Warfarin-amiodarone drug-drug interactions: determination of [I](u)/K(I,u) for amiodarone and its plasma metabolites.

A retrospective clinical evaluation in a cohort of 73 patients receiving stable anticoagulation therapy showed that the addition/elimination of amiodarone resulted in a 6-65% change in warfarin dose requirement. To evaluate the roles of amiodarone and its circulating metabolites in this highly variable inhibitory drug interaction, a liquid chromatography-electrospray ionization-tandem mass spectrometry assay was developed for the quantitation of low concentrations of these compounds in human plasma, using newly synthesized deuterated analogs as internal standards. Inhibition constant (K(I)) values were determined for the inhibition of (S)-warfarin 7-hydroxylation in human liver microsomes by the parent drug and its metabolites, and the unbound drug fractions (f(u)) were measured in order to calculate the ratio of unbound plasma concentration to the microsomal K(I) for the unbound drug ([I](u)/K(I,u)). From these ratios, we predict that a minor metabolite of amiodarone, namely, N,N-didesethylamiodarone (DDEA), is a major contributor to the interaction between warfarin and amiodarone.

Drug interactions update: drugs, herbs, and oral anticoagulation.

Management of warfarin drug interactions is often complicated by lack of information regarding interactions with new drugs and with herbal medicinals. The pharmaceutical industry has increased both the number and quality of drug interaction studies prior to marketing new agents. Interactions may still occur in patients, however, despite negative pre-marketing studies in healthy volunteers. The clinical significance and intensity of warfarin interactions with prescription drugs (e.g., celecoxib, proton pump inhibitors, and selective serotonin reuptake inhibitors) can often be predicted on the basis of known metabolic characteristics of the drugs and warfarin enantiomers. Drug interactions with herbal medicinals are much more difficult to characterize and predict because of the lack of federal regulations regarding safety, efficacy, and manufacturing standards. Published case reports of interactions between warfarin and even the most widely used herbal medicinals are limited. Practitioners are encouraged to report such interactions through the FDA MedWatch program.

Argatroban for prevention and treatment of thromboembolism in heparin-induced thrombocytopenia.

OBJECTIVE: To renew the pharmacology, pharmacokinetics, efficacy adverse events, and cost of argatroban in the prevention and treatment of thromboembolism in patients with heparin-induced thrombocytopenia (HIT). DATA SOURCES: A MEDLINE search (1980 to August 2000) of English-language literature was conducted using the search term argatroban to identify pertinent case reports, clinical trials, abstracts, and review articles. Additional reports were identified from the reference lists compiled in the literature reviewed, as well as from the manufacturer. DATA SYNTHESIS: Argatroban is a synthetic direct thrombin inhibitor indicated for parenteral use in the prevention and treatment of thromboembolism in patients with HIT. Its elimination half-life is approximately 40-50 minutes, and it is primarily eliminated by hepatic metabolism and biliary secretion. Compared with historical controls, argatroban-treated patients with HIT or HIT with thrombosis (HITTS) experienced lower rates of the composite end point of death, amputation, and new thrombosis. Dosing is initiated at 2 microg/kg/min and adjusted to maintain the activated partial thromboplastin time at 1.5-3 times the patient's baseline. In Japan, argatroban is approved for use in acute ischemic stroke and chronic peripheral occlusive disease. It has also been used as an alternative to unfractionated heparin (UFH) in patients with a history of HIT or HITTS undergoing percutaneous coronary intervention and other procedures. Additionally, argatroban has been compared with UFH in patients with acute myocardial infarction who were receiving thrombolytic therapy. Hemorrhage is the primary adverse event associated with argatroban. Argatroban increases the prothrombin time, making assessment of the intensity of warfarin therapy during concurrent administration more complex. CONCLUSIONS: The use of argatroban in patients with HIT and HITTS is associated with improvement in clinical outcomes compared with historical controls. Argatroban offers several practical advantages over other available agents with respect to dosing, monitoring, reversibility of effect with discontinuation of the drug, and cost.

Clinical use of new antithrombotic therapies for medical management of acute coronary syndromes.

Prevention and management of acute coronary syndromes (ACS) are focal points of interest among health care providers. Acute coronary syndromes is an all-encompassing term that refers to unstable angina, non-Q wave myocardial infarction, and Q wave myocardial infarction. These syndromes are usually the result of atherosclerotic plaque rupture leading to thrombus formation in a coronary artery. Heparin and aspirin are traditional antithrombotic treatments. They typically are administered with antiischemic therapies and often with fibrinolytic agents for patients with ST segment elevation associated with acute myocardial infarction. Although aspirin and heparin are important, they have significant limitations that have prompted development of newer antithrombotic approaches. Adenosine diphosphate inhibitors have been evaluated as either alternatives or adjunctive treatment to aspirin. Glycoprotein IIb-IIIa receptor inhibitors, low-molecular-weight heparins, and direct thrombin inhibitors have been studied as concurrent therapy with, or as alternatives to, heparin.

A randomized, crossover comparison of warfarin products in the treatment of chronic atrial fibrillation.

OBJECTIVE: To compare the dosing requirements and international normalized ratios (INRs) associated with two bioequivalent crystalline warfarin sodium products in patients with chronic atrial fibrillation. METHODS: A multicenter, single-blind (prescriber), randomized, crossover evaluation of Apothecon warfarin and DuPont warfarin (Coumadin) was conducted in consenting adults with chronic or paroxysmal atrial fibrillation who had been receiving DuPont warfarin chronically for the prevention of thromboembolism. Patients were randomly assigned to initially either continue DuPont warfarin or receive Apothecon warfarin for four weeks, with weekly evaluation of dosage and INR changes, safety, and efficacy. Subsequently, patients crossed over and received the other product for four weeks. RESULTS: There were 113 patients randomized to receive study treatment. Neither the propensity for a dosage change or an INR change nor the magnitude of a dosage change or INR change appeared related to a particular warfarin product (NS for each variable after each study period). After four weeks of treatment, the same number of patients (n = 7) experienced a > or = 20% change in warfarin dosage from the respective baseline with each product. The number of patients with INRs outside the desired protocol range after four weeks of treatment was similar for both groups (< 1.8, n = 9 for both products, or > 3.2, n = 9 for DuPont, n = 10 for Apothecon). No major hemorrhagic or thromboemoblic events occurred. CONCLUSIONS: The results of this study show that Apothecon warfarin and DuPont warfarin provide equivalent anticoagulation in patients with chronic or paroxysmal atrial fibrillation.

Lepirudin dosing in dialysis-dependent renal failure.

Lepirudin is a direct thrombin inhibitor indicated for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. In patients with normal renal function, a bolus dose of 0.4 mg/kg is injected over 15-20 seconds, followed by a continuous infusion of 0.15 mg/kg/hour adjusted to prolong the activated partial thromboplastin time (aPTT) to 1.5-2.5 times the patient's baseline. Because renal function directly influences lepirudin elimination, patients with renal impairment require significant adjustments in the initial infusion rate. Current recommendations suggest that patients with dialysis-dependent renal failure should receive an initial bolus of 0.2 mg/kg, followed by 0.1 mg/kg every other day if the aPTT falls below the lower limit of the therapeutic range; however, this dosing may result in significant and prolonged overanticoagulation. A review of available literature regarding pharmacokinetics of lepirudin in renal failure suggests considerable variability in patient response over a narrow creatinine clearance range. Because there is no antidote for lepirudin if significant bleeding occurs, lower and less frequent dosing, guided by aPTT results, is recommended.

High-dose bolus lidocaine for chemical cardioversion of atrial fibrillation: a prospective, randomized, double-blind crossover trial.

BACKGROUND: Most drugs used for chemical cardioversion of atrial fibrillation have significant proarrhythmia risk and require close monitoring after administration. Lidocaine has few of the proarrhythmic concerns of most antiarrhythmic drugs and, at high bolus doses, prolongs the atrial refractory period well enough to be effective in converting atrial fibrillation to sinus rhythm. This finding has been previously demonstrated in a dog model. We sought to confirm the animal findings in human beings with lidocaine doses of 1.5 to 2.5 mg/kg. METHODS: Twenty patients with atrial fibrillation scheduled for elective cardioversion were enrolled in this study. In a randomized, double-blind, crossover study design, each patient received intravenous bolus lidocaine or saline. Patients were observed for 10 minutes after the initial bolus to assess efficacy. The second test drug was then delivered if the first was unsuccessful at cardioversion. RESULTS: All 20 patients received both lidocaine and saline placebo therapy in a crossover manner. None of the 20 patients converted to sinus rhythm with either therapy. The 95% confidence interval for effectiveness of lidocaine in this population was 0% to 14%. CONCLUSION: In this population of patients referred for elective cardioversion of atrial fibrillation, high-dose bolus lidocaine was ineffective in converting patients to sinus rhythm. Although this study was not sufficiently powered to rule out a low efficacy of lidocaine (<15%) or a higher efficacy in certain subgroups of atrial fibrillation, routine use of lidocaine for this indication is not warranted.

Influence of warfarin regimen type on clinical and monitoring outcomes in stable patients in an anticoagulation management services.

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.

National survey of training and credentialing methods in pharmacist-managed anticoagulation clinics.

A national survey of pharmacist-managed anticoagulation clinics was conducted to determine how pharmacists are trained to provide care in such clinics. In June 1996 a survey was mailed to 177 pharmacist-managed anticoagulation clinics in the United States. A total of 128 surveys were returned (response rate, 72%). One hundred ten surveys representing 42 states and a variety of institutions were usable. Twenty-five (23%) of the 110 clinics offered an anticoagulation training program for their pharmacists. Most training programs had both didactic and experiential components and had been in existence for one to five years. Thirty-two (29%) of the 110 responding clinics had at least one pharmacist who had completed the ASHP Research and Education Foundation's Anticoagulation Service Traineeship. Twenty-three of the 25 clinics with a training program required successful completion of the program before a pharmacist could practice in the clinic. The overall quality of pharmacists' performance was regularly assessed by 22 of the 25 clinics. Most pharmacist-managed anticoagulation clinics in the United States do not offer formal training in anticoagulation therapy to pharmacists who practice in that setting.

The stroke pharmacopeia: current medical therapies.

Drug therapies that inhibit or reverse thrombus formation are important components of the management of acute ischemic stroke. The role of antiplatelet and anticoagulant therapies in stroke prevention has been defined, but further research is needed to confirm the possible benefits of aspirin, heparin, and low-molecular-weight heparin products in acute ischemic stroke. Recently, double-blind, placebo-controlled studies have evaluated the role of the thrombolytic agents streptokinase and tissue plasminogen activator (t-PA) in patients with acute ischemic stroke. Intravenous t-PA, administered within 3 hours of symptom onset at a dose of 0.9 mg/kg, is safe and effective in carefully selected patients.

Lack of in vitro interaction between heparin and nitroglycerin.

Nitroglycerin has been reported to reduce activated partial thromboplastin time (aPTT) values in patients treated with concurrent heparin and nitroglycerin. However, in vivo studies have yielded conflicting results. In this in vitro evaluation, nitroglycerin was added to samples of pooled plasma from normal volunteers in concentrations of 0, 1, 10, 50, 100, 150, and 200 ng/mL. Preservative-free heparin was then added to the samples to produce final concentrations of 0, 0.3, and 0.6 U/mL. Activated partial thromboplastin time (aPTT) was determined for each sample using a single reagent. There were no significant differences in aPTT values among increasing nitroglycerin concentrations for any of the three levels of heparinization. No direct effect of nitroglycerin on the anticoagulant effect of heparin was observed, as measured by aPTT.

Contemporary use of and future roles for heparin in antithrombotic therapy.

Although heparin therapy is an established component of the prevention and treatment of thromboembolic disease, recent advances have resulted in improvements in the clinical use of this agent. Studies have shown that weight-based dosing influences significantly both the time to reach a therapeutic intensity of anticoagulation and the incidence of thromboembolic recurrence. It is now considered the standard of care. A growing understanding of the variability among activated partial thromboplastin time (aPTT) reagents and the influence of these differences on aPTT outcomes has led to the use of reagent-specific therapeutic ranges for heparin monitoring. Many practitioners now choose to adjust the therapeutic range to correspond to heparin serum concentrations of 0.2-0.4 U/mL rather than the more common practice of prolonging aPTT to 1.5-2.5 times the mean normal aPTT. Pharmaceutical companies have developed low molecular weight heparins to minimize adverse effects associated with unfractionated heparin. More specific thrombin inhibitors are also under investigation with the aim of improving clinical outcomes in coronary syndromes now treated with heparin. Low molecular weight heparins or specific thrombin inhibitors are unlikely to replace unfractionated heparin in the near future. Therefore, optimum dosing and appropriate monitoring of heparin are critically important in the management of thromboembolic disease.

Heparin monitoring in acute thrombosis associated with antiphospholipid antibody syndrome.

Antiphospholipid antibody syndrome is associated with recurrent thromboembolism and the presence of antibodies directed against negatively charged phospholipids. Despite significant hypercoagulability, patients with the disorder often have elevated baseline activated partial thromboplastin times. Although heparin is indicated for the treatment of acute thrombosis, heparin monitoring is complicated by laboratory test interference. A practical treatment approach involves patient-specific screening for a reagent insensitive to the presence of the inhibitor, and determination of a reagent-specific therapeutic range in seconds that corresponds to heparin serum concentrations of 0.2-0.4 U/ml. Other monitoring methods, including using the patient's baseline activated partial thromboplastin time or using an antifactor Xa activity assay, have not been reported or studied but may offer alternatives for heparin monitoring in patients with coagulation laboratory test interference associated with antiphospholipid antibody syndrome.

Influence of bile acid replacement on cyclosporine absorption in a patient with jejunoileal bypass.

Jejunoileal bypass reportedly inhibits the absorption of cyclosporine. In patients with malabsorption syndromes, bile acid replacement has been given to enhance the absorption of cyclosporine. A candidate for heart transplantation with New York Heart Association class IV heart failure and a jejunoileal bypass received cyclosporine alone and with concomitant ursodiol administration to determine whether therapeutic cyclosporine plasma concentrations would be attainable after heart transplantation. There were no differences in peak concentration, time to peak, area under the serum concentration versus time curve, or bioavailability of oral cyclosporine when administered alone or with ursodiol. Plasma cyclosporine concentrations were consistent with those in the general population.