence on dosage decisions in accordance with pre-defined criteria. The Coaguchek S versus laboratory INR regression line (n = 111; r2 = 0.88; P < 0.001) was close to the line of identity, while that of the Hemochron Jr (n = 82; r2 = 0.61; P < 0.001) was not. The overall proportion of dual INR measurements that fulfilled the clinical criteria of agreement was 90% for the Coaguchek S compared with 62% for the Hemochron Jr (P < 0.0001). For laboratory INRs 2.0-2.5, 2.6-4.0 and > 4.0, the proportions of portable measurements that satisfied the clinical criteria for the Coaguchek S versus the Hemochron Jr were 96 versus 63% (P < 0.001), 81 versus 45% (P < 0.04), and 67 versus 17% (P < 0.85), respectively. Warfarin dosing based solely on the portable devices would have resulted in unjustified dose increments in 22% of the patients with the Hemochron Jr device compared with 8% with the Coaguchek S monitor (chi2 = 4.43; P = 0.035). The Coaguchek S monitor provides measurements for INR values within the therapeutic range that agree well with the standard laboratory. The Hemochron Jr measurements result in different dosage adjustments even within the therapeutic range, but especially for INR values > 4.0. For both monitors, agreement of INR measurements with the standard decreases with increasing INR values.

Administration of vitamin K is the common mode of treatment in excessively anticoagulated patients. However, patient's response to vitamin K varies, depending on the vitamin K dose and the route of administration. Another potential source of variation is the pre-treatment INR which has not been accounted for in most previous studies. In the present study the effect of baseline INR on the response to a single dose of intravenous vitamin K (0.5 mg) was studied in 95 episodes of excessively anticoagulated patients (n = 76). In 67 episodes of moderately excessive baseline INR (6-10) mean INR declined from 8.0 +/- 1.2 to 2.6 +/- 0.9 at 24 hours, 59/67 (88%) responding within the first 12 hours and not requiring a second dose. In contrast, in 28 episodes with highly excessive baseline INR (> 10) response was slower; mean INR declining from 13.6 +/- 2.7 to 4.0 +/- 2.1 at 24 hours. In 14/28 of these episodes, patients failed to respond to vitamin K in the first 12 hours and required a second vitamin K dose. We conclude that INR at presentation affects the response to vitamin K and that this INR value should be considered in determining appropriate vitamin K doses.

Background: Elevated plasma total homocysteine (tHcy) concentration is an emerging independent risk factor for hypercoagulability states and cardiovascular diseases. Many disease states and various drug treatment regimens are known to affect plasma tHcy concentration., Objective: To examine the effect of short-term treatment with the low-molecular-weight heparin enoxaparin on plasma tHcy concentrations., Methods: A prospective study was conducted in an outpatient anticoagulation clinic set in a tertiary care referral medical center. Subjects included twenty-four consecutive patients treated with warfarin who were scheduled for short-term enoxaparin treatment. Fasting plasma tHcy concentrations were measured before and after 3 days of enoxaparin treatment in patients who began short-term therapy with enoxaparin because of temporary inadequate anticoagulation (international normalized ratio <1.5). The main outcome measures were the difference in tHcy concentration between baseline and after enoxaparin treatment., Results: tHcy plasma concentrations decreased in most patients (n = 21), did not change in 2, and increased in 1 patient after 3 days of enoxaparin treatment. The decline of tHcy was statistically significant: from 9.8 +/- 3.4 to 7.6 +/- 2.6 micro mol/L (mean +/- SD; p < 0.005). This decline was more prominent in patients with baseline tHcy plasma concentrations above the normal range compared with patients with normal baseline concentrations. Six patients in whom a third sample was obtained 15-30 days after the last enoxaparin injection developed decreased mean tHcy plasma concentrations: from 9.1 +/- 3.0 micro mol/L at baseline to 6.4 +/- 2.0 micro mol/L on day 3 and further to 5.7 +/- 1.8 micro mol/L on days 15-30. No relation was found between age, gender, treatment indication, and average weekly dose of warfarin to the presence or magnitude of tHcy plasma concentration decline., Conclusions: Short-term treatment with enoxaparin reduces plasma tHcy concentrations. Further studies are needed to clarify the mechanism and the clinical significance of enoxaparin's effect.

Background: Treatment of patients with excessive anticoagulation is routinely done by intravenous phytonadione (vitamin K[sub 1]). Oral administration of phytonadione has been shown to be an effective alternative to the intravenous route, but these methods have never been compared directly. Our objective was to compare efficacy and safety of intravenous vs oral phytonadione treatment in patients with excessive anticoagulation without bleeding. Methods: The study was a prospective randomized controlled trial of consecutive patients presenting with excessive anticoagulation without major bleeding. Patients with a baseline international normalized ratio (INR) of 6 to 10 (n = 44, 47 episodes) received either intravenous or oral phytonadione (0.5 mg or 2.5 mg, respectively), and patients with an INR greater than 10 (n = 17, 19 episodes) received 1 mg or 5 mg, respectively. Efficacy and safety end points were sequential INR changes and the proportion of patients achieving therapeutic range (INR, 2-4), overcorrection (INR<2.0), or undercorrection (INR>4.0) INR values. Results: Sixty-six episodes of excessive anticoagulation were studied. In patients with baseline INR 6-10 the response to intravenous phytonadione was more rapid than in the oral group, and the proportion of patients reaching therapeutic range INR at 6 hours (11/24 vs 0/23) and at 12 hours (16/24 vs 8/23) was significantly higher. However, mean ± SD INR values were similar for both groups at 24 hours (2.9 ± 0.8 vs 2.6 ± 0.8). Patients in the intravenous group tended to be more often (7/24 vs 2/23) overcorrected (INR<2). In patients with baseline INR values greater than 10 efficacy and safety were comparable for both routes of administration. Conclusion: Oral administration of phytonadione had similar efficacy and safety as intravenously administered phytonadione and may be suitable for treatment of patients with excessive anticoagulation. [ABSTRACT FROM AUTHOR]