Effect of thrombin inhibition on patients with peripheral arterial obstructive disease: A multicenter clinical trial of argatroban

Matsuo, Takefumi; Kario, Kazuomi; Matsuda, Sachi; Yamaguchi, Nobuo; Kakishita, Eizo

doi:10.1007/bf01064381

Cited by 26 publications

(17 citation statements)

References 13 publications

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“…These results are consistent with our previous findings in a multicenter clinical trial that used argatroban on PAOD patients. 11 Concerning the cerebral metabolism assessed by H-1 MRS, the NAA/Cre ratio of the deep white matter area was significantly lower in the advanced cerebrovascular disease group than in the no cerebrovascular disease group. NAA is located almost entirely in neurons and axons, and it is reduced in several cerebral diseases.…”

Section: Discussionmentioning

confidence: 99%

Effect of Thrombin Inhibition in Vascular Dementia and Silent Cerebrovascular Disease

Kario

Matsuo

Hoshide

et al. 1999

Stroke

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Background and Purpose-Silent cerebrovascular disease (CVD) has been proposed as a predisposing condition for clinically overt stroke and vascular dementia. Recently, we found increased thrombin generation in silent CVD patients. Here, we report the effect of thrombin inhibition using a potent selective thrombin inhibitor on the cerebral metabolism and function in peripheral arterial occlusive disease (PAOD) patients with or without silent CVD. Methods-We examined 17 mild chronic PAOD patients, including 2 cases of vascular dementia. We divided the patients into 2 groups: 1 was the advanced CVD group with multiple lacunar infarction and/or advanced periventricular hyperintensity detected by brain MRI (nϭ12), and the other was the no CVD group that had none of these abnormalities (nϭ5). We assessed the cerebral biochemical compounds in the deep white matter area and cerebellar hemisphere (8 cm 3 ) by proton MR spectroscopy before and after infusion of argatroban (10 mg/d IV) over 2 hours for 7 days. Results-The ratio of N-acetylasparate (NAA) to total creatine (Cre) in the deep white matter area was significantly lower in the advanced CVD group than in the no CVD group, whereas there were no significant differences in this ratio in the cerebellar hemisphere between the 2 groups. In the former group, this decreased NAA/Cre ratio significantly increased after argatroban therapy, whereas there was no change in the latter group. The 2 patients with vascular dementia showed clinical improvement with marked increases in the NAA/Cre ratio and mini-mental score. Conclusions-These results suggest that increased thrombin generation may have some pathophysiological roles in developing vascular dementia and its chronic predisposing conditions. Thrombin inhibition may break this vicious cycle and lead to clinical improvement.

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Section: Discussionmentioning

confidence: 99%

Effect of Thrombin Inhibition in Vascular Dementia and Silent Cerebrovascular Disease

Kario

Matsuo

Hoshide

et al. 1999

Stroke

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“…In the mild stroke subgroup [NIHSS 0-10], both argatroban and heparin tended to be associated with favorable outcomes, but neither achieved significance at the conventional 0.05 level with the singular exception of hemorrhage recurrence. In the moderate stroke subgroup [NIHSS [11][12][13][14][15][16][17][18][19][20][21][22], the individual estimates of treatment effects for both argatroban and heparin indicate dramatic improvement over the no treatment standard relative to the mRS and NIHSS outcome measures, but only heparin achieves significance at alpha level 0.05 for mortality and change in NIHSS score (admission -discharge). In the severe stroke subgroup [NIHSS 23-42], it is perhaps unrealistic to expect a ''favorable'' outcome of mRS 0-2; note, however, that both heparin and argatroban [more so than heparin] have a significantly reduced mortality risk.…”

Section: Resultsmentioning

confidence: 99%

“…Unlike heparin, the direct thrombin inhibitor argatroban effectively inhibits thrombin that is either free or bound to fibrin or clots [1] including clots that are aged or treated with thrombolysis [4]. Argatroban is available for use in the prophylaxis or treatment of thrombosis in heparin induced thrombocytopenia [12], acute atherothrombotic ischemic stroke [8], and chronic arterial occlusion [13]. However, in cardioembolic stroke, argatroban is considered as contraindiced because of the side effect of hemorrhagic formation in Japan, though there is no clear clinical evidence to show that argatroban increases hemorrhage compared with heparin.…”

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confidence: 99%

Efficacy of anti-coagulant treatment with argatroban on cardioembolic stroke

et al. 2007

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Argatroban, which is a thrombin inhibitor, has an indication as a treatment in the acute phase on atherosclerotic ischemic stroke in Japan. Howeve, in cardioembolic stroke, argatroban is considered to be contraindicated with the side effect of hemorrhage, though there is no clear clinical evidence to show that argatroban increases hemorrhagic compared with heparin. The efficacy of anticoagulant treatment with argatroban on cardioembolic stroke was evaluated retrospectively in this study. We identified 3,113 patients from the Japan Standard Stroke Registry Study who had had a cardioembolic ischemic stroke. We excluded patients with the anti-platelet treatment or the combination therapy of anticoagulation. Our analyses are therefore based on a cohort of 2,529 patients who were treated either with heparin, and argatroban, or with no anti-coagulation treatment. With multivariable regression, hemorrhagic it was shown that hemorrhage was significantly reduced in heparin and argatroban treatments in the patients with mild severity. There was no significant difference in the recurrence of ischemic stroke between the treatments. Both argatroban and heparin showed dramatic improvement compared with the no treatment standard, but only heparin achieved statistical significance for mortality and change in NIHSS score (admission to discharge) in the moderate stroke subgroup [NIHSS 11-22]. Both heparin and argatroban [more so than heparin alone] have a significantly reduced mortality risk. From the present study, it is suggested that argatroban may be useful on cardioembolic stroke, increasing the improvement of recovery of stroke severity without increasing the risk of hemorrhage. Further prospective studies are awaited for evaluating better the efficacy of argatroban on cardioembolic stroke.

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“…51,52 In Japan only, argatroban is also licensed for treatment of ischemic complications in patients with chronic peripheral arterial occlusions and for treatment of patients with ischemic stroke. 53,54 Argatroban has also been evaluated in several small, randomized, controlled trials in patients with acute coronary syndromes, but results were inconclusive. [55][56][57] …”

Section: Clinical Trials With Argatrobanmentioning

confidence: 99%

Translational Success Stories

Coppens

Eikelboom

Gustafsson

et al. 2012

Circulation Research

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ReviewTranslational Success Stories highlight how basic discoveries have led to clinical advances (such as the use of new drugs or diagnostic modalities in patients). This initiative reflects the renewed emphasis of our journal on translational research. It is hoped that these articles will stimulate efforts to translate basic insights into clinical practice. Translational Success Stories Development of Direct Thrombin InhibitorsMichiel Coppens, John W. Eikelboom, David Gustafsson, Jeffrey I. Weitz, Jack Hirsh Abstract: Anticoagulants are the cornerstone of therapy for conditions associated with arterial and venous thrombosis.Direct thrombin inhibitors (DTIs) are anticoagulants that bind to thrombin and block its enzymatic activity. The bivalent parenteral DTIs hirudin and bivalirudin were based on the observation that the salivary extracts of medicinal leeches prevented blood from clotting. Key events that facilitated the subsequent development of small molecule active site inhibitors, such as argatroban, were the observation that fibrinopeptide A had antithrombotic properties and determination of the crystal structure of thrombin. Hirudin and argatroban have found their niche for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is approved as an alternative to heparin for patients undergoing percutaneous coronary intervention. The development of orally active direct thrombin inhibitors was challenging because of the need to convert water-soluble, poorly absorbable, active site inhibitors into fat-soluble prodrugs that were then transformed back to the active drug after intestinal absorption. Dabigatran etexilate was the first new oral anticoagulant to be approved for long-term anticoagulant treatment in 6 decades. This Review highlights the development of DTIs as a translational success story; an example in which the combination of scientific ingenuity, structure-based design, and rigorous clinical trials has created a new class of anticoagulants that has improved patient care. (Circ Res. 2012;111:920-929.) Key Words: thrombin Ⅲ anticoagulant Ⅲ drug development D irect thrombin inhibitors (DTIs) are anticoagulants that bind directly to thrombin and block its activity. Prior to their development, the injectable anticoagulants in clinical use were heparin and low-molecular-weight heparins (LMWHs). Both are classified as indirect inhibitors because they have no intrinsic activity; instead, they produce their anticoagulant effect by activating antithrombin. The only class of oral anticoagulants that was available at that time was the vitamin K antagonists (VKAs), such as warfarin.Several key events led to the development of DTIs. The first was the observation in 1884 that salivary secretions of the medicinal leech, Hirudo medicinalis, prevented blood from clotting. 1 This finding subsequently led to the development of hirudin, which was initially extracted from leeches and later obtained via rDNA technology. [2][3][4][5] The second observation, made in 1956 by Bettelheim, was th...

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Effect of thrombin inhibition on patients with peripheral arterial obstructive disease: A multicenter clinical trial of argatroban

Cited by 26 publications

References 13 publications

Effect of Thrombin Inhibition in Vascular Dementia and Silent Cerebrovascular Disease

Effect of Thrombin Inhibition in Vascular Dementia and Silent Cerebrovascular Disease

Efficacy of anti-coagulant treatment with argatroban on cardioembolic stroke

Translational Success Stories

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