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1.
Circulation ; 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38899464

ABSTRACT

There is significant variability in the efficacy and safety of oral P2Y12 inhibitors, which are used to prevent ischemic outcomes in common diseases such as coronary and peripheral arterial disease and stroke. Clopidogrel, a prodrug, is the most used oral P2Y12 inhibitor and is activated primarily after being metabolized by a highly polymorphic hepatic cytochrome CYP2C219 enzyme. Loss-of-function genetic variants in CYP2C219 are common, can result in decreased active metabolite levels and increased on-treatment platelet aggregation, and are associated with increased ischemic events on clopidogrel therapy. Such patients can be identified by CYP2C19 genetic testing and can be treated with alternative therapy. Conversely, universal use of potent oral P2Y12 inhibitors such as ticagrelor or prasugrel, which are not dependent on CYP2C19 for activation, has been recommended but can result in increased bleeding. Recent clinical trials and meta-analyses have demonstrated that a precision medicine approach in which loss-of-function carriers are prescribed ticagrelor or prasugrel and noncarriers are prescribed clopidogrel results in reducing ischemic events without increasing bleeding risk. The evidence to date supports CYP2C19 genetic testing before oral P2Y12 inhibitors are prescribed in patients with acute coronary syndromes or percutaneous coronary intervention. Clinical implementation of such genetic testing will depend on among multiple factors: rapid availability of results or adoption of the concept of performing preemptive genetic testing, provision of easy-to-understand results with therapeutic recommendations, and seamless integration in the electronic health record.

2.
Circulation ; 150(4): 317-335, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39038086

ABSTRACT

For almost two decades, 12-month dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) has been the only class I recommendation on DAPT in American and European guidelines, which has resulted in 12-month durations of DAPT therapy being the most frequently implemented in ACS patients undergoing percutaneous coronary intervention (PCI) across the globe. Twelve-month DAPT was initially grounded in the results of the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which, by design, studied DAPT versus no DAPT rather than the optimal DAPT duration. The average DAPT duration in this study was 9 months, not 12 months. Subsequent ACS studies, which were not designed to assess DAPT duration, rather its composition (aspirin with prasugrel or ticagrelor compared with clopidogrel) were further interpreted as supportive evidence for 12-month DAPT duration. In these studies, the median DAPT duration was 9 or 15 months for ticagrelor and prasugrel, respectively. Several subsequent studies questioned the 12-month regimen and suggested that DAPT duration should either be fewer than 12 months in patients at high bleeding risk or more than 12 months in patients at high ischemic risk who can safely tolerate the treatment. Bleeding, rather than ischemic risk assessment, has emerged as a treatment modifier for maximizing the net clinical benefit of DAPT, due to excessive bleeding and no clear benefit of prolonged treatment regimens in high bleeding risk patients. Multiple DAPT de-escalation treatment strategies, including switching from prasugrel or ticagrelor to clopidogrel, reducing the dose of prasugrel or ticagrelor, and shortening DAPT duration while maintaining monotherapy with ticagrelor, have been consistently shown to reduce bleeding without increasing fatal or nonfatal cardiovascular or cerebral ischemic risks compared with 12-month DAPT. However, 12-month DAPT remains the only class-I DAPT recommendation for patients with ACS despite the lack of prospectively established evidence, leading to unnecessary and potentially harmful overtreatment in many patients. It is time for clinical practice and guideline recommendations to be updated to reflect the totality of the evidence regarding the optimal DAPT duration in ACS.


Subject(s)
Acute Coronary Syndrome , Dual Anti-Platelet Therapy , Platelet Aggregation Inhibitors , Humans , Acute Coronary Syndrome/drug therapy , Acute Coronary Syndrome/therapy , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/adverse effects , Hemorrhage/chemically induced , Percutaneous Coronary Intervention , Time Factors , Treatment Outcome , Prasugrel Hydrochloride/therapeutic use , Prasugrel Hydrochloride/administration & dosage , Prasugrel Hydrochloride/adverse effects , Drug Administration Schedule
3.
Eur Heart J ; 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39042715

ABSTRACT

BACKGROUND AND AIMS: Patients with high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI) are at increased risk of not only bleeding, but also ischaemic events. This study aimed to determine the long-term relative risk of ischaemic and bleeding events in HBR patients. METHODS: This study was a nationwide cohort study, based on the Korean National Health Insurance Review and Assessment Service database. Patients diagnosed with stable angina or acute coronary syndrome and those who underwent PCI in Korea between 2009 and 2018 were included in the analysis. According to the Academic Research Consortium HBR criteria, the total population was divided into HBR and non-HBR groups. The co-primary outcomes were major bleeding events and ischaemic (composite of cardiac death, myocardial infarction, and ischaemic stroke) events. RESULTS: Among a total of 325 417 patients who underwent PCI, 66 426 patients (20.4%) had HBR. During the follow-up period, HBR patients had a higher risk for major bleeding events (23.9% vs. 8.9%, P < .001) and ischaemic events (33.8% vs. 14.4%, P < .001). However, the impact of HBR was significant for major bleeding events [hazard ratio (HR) 3.12, 95% confidence interval (CI) 3.04-3.21, P < .001] and for ischaemic events (HR 2.50, 95% CI 2.45-2.56, P < .001). The HBR group was also associated with a greater risk of all-cause mortality (HR 3.73, 95% CI 3.66-3.79, P < .001). The average annual rate of major bleeding events within the first year after PCI was 5.5% for a single major criterion, and 2.9% for a single minor criterion. CONCLUSIONS: Among patients undergoing PCI, those with HBR were at increased long-term risk for both bleeding and ischaemic events, with a greater risk of mortality compared to non-HBR patients.

4.
Circulation ; 148(5): 442-454, 2023 08.
Article in English | MEDLINE | ID: mdl-37345559

ABSTRACT

Acute postoperative myocardial ischemia (PMI) after cardiac surgery is an infrequent event that can evolve rapidly and become a potentially life-threatening complication. Multiple factors are associated with acute PMI after cardiac surgery and may vary by the type of surgical procedure performed. Although the criteria defining nonprocedural myocardial ischemia are well established, there are no universally accepted criteria for the diagnosis of acute PMI. In addition, current evidence on the management of acute PMI after cardiac surgery is sparse and generally of low methodological quality. Once acute PMI is suspected, prompt diagnosis and treatment are imperative, and options range from conservative strategies to percutaneous coronary intervention and redo coronary artery bypass grafting. In this document, a multidisciplinary group including experts in cardiac surgery, cardiology, anesthesiology, and postoperative care summarizes the existing evidence on diagnosis and treatment of acute PMI and provides clinical guidance.


Subject(s)
Cardiac Surgical Procedures , Coronary Artery Disease , Myocardial Ischemia , Humans , American Heart Association , Myocardial Ischemia/diagnosis , Myocardial Ischemia/etiology , Myocardial Ischemia/therapy , Cardiac Surgical Procedures/adverse effects , Cardiac Surgical Procedures/methods , Coronary Artery Disease/surgery , Coronary Artery Disease/diagnosis , Ischemia , Postoperative Complications/diagnosis , Postoperative Complications/etiology , Postoperative Complications/therapy
5.
Circulation ; 147(25): 1933-1944, 2023 06 20.
Article in English | MEDLINE | ID: mdl-37335828

ABSTRACT

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.


Subject(s)
Acute Coronary Syndrome , Coronary Artery Disease , Percutaneous Coronary Intervention , Thrombosis , Humans , Platelet Aggregation Inhibitors/adverse effects , Coronary Artery Disease/complications , Hemorrhage/etiology , Blood Platelets , Dual Anti-Platelet Therapy/adverse effects , Acute Coronary Syndrome/therapy , Thrombosis/etiology , Percutaneous Coronary Intervention/adverse effects , Treatment Outcome
6.
Am Heart J ; 272: 11-22, 2024 06.
Article in English | MEDLINE | ID: mdl-38458371

ABSTRACT

BACKGROUND: The optimal antiplatelet regimen after percutaneous coronary intervention (PCI) in patients with peripheral artery disease (PAD) is still debated. This analysis aimed to compare the effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients with PAD undergoing PCI. METHODS: In the TWILIGHT trial, patients at high ischemic or bleeding risk that underwent PCI were randomized after 3 months of dual antiplatelet therapy (DAPT) to aspirin or matching placebo in addition to open-label ticagrelor for 12 additional months. In this post-hoc analysis, patient cohorts were examined according to the presence or absence of PAD. The primary endpoint was Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding. The key secondary endpoint was a composite of all-cause death, myocardial infarction (MI), or stroke. Endpoints were assessed at 12 months after randomization. RESULTS: Among 7,119 patients, 489 (7%) had PAD and were older, more likely to have comorbidities, and multivessel disease. PAD patients had more bleeding or ischemic complications than no-PAD patients. Ticagrelor monotherapy compared to ticagrelor plus aspirin was associated with less BARC 2, 3, or 5 bleeding in PAD (4.6% vs 8.7%; HR 0.52; 95%CI 0.25-1.07) and no-PAD patients (4.0% vs 7.0%; HR 0.56; 95%CI 0.45-0.69; interaction P-value .830) and a similar risk of death, MI, or stroke in these 2 groups (interaction P-value .446). CONCLUSIONS: Despite their higher ischemic and bleeding risk, patients with PAD undergoing PCI derived a consistent benefit from ticagrelor monotherapy after 3 months of DAPT in terms of bleeding reduction without any relevant increase in ischemic events. CLINICAL TRIAL REGISTRY INFORMATION:: https://www. CLINICALTRIALS: gov/study/NCT02270242.


Subject(s)
Aspirin , Percutaneous Coronary Intervention , Peripheral Arterial Disease , Platelet Aggregation Inhibitors , Ticagrelor , Humans , Ticagrelor/therapeutic use , Aspirin/therapeutic use , Aspirin/administration & dosage , Peripheral Arterial Disease/complications , Percutaneous Coronary Intervention/methods , Male , Female , Aged , Platelet Aggregation Inhibitors/therapeutic use , Middle Aged , Drug Therapy, Combination , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Dual Anti-Platelet Therapy/methods , Myocardial Infarction/epidemiology , Stroke/prevention & control , Stroke/etiology , Stroke/epidemiology
7.
Arterioscler Thromb Vasc Biol ; 43(2): e83-e93, 2023 02.
Article in English | MEDLINE | ID: mdl-36546322

ABSTRACT

BACKGROUND: Immature or reticulated platelets are associated with impaired efficacy of antiplatelet drugs and adverse events in cardiovascular patients. Their role as a predictive biomarker in patients with acute coronary syndrome treated with potent P2Y12 receptor inhibitors is not fully understood. We aimed to prospectively evaluate reticulated platelets as a predictor of the primary end point of the ISAR-REACT 5 trial consisting of death, myocardial infarction, or stroke at 1 year in patients with acute coronary syndrome randomized to prasugrel or ticagrelor. METHODS: Immature platelet fraction (IPF) was assessed within 48 hours after randomization. Patients were divided based on the IPF median values: the IPFhigh group included patients with IPF>median and the IPFlow group included patients with IPF≤median. Platelet aggregation was assessed using the Multiplate Analyzer and was correlated to IPF. RESULTS: Five hundred seventy-seven patients were included in the study. IPF values in % (median [interquartile range]) within the first 48 hours did not differ between the two study groups: 3.6 (2.5-5.2)% in the prasugrel group and 3.6 (2.5-5.4)% in the ticagrelor group (P=0.882). The incidence of the primary end point was significantly higher in the IPFhigh (IPF>3.6%) group compared with the IPFlow (IPF≤3.6%) group: 13.0% versus 7.2% (HRadj, 1.74 [1.02-3.00]; P=0.044), independently from the assigned drug (Pint=0.159). No significant association between IPF and BARC 3 to 5 bleeding was observed. ADP-induced platelet aggregation correlated significantly with IPF in patients treated with prasugrel (r=0.22; P=0.005) while no correlation was detected in patients treated with ticagrelor (r=0.09; P=0.257). CONCLUSIONS: Independently from drug treatment, IPF was associated with the primary end point and therefore is a promising biomarker for the prediction of adverse cardiovascular events in patients with acute coronary syndrome treated with prasugrel or ticagrelor. REGISTRATION: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01944800.


Subject(s)
Acute Coronary Syndrome , Percutaneous Coronary Intervention , Humans , Ticagrelor/adverse effects , Prasugrel Hydrochloride/adverse effects , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/drug therapy , Platelet Aggregation Inhibitors/adverse effects , Blood Platelets , Treatment Outcome
8.
Eur Heart J ; 44(32): 3059-3072, 2023 08 22.
Article in English | MEDLINE | ID: mdl-37345589

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.


Subject(s)
Acute Coronary Syndrome , Coronary Artery Disease , Myocardial Infarction , Percutaneous Coronary Intervention , Thrombosis , Humans , Platelet Aggregation Inhibitors/adverse effects , Coronary Artery Disease/therapy , Aspirin/therapeutic use , Myocardial Infarction/etiology , Hemorrhage/chemically induced , Hemorrhage/prevention & control , Hemorrhage/complications , Acute Coronary Syndrome/therapy , Thrombosis/etiology , Percutaneous Coronary Intervention/adverse effects , Treatment Outcome
9.
Eur Heart J ; 44(20): 1780-1794, 2023 05 21.
Article in English | MEDLINE | ID: mdl-36988155

ABSTRACT

Remarkable progress has been made in the pharmacological management of patients with cardiovascular disease, including the frequent use of antithrombotic agents. Nonetheless, bleeding complications remain frequent and potentially life-threatening. Therapeutic interventions relying on prompt antithrombotic drug reversal or removal have been developed to assist clinicians in treating patients with active bleeding or an imminent threat of major bleeding due to urgent surgery or invasive procedures. Early phase studies on these novel strategies have shown promising results using surrogate pharmacodynamic endpoints. However, the benefit of reversing/removing antiplatelet or anticoagulant drugs should always be weighed against the possible prothrombotic effects associated with withdrawal of antithrombotic protection, bleeding, and surgical trauma. Understanding the ischemic-bleeding risk tradeoff of antithrombotic drug reversal and removal strategies in the context of urgent high-risk settings requires dedicated clinical investigations, but challenges in trial design remain, with relevant practical, financial, and ethical implications.


Subject(s)
Cardiovascular Diseases , Fibrinolytic Agents , Humans , Fibrinolytic Agents/adverse effects , Hemorrhage/chemically induced , Hemorrhage/prevention & control , Anticoagulants/adverse effects , Cardiovascular Diseases/drug therapy , Platelet Aggregation Inhibitors/adverse effects
10.
Am Heart J ; 258: 17-26, 2023 04.
Article in English | MEDLINE | ID: mdl-36596332

ABSTRACT

BACKGROUND: The mechanisms underlying the increased risk of bleeding that female patients with ST-segment Elevation Myocardial Infarction (STEMI) exhibit, remains unclear. The present report assessed sex-related differences in response to pre-hospital dual antiplatelet therapy (DAPT) initiation in patients with STEMI. METHODS: The COMPARE CRUSH trial randomized patients presenting with STEMI to receive a pre-hospital loading dose of crushed or integral prasugrel tablets in the ambulance. In this substudy, we compared platelet reactivity levels and the occurrence of high platelet reactivity (HPR; defined as platelet reactivity ≥208) between sexes at 4 prespecified time points after DAPT initiation, and evaluated post-PCI bleeding between groups. RESULTS: Out of 633 STEMI patients, 147 (23%) were female. Females compared with males presented with significantly higher levels of platelet reactivity and higher HPR rates at baseline (232 [IQR, 209-256] vs 195 [IQR, 171-220], P < .01, and 76% vs 41%, OR 4.58 [95%CI, 2.52-8.32], P < .01, respectively). Moreover, female sex was identified as the sole independent predictor of HPR at baseline (OR 5.67 [95%CI, 2.56-12.53], P < .01). Following DAPT initiation, levels of platelet reactivity and the incidence of HPR were similar between sexes. Post-PCI bleeding occurred more frequently in females compared with males (10% vs 2%, OR 6.02 [95%CI, 2.61-11.87], P < .01). Female sex was an independent predictor of post-PCI bleeding (OR 3.25 [95%CI, 1.09-9.72], P = .04). CONCLUSIONS: In this contemporary STEMI cohort, female STEMI patients remain at risk of bleeding complications after primary PCI. However, this is not explained by sex-specific differences in the pharmacodynamic response to pre-hospital DAPT initiation.


Subject(s)
Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Female , Humans , Male , Fibrinolytic Agents/therapeutic use , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Percutaneous Coronary Intervention/adverse effects , Platelet Aggregation Inhibitors/adverse effects , Prasugrel Hydrochloride/therapeutic use , ST Elevation Myocardial Infarction/therapy , Treatment Outcome
11.
Semin Thromb Hemost ; 49(8): 816-832, 2023 Nov.
Article in English | MEDLINE | ID: mdl-36223804

ABSTRACT

COVID-19 is associated with endothelial activation in the setting of a potent inflammatory reaction and a hypercoagulable state. The end result of this thromboinflammatory state is an excess in thrombotic events, in particular venous thromboembolism. Pulmonary embolism (PE) has been of special interest in patients with COVID-19 given its association with respiratory deterioration, increased risk of intensive care unit admission, and prolonged hospital stay. The pathophysiology and clinical characteristics of COVID-19-associated PE may differ from the conventional non-COVID-19-associated PE. In addition to embolic events from deep vein thrombi, in situ pulmonary thrombosis, particularly in smaller vascular beds, may be relevant in patients with COVID-19. Appropriate prevention of thrombotic events in COVID-19 has therefore become of critical interest. Several changes in viral biology, vaccination, and treatment management during the pandemic may have resulted in changes in incidence trends. This review provides an overview of the pathophysiology, epidemiology, clinical characteristics, and risk factors of COVID-19-associated PE. Furthermore, we briefly summarize the results from randomized controlled trials of preventive antithrombotic therapies in COVID-19, focusing on their findings related to PE. We discuss the acute treatment of COVID-19-associated PE, which is substantially similar to the management of conventional non-COVID-19 PE. Ultimately, we comment on the current knowledge gaps in the evidence and the future directions in the treatment and follow-up of COVID-19-associated PE, including long-term management, and its possible association with long-COVID.


Subject(s)
COVID-19 , Pulmonary Embolism , Thrombosis , Venous Thromboembolism , Venous Thrombosis , Humans , COVID-19/complications , Post-Acute COVID-19 Syndrome , Pulmonary Embolism/diagnosis , Pulmonary Embolism/epidemiology , Pulmonary Embolism/etiology , Venous Thrombosis/drug therapy , Lung , Venous Thromboembolism/diagnosis , Venous Thromboembolism/drug therapy , Venous Thromboembolism/epidemiology , Thrombosis/drug therapy , Anticoagulants/therapeutic use , COVID-19 Testing
12.
Eur Heart J ; 43(44): 4616-4634, 2022 11 21.
Article in English | MEDLINE | ID: mdl-36130256

ABSTRACT

Transcatheter aortic valve implantation (TAVI) is a minimally invasive procedure, which is used frequently in patients with symptomatic severe aortic valve stenosis. Most patients undergoing TAVI are over 80 years of age with a high bleeding as well as thrombotic risk. Despite the increasing safety of the procedure, thromboembolic events [stroke, (subclinical) valve thrombosis] remain prevalent. As a consequence, antithrombotic prophylaxis is routinely used and only recently new data on the efficacy and safety of antithrombotic drugs has become available. On the other hand, these antithrombotic drugs increase bleeding in a population with unique aortic stenosis-related bleeding characteristics (such as acquired von Willebrand factor defect and angiodysplasia). In this review, we discuss the impact of thromboembolic and bleeding events, the current optimal antithrombotic therapy based on registries and recent randomized controlled trials, as well as try to give a practical guide how to treat these high-risk patients. Finally, we discuss knowledge gaps and future research needed to fill these gaps.


Subject(s)
Aortic Valve Stenosis , Thrombosis , Transcatheter Aortic Valve Replacement , Humans , Aged, 80 and over , Transcatheter Aortic Valve Replacement/adverse effects , Fibrinolytic Agents/therapeutic use , Aortic Valve Stenosis/etiology , Thrombosis/etiology , Hemorrhage/chemically induced , Hemorrhage/prevention & control , Aortic Valve/surgery , Treatment Outcome , Risk Factors
13.
Eur Heart J ; 43(10): 959-967, 2022 Mar 07.
Article in English | MEDLINE | ID: mdl-34918066

ABSTRACT

AIMS: Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS. METHODS AND RESULTS: We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65-0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96-1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments. CONCLUSION: In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS. STUDY REGISTRATION NUMBER: This study is registered in PROSPERO (CRD42021258603). KEY QUESTION: A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored. KEY FINDING: In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality. TAKE HOME MESSAGE: A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome.


Subject(s)
Acute Coronary Syndrome , Percutaneous Coronary Intervention , Humans , Network Meta-Analysis , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/therapeutic use , Prasugrel Hydrochloride/adverse effects , Prasugrel Hydrochloride/therapeutic use , Purinergic P2Y Receptor Antagonists/adverse effects , Purinergic P2Y Receptor Antagonists/therapeutic use , Randomized Controlled Trials as Topic , Ticagrelor/adverse effects , Ticagrelor/therapeutic use , Treatment Outcome
14.
Circulation ; 144(16): 1323-1343, 2021 10 19.
Article in English | MEDLINE | ID: mdl-34662163

ABSTRACT

Contemporary evidence supports device-based transcatheter interventions for the management of patients with structural heart disease. These procedures, which include aortic valve implantation, mitral or tricuspid valve repair/implantation, left atrial appendage occlusion, and patent foramen ovale closure, profoundly differ with respect to clinical indications and procedural aspects. Yet, patients undergoing transcatheter cardiac interventions require antithrombotic therapy before, during, or after the procedure to prevent thromboembolic events. However, these therapies are associated with an increased risk of bleeding complications. To date, challenges and controversies exist regarding balancing the risk of thrombotic and bleeding complications in these patients such that the optimal antithrombotic regimens to adopt in each specific procedure is still unclear. In this review, we summarize current evidence on antithrombotic therapies for device-based transcatheter interventions targeting structural heart disease and emphasize the importance of a tailored approach in these patients.


Subject(s)
Fibrinolytic Agents/therapeutic use , Heart Diseases/drug therapy , Fibrinolytic Agents/pharmacology , Heart Diseases/surgery , Humans
15.
Circulation ; 143(6): 583-596, 2021 02 09.
Article in English | MEDLINE | ID: mdl-33555916

ABSTRACT

A growing number of patients undergoing percutaneous coronary intervention (PCI) with stent implantation also have atrial fibrillation. This poses challenges for their optimal antithrombotic management because patients with atrial fibrillation undergoing PCI require oral anticoagulation for the prevention of cardiac thromboembolism and dual antiplatelet therapy for the prevention of coronary thrombotic complications. The combination of oral anticoagulation and dual antiplatelet therapy substantially increases the risk of bleeding. Over the last decade, a series of North American Consensus Statements on the Management of Antithrombotic Therapy in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention have been reported. Since the last update in 2018, several pivotal clinical trials in the field have been published. This document provides a focused updated of the 2018 recommendations. The group recommends that in patients with atrial fibrillation undergoing PCI, a non-vitamin K antagonist oral anticoagulant is the oral anticoagulation of choice. Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should be given to all patients during the peri-PCI period (during inpatient stay, until time of discharge, up to 1 week after PCI, at the discretion of the treating physician), after which the default strategy is to stop aspirin and continue treatment with a P2Y12 inhibitor, preferably clopidogrel, in combination with a non-vitamin K antagonist oral anticoagulant (ie, double therapy). In patients at increased thrombotic risk who have an acceptable risk of bleeding, it is reasonable to continue aspirin (ie, triple therapy) for up to 1 month. Double therapy should be given for 6 to 12 months with the actual duration depending on the ischemic and bleeding risk profile of the patient, after which patients should discontinue antiplatelet therapy and receive oral anticoagulation alone.


Subject(s)
Anticoagulants/therapeutic use , Atrial Fibrillation/drug therapy , Fibrinolytic Agents/therapeutic use , Percutaneous Coronary Intervention/methods , Administration, Oral , Anticoagulants/pharmacology , Fibrinolytic Agents/pharmacology , History, 21st Century , Humans
16.
Lancet ; 397(10283): 1470-1483, 2021 04 17.
Article in English | MEDLINE | ID: mdl-33865495

ABSTRACT

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: 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. FUNDING: None.


Subject(s)
Dual Anti-Platelet Therapy , Percutaneous Coronary Intervention , Platelet Aggregation Inhibitors/administration & dosage , Platelet Function Tests , Prasugrel Hydrochloride/administration & dosage , Ticagrelor/administration & dosage , Acute Coronary Syndrome/complications , Acute Coronary Syndrome/therapy , Hemorrhage/chemically induced , Humans , Myocardial Infarction/etiology , Stroke/etiology
17.
N Engl J Med ; 381(16): 1524-1534, 2019 10 17.
Article in English | MEDLINE | ID: mdl-31475799

ABSTRACT

BACKGROUND: The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain. METHODS: In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary end point (the safety end point) was bleeding. RESULTS: A total of 4018 patients underwent randomization. A primary end-point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006). The respective incidences of the individual components of the primary end point in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, and definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46). CONCLUSIONS: Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups. (Funded by the German Center for Cardiovascular Research and Deutsches Herzzentrum München; ISAR-REACT 5 ClinicalTrials.gov number, NCT01944800.).


Subject(s)
Acute Coronary Syndrome/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Prasugrel Hydrochloride/therapeutic use , Purinergic P2Y Receptor Antagonists/therapeutic use , Ticagrelor/therapeutic use , Acute Coronary Syndrome/mortality , Acute Coronary Syndrome/therapy , Aged , Coronary Thrombosis/epidemiology , Female , Hemorrhage/chemically induced , Humans , Incidence , Kaplan-Meier Estimate , Male , Middle Aged , Myocardial Infarction/epidemiology , Myocardial Infarction/prevention & control , Percutaneous Coronary Intervention , Platelet Aggregation Inhibitors/adverse effects , Prasugrel Hydrochloride/adverse effects , Purinergic P2Y Receptor Antagonists/adverse effects , Stents , Stroke/epidemiology , Stroke/prevention & control , Ticagrelor/adverse effects
18.
N Engl J Med ; 381(21): 2032-2042, 2019 11 21.
Article in English | MEDLINE | ID: mdl-31556978

ABSTRACT

BACKGROUND: Monotherapy with a P2Y12 inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI). METHODS: In a double-blind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant bleeding among patients who were at high risk for bleeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We also evaluated the composite end point of death from any cause, nonfatal myocardial infarction, or nonfatal stroke, using a noninferiority hypothesis with an absolute margin of 1.6 percentage points. RESULTS: We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus placebo and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval [CI], 0.45 to 0.68; P<0.001). The difference in risk between the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving ticagrelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (difference, -0.06 percentage points; 95% CI, -0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority). CONCLUSIONS: Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke. (Funded by AstraZeneca; TWILIGHT ClinicalTrials.gov number, NCT02270242.).


Subject(s)
Aspirin/therapeutic use , Coronary Disease/therapy , Hemorrhage/chemically induced , Percutaneous Coronary Intervention , Platelet Aggregation Inhibitors/therapeutic use , Ticagrelor/therapeutic use , Aged , Aspirin/adverse effects , Coronary Disease/drug therapy , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Mortality , Myocardial Infarction/epidemiology , Platelet Aggregation Inhibitors/adverse effects , Risk Factors , Stroke/epidemiology , Ticagrelor/adverse effects
19.
Am Heart J ; 250: 1-10, 2022 08.
Article in English | MEDLINE | ID: mdl-35436504

ABSTRACT

BACKGROUND: Optimal dual antiplatelet therapy (DAPT) duration in patients at high bleeding risk (HBR) is not fully defined. We aimed to compare the safety and effectiveness of short-term DAPT (S-DAPT) with longer duration DAPT (L-DAPT) after percutaneous coronary intervention (PCI) with drug eluting stents (DES) in patients at HBR. METHODS: We searched for studies comparing S-DAPT (≤3 months) followed by aspirin or P2Y 12 inhibitor monotherapy against L-DAPT (6-12 months) after PCI in HBR patients. Primary end points of interest were major bleeding and myocardial infarction (MI). Random-effects meta-analyses were performed to calculate odds ratios with 95% CIs. RESULTS: Six randomized trials and 3 propensity-matched studies (n = 16,848) were included in the primary analysis. Compared with L-DAPT (n = 8,422), major bleeding was lower with S-DAPT (n = 8,426) [OR 0.68; 95% CI 0.51-0.89] whereas MI did not differ significantly between the 2 groups [1.16; 0.94-1.44]. There were no significant differences in risks of death, stroke or stent thrombosis (ST) between S-DAPT and L-DAPT groups. These findings were consistent when propensity-matched studies were analysed separately. Finally, there was a numerically higher, albeit statistically non-significant, ST in the S-DAPT arm of patients without an indication for OAC [1.98; 0.86-4.58]. CONCLUSIONS: Among HBR patients undergoing current generation DES implantation, S-DAPT reduces bleeding without an increased risk of death or MI compared with L-DAPT. More research is needed to (1) evaluate risks of late ST after 1 to 3 months DAPT among patients with high ischemic and bleeding risks, (2) defining the SAPT of choice after 1 to 3 months DAPT.


Subject(s)
Coronary Artery Disease , Drug-Eluting Stents , Myocardial Infarction , Percutaneous Coronary Intervention , Thrombosis , Coronary Artery Disease/complications , Coronary Artery Disease/surgery , Drug Therapy, Combination , Drug-Eluting Stents/adverse effects , Hemorrhage/chemically induced , Hemorrhage/complications , Hemorrhage/epidemiology , Humans , Myocardial Infarction/etiology , Percutaneous Coronary Intervention/adverse effects , Platelet Aggregation Inhibitors/therapeutic use , Thrombosis/etiology , Treatment Outcome
20.
Am Heart J ; 252: 26-30, 2022 10.
Article in English | MEDLINE | ID: mdl-35671829

ABSTRACT

The present research letter reports the 1-year clinical outcomes of the randomized COMPARE CRUSH trial, which allocated STEMI patients at first medical contact in the ambulance to receive either crushed or integral tablets of prasugrel loading dose. This trial aimed to investigate whether early enhanced antiplatelet effect constituted by the crushed potent oral P2Y12 inhibitor prasugrel could lead to improved early myocardial reperfusion and clinical outcomes.


Subject(s)
Emergency Medical Services , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Follow-Up Studies , Humans , Percutaneous Coronary Intervention/methods , Platelet Aggregation Inhibitors/therapeutic use , Prasugrel Hydrochloride/therapeutic use , Purinergic P2Y Receptor Antagonists/therapeutic use , ST Elevation Myocardial Infarction/drug therapy , Tablets , Treatment Outcome
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