For more than 10 years, dual antiplatelet therapy with aspirin and clopidogrel has remained the cornerstone of treatment for patients with acute coronary syndrome (ACS). The novel oral P2Y ...purinoceptor 12 (P2Y12)-receptor inhibitors prasugrel and ticagrelor were approved by the FDA for clinical use in 2009 and 2011, respectively. These agents have a faster-acting, more-potent, and more-predictable antiplatelet effect than clopidogrel, which translates into improved clinical outcomes in patients with ACS, albeit at the expense of an increased risk of bleeding. However, some patients continue to experience adverse ischaemic events despite treatment with aspirin and a P2Y12-receptor antagonist, because platelets can remain activated via pathways not inhibited by these agents, such as the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin. Emerging antiplatelet therapies that might address these limitations include intravenous P2Y12 antagonists, oral PAR-1 antagonists, and thromboxane-receptor inhibitors. In this Review, we provide an overview of these novel antiplatelet drugs, including newly approved agents and emerging compounds currently under clinical development, and also discuss evolving concepts and unmet needs related to antiplatelet therapy for the treatment of ACS.
Whether guided selection of antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) is effective in improving outcomes compared with standard antiplatelet therapy remains ...controversial. We assessed the safety and efficacy of guided versus standard selection of antiplatelet therapy in patients undergoing PCI.
For this systematic review and meta-analysis, from Aug 20 to Oct 25, 2020, we searched MEDLINE (via PubMed), Cochrane, Embase, and Web of Science databases for randomised controlled trials and observational studies published in any language that compared guided antiplatelet therapy, by means of platelet function testing or genetic testing, versus standard antiplatelet therapy in patients undergoing PCI. Two reviewers independently assessed study eligibility, extracted the data, and assessed risk of bias. Risk ratios (RRs) and 95% CIs were used with random-effects or fixed-effect models according to the estimated heterogeneity among studies assessed by the I2 index. Coprimary endpoints were trial-defined primary major adverse cardiovascular events and any bleeding. Key secondary endpoints were all-cause death, cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and major and minor bleeding. This study is registered with PROSPERO (CRD42021215901).
3656 potentially relevant articles were screened. Our analysis included 11 randomised controlled trials and three observational studies with data for 20 743 patients. Compared with standard therapy, guided selection of antiplatelet therapy was associated with a reduction in major adverse cardiovascular events (RR 0·78, 95% CI 0·63–0·95, p=0·015) and reduced bleeding, although not statistically significant (RR 0·88, 0·77–1·01, p=0·069). Cardiovascular death (RR 0·77, 95% CI 0·59–1·00, p=0·049), myocardial infarction (RR 0·76, 0·60–0·96, p=0·021), stent thrombosis (RR 0·64, 0·46–0·89, p=0·011), stroke (RR 0·66, 0·48–0·91, p=0·010), and minor bleeding (RR 0·78, 0·67–0·92, p=0·0030) were reduced with guided therapy compared with standard therapy. Risks of all-cause death and major bleeding did not differ between guided and standard approaches. Outcomes varied according to the strategy used, with an escalation approach associated with a significant reduction in ischaemic events without any trade-off in safety, and a de-escalation approach associated with a significant reduction in bleeding, without any trade-off in efficacy.
Guided selection of antiplatelet therapy improved both composite and individual efficacy outcomes with a favourable safety profile, driven by a reduction in minor bleeding, supporting the use of platelet function or genetic testing to optimise the choice of agent in patients undergoing PCI.
None.
Daily administration of low-dose aspirin has proved to be beneficial in preventing recurrent cardiovascular events. However, the role of aspirin for primary prevention in patients with no overt ...cardiovascular disease is more controversial. In fact, in lower risk patients, the modest benefit in reducing serious vascular events can be offset by the increased risk of bleeding, including intracranial and gastrointestinal hemorrhage. Diabetes mellitus has been associated with a substantially increased risk of both first and recurrent atherothrombotic events, which makes aspirin therapy of potential value in these subjects. Moving from general aspects of aspirin pharmacology and specific issues in diabetes mellitus, this article reviews the literature on the topic of aspirin for primary prevention in general, and in subjects with diabetes mellitus in particular, to culminate with arguments pro and con and a practical risk-based algorithm for aspirin initiation in daily practice.
Oral P2Y12 receptor inhibitors are key for secondary prevention of atherothrombotic events in patients with acute coronary syndromes, in particular those undergoing percutaneous coronary intervention ...(PCI)1. Prasugrel and ticagrelor are more potent than clopidogrel, which is characterised by increased rates of high on-treatment platelet reactivity (HPR), a known marker for recurrent ischaemic events, including stent thrombosis.2
Dual antiplatelet therapy (DAPT) is the cornerstone of pharmacological treatment aimed at preventing the atherothrombotic complications in patients with a variety of coronary artery disease (CAD) ...manifestations. Prescribers of DAPT are confronted with a number of challenges that include selecting the appropriate P2Y
inhibitor and determining the optimal duration of DAPT with the scope of minimizing the risk of ischemic and bleeding complications in light of each patient's clinical characteristic and circumstance. Recently, a guideline writing committee from the American College of Cardiology/American Heart Association (ACC/AHA) and a task force from the European Society of Cardiology (ESC) released their respective focused update recommendations on "Duration of DAPT in Patients with CAD" (ACC/AHA) and "DAPT in CAD" (ESC). This paper aims to review the ACC/AHA and ESC updates for DAPT to delineate common domains, consistent messages, and differences in recommended management strategies across the Atlantic.
Dual antiplatelet therapy--the combination of aspirin and a P2Y12-receptor inhibitor--is the cornerstone of treatment of patients with acute coronary syndromes (ACS) and of those undergoing ...percutaneous coronary intervention. Prasugrel and ticagrelor have more prompt, potent, and predictable antiplatelet effects than those of clopidogrel, and result in reduced ischaemic outcomes in patients with ACS, albeit at the expense of an increased risk of bleeding. However, clopidogrel is still very commonly used. Switching between oral P2Y12-inhibiting therapies occurs very frequently in clinical practice for a variety of reasons, which raises the question of which switching approaches are preferable. In 2015, cangrelor (an intravenous P2Y12-receptor inhibitor) was approved for clinical use, which adds to the conundrum of how to switch between intravenous and oral therapies. Differences in the pharmacology of P2Y12-receptor inhibitors, such as their binding sites (competitive or noncompetitive), half-life, and speed of onset and offset of action, are important factors that might lead to drug interactions when switching between agents. In this Review, we provide an overview of the literature on switching antiplatelet treatment strategies with P2Y12-receptor inhibitors, and discuss practical considerations for switching therapies in the acute and chronic phases of disease presentation.
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2, which has posed a significant threat to global health. Although the infection ...is frequently asymptomatic or associated with mild symptoms, in a small proportion of patients it can produce an intense inflammatory and prothrombotic state that can lead to acute respiratory distress syndrome, multiple organ failure, and death. Angiotensin-converting enzyme 2, highly expressed in the respiratory system, has been identified as a functional receptor for severe acute respiratory syndrome coronavirus-2. Notably, angiotensin-converting enzyme 2 is also expressed in the cardiovascular system, and there are multiple cardiovascular implications of COVID-19. Cardiovascular risk factors and cardiovascular disease have been associated with severe manifestations and poor prognosis in patients with COVID-19. More important, patients with COVID-19 may have thrombotic and coagulation abnormalities, promoting a hypercoagulable state and resulting in an increased rate of thrombotic and thromboembolic events. This review will describe the pathophysiological characteristics of the cardiovascular involvement following infection by severe acute respiratory syndrome coronavirus-2, with a focus on thrombotic and thromboembolic manifestations and implications for antithrombotic management.
Patients with diabetes mellitus (DM) are characterized by enhanced thrombotic risk attributed to multiple mechanisms including hyperreactive platelets, hypercoagulable status, and endothelial ...dysfunction. As such, they are more prone to atherosclerotic cardiovascular events than patients without DM, both before and after coronary artery disease (CAD) is established. In patients with DM without established CAD, primary prevention with aspirin is not routinely advocated because of its increased risk of major bleeding that largely offsets its ischemic benefit. In patients with DM with established CAD, secondary prevention with antiplatelet drugs is an asset of pharmacological strategies aimed at reducing the risk of atherosclerotic cardiovascular events and their adverse prognostic consequences. Such antithrombotic strategies include single antiplatelet therapy (eg, with aspirin or a P2Y12 inhibitor), dual antiplatelet therapy (eg, aspirin combined with a P2Y12 inhibitor), and dual-pathway inhibition (eg, aspirin combined with the vascular dose of the direct oral anticoagulant rivaroxaban) for patients with chronic ischemic heart disease, acute coronary syndromes, and those undergoing percutaneous coronary intervention. Because of their increased risk of thrombotic complications, patients with DM commonly achieve enhanced absolute benefit from more potent antithrombotic approaches compared with those without DM, which most often occurs at the expense of increased bleeding. Nevertheless, studies have shown that when excluding individuals at high risk for bleeding, the net clinical benefit favors the use of intensified long-term antithrombotic therapy in patients with DM and CAD. Several studies are ongoing to establish the role of novel antithrombotic strategies and drug formulations in maximizing the net benefit of antithrombotic therapy for patients with DM. The scope of this review article is to provide an overview of current and evolving antithrombotic strategies for primary and secondary prevention of atherosclerotic cardiovascular events in patients with CAD and DM.
Abstract
Coronary artery disease (CAD) is one of the leading causes of death globally, and antiplatelet therapy is crucial for both its prevention and treatment. Antiplatelet drugs such as aspirin ...and P2Y12 inhibitors are commonly used to reduce the risk of thrombotic events, including myocardial infarction, stroke, and stent thrombosis. However, the benefits associated with the use of antiplatelet drugs also come with a risk of bleeding complications. The ever-growing understanding of the poor prognostic implications associated with bleeding has set the foundations for defining strategies that can mitigate such safety concern without any trade-off in antithrombotic protection. To this extent, personalised antiplatelet therapy has emerged as a paradigm that optimizes the balance between safety and efficacy by customizing treatment to the individual patient's needs and risk profile. Accurate risk stratification for both bleeding and thrombosis can aid in selecting the optimal antiplatelet therapy and prevent serious and life-threatening outcomes. Risk stratification has traditionally included clinical and demographic characteristics and has expanded to incorporate angiographic features and laboratory findings. The availability of bedside platelet function testing as well as rapid genotyping assays has also allowed for a more individualized selection of antiplatelet therapy. This review provides a comprehensive overview of the current state of the art and future trends in personalised antiplatelet therapy for patients with CAD, with emphasis on those presenting with an acute coronary syndrome and undergoing percutaneous coronary revascularization. The aim is to provide clinicians with a comprehensive understanding of personalised antiplatelet therapy and facilitate informed clinical decision-making.
Graphical Abstract
Graphical Abstract
Proposed strategies for tailoring antithrombotic therapy according to individual ischaemic and bleeding risk. Patients at high risk of ischemic events and low risk of bleeding may benefit from an intensified antiplatelet therapy regimen (e.g., escalation), while those at high risk of bleeding and low risk of ischemic events require a less intensive and more cautious approach (e.g, de-escalation). In patients at low risk of ischemic events and low risk of bleeding the benefits of antiplatelet therapy may not outweigh the risks, while patients who have high risks of both ischemic and bleeding events require a delicate balance, as the approach to managing their conditions must weigh the potential benefits against the potential risks. Abbreviations: PFT, platelet function testing. Adapted from Cao et al.1
Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the cornerstone of pharmacological treatment to optimize clinical outcomes in patients with ST-segment elevation myocardial ...infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Intravenous anticoagulant drugs available for PPCI include the indirect thrombin inhibitors unfractionated heparin and low-molecular-weight heparin, and the direct thrombin inhibitor bivalirudin. Intravenous antiplatelet drugs mainly include glycoprotein IIb/IIIa inhibitors and the P2Y
-receptor inhibitor cangrelor. Dual antiplatelet therapy with aspirin and an oral P2Y
-receptor inhibitor is pivotal for the acute and long-term treatment of patients with STEMI undergoing PPCI. Prasugrel and ticagrelor provide a more prompt, potent, and predictable antiplatelet effect compared with clopidogrel, which translates into better clinical outcomes. Therefore, these agents are the first-line treatment in PPCI. However, patients can still experience adverse ischaemic events, which might be in part attributed to alternative pathways triggering thrombosis. Thrombin has an important role, suggesting the need for strategies directly targeting circulating thrombin or other factors of the coagulation cascade, such as oral anticoagulants (rivaroxaban), and the thrombin receptor on the platelet membrane (vorapaxar). In this Review, we provide an overview of currently available antithrombotic therapies used in patients with STEMI undergoing PPCI, results from pivotal clinical trials and their implications for guidelines, as well as recommendations for clinical practice.
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