Hepatic Findings in Long-Term Clinical Trials of Ximelagatran

Lee, William M.; Larrey, Dominique; Olsson, Rolf; Lewis, James H.; Keisu, Marianne; Auclert, Laurent; Sheth, Sunita

doi:10.2165/00002018-200528040-00006

Cited by 184 publications

(125 citation statements)

References 44 publications

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“…However, the drug was withdrawn from further development early in 2006 based on unexpected adverse liver events and the drug's hepatic profile. 8 Despite this, as the first of its kind to be studied in large and long-term clinical trials, data regarding its efficacy and safety are still valid and relevant to further development of drugs in this class and to an understanding of the potential mechanisms of the hepatotoxicity. This study has shown that the elderly, in particular elderly women, appear to be more susceptible to developing elevated transaminase values, consistent with other studies on adverse drug effects that have demonstrated older women to be most susceptible.…”

Section: Discussionmentioning

confidence: 99%

“…Ximelagatran, the first oral DTI investigated in large phase III studies, the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III 6 and SPORTIF V trials, 7 was found to be as effective as warfarin in preventing stroke in AF. However, owing to concerns regarding the risk of severe hepatotoxicity, 8 ximelagatran was withdrawn from further development in 2006. Nonetheless, other drugs in this class are in development, and data regarding the efficacy and safety of the only oral DTI studied in large clinical trials remain relevant to the development of other oral DTIs and understanding their potential for toxicity.…”

mentioning

confidence: 99%

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Direct Thrombin Inhibition and Stroke Prevention in Elderly Patients With Atrial Fibrillation

Ford

Choy

Deedwania

et al. 2007

Stroke

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on behalf of the SPORTIF III, V Investigators Background and Purpose-Warfarin prevents stroke in atrial fibrillation (AF); however, concerns regarding international normalized ratio control and hemorrhage limit its use in the elderly. The oral direct thrombin inhibitors (DTIs) are potential alternatives to warfarin, offering fixed dosing without drug and dietary interactions and the need for international normalized ratio monitoring. Although ximelagatran, a DTI studied in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation trials, has been withdrawn, development of other DTIs continues. We report our experience in elderly high-risk AF patients on ximelagatran compared with warfarin therapy. Methods-Data from patients with AF and stroke risk factors randomized in Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation III and V trials to ximelagatran or warfarin were analyzed for stroke/systemic emboli, bleeding, and raised alanine aminotransferase levels in those Ն75 (nϭ2804) and Ͻ75 (nϭ4525) years. Results-Ximelagatran was as effective as warfarin in reducing stroke/systemic emboli in the elderly (2.23%/y with ximelagatran vs 2.27%/y with warfarin) as in younger patients (1.25%/y vs 1.28%/y). Total bleeds were significantly lower with ximelagatran compared with warfarin in elderly (40% vs 45%, Pϭ0.01) and younger (27% vs 35%, PϽ0.001) patients. Raised alanine aminotransferase values (Ͼ3-fold elevation) among ximelagatran patients were more common in older (7.5% old vs 5.3% young) patients, particularly women (9.5% elderly women vs 6.1% elderly men). Conclusions-In high-risk elderly AF patients, ximelagatran is as effective as warfarin with less bleeding, but alanine aminotransferase elevations are common, particularly in elderly women. Oral DTIs for stroke prevention show promise in elderly patients.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Direct Thrombin Inhibition and Stroke Prevention in Elderly Patients With Atrial Fibrillation

Ford

Choy

Deedwania

et al. 2007

Stroke

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“…Ximelagatran was the first oral direct thrombin inhibitor and had confirmed efficacy for prevention and treatment of VTE, stroke prevention and recurrent coronary events after acute myocardial infarction. But it was withdrawn by AstraZeneca in the year 2006 because of liver toxicity [6,7] . However, the new drugs available are still far away from fulfilling the desired objectives because, currently available anticoagulant therapy faces some limitations including inability to inhibit the clot-bound thrombin, variable patient responses, heparin-induced thrombocytopenia (HIT) and the enhanced chance of bleeding [8] .…”

Section: Research Papermentioning

confidence: 99%

3D QSAR and Pharmacophore Modelling of Selected Benzimidazole Derivatives as Factor IXa Inhibitors

Kumbhar¹,

Choudhari²,

Bhatia³

2017

pharmaceutical-sciences

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“…But it was withdrawn by AstraZeneca in the year 2006 because of liver toxicity. 13,14 Currently available anticoagulant therapy suffer from some limitations including inability to act on the clot bound thrombin, variable patient responses, heparininduced thrombocytopenia (HIT) and the enhanced chance of bleeding. 15,16 …”

Section: Anticoagulantsmentioning

confidence: 99%

Factor VIIa and Factor IXa Inhibitors as Anticoagulants: A Review

Sahadeo¹,

Balkrishna²,

Suresh³

et al. 2017

IJPER

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Introduction: Anticoagulants are used as preventive agents in deep vein thrombosis to prevent blood clots, venous and arterial thromboembolism, but the current therapy of anticoagulants have several limitations like patient variable response, enhanced chances of bleeding and heparin-induced thrombocytopenia (HIT). Factor VIIa and factor IXa play an important role in coagulation cascade and hence are promising targets for drug development. FIXa has been targeted by various means including oral inhibitors (TTP889), monoclonal antibodies (SB249417) and RNA aptamers which have passed various phases of clinical trials. Objectives: Though advances in development of inhibitors of FVIIa/TF and FIXa have reached various phases of clinical trials none of the clinical trial candidates have reached the market. Methodology: This review summarizes available information on FVIIa/TF and FIXa, their active site, crystallographic structure, available inhibitors, earlyphase clinical trial study and also the recent efforts in the discovery of FVIIa/TF and FIXa inhibitors. Summary: Despite the fact that more complexity is observed in designing of anticoagulant as FVIIa/TF complex and FIXa inhibitors, these will remain an important and validated target for the design and development of anticoagulants.

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Hepatic Findings in Long-Term Clinical Trials of Ximelagatran

Cited by 184 publications

References 44 publications

Direct Thrombin Inhibition and Stroke Prevention in Elderly Patients With Atrial Fibrillation

Direct Thrombin Inhibition and Stroke Prevention in Elderly Patients With Atrial Fibrillation

3D QSAR and Pharmacophore Modelling of Selected Benzimidazole Derivatives as Factor IXa Inhibitors

Factor VIIa and Factor IXa Inhibitors as Anticoagulants: A Review

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