Acute coronary syndromes with high thrombotic burden: therapeutic innovations

Abstract Antiplatelet agents represent one of the cornerstones of drug therapy for acute coronary syndromes (ACS). In the last decade, the arrival of prasugrel and ticagrelor, faster and more powerful oral platelet receptor P2Y12 inhibitors compared to clopidogrel, significantly improved platelet inhibition in patients with ACS. However, the reduction of thrombotic risk came at the cost of increased bleeding risk. Despite having similar indications, prasugrel and ticagrelor have different characteristics and methods of use, essentially due to a different design of the trials in which they have been studied. The optimal use of these antiplatelets in clinical practice should therefore be tailored in individual patients. In the acute phase of ACS with high thrombotic burden, all oral P2Y12 inhibitors have limitations, mainly due to the delay of onset of action related to oral administration. In this scenario, parenteral antiplatelet agents (glycoprotein inhibitors IIb/IIIa and cangrelor) may play a key role in case of percutaneous coronary interventions of high thrombotic coronary lesions and in the prevention of early thrombotic complications. Cangrelor, an intravenous inhibitor of the P2Y2 receptor, has peculiar pharmacokinetic and pharmacodynamic characteristics that make it particularly suitable to be used as an antiplatelet during coronary angioplasty as it achieves a rapid and powerful antiplatelet effect in patients not pretreated with oral medications, and has a favourable safety profile in relation to the bleeding risk.

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High-dose clopidogrel, prasugrel or ticagrelor: trying to unravel a skein into a ball

Drugs and Therapy Studies ◽

10.4081/dts.2011.e13 ◽

2011 ◽

Vol 1 (1) ◽

pp. 13

Author(s):

Alessandro Aprile ◽

Raffaella Marzullo ◽

Giuseppe Biondi Zoccai ◽

Maria Grazia Modena

Keyword(s):

Acute Coronary Syndromes ◽

Antiplatelet Agents ◽

Bleeding Risk ◽

Coronary Intervention ◽

Platelet Inhibition ◽

High Dose ◽

Comprehensive Overview ◽

Increased Risk ◽

Coronary Syndromes ◽

Artery Disease

Antiplatelet therapy is a mainstay in the management of coronary artery disease. Indeed, optimal and rapid inhibition of platelet function is a key therapeutic goal in patients with acute coronary syndromes and those undergoing percutaneous coronary intervention. Currently, dual antiplatelet treatment with aspirin and clopidogrel is the gold standard care in patients with acute coronary syndromes or receiving coronary stents without prohibitive bleeding risk. However, recent data show that the efficacy of clopidogrel is hampered by its slow and variable platelet inhibition, with ensuing increased risk of ischemic events, including death, myocardial infarction and stent thrombosis. Novel agents such as prasugrel and ticagrelor have been developed to clopidogrel limits and thus improve cardiovascular outcomes. This article presents a comprehensive overview of the benefits and limitations of current and shortly available antiplatelet agents, providing detailed arguments in favor and against prasugrel and ticagrelor.

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Is there Sex-related Outcome Difference According to oral P2Y12 Inhibitors in Patients with Acute Coronary Syndromes? A Systematic Review and Meta-Analysis of 107,126 Patients

Current Vascular Pharmacology ◽

10.2174/1570161116666180123092054 ◽

2019 ◽

Vol 17 (2) ◽

pp. 191-203

Author(s):

Oliver Brown ◽

Jennifer Rossington ◽

Gill Louise Buchanan ◽

Giuseppe Patti ◽

Angela Hoye

Keyword(s):

Systematic Review ◽

Acute Coronary Syndromes ◽

Meta Analysis ◽

Indirect Comparison ◽

Bleeding Risk ◽

Cardiovascular Death ◽

P2y12 Inhibitors ◽

Significant Difference ◽

Coronary Syndromes ◽

Randomised Controlled

Background and Objectives: The majority of patients included in trials of anti-platelet therapy are male. This systematic review and meta-analysis aimed to determine whether, in addition to aspirin, P2Y12 blockade is beneficial in both women and men with acute coronary syndromes. Methods: Electronic databases were searched and nine eligible randomised controlled studies were identified that had sex-specific clinical outcomes (n=107,126 patients). Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated for a composite of cardiovascular death, myocardial infarction or stroke (MACE), and a safety endpoint of major bleeding for each sex. Indirect comparison analysis was performed to statistically compare ticagrelor against prasugrel. Results: Compared to aspirin alone, clopidogrel reduced MACE in men (RR, 0.79; 95% CI, 0.68 to 0.92; p=0.003), but was not statistically significant in women (RR, 0.88; 95% CI, 0.75 to 1.02, p=0.08). Clopidogrel therapy significantly increased bleeding in women but not men. Compared to clopidogrel, prasugrel was beneficial in men (RR, 0.84; 95% CI, 0.73 to 0.97; p=0.02) but not statistically significant in women (RR, 0.94; 95% CI, 0.83 to 1.06; p=0.30); ticagrelor reduced MACE in both men (RR, 0.85; 95% CI, 0.77 to 0.94; p=0.001) and women (RR, 0.84; 95% CI, 0.73 to 0.97; p=0.02). Indirect comparison demonstrated no significant difference between ticagrelor and prasugrel in either sex. Compared to clopidogrel, ticagrelor and prasugrel increased bleeding risk in both women and men. Conclusion: In summary, in comparison to monotherapy with aspirin, P2Y12 inhibitors reduce MACE in women and men. Ticagrelor was shown to be superior to clopidogrel in both sexes. Prasugrel showed a statistically significant benefit only in men; however indirect comparison did not demonstrate superiority of ticagrelor over prasugrel in women.

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Ticagrelor versus Clopidogrel in high bleeding risk patients presenting with Acute Coronary Syndromes: insights from the multicenter START-ANTIPLATELET registry

European Heart Journal ◽

10.1093/ehjci/ehaa946.1730 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

F Gragnano ◽

E Moscarella ◽

P Calabro' ◽

A Cesaro ◽

P.C Pafundi ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Coronary Syndromes ◽

Bleeding Risk ◽

Coronary Intervention ◽

P Value ◽

Bleeding Events ◽

P2y12 Inhibitors ◽

Coronary Syndromes ◽

High Bleeding Risk

Abstract Background Optimal dual antiplatelet therapy in high bleeding risk (HBR) patients with acute coronary syndromes (ACS) remains debated. Although current guidelines recommend the use of potent P2Y12 inhibitors in these patients (according to the labeled indications), clopidogrel is frequently used in clinical practice based on a perceived advantage in terms of safety in the HBR population. Purpose We sought to investigate the use of clopidogrel versus ticagrelor in consecutive HBR ACS patients and their impact on ischemic and bleeding events at 1 year. Methods ACS patients enrolled in the START-ANTIPLATELET registry with at least 1 HBR criterion were included in the present analysis and stratified according to DAPT type (clopidogrel versus ticagrelor). The primary endpoint was net adverse clinical endpoint (NACE), defined as a composite of all-cause death, myocardial infarction, stroke, and major bleeding. The secondary endpoints were major adverse cardiac and cerebral events (MACE), defined as a composite of all-cause death, myocardial infarction and stroke, each individual component of NACE and MACE, and target vessel revascularization. Results Among a total of 1,209 patients with 1-year follow-up in the registry, 383 patients were considered at HBR, of whom 174 (45.4%) were on clopidogrel and 209 (54.6%) on ticagrelor. Clopidogrel was more likely to be administered in patients at increased ischemic and bleeding risk, while ticagrelor in those undergoing percutaneous coronary intervention. Mean DAPT duration was longer in the ticagrelor group than in the clopidogrel group (10.40±4.29 versus 9.35±5.4; p-value=0.03). At 1-year follow-up, the risk of NACE and MACE events was significantly higher in the clopidogrel than in the ticagrelor group (NACE: HR 1.82; 95% CI 1.07–3.09; p-value=0.02; MACE: HR 1.83; 95% CI 1.04–3.24; p-value=0.03) (Figure). After multivariate adjustment for clinical and procedural characteristics, no difference in NACEs nor MACEs was observed between patients on clopidogrel versus ticagrelor (NACE: adjusted HR 1.27; 95% CI 0.71–2.27; p-value=0.42; MACE: adjusted HR 1.19; 95% CI 0.63–2.24; p-value=0.59) (Figure). Age, number of HBR criteria, and mean DAPT duration were independent predictors of NACEs. Conclusions In a real-world ACS registry, approximately 50% of patients are at HBR and frequently treated with clopidogrel. In HBR ACS patients, no difference was observed in ischemic and bleeding events between clopidogrel and ticagrelor after adjustment for potential confounders. Kaplan-Meier curves at 1-year follow-up. Funding Acknowledgement Type of funding source: None

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Optimal P2Y12 inhibition in older adults with acute coronary syndromes: a network meta-analysis of randomized controlled trials

European Heart Journal - Cardiovascular Pharmacotherapy ◽

10.1093/ehjcvp/pvaa101 ◽

2020 ◽

Author(s):

Claudio Montalto ◽

Nuccia Morici ◽

Andrea Raffaele Munafò ◽

Antonio Mangieri ◽

Alessandro Mandurino-Mirizzi ◽

...

Keyword(s):

Older Adults ◽

Stent Thrombosis ◽

Primary Endpoint ◽

Acute Coronary Syndromes ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Bleeding Risk ◽

P2y12 Inhibitors ◽

Fixed Proportion ◽

Coronary Syndromes

Abstract Aims Dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor on top of aspirin is the cornerstone of therapy after acute coronary syndromes (ACS). Nonetheless, the safest and most efficacious P2Y12 for older patients who are both at high ischaemic and bleeding risk remains uncertain. We aimed to examine the effect of available P2Y12 inhibitors on ischaemic and bleeding endpoints in older adults with ACS. Methods and results Randomized clinical trials that reported separately the results of adults older >70 years for at least the primary endpoint [composite of death, myocardial infarction (MI), and stroke]. Seven studies (14 485 patients-years) were included. Network meta-analysis showed that prasugrel was associated with similar occurrence of the primary endpoint and of a secondary ischaemic endpoint (composite of MI and stroke) and was most likely the best treatment [Surface Under the Cumulative Ranking curve Analysis (SUCRA) 54.5 and 59.8, respectively]. With regards to major bleedings, clopidogrel showed the highest likelihood of event reduction (SUCRA 70.1%), while ticagrelor of stent thrombosis (SUCRA 55.6%). Our meta-regression with a fixed proportion of patients managed invasively of 100% confirmed these trends with increasing SUCRA. Conclusion Among older subjects with ACS, DAPT should be balanced upon ischaemic and bleeding risks as prasugrel is associated with the highest probability of reduction of ischaemic events and clopidogrel of bleedings. Ticagrelor had highest SUCRA for stent thrombosis reduction but seems suboptimal in older adults.

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Inflammatory Bowel Disease and Acute Coronary Syndromes: From Pathogenesis to the Fine Line Between Bleeding and Ischemic Risk

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa160 ◽

2020 ◽

Cited By ~ 2

Author(s):

Martino Pepe ◽

Eugenio Carulli ◽

Cinzia Forleo ◽

Marco Moscarelli ◽

Ottavio Di Cillo ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Acute Coronary Syndromes ◽

Pathological Condition ◽

Coronary Vessels ◽

Bleeding Risk ◽

Thrombotic Risk ◽

Proinflammatory Mediators ◽

Coronary Syndromes ◽

Inflammatory Bowel

Abstract Inflammatory bowel disease (IBD) is a pathological condition that first involves the gastrointestinal wall but can also trigger a systemic inflammatory state and thus extraintestinal manifestations. Systemic inflammation is probably secondary to the passage of bacterial products into the bloodstream because of altered intestinal permeability and the consequent release of proinflammatory mediators. Inflammation, through several diverse pathophysiological pathways, determines both a procoagulative state and systemic endothelial dysfunction, which are both deemed to be responsible for venous and arterial thromboembolic adverse events. The management of systemic thrombotic complications is particularly challenging in this category of patients, who also present a high bleeding risk; what is more, both bleeding and thrombotic risks peak during the active phases of the disease. The literature suggests that treating physicians have been, so far, more heavily influenced by concerns about bleeding than by the thrombotic risk. Despite the absence of data provided by large cohorts or randomized studies, the high risk of arterial and venous atherothrombosis in patients with IBD seems unquestionable. Moreover, several reports suggest that when arterial thromboembolism involves the coronary vessels, causing acute coronary syndromes, ischemic complications from antithrombotic drug undertreatment are frequent and severe. This review aims to shed light on the tricky balance between the ischemic and hemorrhagic risks of patients with IBD and to highlight how difficult it is for clinicians to define a tailored therapy based on a case-by-case, careful, and unprejudiced clinical evaluation.

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Antithrombotic Therapy in Acute Coronary Syndromes: Current Evidence and Ongoing Issues Regarding Early and Late Management

Thrombosis and Haemostasis ◽

10.1055/s-0040-1722188 ◽

2021 ◽

Author(s):

Paul Guedeney ◽

Jean-Philippe Collet

Keyword(s):

Thrombus Formation ◽

Antiplatelet Agents ◽

Bleeding Risk ◽

Coronary Intervention ◽

Therapeutic Strategies ◽

Added Value ◽

Current Evidence ◽

Onset Of Action ◽

P2y12 Inhibitors ◽

Coronary Syndrome

AbstractA few decades ago, the understanding of the pathophysiological processes involved in the coronary artery thrombus formation has placed anticoagulant and antiplatelet agents at the core of the management of acute coronary syndrome (ACS). Increasingly potent antithrombotic agents have since been evaluated, in various association, timing, or dosage, in numerous randomized controlled trials to interrupt the initial thrombus formation, prevent ischemic complications, and ultimately improve survival. Primary percutaneous coronary intervention, initial parenteral anticoagulation, and dual antiplatelet therapy with potent P2Y12 inhibitors have become the hallmark of ACS management revolutionizing its prognosis. Despite these many improvements, much more remains to be done to optimize the onset of action of the various antithrombotic therapies, for further treating and preventing thrombotic events without exposing the patients to an unbearable hemorrhagic risk. The availability of various potent P2Y12 inhibitors has opened the door for individualized therapeutic strategies based on the clinical setting as well as the ischemic and bleeding risk of the patients, while the added value of aspirin has been recently challenged. The strategy of dual-pathway inhibition with P2Y12 inhibitors and low-dose non-vitamin K antagonist oral anticoagulant has brought promising results for the early and late management of patients presenting with ACS with and without indication for oral anticoagulation. In this updated review, we aimed at describing the evidence supporting the current gold standard of antithrombotic management of ACS. More importantly, we provide an overview of some of the ongoing issues and promising therapeutic strategies of this ever-evolving topic.

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Did Prasugrel and Ticagrelor Offer the Same Benefit in Patients with Acute Coronary Syndromes after Percutaneous Coronary Interventions Compared to Clopidogrel? Insights from Randomized Clinical Trials, Registries and Meta-analysis

Current Pharmaceutical Design ◽

10.2174/1381612824666180108121834 ◽

2018 ◽

Vol 24 (4) ◽

pp. 465-477 ◽

Cited By ~ 4

Author(s):

Alfredo E. Rodriguez ◽

Alfredo M. Rodriguez-Granillo ◽

Sergio D. Ascarrunz ◽

Francisco Peralta-Bazan ◽

Mi Y. Cho

Keyword(s):

Clinical Trials ◽

Acute Coronary Syndromes ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Indirect Comparison ◽

Bleeding Risk ◽

Cardiac Events ◽

P2y12 Inhibitor ◽

P2y12 Inhibitors ◽

Coronary Syndromes

Background: According to ACC/ AHA guidelines, a minimum of 1 year of dual anti- platelet therapy (DAPT) consisting of aspirin and a platelet ADP-receptor antagonist (P2Y12 inhibitor) is recommended for patients presenting acute coronary syndromes (ACS), regardless of which type of revascularization is performed during the acute event. Methods: The purpose of this presentation was to review the present data either from a direct randomized comparison among the three compounds and also large prospective observational registries and meta-analysis were analyzed in detail. With this aim, we performed an extensive large search from PubMed/Medline Journals identifying studies comparing fashion the new P2Y12 inhibitors in patients with ACS including ST elevation myocardial infarction (STEMI) in direct and indirect manner. Results: Pivotal large randomized clinical trials (RCT) in patients with ACS including STEMI, comparing clopidogrel, a first generation P2Y12 inhibitor against the newer prasugrel and ticagrelor showed major efficacy advantages of the latters although both drugs had more bleeding risk than clopidogrel. Direct comparisons of prasugrel and ticagrelor from large RCT are not yet available, however, several observational registries and metaanalysis reported results from an indirect comparison between both compounds. Major findings and limitations of each of these studies were identified, highlighted and discussed. Conclusion: Prasugrel and ticagrelor are both more effective than clopidogrel to prevent adverse cardiac events in patients with ACS. Compared to ticagrelor, prasugrel appears to be more effective in patients with STEMI, although lack of randomized data didn’t allow to draw definitive conclusions.

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P2Y12-receptor-inhibiting antiplatelet strategies in acute coronary syndromes

Hämostaseologie ◽

10.5482/hamo-13-08-0044 ◽

2014 ◽

Vol 34 (01) ◽

pp. 20-28 ◽

Cited By ~ 3

Author(s):

K. Huber ◽

T. Höchtl

Keyword(s):

Acute Coronary Syndromes ◽

Bleeding Risk ◽

P2y12 Receptor ◽

Antiplatelet Drugs ◽

Major Adverse Cardiovascular Events ◽

Onset Of Action ◽

High Expectations ◽

Coronary Syndromes ◽

Underweight Patients ◽

Special Patient

SummaryAntiplatelet therapy in acute coronary syndromes is essential for preventing stent thrombosis and for reducing major adverse cardiovascular events. Treatment strategy has changed over the last years by frequent use of more active agents inhibiting the ADP mediated activation of platelets instead of clopidogrel, such as prasugrel and ticagrelor. Compared to clopidogrel these modern antiplatelet drugs showed a significant reduction of efficacy endpoints as well as an acceptable safety profile in large multicenter randomized trials (TRITON TIMI 38, PLATO). Going in with higher efficacy a generally higher bleeding risk of prasugrel could be reduced by optimizing the maintenance dose in elderly and underweight patients (TRILOGY-ACS). However even prasugrel and ticagrelor have shown a delayed onset of action in special patient populations (e.g. STEMI) suggesting that the optimal ADP inhibitor has not been found yet. Results of the CHAMPION PHOENIX trial indicate that cangrelor, an intravenous agent, might fulfill these high expectations of an ideal platelet inhibitor in the first hours of an ACS in special patient cohorts.This review summarizes the results of most important clinical studies investigating the novel P2Y12 receptor inhibiting antiplatelet drugs.

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