Development Of Antithrombotic Therapies Research Articles

Effectiveness of Different P2Y12 Inhibitors on Coronary Flow in Patients with ST-Elevation Myocardial Infarction

Abstract Background: ST-segment elevation myocardial infarction (STEMI) is a clinical syndrome with high mortality. The main purpose of STEMI treatment is to achieve optimal revascularization for tissue perfusion. Besides the innovations in revascularization strategies, developments in antithrombotic therapy resulted in a significant reduction in STEMI-related mortality. Reperfusion can be demonstrated by resolution of ST-segment elevation (STR), TIMI frame count (TFC), and myocardial blush grade (MBG). Aim of the study: In our study, we investigated the effects of P2Y12 inhibitors clopidogrel, prasugrel, and ticagrelor on reperfusion parameters such as TFC, MBG, and STR, after primary percutaneous coronary intervention (pPCI) in STEMI. Material and Methods: The study was a retrospective analysis of STEMI patients who underwent successful pPCI. A total of 120 patients were included in the study as 3 equal groups according to the type of P2Y12 inhibitor administered in loading dose in the acute phase, and reperfusion parameters were compared between the groups. Results: There was no statistically significant difference between the groups in terms of baseline demographic, clinical, and angiographic parameters. Evaluation of reperfusion parameters indicated that STR, MBG, angina relief after pPCI and corrected TFC (cTFC) were significantly different between the groups (p <0.05). In post-hoc analysis, the percentage of change in STR, MBG, angina relief after pPCI, and cTFC was significantly higher in the prasugrel group (p <0.017). Conclusion: In STEMI patients undergoing pPCI, the analysis of tissue level reperfusion parameters indicates a superior effect of prasugrel compared with other P2Y12 inhibitors used to achieve reperfusion.

Dual pathway therapy in acute coronary syndrome

In 10% of patients, who suffer an acute coronary syndrome (ACS), a major cardiovascular event occurs despite optimal therapy. The occlusion of the vessel is driven by atherothrombosis, which arises from platelet activation and activation of the coagulation cascade. In the last decade the secondary prevention continuously improved by development of dual anti-platelet therapy with new P2Y12-inhibitors such as clopidogrel, prasugrel, and ticagrelor. Until recently, the coagulation cascade was not targeted in secondary prevention. The coagulation factor Xa plays a crucial role in thrombosis and is elevated in patients after acute coronary syndrome, therefore representing an attractive target for novel therapies in ACS. Former studies with vitamin K antagonists showed reduction of cardiovascular events but increased major bleedings. Two phase-3 trials investigated the role of novel oral anticoagulant agents on top of aspirin and clopidogrel in patients with ACS. The APPRAISE-2 study, which tested the oral factor Xa inhibitor apixaban was prematurely terminated because of an increase of major bleedings in the absence of an effect on cardiovascular events. In contrast, the ATLAS ACS2 TIMI-51 trial interrogating the oral factor Xa inhibitor rivaroxaban in a low dose regimen showed significant reduction of cardiovascular events as well as total mortality. Thus, add-on treatment with low dose rivaroxaban emerged as a new option for patients with ACS. This review illustrates recent advances in the development of antithrombotic therapy in acute coronary syndromes, provides guidance on which patients should receive which therapy for secondary prevention of events, and points out potentially fruitful new strategies for the future of antithrombotic treatment in ACS.

Treatment of venous thromboembolism with new oral anticoagulants according to patient risk.

Recent developments in antithrombotic therapy have provided us with choices between unfractionated heparin, low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA), and inhibitors against factor Xa or against thrombin for the management of venous thromboembolism. The factors that influence our decision should be efficacy, safety, convenience, and, when there is weak evidence, also patient values and preferences. The available options have largely similar efficacy, the documented exception being LMWH as superior to VKA in patients with active cancer. For the majority of patients we have today strong evidence regarding safety from large randomized trials, but this does not apply to many of the subsets of patients. In this review the choice of treatment is focused on the risks that are known or can be predicted for the individual patient. Three principal decision points on how to tailor the therapy individually are discussed-at diagnosis, for hospitalized patients at the time of discharge and finally after 3 to 6 months.

Lessons Learned from Negative Clinical Trials Evaluating Antithrombotic Therapy for Ischemic Heart Disease

The clinical trials that failed to demonstrate significant efficacy may not result in development of new therapy but contribute to better understanding of antithrombotic therapy for ischemic heart disease. Negative trials provide important messages about how to interpret and understand the results of clinical trials and apply these results to clinical practices. Although every aspect of clinical trials may influence the outcomes of trials and interpretation of their results, selection of study subjects, endpoints, and measuring risk/benefit are crucial to success of clinical trial. We will review the recent key negative trials on antithrombotic therapy for ischemic heart disease and discuss about their results and implications. The challenge in the future for the development of antithrombotic therapies is to leverage these "lessons learned" from negative clinical trials to improve the design, conduct, and interpretation of future randomized clinical trials.

Mouse models to study von Willebrand factor structure-function relationships in vivo

Von Willebrand factor (VWF) structure-function relationship has been studied only through in vitro approaches. The VWF-deficient mouse model has been extremely useful to examine the in vivo function of VWF but does not allow a more subtle analysis of the relative importance of its different domains. However, considering the large size of VWF and its capacity to interact with various ligands in order to support platelet adhesion and aggregation, the necessity to evaluate independently these interactions appeared increasingly crucial. A recently developed technique, known as hydrodynamic injection, which allows transient expression of a transgene by mouse hepatocytes, proved very useful in this regard. Indeed, transient expression of various VWF mutants in VWF-deficient mice contributed to improve our knowledge about the role of VWF interaction with subendothelial collagens and with platelets receptors in VWF roles in haemostasis and thrombosis. These findings can provide new leads in the development of anti-thrombotic therapies.

Reduced incidence of ischemic stroke in patients with severe factor XI deficiency

AbstractInherited disorders of hemostasis are natural models for investigating mechanisms of thrombosis and development of antithrombotic therapy. Because mice with total factor XI deficiency are protected against ischemic stroke and do not manifest excessive bleeding, we investigated the incidence of ischemic stroke in patients with severe inherited factor XI deficiency. Incidence of ischemic stroke in 115 patients aged 45 years or more with severe factor XI deficiency (activity less than 15 U/dL) was compared with incidence in the Israeli population as estimated from a stroke survey of 1528 patients. Adjustment for major risk factors of stroke (hypertension, diabetes mellitus, hypercholesterolemia, current smoking) was based on comparison of their prevalence in the stroke survey to an Israeli health survey of 9509 subjects. Incidence of myocardial infarction in the factor XI cohort was also recorded. After adjustment for the 4 major risk factors of ischemic stroke, the expected incidence of ischemic stroke was 8.56 compared with one observed (P = .003). The reduced 1:115 incidence of ischemic stroke contrasted with a 19:115 incidence of myocardial infarction, similar to the expected incidence. Thus, severe factor XI deficiency probably is protective against ischemic stroke but not against acute myocardial infarction.

Recent Developments in Antithrombotic Therapy: Will Sodium Warfarin Be a Drug of the Past?

Warfarin and heparin have formed the mainstay in the prophylaxis of deep vein thrombosis (DVT), stroke prevention in atrial fibrillation, and treatment of thromboembolic disease (TED). However, these choices are hampered by difficult administration, interactions with other medications, side effect profile, and limited indications for treatment. Anti-factor Xa (anti-Xa) inhibitors have already entered the drug market with the drug Fondaparinux being the first anti-Xa inhibitor to be approved for use in the U.S. by the Food and Drug Administration (FDA), and other drugs such as idraparinux being currently in development. A new class of medications, known as direct thrombin inhibitors (DTI), includes the parental agents lepirudin, argatroban and bivalirudin which have been approved by the FDA and the oral agents ximelagatran, melagatran and dabigatran. The latter three drugs which are oral DTIs may soon replace warfarin and heparin as the preferred medications for DVT prophylaxis and for reducing the relative risk of stroke. These drugs do not rely on blocking serine proteases nor do they require a co-factor (antithrombin III) like unfractionated heparin (UFH) or low molecular weight heparin (LMWH). DTIs are rapid in onset, easy to administer, do not interact with other medications or foods, have limited side effects, and can be administered in a fixed dose. The DTI ximelagatran has already been approved in several European and Asian countries, and over a dozen randomized clinical trials have been conducted demonstrating its performance to be on par with warfarin. However, approval by the FDA in the U.S. remains pending in view of reported incidences of elevations in hepatic enzymes that are currently under evaluation. This review examines the role of DTIs in the prevention and treatment of TED and the recent patents reported in the literature.

Developments in antithrombotic therapy: state of the art anno 1996

This review aims to discuss recent developments in antithrombotic therapy. New and specific inhibitors of platelet dependent thrombosis appear to moderately improve the outcome in coronary vascular disease. Further studies will need to address the cost-benefit ratio of this additional intervention. Hirudin and analogues are potent inhibitors of thrombin, and are clinically efficious, but at current dosage levels still complicated by bleeding. Low molecular weight heparin have markedly improved the efficacy of prevention and treatment of venous thromboembolism.

Recent developments in antithrombotic therapy

Recent developments in antithrombotic therapy

Recent developments in antithrombotic therapy.

Thrombosis is one of the most important disease phenomena responsible for disability and death. Recent studies involving the prevention and treatment of this condition are reviewed. It is now well documented that the response to anticoagulant therapy is largely dependent on the selection of suitable patients and on the use of adequate therapeutic dosage of the anticoagulant drugs under investigation. Studies that have not fulfilled this requirement have consistently failed to achieve favorable therapeutic response. The potential clinical use of Malayan pit viper venom-fraction 6 (Arvin®), urokinase, and purified streptokinase, each a potent antithrombotic agent, is now under intensive investigation. The status of these studies is reviewed. Platelet thrombi have been resistant to treatment, and new studies with acetylsalicylic acid and other drugs are under way. Many drugs interact in a variety of ways with oral anticoagulants, and this must be considered in the application of anticoagulant therapy.