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Commencing Volume 19, Issue 1, MedReviews has ceased the publication of this journal. Reviews in Cardiovascular Medicine will continue to be published by IMRPress, Ltd. (www.imrpress.org)

Volume 5, Supplement 5, 2004

Volume 5, Supplement 5, 2004

Table of Contents

Ximelagatran: Pharmacokinetics and Pharmacodynamics of a New Strategy for Oral Direct Thrombin Inhibition
<p>Because thrombin is central to the development and propagation of both arterial and venous thrombi, it is a logical therapeutic target. Direct thrombin inhibitors, such as ximelagatran, offer the distinct advantage of inhibiting fibrin-bound as well as free thrombin. The pharmacokinetics and pharmacodynamics of ximelagatran are predictable across a broad spectrum of patients. The half-life of melagatran, ximelagatran’s active metabolite, is consistent with twice-daily dosing and fixed-dose administration without the need for monitoring. There have been no known drug interactions with ximelagatran, and the agent is not metabolized by the hepatic cytochrome P-450 system. For these reasons, orally active direct thrombin inhibitors such as ximelagatran will likely become the standard for long-term anticoagulation. [Rev Cardiovasc Med. 2004;5(suppl 5):S4-S11]</p>
The Potential for Changing Prescribing Patterns from Warfarin to Oral Direct Thrombin Inhibitors: Clinical Scenarios
Food and Drug Administration (FDA) for approval as an anticoagulant to manage thromboembolic disorders and prevent systemic embolism in patients with atrial fibrillation. If ximelagatran is approved, clinicians will have to decide which patients are candidates for this therapy, how to switch patients from warfarin to ximelagatran, and, if necessary, how to switch patients from ximelagatran to warfarin. In addition, clinicians will need to consider their approach to treating patients with new-onset atrial fibrillation as well as conditions that may require an adjustment in dosing. This article highlights some of these issues as well as current data that provide guidance on how to manage them; however, answers to other questions will not be available until after the FDA approves the package insert material and data from the SPORTIF trial become available. Therefore, clinicians should diligently follow the medical literature regarding the latest information on this agent. [Rev Cardiovasc Med. 2004;5(suppl 5):S12-S21]
Changing the Guard in Long-Term Anticoagulation: Clinical and Economic Implications
The topic of anticoagulant prescription in patients with nonvalvular atrial fibrillation, for the primary and secondary prevention of stroke, provides a forum for discussion of current challenges in anticoagulation management and ways in which the introduction of ximelagatran will provide an opportunity to overcome many of them. Anticoagulation with warfarin has been shown to reduce stroke rates by 68%, providing significant net monetary savings. However, physician fear of hemorrhagic side effects, the need for regular INR monitoring, food and drug interactions, and patient noncompliance have all played a part in either suboptimal utilization or complete avoidance of anticoagulant therapy, even in patients at high risk for stroke. Ximelagatran, a new oral direct thrombin inhibitor, circumvents most of these problems and provides a more physician- and patient-friendly method of stroke prophylaxis. With the utilization of this new anticoagulation method, the incidence of stroke in high risk groups, and the corresponding quality-of-life and economic impact, can potentially be greatly reduced. [Rev Cardiovasc Med. 2004;5(suppl 5):S22-S29]
New Possibilities in Anticoagulant Management of Atrial Fibrillation
Warfarin therapy achieving an International Normalized Ratio between 2 and 3 has been shown to be effective in preventing stroke. However, warfarin administration is problematic because of its variable dose, interaction with numerous foods and drugs, narrow therapeutic range, need for chronic anticoagulation monitoring, and long onset and offset of action, which all contribute to the significant underuse of warfarin in patients with atrial fibrillation at risk for stroke despite clear indication for its use. This has led to new approaches. Studies with idraparinux (AMADEUS), a factor 10a inhibitor, and with aspirin and clopidogrel (ACTIVE), both platelet inhibitors, are on-going. Studies with ximelagatran (Stroke Prevention by Oral Thrombin Inhibition in Atrial Fibrillation [SPORTIF] trials III and V), an oral direct thrombin inhibitor, have been completed. They compared ximelagatran with warfarin in patients with nonvalvular atrial fibrillation at risk for stroke. The studies demonstrated that ximelagatran is not inferior to warfarin. Moreover, ximelagatran has rapid onset and offset of action, fixed oral dosing without the need for anticoagulation monitoring, low potential for food and drug interactions, and a therapeutic margin wider than that of warfarin. We anticipate further studies to demonstrate definitively that the small percentage of patients (0.5%) with elevation of both alanine aminotransferase (ALT) and bilirubin levels can be managed safely, thereby making ximelagatran a promising option for preventing thromboembolism in patients with atrial fibrillation at risk for stroke. [Rev Cardiovasc Med. 2004;5(suppl 5):S30-S38]
Reducing Cardiac Events After Acute Coronary Syndromes
Coronary heart disease is the number one cause of death in the world and acute coronary syndromes (ACS) continue to be associated with high rates of morbidity. ACS refers to the spectrum of acute myocardial ischemia, including unstable angina, ST segment elevation myocardial infarction (STEMI), and acute MI without ST segment elevation (NSTEMI). Current guidelines indicate both aspirin and glycoprotein IIb/IIIa receptor antagonists (if catheterization/revascularization are planned) as class IA recommendations in ACS. Anticoagulant therapy, in the form of heparin, is a class IA recommendation for the acute hospital phase of ACS. The risk of recurrent thrombotic events following ACS remains high in the post-hospital phase, creating a rationale for the use of oral direct thrombin inhibitors such as ximelagatran, in both the acute and long-term settings. The Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent and Myocardial Damage (ESTEEM) trial, a placebo-controlled, double-blind study of post-MI patients, evaluated 4 dosing regimens of ximelagatran versus placebo in the initial months following an ACS and found an encouraging reduction in the end points of death, MI, and stroke with the use of an oral direct thrombin inhibitor. [Rev Cardiovasc Med. 2004;5(suppl 5):S39-S46]