Prevention Of Atherothrombosis Research Articles

Low-dose aspirin for the prevention of atherosclerotic cardiovascular disease.

During the past 30 years, several developments have occurred in the antiplatelet field, including the role of aspirin in primary prevention of atherosclerotic cardiovascular disease. There have been several attempts to develop antiplatelet drugs more effective and safer than aspirin and a shift in emphasis from efficacy to safety, advocating aspirin-free antiplatelet regimens after percutaneous coronary intervention. Evidence supporting a chemopreventive effect of low-dose aspirin against colorectal (and other digestive tract) cancer has also strengthened. The aim of this article is to revisit the role of aspirin in the prevention of atherothrombosis across the cardiovascular risk continuum, in view of developments in the antiplatelet field. The review will offer a clinical perspective on aspirin's mechanism of action, pharmacokinetics, and pharmacodynamics. This will be followed by a detailed discussion of its clinical efficacy and safety.

GPVI inhibition: Advancing antithrombotic therapy in cardiovascular disease.

Glycoprotein (GP) VI (GPVI) plays a major role in thrombosis but not haemostasis, making it a promising antithrombotic target. The primary role of GPVI on the surface of platelets is a signalling receptor for collagen, which is one of the most potent thrombotic sub-endothelial components that is exposed by atherosclerotic plaque rupture. Inhibition of GPVI has therefore been investigated as a strategy for treatment and prevention of atherothrombosis, such as during stroke and acute coronary syndromes. A range of specific GPVI inhibitors have been characterized, and two of these inhibitors, glenzocimab and revacept, have completed Phase II clinical trials in ischaemic stroke. In this review, we summarize mechanisms of GPVI activation and the latest progress of clinically tested GPVI inhibitors, including their mechanisms of action. By focusing on what is known about GPVI activation, we also discuss whether alternate strategies could be used to target GPVI.

Cyclooxygenase Inhibitors and Cancer: The Missing Pieces.

At 125, aspirin still represents the cornerstone of anti-platelet therapy for the acute treatment and long-term prevention of atherothrombosis. The development of a selective regimen of low-dose aspirin for the inhibition of platelet thromboxane production was key to maximizing its antithrombotic efficacy and minimizing its gastrointestinal toxicity. Based on about 50 observational studies, published over the past 30 years, aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The apparent chemopreventive effect of aspirin has been confirmed in post-hoc analyses of randomized cardiovascular trials and their meta-analyses. Moreover, prevention of sporadic colorectal adenoma recurrence was demonstrated by randomized controlled trials of low-dose aspirin and selective cyclooxygenase-2 inhibitors. A single placebo-controlled randomized trial of aspirin has shown long-term colorectal cancer prevention in patients with the Lynch syndrome. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the existing evidence for a chemopreventive effect of aspirin and other cyclooxygenase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle. SIGNIFICANCE STATEMENT: Low-dose aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the evidence for a chemopreventive effect of aspirin and other cyclooxygenase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle.

Vitamin D3 and Omega-3 Fatty Acids: A New Approach for Cardiovascular Prevention.

The combination of vitamin D3 and omega-3 fatty acid has been shown to reduce oxidized low-density lipoprotein levels in patients with vitamin D deficiency. We hereby discuss the possible impact of supplementation with either or both for atherothrombosis prevention, and highlight their potentially beneficial impact for cardiovascular prevention.

Eligibility and Implementation of Rivaroxaban for Secondary Prevention of Atherothrombosis in Clinical Practice-Insights From the CANHEART Study.

Background The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial decreased major adverse cardiovascular events with very low-dose rivaroxaban and aspirin in patients with coronary artery disease and peripheral artery disease. We examined the eligibility and potential real-world impact of this strategy on the COMPASS-eligible population. Methods and Results COMPASS eligibility criteria were applied to the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) registry, a population-based cohort of Ontario adults. We compared 5-year major adverse cardiovascular eventsand major bleeding rates stratified by COMPASS eligibility and by clinical risk factors. We applied COMPASS trial rivaroxaban/aspirin arm hazard ratios to estimate the potential impact on the COMPASS-eligible cohort. Among 362 797 patients with coronary artery disease or peripheral artery disease, 38% were deemed eligible, 47% ineligible, and 15% indeterminate. Among eligible patients, a greater number of risk factors was associated with higher rates of cardiovascular outcomes, whereas bleeding rates increased minimally. Over 5 years, applying COMPASS treatment effects to eligible patients resulted in a 2.4% absolute risk reduction of major adverse cardiovascular events and a number needed to treat of 42, and a 1.3% absolute risk increase of major bleeding and number needed to harm (NNH) of 77. Those with at least 2 risk factors had a 3.0% absolute risk reduction of major adverse cardiovascular events (number needed to treat =34) and a 1.6% absolute risk increase of major bleeding (number needed to harm =61). Conclusions Implementation of very-low-dose rivaroxaban therapy would potentially impact 2 in 5 patients with atherosclerotic disease in Ontario. Eligible individuals with 2 comorbidities represent a high-risk subgroup that may derive the greatest benefit-to-risk ratio. Selection of patients with high-risk predisposing factors appears appropriate in routine practice.

Low-dose aspirin for the prevention of atherothrombosis across the cardiovascular risk continuum

Abstract At the 2021 International Aspirin Foundation Symposium of Oriental Congress of Cardiology, a panel of distinguished cardiologists from around the world gathered to present their recent research findings and discuss viewpoints of aspirin use along the entire continuum of cardiovascular disease (CVD) prevention in the general population as well as in specific patient groups. Aspirin produces long-lasting effects on platelet function and cumulative inhibition of platelet thromboxane production by irreversibly inactivating the prostaglandin H-synthase (PGHS). Consistent with saturability of platelet cyclooxygenase 1 (COX-1) inactivation and thromboxane A2 (TXA2) suppression at low doses, a body of convincing evidence showed no additional benefit from high versus low-dose aspirin. Trials of aspirin as primary prevention trials are challenging due to the low event rate and reduced patient compliance over time. Nevertheless, evidence from the ASCEND and TIPS3 trials supported the benefit of aspirin in primary cardiovascular prevention. The Chinese population has among the highest CVD risk in the world. Significant achievement has been made in this respect. For example, the benefit of aspirin use as primary prevention is now recognized in the Chinese guidelines similar to the US, European guidelines, with some unique features that are helpful for the Chinese population (eg, greater emphasis on dynamical reassessment of risk versus benefit). As secondary prevention in patients with transient ischaemic attack (TIA) and minor stroke, low-dose aspirin reduces the risk of major recurrent stroke as well as stroke severity. Peripheral arterial disease (PAD) management and screening is of growing importance. The COMPASS and VOYAGER studies provide new evidence for dual-pathway inhibition (DPI) antithrombotic therapy with low-dose aspirin and reduced-dose rivaroxaban. A major concern with the use of aspirin is the risk of gastrointestinal (GI) bleeding. Strategies to protect patients include eradication of Helicobacter pylori infection and co-prescription of proton pump inhibitors. Different P2Y12 inhibitors and low-dose aspirin have similar levels of bleeding risk, but the risk is magnified when these agents are taken together.

Dual pathway inhibition in atherothrombosis prevention: yes, now we can!

Despite ongoing developments, prevention and treatment of atherothrombotic cardiovascular disease remains a common challenge. Antithrombotic options for cardiocerebrovascular disease prevention involves a choice between dual antiplatelet therapy (DAPT) and dual pathway inhibition (DPI), which includes an antiplatelet agent and a reduced dose anticoagulant agent. In selected patients at high risk of event and low risk of bleeding, especially those undergoing recent and complex coronary revascularization using drug-eluting stents (DES) ("revascularization-driven effect"), DAPT is superior to single antiplatelet therapy with aspirin. DPI involves a wider potential range of treatment and is superior to single antiplatelet therapy with aspirin, particularly in patients with atherothrombotic involvement in different vascular beds both previously revascularized and not ("no revascularization-driven effect"). After nearly thirty years of randomized trials and observational registries, we have sufficient data to customize antithrombotic therapy in patients at high cardiovascular risk. Therefore, "atherothrombosis stakeholders" must identify the right patient for the right therapy to ensure high levels of efficacy and safety with the best of current therapeutic opportunities.

Nutraceuticals and Atherothrombosis: A Glance to Human Trials

The leading causes of death worldwide are ischaemic heart disease and stroke. These Cardiovascular Diseases (CVDs) are two of the main clinical manifestations of atherothrombosis. Above all, the major causes of this complex condition include genetic susceptibility along with lifestyle habits or behavioral risk factors such as smoking, physical inactivity, alcohol abuse, and unhealthy diets. The most important way to prevent atherothrombotic events is through lifestyle optimization. In particular, nutritional intervention plays a key role in the treatment and prevention of atherothrombosis, with specific dietary patterns as potential modulators of cardiovascular health. Nutraceuticals are substances derived from food and offer health benefits along with their nutritional value and could become promising agents in the prevention and treatment of CVDs, particularly for individuals or populations with low adherence to certain dietary patterns. However, for most nutraceuticals, the evidence for their use in cardiovascular health is limited and requires further attention. This review will summarize some nutraceuticals with strong evidence from large sample size randomized controlled trials for the primary or secondary prevention of CVDs.

Role for PARS and Thrombin-Gpibα Interaction for Thrombin Induced Procoagulant Platelet Formation

Procoagulant platelets, a subpopulation of platelets which support thrombin generation, play a role in regulating pathological thrombosis. Using a novel flow cytometry assay (Hua et at, Blood 2015) to identify procoagulant platelets based upon the cell death marker GSAO and activation marker P-selectin, we found that patients with angiogram proven coronary artery disease had heightened thrombin procoagulant platelet formation compared to healthy controls, (25.2% vs 12.2%, p<0.001). Inhibition of this is an attractive target for atherothrombosis prevention. However, the mechanism of thrombin induced procoagulant platelet formation remains controversial with discrepant results regarding requirement for the thrombin binding domain of N terminal GPIbα (Dorman et al, Blood 2000 and Ravanat et al, Blood 2010) and recent reports implicating PAR4 (French et al JTH, 2016). Here we use a recently described novel assay to investigate the roles of PARs and GPIbα measuring procoagulant platelets by FACS (GSAO+/P-selectin+) in whole blood, plasma and washed platelets after treatment with heparin, PAR and GPIbα inhibitors prior to thrombin or PAR agonist stimulation.First, using active site inhibited PPACK-thrombin we demonstrated that catalytically active thrombin is required for procoagulant platelet formation in our in vitro system. PAR1 and PAR4 are implicated in procoagulant platelet formation, however, preincubation with combination of PAR1 and PAR 4 inhibitors (vorapaxar and a PAR4 polyclonal inhibitory antibody), resulted in only partial inhibition of thrombin induced procoagulant platelets (reduction 40%±5.7%, p<0.01) suggesting a role for an additional non-PAR pathway. Thrombin-GPIbα interaction was implied when competition studies with recombinant soluble GPIbα, glycocalicin showed a 49%±7.7% reduction. Involvement of the N-terminus of GPIbα was confirmed by a 39.5%±2.9% reduction after cleavage of GPIbα proximal to the thrombin binding site by NK protease. Pretreatment with PAR1 inhibitor after NK protease cleavage of GPIbα reduced thrombin stimulated procoagulant platelet formation to unstimulated levels implying both PAR cleavage and GPIbα-thrombin interaction is required for thrombin induced procoagulant platelet formation.Consistent with a role of thrombin-GPIbα interaction, we noted a reduction in thrombin induced procoagulant platelets after heparin bolus in patients undergoing coronary angiogram (16.3±10.5% vs 6.1%±2.4%, p<0.001). Heparin is known to known to displace thrombin from GPIbα in addition to anti-thrombin effects via enhancement of antithrombin (AT). Using platelets resuspended in AT-deficient plasma, we demonstrated high dose heparin suppressed procoagulant platelet formation via an AT-independent mechanism, this was confirmed by heparin suppression of thrombin induced procoagulant platelets in washed platelets. In similar experiments, the heparinoid danaparoid, which has no anti-thrombin effect, also inhibited thrombin induced procoagulant platelet formation. Heparin inhibition was not due to PAR inhibition as heparin had no effect on direct PAR activation by PAR1 agonist TRAP or PAR4 agonist AYPGKF. These data suggest heparin has a direct effect on platelets in suppression of thrombin induced procoagulant platelet formation, most likely relating to displacement of thrombin from GPIbα.Together this data indicates that a thrombin-GPIbα interaction via the N terminal fragment is required in addition to thrombin mediated PAR activation. This mechanism is a potential target for modifying atherothrombotic risk.Figure 1: Whole blood was treated with PAR1 and PAR4 inhibitors and washed platelets were treated with glycocalicin, NK protease or NK and PAR1 inhibitor prior to thrombin stimulation (2 U/mL). Data are expressed as fold change from vehicle control ((*p<0.05; **p<0.01, statistics are calculated for n≥3). Figure 2: Plasma, washed platelets or whole blood were treated or not with heparin (12.8 U/ml) prior to thrombin stimulation (2 U/mL), PAR1 (20 µM) or PAR4 (300 µM) agonists. Data are expressed as the ratio of heparin-treated sample to untreated (***p<0.001, statistics are calculated for n≥3). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment.

Atherosclerosis is a chronic inflammatory disease in which atherothrombotic complications lead to cardiovascular morbidity and mortality. At advanced stages, myocardial infarction, ischaemic stroke, and peripheral artery disease, including major adverse limb events, are caused either by acute occlusive atherothrombosis or by thromboembolism. Endothelial dysfunction, vascular smooth muscle cell activation, and vascular inflammation are essential in the development of acute cardiovascular events. Effects of the coagulation system on vascular biology extend beyond thrombosis. Under physiological conditions, coagulation proteases in blood are pivotal in maintaining haemostasis and vascular integrity. Under pathological conditions, including atherosclerosis, the same coagulation proteases (including factor Xa, factor VIIa, and thrombin) become drivers of atherothrombosis, working in concert with platelets and vessel wall components. While initially atherothrombosis was attributed primarily to platelets, recent advances indicate the critical role of fibrin clot and plasma coagulation factors. Mechanisms of atherothrombosis and hypercoagulability vary depending on plaque erosion or plaque rupture. In addition to contributing to thrombus formation, factor Xa and thrombin can affect endothelial dysfunction, oxidative stress, vascular smooth muscle cell function as well as immune cell activation and vascular inflammation. By these mechanisms, they promote atherosclerosis and contribute to plaque instability. In this review, we first discuss the postulated vasoprotective mechanisms of protease-activated receptor signalling induced by coagulation enzymes under physiological conditions. Next, we discuss preclinical studies linking coagulation with endothelial cell dysfunction, thromboinflammation, and atherogenesis. Understanding these mechanisms is pivotal for the introduction of novel strategies in cardiovascular prevention and therapy. We therefore translate these findings to clinical studies of direct oral anticoagulant drugs and discuss the potential relevance of dual pathway inhibition for atherothrombosis prevention and vascular protection.

Combined Antithrombotic Therapy in Patients with a Stable Atherosclerotic Cardiovascular Diseases: What Direction did COMPASS Show?

In patients with stable ischemic heart disease (IHD) and/or peripheral artery disease (PAD), current secondary prevention, including the antiplatelet monotherapy, is associated with a significant residual risk of recurrent cardiovascular complications (CVC). Practical application of results from many modern studies evaluating the effect of secondary prevention of atherothrombosis is complicated. An additional influence on coagulation may play a key role in prevention of atherothrombosis. In the COMPASS study, adding rivaroxaban 2.5 mg, b.i.d., to the acetylsalicylic acid (ASA) monotherapy significantly reduced the risk of death from cardiovascular complications, myocardial infarction or stroke, or all-cause death compared to the ASA monotherapy, in patients with IHD or PAD. The combination antithrombotic therapy was associated with an increased risk of major, but not fatal, or intracranial bleeding. In addition, PAD patients had a reduced risk of severe ischemic lower limb complications, including amputations. According to the subgroup analysis in the COMPASS study, supplementing ASA with rivaroxaban 2.5 mg, b.i.d., may appear most beneficial for patients with stable atherosclerotic disease and with a high risk of severe CVC without causing an increased risk of bleeding.

Atherothrombosis Prevention and Treatment with Anti-interleukin-1 Agents

Despite major advances in terms of prevention, diagnosis, risk-stratification, management and rehabilitation, atherosclerosis and atherothrombosis continue to have major morbidity and mortality implications worldwide. Since the unraveling of the pivotal role of inflammation in atherothrombosis pathophysiology, several focused treatments have been proposed with the ultimate goal of preventing or treating myocardial infarction, stroke, and peripheral artery disease. In particular, given the centrality of interleukin-1 (IL-1), targeted anti-IL-1 agents have attracted substantial attention and efforts. Yet, uncertainty persists on the real risk-benefit and cost-benefit balance of anti-IL-1 agents in patients with or at risk of atherothrombosis. Several trials have been recently completed on atherothrombosis prevention and treatment with anti-IL-1 agents, ranging, for instance, from the large Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial to the series of translational studies conducted within the Virginia Commonwealth University-Anakinra Remodeling Trial (VCU-ART) platform. In light of the present scoping umbrella review, it appears evident that anti-IL-1 agents can reduce systemic inflammation and improve surrogate markers of cardiac and vascular function, with potential benefits on the risk of new/worsening heart failure. One trial suggested an increased risk of major adverse events with anti-interleukin-1 agents, possibly due to a rebound phenomenon, but this was based on a post-hoc analysis of a small number of events, and it was not supported by all other pertinent trials. The CANTOS study showed a potential hazard due to an increased risk of fatal infections, but the effect size was rather small. In addition, cost issues limit the foreseeable scope of these treatment strategies in unselected patients, calling instead for more refined prescribing. The evidence base on the risk-benefit and cost-benefit profile of anti-IL-1 agents for atherothrombosis prevention and treatment has expanded substantially in the last decade. While largely dominated by the landmark CANTOS trial, effect estimates also including the VCU-ART trials suggest complex short- and long-term effects which may prove favorable in carefully selected patients with acute or chronically sustained inflammation. Conversely, more liberal use appears less promising, and further studies with currently available agents or novel ones are eagerly needed to better define their role in the era of precision molecular medicine.

Modulation of Nitric Oxide Synthases by Oxidized LDLs: Role in Vascular Inflammation and Atherosclerosis Development.

The maintenance of physiological levels of nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to the activation of iNOS under different stress conditions, leads to endothelial dysfunction and, in the late stages, to the development of atherosclerosis. Oxidized LDLs (oxLDLs) represent the major candidates to trigger biomolecular processes accompanying endothelial dysfunction and vascular inflammation leading to atherosclerosis, though the pathophysiological mechanism still remains to be elucidated. Here, we summarize recent evidence suggesting that oxLDLs produce significant impairment in the modulation of the eNOS/iNOS machinery, downregulating eNOS via the HMGB1-TLR4-Caveolin-1 pathway. On the other hand, increased oxLDLs lead to sustained activation of the scavenger receptor LOX-1 and, subsequently, to NFkB activation, which, in turn, increases iNOS, leading to EC oxidative stress. Finally, these events are associated with reduced protective autophagic response and accelerated apoptotic EC death, which activates atherosclerotic development. Taken together, this information sheds new light on the pathophysiological mechanisms of oxLDL-related impairment of EC functionality and opens new perspectives in atherothrombosis prevention.

Advances in Antithrombotic Therapy.

Thrombosis remains a major cause of morbidity and mortality. Consequently, advances in antithrombotic therapy are needed to reduce the disease burden. This article focuses on 2 such advances. First, the prevention of atherothrombosis in patients with coronary or peripheral artery disease, which has been enhanced by the finding that the combination of low-dose rivaroxaban plus aspirin is superior to aspirin alone for prevention of recurrent ischemic events. However, this benefit comes at the cost of increased bleeding albeit not fatal bleeding. To overcome this problem, the second advance is the identification of factor XI as a target for new anticoagulants that are potentially safer than those currently available.

Progression of Multifaceted Immune Cells in Atherosclerotic Development.

Atherosclerosis is a major cause of morbidity and mortality due to cardiovascular diseases, such as coronary artery disease, stroke, and peripheral vascular disease, that are associated with thrombosis-induced organ infarction. In Westernized countries, the high prevalence of obesity-induced insulin resistance is predicted to be a major factor leading to atherosclerotic vascular disease. Both genetic and environmental factors interfere with immune responses in atherosclerosis development with chronic and non-resolving states. The most known autoimmune disease therapy is cytokine-targeted therapy, which targets tumor necrosis factor-α and interleukin (IL)-17 antagonists. Recently, a clinical trial with the anti-IL-1β antibody (canakinumab) had shown that the anti-inflammatory effects in canakinumab-treated subjects play a critical role in reducing cardiovascular disease prevalence. Recent emerging data have suggested effective therapeutics involving anti-obesity and anti-diabetic agents, as well as statin and anti-platelet drugs, for atherothrombosis prevention. It is well-known that specialized immune differentiation and activation completely depends on metabolic reprogramming mediated by mitochondrial dynamics in distinct immune cells. Therefore, there is a strong mechanistic link between metabolism and immune function mediated by mitochondrial function. In this review, we describe that cellular metabolism in immune cells is strongly interconnected with systemic metabolism in terms of diverse phenotypes and activation.

Designing Natural Product Hybrids Bearing Triple Antiplatelet Profile and Evaluating Their Human Plasma Stability.

Cardiovascular diseases (CVDs) are becoming major contributors to the burden of disease due to genetic and environmental factors. Despite current standard oral care, cardiovascular risk remains relatively high. A triple antiplatelet therapy with a cyclooxygenase-1 (COX-1) inhibitor, a P2Y12 receptor antagonist, and a protease-activated receptor-1 (PAR-1) antagonist has been established in the secondary prevention of atherothrombosis in patients with acute myocardial infraction and in those with peripheral artery disease. However, due to the combinatorial use of three different drugs, patients receiving this triple therapy are exposed to enhanced risk of bleeding. Conforming to polypharmacology principles, the discovery of a single compound that can simultaneously block the three platelet activation pathways (PAR-1, P2Y12, and COX-1) is of importance. Natural products have served as an inexhaustiblesource of bioactive compounds presenting a diverse pharmaceutical profile, including anti-inflammatory, antioxidant, anticancer, and antithrombotic activity. Indeed, principal component analysis indicated that natural products have the potential to inhibit the three aforementioned pathways, though existed reports refer to single inhibition mechanism on specific receptor(s) implicated in platelet activation. We thus set out to explore possibilities thattake advantage of this potential of natural products and shape the basis to produce novel compounds that could simultaneously target PAR-1, P2Y12, and COX-1 platelet activation pathways. Polyunsaturated fatty acids (PUFAs) have multiple effects leading to improvements in blood pressure and cardiac function and arterial compliance. A promising approach to achieve the desirable goal is the bioconjugation of natural products with PUFAs. Herein, we describe the principles that should be followed to develop molecular hybrids bearing triple antiplatelet activity profile.

Protease-Activated Receptor 1 Inhibitors: Novel Antiplatelet Drugs in Prevention of Atherothrombosis.

Protease-activated receptor (PAR)-1 inhibitors have recently become popular in the use of atherosclerosis among clinicians. Atherosclerosis can cause cardiovascular and cerebrovascular events leading to one of the major causes of mortality worldwide. Thrombin-mediated platelets can cause atherosclerotic plaques, and these platelets are activated by thrombin through the PAR-1. Vorapaxar and atopaxar are novel antiplatelet drugs that inhibit the thrombin-induced platelet activation by antagonizing the PAR-1. The objective of this article is to review the mechanism of action of vorapaxar and atopaxar and explain the rationale for using them in atherothrombosis patients including myocardial infarction, peripheral arterial disease, and stroke.

Antithrombotic therapy in the elderly - are there differences?

Atherothrombotic disease increase with age and that the prevalence of the elderly population is continuously growing. Antithrombotic therapy represents the cornerstone of prevention of atherothrombosis. The choice of the antithrombotic therapy in elderly patients remains an ongoing challenge. Althoug the benefits of antiplatelet therapy in the elderly are demonstrated, the elderly are generally more vulnerable to the adverse effects of antithrombotic drugs. Because of them, understanding strategies of antithrombotic management in elderly is important.

Optimal duration of dual antiplatelet therapy after acute coronary syndromes and coronary stenting

### Learning objectives Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 receptor antagonist (either a thienopyridine (clopidogrel or prasugrel) or a cyclopentyl-triazolopyrimidine (ticagrelor)) is the cornerstone of antithrombotic...

Vorapaxar in the secondary prevention of atherothrombosis

Dual antiplatelet therapy with aspirin, a platelet cyclooxygenase-1 inhibitor and P2Y12 receptor blockers, remains the major drug strategy to prevent ischemic event occurrence in patients with acute coronary syndromes and in patients undergoing coronary stenting, but there some limitations that can be overcome by targeting novel targets. Unlike direct thrombin inhibitors that bind directly to thrombin, targeting the platelet thrombin receptor, protease activated receptor (PAR)-1, may offer a better choice for the attenuation of atherosclerosis progression, thrombus-mediated ischemic events and restenosis without interfering with primary hemostasis. Vorapaxar – a synthetic analogue of himbacine, is a high affinity and highly selective PAR-1 antagonist that can effectively inhibit thrombin-induced platelet aggregation. In the TRACER trial, the addition of vorapaxar to standard therapy in patients with non-stent thrombosis-elevation- acute coronary syndromes did not significantly reduce the primary composite end point occurrence of cardiovascular (CV) death, myocardial infarction (MI), stroke, hospitalization for ischemia, or urgent revascularization, but significantly increased the GUSTO moderate and severe bleeding (p < 0.001) and intracranial hemorrhage (ICH). In the TRA 2°P-TIMI 50 trial, in patients with a history of MI and peripheral arterial disease (PAD) (67% of the total population), the end point of CV death, MI, or stroke was significantly (20%) reduced with vorapaxar whereas GUSTO moderate or severe bleeding was increased (1.5-fold), but not ICH or fatal bleeding and the net clinical outcome favoring the vorapaxar therapy. Based on these favorable results, the FDA approved vorapaxar for the reduction of thrombotic cardiovascular events in patients with prior MI or with PAD for long term therapy. A careful patient selection is needed to balance efficacy versus safety. At this time, patients with high risk for recurrent ischemic event occurrence such as patients with diabetes mellitus and previous MI can be safely treated with vorapaxar for long-term therapy.