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In a prospective, randomized study at two university hospitals, the authors examined how effectively housestaff physicians (n = 36) managed the initiation of warfarin therapy compared with a computer-assisted dosing regimen (n = 39) using the software program Warfcalc, which was managed by one of the authors. Target prothrombin time ratios were selected by the physicians. Study endpoints included: the time to reach a therapeutic prothrombin ratio, the time to reach a stable therapeutic dose, the number of patients transiently overanticoagulated, the number of bleeding complications, and the accuracy of the predicted maintenance dose, which was assessed at steady-state 10-14 days later. Computer-assisted dosing consistently out-performed the physicians: a stable therapeutic dose was achieved 3.7 days earlier (p = 0.002), fewer patients were overanticoagulated (10% versus 41%), and the predicted maintenance dose was in the therapeutic range in 85% of the computer-dosed patients versus 42% of the physician group (p less than 0.002). For physicians who did not routinely manage warfarin therapy, computer-assisted dosing improved the accuracy of dosing and shortened the time required to achieve a stable therapeutic dose. [ABSTRACT FROM AUTHOR]

Examines the association between steady-state heparin dose requirements and the variables, weight, age, sex, medical diagnosis, and the thromboplastin reagent used to measure the activated partial thromboplastin time (aPPT). Methodology used in study; Difference observed in the steady-state heparin requirements among patients with deep vein thrombosis (DVT) when compared with patients with coronary artery disease (CAD); Concluding remarks.

Results of studies of 15 adults placed on quinidine therapy after their serum digoxin concentrations were stabilized showed significantly increased digoxin concentrations. The average digoxin concentration before quinidine therapy was 0.75 +/- 0.28 ng/mL and after 4 days of quinidine therapy was 1.41 +/- 0.43 ng/mL. During this period, the renal clearance of digoxin decreased from 53.4 +/- 21 mL/min . 1.73 m to 35.3 +/- 12.6 mL/ min . 1.73 m. No significant correlation was found between the individual rise in serum digoxin concentrations and the rise in serum quinidine concentrations. These results suggest that serum digoxin concentration should be monitored closely for at least the first 4 days of quinidine therapy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Aging and the anticoagulant response to warfarin therapy" by J. H. Gurwitz, D. Ross-Degnan, I. Choodnovskiy, and others which was printed in a 1992 issue of the journal.

We have taken a stepwise approach to improving the dosing of continuous intravenous heparin in patients with acute coronary syndromes. Our primary objective was to use computer modeling to develop a nomogram for managing heparin therapy and to put in place a continuous quality monitoring system to evaluate the nomogram's effectiveness. We prospectively collected data on 41 patients with unstable angina or myocardial infarction who were treated with heparin. Their response to heparin was computer modeled and the dose to achieve an activated partial thromboplastin time (aPTT) ratio of 2.0 was established. This dose was regressed against all demographic characteristics to establish predictors of heparin dose (phase I). The regression formula was used prospectively in 110 patients to initiate the infusion rate of heparin and a bolus dose to achieve an aPTT ratio of 2.5. Subsequent dosage adjustments were achieved by computer modeling the patient's aPTT response (phase II). A nomogram was developed that simulated the decisions achieved using computer-assisted methods. This was retrospectively tested and then prospectively tested in 50 patients using nursing staff (phase IV). The nomogram was then made generally available (phase IV) and has been tested in an additional 310 patients. Phase I: Of the original 41 patients, 32% of the aPTT ratios were in the therapeutic range, 36% were supratherapeutic, and 32% were subtherapeutic after the first 24 hours. Phases II and III resulted in 85% of the aPTT ratios between 1.5 and 2.5 at 24 hours. Phase 4 had similar results in 310 patients. The use of computer-assisted or a computer-generated nomogram to adjust heparin therapy results in better control of heparin therapy than using standard methods. [ABSTRACT FROM AUTHOR]

Status epilepticus and acute repetitive seizures still pose a management challenge despite the recent advances in the field of epilepsy. Parenteral formulations of old anticonvulsants are still a cornerstone in acute seizure management and are approved by the FDA. Intravenous levetiracetam (IV LEV), a second generation anticonvulsant, is approved by the FDA as an adjunctive treatment in patients 16 years or older when oral administration is not available. Data have shown that it has a unique mechanism of action, linear pharmacokinetics and no known drug interactions with other anticonvulsants. In this paper, we will review the current literature about the pharmacology and pharmacokinetics of IV LEV and the safety profile of this new anticonvulsant in acute seizure management of both adults and children.

Traumatic brain injury (TBI) can cause seizures and the development of epilepsy. The incidence of seizures varies from 21% in patients with severe brain injuries to 50% in patients with war-related penetrating TBI. In the acute and sub-acute periods following injury, seizures can lead to increased intracranial pressure and cerebral edema, further complicating TBI management. Anticonvulsants can be used for seizure prophylaxis according to the current Parameters of Practice and Guidelines in a subset of severe TBI patients, and for a limited time window. Phenytoin is the most widely prescribed anticonvulsant in these patients. Intravenous levetiracetam, made available in 2006, is now being considered as a viable option in acute care settings if phenytoin is unavailable or not feasible due to side-effects. We discuss current data regarding the role of intravenous levetiracetam in seizure prophylaxis of severe TBI patients and the need for future studies.

Levetiracetam, trade name Keppra, is a new second generation antiepileptic drug that is being increasingly used in brain tumor patients. In patients suffering with brain tumors, seizures are one of the leading neurologic complications being seen in more than 30% of patients. Unlike other antiepileptic drugs, levetiracetam is proposed to bind to a synaptic vesicle protein inhibiting calcium release. Brain tumor patients are frequently on chemotherapy or other drugs that induce cytochrome P450, causing significant drug interactions. However, levetiracetam does not induce the P450 system and does not exhibit any relevant drug interactions. Intravenous delivery is as bioavailable as the oral medication allowing it to be used in emergency situations. Levetiracetam is an attractive option for brain tumor patients suffering from seizures, but also can be used prophylactically in patients with brain tumors, or patients undergoing neurological surgery. Emerging studies have also demonstrated that levetiracetam can increase the sensitivity of Glioblastoma tumors to the chemotherapy drug temozolomide. Levetiracetam is a safe alternative to conventional antiepileptic drugs and an emerging tool for brain tumor patients combating seizures.

Intractable epilepsy in children poses a serious medical challenge. Acute repetitive seizures and status epilepticus leads to frequent emergency room visits and hospital admissions. Delay of treatment may lead to resistance to the first-line anticonvulsant therapies. It has been shown that these children continue to remain intractable even after acute seizure management with approved Food and Drug Administration (FDA) agents. Intravenous levetiracetam, a second-generation anticonvulsant was approved by the FDA in 2006 in patients 16 years and older as an alternative when oral treatment is not an option. Data have been published showing that intravenous levetiracetam is safe and efficacious, and can be used in an acute inpatient setting. This current review will discuss the recent data about the safety and tolerability of intravenous levetiracetam in children and neonates, and emphasize the need for a larger prospective multicenter trial to prove the efficacy of this agent in acute seizure management.

Background. Hemiplegic migraine is a rare type of migraine that may present in children and adolescents. Both familial and sporadic hemiplegic migraines have similar prevalence and clinical characteristics. Patient. We report an adolescent with sporadic hemiplegic migraine who previously had a similar attack in the past and who was initially evaluated for a possible acute ischemic event. Results. Magnetic resonance angiography showed dilatation of the left middle cerebral artery that resolved in a follow-up study. She was also found to have a ATP1A2 (c.2273 G>C) mutation and a heterozygous prothrombin mutation. Conclusions. We suggest that patients with sporadic hemiplegic migraine be tested for both ATP1A2 mutations which in some cases may be pathogenic, and prothrombin mutations which increase the stroke risk for this patient population.

Partial seizures can be misdiagnosed as panic attacks. There is considerable overlap of symptoms between temporal lobe seizures and panic attacks making the diagnosis extremely challenging. Temporal lobe seizures can present with intense fear and autonomic symptoms which are also seen in panic disorders. This results in delay in diagnosis and management. We report an interesting case of a young woman who was diagnosed with right temporal lobe seizures with symptoms suggestive of a panic attack.

Objective: To assess whether the degree of labor pain at the initiation of neuraxial analgesia is associated with mode of delivery., Methods: Nulliparous women who presented to the labor department for an induction of labor, who were between 37 and 41 weeks of gestation, and who requested labor epidural analgesia with a pain score of 0-3 (low pain) and a cervical dilatation less than 4 cm were assessed retrospectively. Maternal and neonatal outcome including mode of delivery and duration of labor were compared with a similar group of women with pain scores of 4-6 (moderate pain), and 7-10 (severe pain). Assessing whether there was an association between pain level at the time of epidural and operative delivery rates was analyzed using a chi test for trend and by logistic regression to include potentially relevant covariates., Results: We found 185 nulliparous women with low pain and compared them with a randomly selected equal number of women in each of the other pain groups. There was no significant association between pain groups in terms of duration of the first or second stage of labor or mode of delivery. Women with low pain had an operative delivery rate (instrumental assisted vaginal delivery plus cesarean delivery) of 49%, compared with 45% and 45% in those with moderate and severe pain, respectively (P=.40)., Conclusion: We did not find an association between the degree of labor pain at initiation of epidural analgesia and mode of delivery or duration of labor., Level of Evidence: II.

Background: During 2008 seven practice improvement projects were conducted in an acute-care hospital under the banner of The Older Person and Improving Care (TOPIC 7). Each project team examined a discrete aspect of care of the elderly and this project focus was on pain management and in particular assessment of the older person with communication difficulties., Aims: The project intended to assess current practice and implement changes to match best practice in the management of pain in the older person within an acute-care setting., Methods: A multidisciplinary team was recruited to conduct the project. The pain team with the other six TOPIC 7 teams was facilitated by a coordinating team. The project was divided into four phases. Phase one was designated as Describing, where the clinical issue was identified and focused to priority areas. It was decided to focus on the elderly who were unable to verbally communicate their pain management needs. Standards of practice relevant to the area of practice were sourced to guide practice improvement. Phase two was Measuring activity where clinical audits were used to measure current practice and compare this with the appropriate standards. Phase three was Taking action where a range of practice improvement activities were implemented including the introduction of the Abbey Pain Scale. The final phase was designated as Review and share where the impact of the project activities was measured with a follow-up audit and the results were disseminated., Results: Initial results showed a need for increased awareness of the difficulties in the pain assessment and management of older persons who cannot verbally communicate their needs. Seventy-eight per cent of patients had a documented pain assessment in the previous 24 h on audit. However, 83% of these assessments were only a general comment in the patient records. No tools were available for completing a systematic assessment that was reliable and reproducible. Sixty-two per cent of patients did not have analgesia administered 1 h before mobilising or having a significant dressing completed. Reaudit, posteducation sessions, showed an increase in the awareness in the complexities involved in caring for this group of patients. An alternate, specific tool (Abbey Pain Scale) was utilised well by staff and acted as a prompt in reminding staff to assess the pain levels of their elderly patients., Conclusions: Globally, pain in the older person is poorly managed. Pain in older persons who are unable to communicate or who have difficulty in communicating their needs is even more poorly managed. However, the availability of an appropriate tool and an increased awareness of this issue can have a significant and real impact on the pain management of this group of patients., (© 2009 The Authors. Journal Compilation © Blackwell Publishing Asia Pty Ltd.)

Recombinant nematode anticoagulant protein-2 (rNAPc2) is an antithrombotic protein under development by Nuvelo as a potential therapeutic agent for the treatment of major acute cardiovascular disease such as unstable angina and myocardial infarction. Phase II clinical trials were ongoing in January 2004, although development for deep vein thrombosis had been suspended by Dendreon due to a requirement for a partner to assist with additional phase II clinical trials.

BIBR-1048, a thrombin inhibitor and an orally-active prodrug of BIBR-953ZW, is under development by Boehringer Ingelheim as a potential antithrombotic agent [331881]. By 1999, BIBR-1048 was in phase II clinical trials for thromboembolism and the prevention of stroke due to atrial fibrillation [331881]; by April 2002, proof-of-principle had been demonstrated in phase II trials in deep vein thrombosis [446554]. In July 2001, the company revealed that an IND was expected to be filed for BIBR-953ZW in 2002 [415884].

This study was performed to compare the computer-based and physician-based management of warfarin therapy after total hip arthroplasty (THA). The computer-assisted and control groups of patients were placed on warfarin postoperatively and followed for a 1-month period. A significant difference (P<.05) was found between the mean number of days needed to reach therapeutic anticoagulation in the control group (4.7+/-3.0 days) and the experimental group (2.8+/-1.4 days) and the proportion of patients in each group who were discharged with a subtherapeutic international normalized ratio (INR) (INR <1.5). The computer-based management of warfarin therapy was more efficient than unaided physician-based management and therefore may lead to improved, cost-effective patient care by reducing length of hospital stay and complications attributable to nontherapeutic anticoagulation in THA patients.

Alfa Wassermann, in collaboration with Opocrin, is developing Desmin 370, an antithrombotic agent which is in phase III clinical trials for the treatment of deep vein thrombosis, and may have potential in the treatment of pulmonary embolism. The antithrombotic effect is attributed to the inhibition of thrombin generation, potentiation of heparin cofactor II activity, and local fibrinolytic effects. Opocrin is the product patent holder (EP-00221977 and US-04973580), while Alfa Wassermann is the developer and responsible for the clinical research.

Objective: To determine the relative contribution of changes in the plasma warfarin level to variation in the serial steady-state prothrombin times., Methods: This was a prospective observational cohort study performed at two outpatient anticoagulation clinics. Serial prothrombin times and paired plasma total warfarin levels were determined in a convenience sample of otherwise healthy patients who required long-term oral anticoagulation therapy with warfarin., Results: Serial measurements were obtained from 129 patients, 60 of whom provided three or more serial samples. Analysis of covariance showed a highly significant (p = 0.0001) relationship between the anticoagulant effect and the logarithm of the warfarin concentration (R2 = 0.75), with 15.3% of the total variance attributable to the effect of warfarin and 31.1% attributable to individual variation in sensitivity to warfarin. In an analysis of the subjects who had three or more serial measurements, the mean weighted correlation coefficient for the relationship between the logarithm of the warfarin concentration and the anticoagulant response varied widely, from strongly negative to strongly positive, and as the range of observed prothrombin times increased, stronger positive correlation was observed., Conclusions: In this cohort, the plasma warfarin level was a strong predictor of observed changes in serial prothrombin time measurements. However, the correlation between clotting times and warfarin levels varied widely among subjects, particularly when the range of observed prothrombin times was moderate. This suggests that in these subjects, other factors, such as measurement error or pharmacodynamic changes, played a major role.

Background: Expert consultation by means of established practice guidelines has been shown to lead to improved accuracy of inpatient anticoagulation therapy, with a reduction in the frequency of hemorrhagic complications. We evaluated a different strategy to improve the accuracy of in-hospital anticoagulation: pharmacy-based, computer-assisted dosing of intravenous heparin therapy., Methods: Patients treated with computer-assisted dosing of heparin (N = 131) were compared with a randomly selected historical cohort (N = 57) in whom heparin therapy was managed by the primary physician. All patients treated by the pharmacy team received a bolus of heparin, 70 U/kg of ideal body weight, except for patients with pulmonary embolism, who received 100 U/kg of ideal body weight. A computer-generated infusion dose was selected (generally 13 to 16 U/kg per hour). The target was an activated partial thromboplastin time (APTT) ratio of 1.8 times the patient's baseline APTT, with a therapeutic range of 1.5 to 2.5 times baseline. Computer-assisted dosage recommendations were generated after each APTT measurement., Results: In the historical control group, 62% of the patients achieved a therapeutic APTT during the first 24 hours; 17% failed to reach a therapeutic level by 48 hours. The median time to reach a therapeutic APTT was 15 hours. Of all 696 APTTs in this group, 42% were below, 43% in, and 15% above the therapeutic range. In the computer-assisted group, 90% achieved a therapeutic APTT within 24 hours (P < .001); 97% had a therapeutic APTT by 48 hours (P < .01). The median time to achieve a therapeutic APTT was 7 hours (P < .001). Of all 880 APTTs in this group, 17% were below, 75% in, and 8% above the therapeutic range (P < .001)., Conclusions: Pharmacy-based, computer-assisted dosing of heparin is feasible and results in faster and more accurate anticoagulant dosing.

Failure to adequately anticoagulate the blood of patients receiving recombinant tissue plasminogen activator (TPA) leads to greater rates of rethrombosis. In a multicentered, randomized trial in 51 patients we compared the ability to achieve and maintain therapeutic anticoagulation by use of computer-assisted heparin therapy or the GUSTO (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) heparin nomogram guidelines in patients with myocardial infarction treated with recombinant TPA. Heparin therapy was initiated with either computer-generated starting doses or GUSTO guideline starting doses. Activated partial thromboplastin times were measured every 6 to 8 hours for the first 24 hours. The therapeutic range used in this trial was 1.5 to 2.5 times the patient's baseline activated partial thromboplastin time (APTT). Ninety-four percent of the APTT ratios in the computer group were equal to or greater than 1.5 in the first 24 hours compared with 78% in the GUSTO group (p < 0.009). No significant difference in bleeding was found (7.7% for GUSTO; 4.2% for computer). Incremental time-dependent changes in heparin dose were found (day 1, 1110 +/- 243 units/hr, APTT ratio = 2.5 +/- 1.4; day 3, 1380 +/- 374 units/hr, APTT ratio, 1.9 +/- 0.4). Computer-assisted heparin therapy TPA results in superior anticoagulation accuracy compared with the GUSTO guidelines. In addition, the pharmacodynamic response to heparin changes in the 2 to 3 days after administration of TPA, leading to greater heparin requirements.

In a prospective, randomized clinical trial we compared the efficacy of subcutaneously (SC) administered (every 8 h) calcium heparin to intravenous (IV) sodium heparin in the treatment of proximal deep-vein thrombosis (DVT). A secondary objective was to give enough heparin to achieve a therapeutic anticoagulant effect by the end of the first 24 h. Five of 36 patients (14%) in the SC heparin group failed to achieve a therapeutic anticoagulant effect by the end of the first 24 h compared to 2 of 23 patients (9%) in the IV group (p = NS; 95% CI for true difference = -11.7% to 22.1%). Two of 31 patients (6.5%) in the SC group had venographic evidence of clot propagation compared to 1 of 19 patients (5.3%) in the IV group (p = NS; 95% CI for true difference = -12.4% to 14.8%). The rate of major hemorrhagic complications was similar in each group (approximately 15%). We conclude: (1) using a large initial dose of SC heparin, a therapeutic anticoagulant effect can be readily achieved within 24 h, and (2) combining the results of this trial with previous studies, the efficacy of SC administered calcium appears to be comparable to IV sodium heparin.

In a prospective, randomized clinical trial, we compared the accuracy of warfarin dosage-adjustments predictions using a computer program to the skill of an experienced anticoagulation nurse-specialist. The computer program predicts the steady state warfarin dose by applying Bayesian forecasting techniques to a mathematical model of the dynamic pharmacologic response to warfarin. Fifty patients who were receiving chronic warfarin therapy and who required a dosage adjustment because their prothrombin time was greater than or equal to 2 s away from their target prothrombin time were enrolled. The baseline characteristics of each group were similar, including the mean of the absolute value of the differences between initial prothrombin times and corresponding target prothrombin times. After a new a new warfarin dose was predicted, the prothrombin time was measured at least 7 days after dosage adjustment. Overall, the results in each group were comparable. There was no significant difference between groups and the mean of the absolute value of the differences between final prothrombin times and target prothrombin times, nor was there a difference in the proportion of patients who had a final prothrombin time within 2 s of the target prothrombin time. We conclude that the accuracy of warfarin dosage adjustments made using computer modeling is comparable to the skill of an anticoagulation nurse-specialist.

Our objective was to evaluate the effectiveness of a computer program to predict daily prothrombin time (PT) response to warfarin therapy using prospectively collected data. The program's predictive performance (precision) and accuracy (bias) were evaluated using fraction mean absolute error and fraction mean error, respectively. We analyzed data from 40 patients using from zero to nine PT feedbacks. The fraction mean absolute error varied from 0.058 to 0.13. The program utilized a pharmacokinetic/pharmacodynamic Bayesian forecasting system to predict prothrombin response.

Recent theoretical work has suggested that radiochemical impurities can significantly alter the binding results for highly protein-bound drugs. We compared protein binding of warfarin by ultrafiltration and equilibrium dialysis with 98% radiochemically pure [14C]warfarin. Ultrafiltration and equilibrium dialysis were performed at 37 degrees C and pH 7.45 on the plasma of patients receiving chronic warfarin therapy. Binding to plasma from seven patients were measured in duplicate by both a nonspecific radioisotopic technique and a specific HPLC technique. The nonspecific technique gave percentage of free warfarin values of 1.84 +/- 0.11 (mean +/- SD) and 1.59 +/- 0.14 for ultrafiltration and equilibrium dialysis, respectively. The HPLC procedure yielded a percentage of free warfarin by ultrafiltration of 0.969 +/- 0.203 and a value of 0.690 +/- 0.095 by equilibrium dialysis (p less than 0.05). The HPLC procedure for protein binding was performed on plasma samples from 12 additional patients and yielded a percentage of free warfarin of 1.01 +/- 0.69 by ultrafiltration and 0.44 +/- 0.34 by equilibrium dialysis (p less than 0.05). It can be concluded that radiochemical impurities may lead to significant overestimation of the percentage of free warfarin. Ultrafiltration yielded a higher percentage of free warfarin than did equilibrium dialysis, but the ability to distinguish binding differences among patients was similar.

We have studied 19 male patients whose theophylline therapy was individualized by a clinical pharmacokinetics service and 34 male patients with empirically derived dosages. All patients were admitted to the medical intensive care unit. Patients in the pharmacokinetics group had fewer adverse reactions (15.7 vs. 50%), shorter intensive care unit stay (6.6 +/- 5.5 vs. 12.4 +/- 16.3 days), shorter hospital stay (15.4 +/- 10 vs. 22.3 +/- 14.1 days), and a shorter period of time to be placed on oral therapy (5.2 +/- 3.1 vs. 8.6 +/- 7.2 days) than the group with empirically derived regimens. The pharmacokinetic method used to individualize theophylline therapy offered an accurate and efficient method of achieving therapeutic concentrations. We conclude that the use of clinical pharmacokinetics to individualize theophylline therapy offers substantial benefits over empirical assessments.

The predictive performance of a Bayesian computer program using prothrombin-time (PT) response data with and without warfarin plasma concentrations to forecast patients' PTs at the time of hospital discharge was evaluated. A log-linear pharmacokinetic-pharmacodynamic model was used to describe and predict warfarin dose response in patients recently started on warfarin sodium. Individual patients' pharmacodynamic variables relating warfarin concentration to clotting-factor synthesis were obtained by Bayesian nonlinear regression analysis. Pharmacokinetic values for warfarin clearance and volume of distribution were either calculated using nonlinear regression from measured plasma warfarin concentrations or estimated based on literature-derived population regression equations. Percent mean absolute prediction error (precision) and prediction error (bias) for PT predictions were compared among and between analysis methods that used only literature data to estimate PT response and methods that used zero to five PTs with or without warfarin plasma concentrations. Eleven women and eight men completed the study. Predictions after four days of warfarin therapy using PT measurements beginning after either the first or third warfarin dose were clinically useful regardless of whether warfarin concentrations were used in the predictions. Predictions using fewer than four PT measurements were imprecise and biased. The Bayesian method in this study provided good predictions of PTs immediately before hospital discharge based on warfarin dosing and PT response after either four or five days of therapy. The use of warfarin plasma concentrations in the pharmacokinetic-pharmacodynamic model used here appears unwarranted.

The ability of a pharmacokinetic/pharmacodynamic Bayesian forecasting computer program to predict prothrombin response to warfarin therapy was investigated. The performance of the program was evaluated retrospectively in an inpatient study population of 45 subjects. Predictions of prothrombin response at discharge, based on zero to five serially measured prothrombin ratios, were compared. Precision of prediction was measured by root mean squared error (rmse), bias was measured by average prediction error, and significance (p less than 0.05) was determined by 95% confidence intervals and correlation coefficients. Eleven (3.8%) predictions exceeded established limitations of the pharmacokinetic/pharmacodynamic model and were excluded from data analysis. Correlations between measured and predicted prothrombin ratios for all methods were significant. The five prothrombin ratio feedbacks provided the most accurate predictions (rmse 0.219). These predictions were significantly better than the population parameter (rmse 0.418), one (rmse 0.401), and two (rmse 0.459) prothrombin ratio feedback predictions. The predictions based on population parameters and one prothrombin ratio feedback were significantly biased. When provided with sufficient feedback, the bias was not apparent and the predictive performance improved with each additional prothrombin ratio. The predictive performance of the four and five prothrombin ratio feedbacks is sufficient to provide clinically useful dosage guidelines early in the course of warfarin therapy. The population parameter estimates require further delineation in order to improve the performance of limited prothrombin ratio feedback predictions.

In a prospective, randomized study at two university hospitals, the authors examined how effectively housestaff physicians (n = 36) managed the initiation of warfarin therapy compared with a computer-assisted dosing regimen (n = 39) using the software program Warfcalc, which was managed by one of the authors. Target prothrombin time ratios were selected by the physicians. Study endpoints included: the time to reach a therapeutic prothrombin ratio, the time to reach a stable therapeutic dose, the number of patients transiently overanticoagulated, the number of bleeding complications, and the accuracy of the predicted maintenance dose, which was assessed at steady-state 10-14 days later. Computer-assisted dosing consistently out-performed the physicians: a stable therapeutic dose was achieved 3.7 days earlier (p = 0.002), fewer patients were overanticoagulated (10% versus 41%), and the predicted maintenance dose was in the therapeutic range in 85% of the computer-dosed patients versus 42% of the physician group (p less than 0.002). For physicians who did not routinely manage warfarin therapy, computer-assisted dosing improved the accuracy of dosing and shortened the time required to achieve a stable therapeutic dose.

The prothrombin time (PT) is frequently performed to monitor anticoagulant therapy. Although relatively simple to perform, it requires venipuncture and laboratory resources for sample handling and analysis. A recently developed capillary whole blood device that uses fingerstick samples was evaluated. Paired capillary whole blood and reference plasma PTs were performed in 858 samples from 732 subjects. The PT for normal volunteers (n = 193) was 11.8 +/- 0.9 seconds with the use of the new instrument and 12.1 +/- 0.5 seconds with the use of the reference method. In samples from 539 patients receiving anticoagulants, the correlation coefficient between the two methods was 0.96. Venous whole blood without anticoagulant and capillary whole blood gave equivalent results, which suggests that the fingersticks do not effect the quality of the specimen. Variation in hematocrit between 23.4% (0.34) and 53.8% (0.538) did not alter the performance of the instrument. The new instrument is easy to use and may allow testing by nonlaboratory personnel and patients. It obviates the need for venipuncture, provides immediate results, and appears to be comparable in accuracy to current reference methods.

Previous work by Bloedow et al. evaluated the effect of warfarin on diltiazem binding. Unbound diltiazem remained constant (22.5 +/- 3.6 per cent) in the presence of warfarin. We studied 10 patients, 51 to 72 years old, who were receiving warfarin as an anticoagulant for valvular replacement, thrombosis, or embolus. Our study demonstrates that a single 120-mg oral diltiazem dose, sufficient to cause hemodynamic changes, does not displace warfarin from plasma binding sites.