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Background after hospitalisation for cardiac disease, older patients are at high risk of readmission and death. Objective the cardiac care bridge (CCB) transitional care programme evaluated the impact of combining case management, disease management and home-based cardiac rehabilitation (CR) on hospital readmission and mortality. Design single-blind, randomised clinical trial. Setting the trial was conducted in six hospitals in the Netherlands between June 2017 and March 2020. Community-based nurses and physical therapists continued care post-discharge. Subjects cardiac patients ≥ 70 years were eligible if they were at high risk of functional loss or if they had had an unplanned hospital admission in the previous 6 months. Methods the intervention group received a comprehensive geriatric assessment-based integrated care plan, a face-to-face handover with the community nurse before discharge and follow-up home visits. The community nurse collaborated with a pharmacist and participants received home-based CR from a physical therapist. The primary composite outcome was first all-cause unplanned readmission or mortality at 6 months. Results in total, 306 participants were included. Mean age was 82.4 (standard deviation 6.3), 58% had heart failure and 92% were acutely hospitalised. 67% of the intervention key-elements were delivered. The composite outcome incidence was 54.2% (83/153) in the intervention group and 47.7% (73/153) in the control group (risk differences 6.5% [95% confidence intervals, CI −4.7 to 18%], risk ratios 1.14 [95% CI 0.91–1.42], P = 0.253). The study was discontinued prematurely due to implementation activities in usual care. Conclusion in high-risk older cardiac patients, the CCB programme did not reduce hospital readmission or mortality within 6 months. Trial registration Netherlands Trial Register 6,316, https://www.trialregister.nl/trial/6169

OBJECTIVES We sought to quantify the impact of adding an intravenous loading dose to a subcutaneous regimen of enoxaparin in patients with an acute coronary syndrome (ACS). BACKGROUND It is unclear whether an intravenous (M loading dose of enoxaparin should be added to a subcutaneous (SQ) regimen in patients with ACS. METHODS Patients admitted with ACS were randomized to IV + SQ(n = 14) or SQ alone (n = 11) enoxaparin treatment. Coagulation markers were measured at nine time points during the first 24 h of treatment. RESULTS The TV + SQ therapy immediately resulted in therapeutic anti-Xa levels, which remained significantly higher for 6 h compared with SQ alone, without reaching excessively high levels. A rapid decrease of plasma prothrombin fragments 1 + 2 (F1 + 2) levels was observed as soon as 5 min after the IV injection (33% lower; p = 0.007), and these levels remained lower up to 2 h after the start of treatment compared with SQ alone. The ex vivo thrombin generation time was maximally prolonged at 5 min post-injection in the IV + SQ group and remained significantly prolonged up to 6 h post-injection compared with SQ alone. The tissue factor pathway inhibitor plasma activity was immediately increased by 194% with IV + SQ, whereas the maximum increase with SQ alone was 47% at 3 h. CONCLUSIONS Therapeutic plasma levels of enoxaparin are achieved significantly earlier by an IV + SQ regimen compared with SQ alone, without leading to unacceptably high levels. As the risk of thrombotic complications is greatest early after admission, the observed differences in antithrombotic effects may translate into a clinical benefit. However, this remains to be established. (C) 2003 by the American College of Cardiology Foundation

OBJECTIVES We investigated the safety and pharmacodynamics of escalating doses of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients undergoing elective coronary angioplasty. BACKGROUND Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex, which has the potential to reduce the risk of thrombotic complications in coronary artery disease. METHODS In a randomized, double-blinded, dose-escalation, multicenter trial, 154 patients received placebo or rNAPc2 at doses of 3.5, 5.0, 7.5, and 10.0 mug/kg body weight as a single subcutaneous administration 2 to 6 h before angioplasty. All patients received aspirin, unfractionated heparin during angioplasty, and clopidogrel in case of stent implantation. RESULTS Minor bleeding rates for the doses 3.5 to 7.5 mug/kg were comparable to that with placebo (6.7%), whereas an incidence of 26.9% was observed at the 10.0-mug/kg dose level (p

Background— The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether recombinant factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux. Methods and Results— In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 μg/kg; n=8), fondaparinux and placebo (n=4), or placebo and rFVIIa (n=4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the prolonged activated partial thromboplastin and prothrombin times and reversed the decrease in prothrombin activation fragments 1+2 (F 1+2 ), as observed with fondaparinux alone. Thrombin-generation time and endogenous thrombin potential, which were inhibited by fondaparinux, normalized up to 6 hours after rFVIIa injection. Conclusions— rFVIIa is capable of normalizing coagulation times and thrombin generation during fondaparinux treatment. The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.

Objectives: This study compared rebound coagulation in patients with acute coronary syndrome patients after discontinuation of unfractionated heparin (UFH) or low-molecular-weight heparin (...

Plaque disruption with superimposed thrombosis is the main cause of acute coronary events such as acute myocardial infarction and unstable angina. Among other factors, tissue factor seems to play an important role determining plaque thrombogenicity. Tissue factor is a potent initiator of the coagulation cascade situated within the vessel wall and is highly exposed to the blood after plaque rupture. Several mediators involved in the process of atherosclerotic plaque formation are capable of inducing tissue factor expression in cells such as monocytes, macrophages and endothelial cells, which under normal conditions do not express tissue factor or to a limited extent only. The increased expression of tissue factor is not limited to the plaque but is also found in circulating monocytes in patients with acute coronary syndromes. In addition, studies have shown an important contribution of tissue factor in the pathogenesis of thrombosis and restenosis after balloon angioplasty, Recent basic studies focus on the therapeutic inhibition of tissue factor. Specific and non-specific inhibitors of tissue factor or the tissue factor/factor VIIa complex have been developed or identified, and have been tested in experimental studies. Clinical studies are currently being initiated. In this review, we present the current knowledge on the role of tissue factor in atherosclerosis, arterial intervention and potential pharmacological approaches, with focus on acute coronary syndromes. (C) 2002 Elsevier Science B.V. All rights reserved

SummarySystemic activation of coagulation leading to disseminated intravascular coagulation (DIC) is an important feature in patients with severe sepsis. Tissue factor has been shown to play a primary role in this pathological response, as revealed by the use of specific inhibitors and antagonists of the tissue factor/factor VIIa pathway. This class of agents has been demonstrated to attenuate the coagulation response in human volunteers with induced low-grade endotoxemia and to reduce mortality in primate models of Gram-negative sepsis. The efficacy of these agents in attenuating the activation of coagulation and formation of microvascular thrombosis in sepsis may depend on the mechanism of inhibition. Here we demonstrate the efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits the tissue factor/factor VIIa complex by a novel mechanism, in a model of endotoxin-induced coagulation activation in chimpanzees.Administration of a low dose of Gram-negative endotoxin induced marked increases of thrombin generation as measured by plasma levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes, which were completely blocked by rNAPc2. In chimpanzees receiving rNAPc2 alone, there was a significant reduction in the activation of factor X but not factor IX, compared to animals receiving placebo. In contrast to the effect of rNAPc2 on thrombin generation, there was no effect of this inhibitor on the well known enhanced systemic fibrinolytic response induced by endotoxin.In conclusion, the recombinant peptide rNAPc2 is an effective inhibitor of tissue factor-driven thrombin generation during low grade endotoxemia. These results suggest that rNAPc2 may be a promising therapeutic option to inhibit coagulation activation in patients with sepsis.

Background — It is pathophysiologically conceivable that genetic variations in coagulation and fibrinolytic proteins are associated with the risk of myocardial infarction. Methods and Results — We performed a literature search to identify published case-control studies correlating the factor V Leiden or prothrombin G20210A mutations or fibrinogen G−455A or plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms with the risk of myocardial infarction. Studies were included only if they used solid diagnostic criteria and complied with published methodological criteria. A common OR with corresponding 95% CI was calculated for the risk of myocardial infarction in a fixed-effect model according to Mantel-Haenszel. The factor V Leiden and prothrombin G20201A mutations did not significantly correlate with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67, P =0.12 and OR 0.89, 95% CI 0.59 to 1.35, P =0.6, respectively). Inclusion of the studies that investigated young patients (P =0.02). Homozygosity for the fibrinogen −455A allele was significantly associated with a decreased risk of myocardial infarction (OR 0.66, 95% CI 0.44 to 0.99, P =0.04), whereas the PAI-1 4G4G genotype was significantly associated with increased risk (OR 1.20, 95% CI 1.04 to 1.39, P =0.04). Conclusions — Associations between these genetic variations and myocardial infarction were weak or absent. In the absence of clinical implications, our results indicate that screening of patients with myocardial infarction for these genetic variations is not warranted.