Current and Novel Antiplatelet Therapies for the Treatment of Cardiovascular Diseases

Over the last decades, antiplatelet agents, mainly aspirin and P2Y12 receptor antagonists, have significantly reduced morbidity and mortality associated with arterial thrombosis. Their pharmacological characteristics, including pharmacokinetic/pharmacodynamics profiles, have been extensively studied, and a significant number of clinical trials assessing their efficacy and safety in various clinical settings have established antithrombotic efficacy. Notwithstanding, antiplatelet agents carry an inherent risk of bleeding. Given that bleeding is associated with adverse cardiovascular outcomes and mortality, there is an unmet clinical need to develop novel antiplatelet therapies that inhibit thrombosis while maintaining hemostasis. In this review, we present the currently available antiplatelet agents, with a particular focus on their targets, pharmacological characteristics, and patterns of use. We will further discuss the novel antiplatelet therapies in the pipeline, with the goal of improved clinical outcomes among patients with atherothrombotic diseases.

Easy and effective analytical method of carbendazim, dimethomorph, and fenoxanil from Protaetia brevitarsis seulensis using LC-MS/MS

Traditionally in Korea, Protaetia brevitarsis seulensis (white-spotted flower chafer) has been used as a medicine, and recently has attracted increased attention due to its antithrombotic efficacy. Some of spent mushroom compost or fermented oak sawdust, a feedstock for P. brevitarsis, were contaminated with three fungicides, carbendazim, dimethomorph, and fenoxanil, which could be transferred to the insect. This study was aimed to optimize a simple extraction method combined with liquid chromatography tandem mass spectrometry and apply it to the real samples. After the pulverized samples (5 g) were extracted with acetonitrile (10 mL) and formic acid (100 μL), fat and lipids in the samples were slowly precipitated at -20°C for 24 hours. After eight different clean-up methods were investigated, the mixture of 150 mg MgSO4/25 mg PSA/25 mg C18 was selected due to optimal recovery of the target compounds. Recovery (77.9%‒80.8% for carbendazim, 111.2%‒116.7% for dimethomorph, and 111.9%‒112.5% for fenoxanil) was achieved with reasonable relative standard deviation (<5.5%) The analytical method developed in this study was used to analyze three compounds in the 24 insect samples donated by the insect farm owners but no target compounds were detected. These results can provide important data for establishing the pesticide safety standards for P. brevitarsis before the medical applications.

Thrombus-targeting therapy with apyrase-annexin V fusion attenuates thrombosis without bleeding

Antithrombotic therapy is essential to prevent thrombotic reocclusion in patients with acute myocardial infarction, stroke, or venous thromboembolism. However, current antithrombotic drugs cause bleeding that limits dose and clinical effectiveness. Previously, we reported that APT102 (AZD3366), a human apyrase optimized to scavenge extracellular ADP and ATP, exhibited potent antiplatelet efficacy without bleeding in experimental myocardial infarction and stroke. Here we describe APT402, an optimized fusion of APT102 and annexin V that uniquely inhibits both platelet and coagulation components of thrombus growth. APT402 preferentially bound to injured vessels and thrombus and prevented thrombotic occlusion in arterial and venous thrombosis models, without increasing bleeding. Thus, APT402 breaks the confounding link between antithrombotic efficacy and bleeding, pioneering a safe and effective approach to prevent and treat a broad range of thrombotic diseases, and may be particularly useful in clinical conditions associated with high bleeding risks.

The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. Results: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. Conclusion: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans.

Managing Life-Threatening Bleeding in Patient with High Plasma Concentration of Dabigatran with Thromboelastogram, Idarucizumab and Renal Replacement Therapy

We present a case of patient with spontaneous cardiac tamponade related to a very high 2-plasma concentration of dabigatran, an oral direct-acting thrombin inhibitor. By selectively inhibiting thrombin alone, dabigatran may have antithrombotic efficacy while preserving some other hemostatic mechanisms in the coagulation system and thus potentially mitigating the risk of bleeding. Nonetheless, serious bleeding can occur with dabigatran. We illustrate the management of this life threatening hemorrhagic complication by the combination of cardiac surgery, antagonization of the anticoagulant effect (using Idarucizumab, an humanized monoclonal antibody fragment and continuous renal replacement therapy), and monitoring of the effects on coagulation by thromboelastogram.

Managing Life-Threatening Bleeding in Patient with High Plasma Concentration of Dabigatran with Thromboelastogram, Idarucizumab and Renal Replacement Therapy

We present a case of patient with spontaneous cardiac tamponade related to a very high 2-plasma concentration of dabigatran, an oral direct-acting thrombin inhibitor. By selectively inhibiting thrombin alone, dabigatran may have antithrombotic efficacy while preserving some other hemostatic mechanisms in the coagulation system and thus potentially mitigating the risk of bleeding. Nonetheless, serious bleeding can occur with dabigatran. We illustrate the management of this life threatening hemorrhagic complication by the combination of cardiac surgery, antagonization of the anticoagulant effect (using Idarucizumab, an humanized monoclonal antibody fragment and continuous renal replacement therapy), and monitoring of the effects on coagulation by thromboelastogram.

Bivalirudin vs. Heparin on Radial Artery Thrombosis during Transradial Coronary Intervention: An Optical Coherence Tomography Study

Objectives. This study aimed to evaluate the antithrombotic efficacy between bivalirudin and unfractionated heparin (UFH) on radial artery thrombosis (RAT) during transradial coronary intervention (TRI) by optical coherence tomography (OCT). Methods and Results. We consecutively reviewed a total of 307 patients who underwent radial artery OCT inspection after TRI in our centre from October 2017 to January 2019; afterwards, 211 screened patients were divided into the UFH group (n = 144) and the bivalirudin group (n = 67) according to their anticoagulation strategy during TRI. The thrombosis in the radial artery was observed in 51 cases (24.17%) with a median thrombus volume of 0.054 mm3 (0.024, 0.334) and median thrombus score of 7 (4, 15). Thrombus occurred in 28 cases in the bivalirudin group with an incidence of 41.8%, which was significantly higher than that in the UFH group (n = 23, 16.0%, P<0.001). This difference was even more remarkable after propensity score matching (bivalirudin group n = 22, 42.3% vs. UHF group n = 11, 13.9%, P<0.001). Multivariate logistic analysis revealed that bivalirudin increased the RAT risk by 3.872 times (95% CI 2.006–8.354, P<0.001) after adjustment for the other predictors. Conclusion. In this present study, the use of bivalirudin was associated with a higher risk of RAT than UFH. It highlighted UFH should be a more considerable choice to prevent radial artery access thrombosis in TRI.

New Antithrombotic Drugs in Acute Coronary Syndrome

In recent years, much progress has been made in the field of antithrombotic drugs in acute coronary syndrome (ACS) treatment, as reflected by the introduction of the more potent P2Y12-inhibitors prasugrel and ticagrelor, and novel forms of concomitant anticoagulation, such as fondaparinux and bivalirudin. However, despite substantial improvements in contemporary ACS treatment, there remains residual ischemic risk in this group and hence the need for even more effective antithrombotic drugs, while balancing antithrombotic efficacy against bleeding risk. This review discusses recently introduced and currently developed antiplatelet and anticoagulant drugs in ACS treatment.

Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome

Acute coronary syndrome and atrial fibrillation are both common and can occur in the same patient. Combination therapy with dual antiplatelet therapy and oral anticoagulation increases risk of bleeding. Where the two conditions coexist, careful consideration is needed to determine the optimal antithrombotic treatment to reduce the risks of future ischaemic events associated with both conditions. Choices can be made in intraprocedural anticoagulation, type and dosing of oral anticoagulant, duration of combination therapy, and selection of P2Y12 inhibitor including genetic testing. This review article provides an overview of the available evidence to support clinicians in finding the delicate balance between antithrombotic efficacy and bleeding risk in patients with acute coronary syndrome and atrial fibrillation.

Novel Antiplatelet Agents in Cardiovascular Disease

Antiplatelet therapy reduces atherothrombotic risk and has therefore become a cornerstone in the treatment of cardiovascular disease. Aspirin, adenosine diphosphate P2Y12 receptor antagonists, glycoprotein IIb/IIIa inhibitors, and the thrombin receptor blocker vorapaxar are effective antiplatelet agents but significantly increase the risk of bleeding. Moreover, atherothrombotic events still impair the prognosis of many patients with cardiovascular disease despite established antiplatelet therapy. Over the last years, advances in the understanding of thrombus formation and hemostasis led to the discovery of various new receptors and signaling pathways of platelet activation. As a consequence, many new antiplatelet agents with high antithrombotic efficacy and supposedly only moderate effects on regular hemostasis have been developed and yielded promising results in preclinical and early clinical studies. Although their long journey from animal studies to randomized clinical trials and finally administration in daily clinical routine has just begun, some of the new agents may in the future become meaningful additions to the pharmacological armamentarium in cardiovascular disease.