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Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Ximelagatran (Figure 7.9) is the oral, double prodrug of melagatran. It was the first oral direct thrombin inhibitor developed. The approval of ximelagatran in Europe was given for prevention of venous thromboembolism in major elective orthopedic surgeries. However, ximelagatran was removed from the European market approximately 20 months later because therapy greater than 35 days was associated with a risk of hepatotoxicity [70–71].
Orthopaedic Pharmacology
Published in Manoj Ramachandran, Tom Nunn, Basic Orthopaedic Sciences, 2018
Manoj Ramachandran, Daud Chou, Natasha Rahman
Direct thrombin inhibitors (DTIs) act as anticoagulants by competitively and directly inhibiting the enzyme thrombin (Figure 4.2). They are taken orally, require no therapeutic drug monitoring and have no reported significant drug interactions. A phase III study, comparing dabigatran with enoxaparin, confirmed their equal efficacy in preventing thrombosis, with a similar risk profile. Dabigatran has been authorised for use as thromboprophylaxis following hip and knee arthroplasty. Ximelagatran was discontinued in 2006 due to fears of increased hepatotoxicity and myocardial infarctions.
Azithromycin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Azithromycin increased the exposure of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, although the activated partial thromboplastin time (APTT) was not significantly altered (Dorani et al., 2007).
Investigational drugs for the treatment of acute myocardial infarction: focus on antiplatelet and anticoagulant agents
Published in Expert Opinion on Investigational Drugs, 2019
Srikanth Yandrapalli, Gabriela Andries, Shashvat Gupta, Abdel Rahman Dajani, Wilbert S. Aronow
Ximelagatran is an oral direct thrombin inhibitor and the first novel oral anticoagulant that has been studied for prevention of thromboembolic events post ACS [66]. In the ESTEEM (Efficacy and Safety of The Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent Myocardial Damage) trial, patients with ACS (within 14 days of initial event) were randomized to receive one of four doses of oral ximelagatran (24 mg BID, 36 mg BID, 48 mg BID, or 60 mg BID) versus placebo [67]. Primary outcome was the occurrence of the composite clinical endpoint of all-cause death, non-fatal AMI, and severe recurrent ischemia. The investigators found that the combination of ximelagatran and aspirin significantly reduced the primary endpoint compared with aspirin alone. However, the frequency of major and minor bleeding events and elevation of liver enzymes were higher in the ximelagatran group. The design of this trial did not reflect current recommended practice: patients receiving other antiplatelet agents (aside from aspirin), having had PCI in the past 4 months, or planned to have PCI within 60 days were excluded. Fifty percent of patients in the trial were treated with fibrinolytic therapy [67]. Currently, ximelagatran has been removed from market primarily because of safety reasons related to the drug’s adverse effects on liver function [68].
Successes, failures, and future prospects of prodrugs and their clinical impact
Published in Expert Opinion on Drug Discovery, 2019
Ximelagatran (24 in Figure 3), a direct thrombin inhibitor and prodrug of melagatran, was expected to be successful before the discovery and marketing of dabigatran. During phase III clinical trials, hepatotoxicity was reported leading to the withdrawal of the drug. According to retrospective study by Southworth, it was possible to recognise the hepatotoxic potential of the drug before phase III, thus saving time and cost [74].
Dual pathway inhibition in patients with atherosclerotic disease: pharmacodynamic considerations and clinical implications
Published in Expert Review of Clinical Pharmacology, 2023
Mattia Galli, Francesco Franchi, Fabiana Rollini, Luis Ortega-Paz, Domenico D’Amario, Raffaele De Caterina, Roxana Mehran, C Michael Gibson, Dominick J. Angiolillo
Randomized controlled trials (RCTs) testing a DPI strategy versus standard antiplatelet therapy in patients with CVD using different dosing regimens of NOACs in association with SAPT or DAPT have shown mixed results. Table 1 provides a summary of RCTs comparing a DPI with NOAC versus antiplatelet therapy in patients with CVD. The first study testing a DPI strategy was ESTEEM, randomizing 1883 ACS patients to ximelagatran at doses of 24, 36, 48, or 60 mg bid, or placebo, respectively, for 6 months [35]. All patients received aspirin 160 mg once daily. The primary efficacy outcome including all-cause death, non-fatal myocardial infarction (MI), and severe recurrent ischemia was reduced with ximelagatran compared with placebo and major bleeding events were overall rare [35]. There was no indication of a dose-response between the ximelagatran groups in either bleeding or ischemic outcomes. Ximelagatran was, however, discontinued due to hepatic toxicity. RUBY-1 compared six darexaban regimens [5 mg bid, 10 mg once daily (od) 15 mg bid, 30 mg od, 30 mg bid or 60 mg od] or placebo, on top of DAPT among 1279 patients with recent high-risk NSTEMI [36]. There was a dose-related two- to four-fold increase in the primary outcome of major or clinically relevant non-major bleeding (CRNMB). The main efficacy outcome was a composite of death, stroke, MI, systemic thromboembolism, and severe recurrent ischemia did not differ between groups, but the study was underpowered for efficacy. Further testing with darexaban was halted. REDEEM used dabigatran 50, 75, 110, or 150 mg bid plus DAPT versus placebo plus DAPT in 1861 ACS patients and found a dose-dependent increase in major or clinically relevant minor bleeding without any difference in ischemic events (MI or stroke), although the study was underpowered for efficacy [37]. ATLAS ACS-TIMI 46 used rivaroxaban 5, 10, 15, or 20 mg od or bid plus SAPT or DAPT versus placebo plus SAPT or DAPT in 3491 ACS patients [38]. There was a dose-dependent increase in bleeding events, with the primary safety outcome being clinically significant bleeding. The primary efficacy endpoint of death, MI, stroke, or severe recurrent ischemia requiring revascularization did not differ among groups, but rivaroxaban reduced the main secondary efficacy endpoint of death, MI, or stroke compared with placebo [38]. Rivaroxaban 2.5 mg bid on top of SAPT or DAPT was associated with a favorable safety and efficacy profile. Finally, APPRAISE-1 tested apixaban (2.5 mg bid, 10 mg od, 10 mg od, or 20 mg od) on top of SAPT or DAPT in 1715 ACS patients and APPRAISE-J tested apixaban 2.5 mg bid or 5 mg bid versus placebo among 151 Japanese ACS patients [39,40]. While APPRAISE-J was terminated before completion after enrolling only 151 patients based on the results of the APPRAISE-2 trial (see below), APPRAISE-1 found a dose-related increase in the primary safety endpoint of major/clinically relevant non-major (CRNM) bleeding with a trend toward a reduction in ischemic events (CV death, MI, severe recurrent ischemia, or ischemic stroke) with the addition of apixaban. Apixaban 2.5 mg twice daily and 10 mg once daily resulted in lower rates of ischemic events compared with placebo.