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Biomedical subjects

William E Dager

Publications and source records attributed to William E Dager.

At least 19 recordsLinked to original sources
PubMed2006

Choosing the appropriate antithrombotic agent for the prevention and treatment of VTE: a case-based approach.

OBJECTIVE: To review the risk of venous thromboembolism (VTE) in various patient populations and evaluate the agents available for the prevention and treatment of VTE using a case-based approach. DATA SOURCES: A MEDLINE search (1995-July 2006) was conducted to identify relevant literature. Additional references were reviewed from selected articles. STUDY SELECTION AND DATA EXTRACTION: Articles related to the prevention of VTE in orthopedic surgery, general surgery, and medically ill patients, as well as the treatment of VTE, were reviewed. DATA SYNTHESIS: Pharmacologic options for the prevention and treatment of VTE include warfarin, unfractionated heparin (UFH), low-molecular-weight heparins (LMWH), and fondaparinux. Current guidelines support the use of warfarin, LMWH, or fondaparinux for VTE prophylaxis following lower limb major orthopedic surgery. For VTE prophylaxis in hospitalized medical patients or patients undergoing general surgery, use of UFH and LMWH is supported; however, recent data on fondaparinux suggest that it is also effective in these patient populations. The use of UFH or LMWH (both in conjunction with warfarin) for treatment of acute deep venous thrombosis or nonmassive pulmonary embolism is recommended. Recent data suggest that fondaparinux (in conjunction with warfarin) is also effective for the treatment of VTE. A variety of pharmacokinetic, pharmacodynamic, and pharmacoeconomic factors differentiate each agent for the various indications. CONCLUSIONS: Currently, a "one-size-fits-all" anticoagulant is not available for treatment of VTE. A variety of patient factors, including type of surgery, medical indication, thrombotic risk factors, bleeding risk, history of heparin-induced thrombocytopenia, and a variety of comorbid conditions can affect the safety, efficacy, and selection of appropriate VTE therapy.

Aged↗
PubMed2006

Racial and gender differences in the incidence of recurrent venous thromboembolism.

Men have been reported to have a higher incidence of recurrent venous thromboembolism than women. However, it is not known if this gender effect holds among different racial/ethnic groups and for both venous thrombosis and pulmonary embolism. We conducted a retrospective analysis of 18- to 65-year-old Caucasian, African-American and Hispanic cases hospitalized in California with unprovoked venous thromboembolism. The principal outcome was recurrent venous thromboembolism 7-60 months after the index event. Among 11,514 cases that were followed for a mean of 3.0 years, men had a significantly higher rate (events/100 patient-years) of recurrent venous thromboembolism than women for both venous thrombosis [rate ratio (RR) = 1.5, 95% confidence interval (CI):1.3-1.8] and pulmonary embolism [RR = 1.3, 95%CI:1.0-1.6]. Among men the recurrence rate did not vary significantly between the racial/ethnic groups (p > 0.05). However, the recurrence rate among Hispanic women with venous thrombosis was significantly higher than in Caucasian women (p < 0.001) and was comparable to the rate in men. Both Hispanic and African-American women with pulmonary embolism had a higher recurrence rate compared with Caucasian women (p < 0.02) that was comparable to the rate in men. We conclude that women in California had a 40% lower risk of recurrent venous thromboembolism compared to men. Rates were comparable among men of different races, but there were significant inter-racial differences among women, which also varied with the type of initial event. The effect of gender on the risk of recurrent venous thromboembolism can not be generalized because it varies between racial/ethnic groups and with the type of index event.

Adolescent↗
PubMed2006

Pharmacotherapy considerations in advanced cardiac life support.

Cardiac arrest and sudden cardiac death remain major causes of mortality. Early intervention has been facilitated by emergency medical response systems and the development of training programs in basic life support and advanced cardiac life support (ACLS). Despite the implementation of these programs, the likelihood of a meaningful outcome in many life-threatening situations remains poor. Pharmacotherapy plays a role in the management of patients with cardiac arrest, with new guidelines for ACLS available in 2005 providing recommendations for the role of specific drug therapies. Epinephrine continues as a recommended means to facilitate defibrillation in patients with pulseless ventricular tachycardia or ventricular fibrillation; vasopressin is an alternative. Amiodarone is the primary antiarrhythmic drug that has been shown to be effective for facilitation of defibrillation in patients with pulseless ventricular tachycardia or fibrillation and is also used for the management of atrial fibrillation and hemodynamically stable ventricular tachycardia. Epinephrine and atropine are the primary agents used for the management of asystole and pulseless electrical activity. Treatment of electrolyte abnormalities, severe hypotension, pulmonary embolism, acute ischemic stroke, and toxicologic emergencies are important components of ACLS management. Selection of the appropriate drug, dose, and timing and route of administration are among the many challenges faced in this setting. Pharmacists who are properly educated and trained regarding the use of pharmacotherapy for patients requiring ACLS can help maximize the likelihood of positive patient outcomes.

Advanced Cardiac Life Support↗
PubMed2006

Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin.

STUDY OBJECTIVE: To assess the effectiveness of using low-dose recombinant activated factor VII (rFVIIa) to reverse the effects of warfarin in critically ill patients with major bleeding events. DESIGN: Prospective observational study. SETTING: Intensive care unit of a 500-bed university-affiliated hospital. PATIENTS: Sixteen nonhemophiliac patients who had been receiving warfarin and had an acute major bleeding event. INTERVENTION: Patients received rFVIIa 1.2 mg for reversal of anticoagulation. MEASUREMENTS AND MAIN RESULTS: Patients were identified from clinical pharmacology consult service electronic tracking records, and their data were cross-checked with the pharmacy information system. Information collected for each patient included extent of bleeding and magnitude of elevation in international normalized ratio (INR). A mean +/- SD dose of rFVIIa 16.3 +/- 4.1 microg/kg (range 11-25 microg/kg) reduced the mean INR from 2.8 +/- 1.6 (range 1.44-6.34) to 1.07 +/- 0.27 (range 0.86-1.92, p<0.001). A rapid onset of response for achieving a desirable hemostatic effect was observed in 14 of the 16 patients. CONCLUSION: Low-dose rFVIIa appears to be an effective, rapid reversal modality for major bleeding events in the presence of warfarin and an elevated INR. The agent's response is quicker than that expected with fresh frozen plasma combined with vitamin K. In emergency situations, rFVIIa 1.2 mg can be used to reverse the anticoagulant effect of warfarin and other vitamin K antagonists without inducing a hypercoagulable state; the product, however, is expensive.

Adolescent↗
PubMed2005

Aminoglycosides in intermittent hemodialysis: pharmacokinetics with individual dosing.

BACKGROUND: Data are limited on aminoglycoside pharmacokinetic differences between acute renal failure (ARF) and chronic kidney disease (CKD) or infection survival when maintaining peak and pre-hemodialysis serum concentrations between 7 and 10 and 3.5 and 5 mg/L, respectively. OBJECTIVE: To report aminoglycoside pharmacokinetic observations in a consecutive series of patients receiving intermittent hemodialysis (IHD), including treatment impact of patient-specific dosing regimens. METHODS: In this prospective study, all calculated pharmacokinetic parameters used concentrations drawn more than 12 hours after the initial dose and peak concentrations at least 2 hours after the dose. Analysis included pharmacokinetic parameters in stage 5 CKD, ARF, impact of the dialysis prescription, and treatment results of individualized dosing regimens lasting more than 4 days. RESULTS: Consecutive patients with IHD (N = 167) receiving 216 courses of aminoglycosides were evaluated. The mean +/- SD volume of distribution was 0.39 +/- 0.15 L/kg ideal body weight, and elimination half-life during dialysis was 4.2 +/- 2.3 hours. The elimination half-life off IHD was 30% shorter in ARF (31.9 +/- 20.8 h) versus 45.7 +/- 24.2 hours in CKD (p < 0.001). Mean extrapolated peak concentrations and pre-IHD levels were 7.7 +/- 1.6 and 3.9 +/- 1.2 mg/L, respectively. A 91% treatment success rate was observed in 117 individualized treatment courses in 100 patients receiving greater than or equal to 5 days of aminoglycoside therapy. CONCLUSIONS: A large variability in aminoglycoside pharmacokinetic parameters in IHD exists, with aminoglycoside elimination off IHD significantly faster in ARF. Individualized regimens using serum concentrations drawn in patients requiring treatment (non-synergistic) targeting peak concentrations of 7-10 mg/L and pre-hemodialysis serum concentrations of 3.5-5 mg/L appears successful for eradicating infections.

Acute Kidney Injury↗
PubMed2005

Tinzaparin in outpatients with pulmonary embolism or deep vein thrombosis.

BACKGROUND: The low-molecular-weight heparins (LMWHs) have been shown to be effective in the outpatient treatment of deep vein thrombosis (DVT). Data regarding outpatient use of any LMWH in pulmonary embolism (PE) or tinzaparin in DVT while transitioning therapy to a vitamin K antagonist are limited. OBJECTIVE: To determine the safety and efficacy of tinzaparin in patients with either DVT or PE being transitioned to warfarin during LMWH therapy in the outpatient setting. METHODS: All patients who were treated with at least one outpatient dose of tinzaparin for venous thromboembolism (VTE) were identified. Charts of all patients followed within the University of California Davis healthcare system were reviewed. The incidence of bleeding and recurrent thromboembolism over a minimum of the first 4 weeks to a maximum of 12 weeks after initiating anticoagulation was assessed. RESULTS: A total of 178 patients with acute VTE were treated with tinzaparin, and outcomes could be determined in 140 cases. Forty-seven percent of these patients had objectively documented PE. Only one (0.7%) case of recurrent VTE was observed. Major bleeding was documented in 5 (3.6%) and minor bleeding in 8 (5.8%) patients. Two bleeding events, both major, occurred during tinzaparin therapy. CONCLUSIONS: Outpatient use of tinzaparin during transition to warfarin therapy in the treatment of VTE, including PE, appears to be feasible in patients who are judged candidates for home therapy.

Adolescent↗
PubMed2004

Ximelagatran: an oral direct thrombin inhibitor.

OBJECTIVE: To present the chemistry, pharmacology, and pharmacokinetics of ximelagatran, an oral direct thrombin inhibitor (DTI), and to review available comparative clinical trial data evaluating its efficacy and safety relative to other antithrombotic agents in the prevention and treatment of thromboembolism. DATA SOURCES: A search of the PubMed and Cochrane databases (1995-August 2004), supplemented by a manual search of article bibliographies, conference abstracts, and data on file from the manufacturer, was conducted. Key search terms were ximelagatran, melagatran, H376/95, and direct thrombin inhibitors. STUDY SELECTION AND DATA EXTRACTION: Pertinent information from available clinical trials, including study design, patient demographics, dosing regimens, anticoagulant comparators, methods for evaluating effectiveness, treatment outcomes, adverse events, and pharmacokinetic and pharmacodynamic evaluations, was extracted. DATA SYNTHESIS: Ximelagatran is an orally administered DTI under development for use in the treatment of venous thromboembolism (VTE), long-term prevention of a second VTE event, stroke secondary to atrial fibrillation, prevention of VTE after orthopedic procedures, and recurrent ischemic events after acute myocardial infarction. CONCLUSIONS: Ximelagatran, in twice-daily doses of 24 or 36 mg, is an alternative to low-molecular-weight heparins or warfarin in thromboprophylaxis following orthopedic knee replacement, atrial fibrillation, or initial treatment of VTE. Improved outcomes versus placebo were seen in the long-term prevention of VTE in patients who completed an initial 6 months of treatment. Liver-related effects need further clarification.

Adult↗
PubMed2004

Comparing direct thrombin inhibitors using aPTT, ecarin clotting times, and thrombin inhibitor management testing.

BACKGROUND: Patients with heparin-induced thrombocytopenia and thrombosis may be acutely anticoagulated with direct thrombin inhibitors (DTIs). The anticoagulation is typically monitored using the activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). OBJECTIVE: To compare 14 methods for measuring aPTT, as well as ECT and thrombin inhibitor management test (TIM), in samples containing DTIs. METHODS: DTIs were added to pooled normal plasma to achieve low (0.1-1.2 microg/mL) and high (1.5-8.0 microg/mL) drug concentrations. Each low-concentration DTI sample was tested using all aPTT reagents, while each low- and high-concentration DTI was tested using the ECT and TIM. RESULTS: All aPTT reagents had a significant dose-dependent correlation with drug concentration. Only Actin FSL and APTT-S demonstrated equivalent aPTT ratios obtained from any DTI. The TAS-aPTT was the most sensitive aPTT reagent to argatroban, with the aPTT ranging from 52.7 to 121.2 seconds corresponding to 0.1 to 1.2 microg/mL of drug concentration. The TAS-aPTT and Pathromtin were the most sensitive aPTT reagents to bivalirudin, with aPTTs of 87.4 seconds and 101.5 seconds, respectively, at 1.2 microg/mL of drug. Pathromtin was the most sensitive aPTT reagent to lepirudin, with a maximum aPTT of 108.9 seconds at 1.2 microg/mL of drug. There was no statistically significant difference between the TIM and ECT clotting times for each DTI. Lepirudin and bivalirudin ECT and TIM clotting times were equivalent. CONCLUSIONS: There are unique differences between reagent manufacturers in the monitoring of DTIs. Acceptable alternatives to aPTT monitoring of DTI anticoagulation include the ECT and TIM.

Arginine↗
PubMed2004

Anti-Xa stability of diluted enoxaparin for use in pediatrics.

BACKGROUND: The use of enoxaparin in low-weight pediatric patients is becoming common practice. Anti-Xa stability of unit-dose syringes prepared after dilution beyond one day is presently unknown. OBJECTIVE: To evaluate the anti-Xa stability of diluted enoxaparin stored in glass vials and tuberculin syringes. METHODS: Four separate batches of enoxaparin were diluted with sterile water to a final concentration of 20 mg/mL (2000 IU/mL) and aliquoted into plastic 1-mL syringes containing 6 mg (0.3 mL) or maintained in the glass vial. Syringes were stored at room temperature or under refrigeration. The glass vial used for diluting was stored at room temperature. The anti-Xa activity was measured on the date of preparation to 4 weeks. Statistical comparisons determined whether differences in anti-Xa activity in diluted enoxaparin are affected by the storage medium or temperature. A paired t-test was used to determine any significant differences between the anti-Xa activity on date of preparation (baseline) and subsequent time periods, with p < 0.05 considered statistically significant. RESULTS: The mean baseline anti-Xa activity was 2607 IU/mL (95% CI 2300 to 2914). No measurable decrease occurred in diluted enoxaparin anti-Xa activity in the glass vial maintained over the 4-week period. Compared with the glass vial, room temperature and refrigerated syringe samples had trending decreases of anti-Xa activity at weeks 3 and 4, but did not reach statistical significance. CONCLUSIONS: A nonsignificant decrease in anti-Xa activity occurred starting at day 22 for the diluted enoxaparin in tuberculin syringes, regardless of storage temperature. Storage up to 4 weeks of diluted enoxaparin in glass or prefilled syringes does not result in a statistically significant loss of anticoagulant potential, as measured by anti-Xa activity.

Anticoagulants↗
PubMed2004

Variability of plasma anti-Xa activities with different lots of enoxaparin.

BACKGROUND: Previous studies have indicated the variability of anti-Xa activity in different sources of heparin and the variability of different methods used for measuring anti-Xa activity. Manufacturers of low-molecular-weight heparins (LMWHs) determine each lot's anti-Xa activity against the World Health Organization standard, but little information is known about anti-Xa activity variation between lots of LMWH and the impact on reported anti-Xa activity in patient samples. OBJECTIVE: To determine the variation of plasma anti-Xa activity in patients receiving enoxaparin when different lots of enoxaparin are used for test calibration. METHODS: We obtained 7 lots of enoxaparin containing approximately 10,000 IU/mL and one lot containing approximately 15,000 IU/mL of anti-Xa activity. For each lot, a 2.0 anti-Xa IU/mL dilution was prepared and a calibration curve performed using a chromogenic method. To test the variation in reported results between the different calibration lots, 20 patient samples were tested. Nineteen patients receiving enoxaparin and one patient not receiving enoxaparin (negative control) were tested in a blinded fashion, and the changes in light absorbance recorded. Anti-Xa activity results from tested plasmas were then extrapolated from each enoxaparin lot calibration curve. RESULTS: Using Student's paired t-test, there were statistically significant differences between the plasma anti-Xa activities generated from the various enoxaparin lots. In the range of 0.5-1.0 IU/mL of anti-Xa activity, 3 (4.2%) samples had a >0.2 IU/mL difference (maximum difference 0.33 IU/mL) in anti-Xa activity between 2 lots of enoxaparin. For samples that had supratherapeutic anti-Xa activities (1.0-1.5 IU/mL anti-Xa activity), there was a wider variation (>0.2 IU/mL) in anti-Xa activity, which may have resulted in a dosing change. CONCLUSIONS: The statistical differences in plasma anti-Xa activities noted between enoxaparin lots are not clinically significant. However, anti-Xa activities in the upper therapeutic and supratherapeutic ranges (>1.0 IU/mL of anti-Xa activity) resulted in a deviation of >0.3 IU/mL in reported anti-Xa activity, which may result in dosing changes.

Anticoagulants↗
PubMed2004

Lepirudin in heparin-induced thrombocytopenia and extracorporeal membranous oxygenation.

OBJECTIVE: To report a case of intermediate-probability suspected heparin-induced thrombocytopenia (HIT) treated with lepirudin in a patient requiring continuous extracorporeal membranous oxygenation (ECMO). CASE SUMMARY: A 17-year-old girl was admitted with multiple traumatic injuries including severe bilateral pulmonary contusions. Within 48 hours, she developed progressive pulmonary failure despite mechanical ventilation, and was placed on ECMO. Anticoagulation of the ECMO circuit was facilitated by unfractionated heparin (UFH). The platelet count of 116 x 10(3)/mm(3) after initiation of ECMO gradually decreased over 5 days to 44 x 10(3)/mm(3). On ECMO day 5, a highly positive enzyme-linked immunosorbent assay for HIT antibodies was reported, and the UFH infusion was discontinued. Lepirudin was immediately started with a bolus of 0.1 mg/kg, followed by an infusion of 0.12 mg/kg/h, with a target activated partial thromboplastin time (aPTT) ratio approximately 2 times control. The ECMO circuit was maintained without any unexpected bleeding complications or thrombosis for 6 additional days until the patient died secondary to pulmonary failure after ECMO was removed. DISCUSSION: Use of ECMO typically requires continuous infusion of UFH to keep the circuit from clotting. In patients with HIT, alternative anticoagulation using a direct thrombin inhibitor may be warranted. Lepirudin was effectively used to maintain the circuit despite continued presence of heparin molecules impregnated into the ECMO circuit tubing. The aPTT was successfully used to monitor and adjust the lepirudin infusion. CONCLUSIONS: In patients requiring ECMO in the presence of HIT, anticoagulation of the ECMO circuit may be accomplished using a continuous infusion of a direct thrombin inhibitor such as lepirudin.

Adolescent↗
PubMed2004

Ximelagatran: a new antithrombotic option in atrial fibrillation.

Treatment strategies in patients with atrial fibrillation typically involve pharmacologic or interventional invasive therapies to suppress the rhythm, control ventricular contraction rates, or prevent thromboembolic complications. Current therapies used for rhythm conversion in atrial fibrillation may have undesirable risks or side effects that limit this approach. Lifelong anticoagulation may be necessary to prevent the formation of thrombus in the left atrial chamber that can travel into the cerebral circulation to cause a stroke. Currently, warfarin is the most commonly prescribed anticoagulant for this purpose. Unfortunately, many patients with atrial fibrillation may not receive warfarin because of the difficulties in dosing and maintaining desirable target goals. The oral direct thrombin inhibitor ximelagatran has several pharmacologic properties that provide a unique and potentially desirable treatment option. Clinical studies have demonstrated that ximelagatran, administered in twice-daily doses of 36 mg, is non-inferior to warfarin for thromboprophylaxis against stroke or systemic embolism in atrial fibrillation. The pharmacology of ximelagatran and clinical trials with its use in atrial fibrillation is reviewed.

Animals↗
PubMed2004

Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values.

Direct thrombin inhibitors (DTIs) represent a new class of promising anticoagulation agents. The DTIs frequently are used to provide initial anticoagulation, with long-term therapy requiring eventual transition to coumarins. Unfortunately, DTIs not only prolong the activated partial thromboplastin time but also can affect international normalized ratio (INR) values. We approximated the DTI effect on INRs by each drug to pooled plasma at concentrations between 0.1 and 1.2 microg/mL. We then concurrently tested these samples using 14 prothrombin time (PT) reagents. By using repeated measures analysis of variance, we found significant differences (P < .05) between the median INRs for lepirudin and argatroban for all PT reagents, between lepirudin and bivalirudin for all reagents except PT-Fibrinogen HS Plus (P = .07), and between bivalirudin and argatroban for all reagents except Thromborel S (P = .05). The DTI effect on INRs was dependent on drug, drug concentration, and reagent. Argatroban had the most effect on INRs, while lepirudin had the least effect. Reagents with a lower international sensitivity index were less affected by DTI; ThromboMax HS was the least sensitive PT reagent to any DTI.

Antithrombins↗