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Expert Review of Clinical Pharmacology Oct 2022Platelets play a key role in arterial thrombosis and antiplatelet therapy is pivotal in the treatment of cardiovascular disease. Current antiplatelet drugs target... (Review)
Review
INTRODUCTION
Platelets play a key role in arterial thrombosis and antiplatelet therapy is pivotal in the treatment of cardiovascular disease. Current antiplatelet drugs target different pathways of platelet activation and show specific pharmacodynamic and pharmacokinetic characteristics, implicating clinically relevant drug-drug interactions.
AREAS COVERED
This article reviews the role of platelets in hemostasis and cardiovascular thrombosis, and discusses the key pharmacodynamics, drug-drug interactions and reversal strategies of clinically used antiplatelet drugs.
EXPERT OPINION
Antiplatelet therapies target distinct pathways of platelet activation: thromboxane A synthesis, adenosine diphosphate-mediated signaling, integrin αβ (GPIIb/IIIa), thrombin-mediated platelet activation via the PAR1 receptor and phosphodiesterases. Key clinical drug-drug interactions of antiplatelet agents involve acetylsalicylic acid - ibuprofen, clopidogrel - omeprazole, and morphine - oral P2Y inhibitors, all of which lead to an attenuated antiplatelet effect. Platelet function and genetic testing and the use of scores (ARC-HBR, PRECISE-DAPT, ESC ischemic risk definition) may contribute to a more tailored antiplatelet therapy. High on-treatment platelet reactivity presents a key problem in the acute management of ST-elevation myocardial infarction (STEMI). A treatment strategy involving early initiation of an intravenous antiplatelet agent may be able to bridge the gap of insufficient platelet inhibition in high ischemic risk patients with STEMI.
Topics: Humans; Platelet Aggregation Inhibitors; ST Elevation Myocardial Infarction; Drug Therapy, Combination; Clopidogrel; Thrombosis; Purinergic P2Y Receptor Antagonists
PubMed: 36065676
DOI: 10.1080/17512433.2022.2121702 -
British Journal of Haematology Jun 2017The story of the discovery of aspirin stretches back more than 3500 years to when bark from the willow tree was used as a pain reliever and antipyretic. It involves an... (Review)
Review
The story of the discovery of aspirin stretches back more than 3500 years to when bark from the willow tree was used as a pain reliever and antipyretic. It involves an Oxfordshire clergyman, scientists at a German dye manufacturer, a Nobel Prize-winning discovery and a series of pivotal clinical trials. Aspirin is now the most commonly used drug in the world. Its role in preventing cardiovascular and cerebrovascular disease has been revolutionary and one of the biggest pharmaceutical success stories of the last century.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antipyretics; Aspirin; Cardiovascular Diseases; Drug Discovery; Forecasting; Hematologic Diseases; Hemorrhage; History, 18th Century; History, 19th Century; History, 20th Century; History, 21st Century; History, Ancient; Plant Bark; Platelet Aggregation Inhibitors; Salix
PubMed: 28106908
DOI: 10.1111/bjh.14520 -
The Canadian Journal of Cardiology May 2022Patients with widespread atherosclerosis such as peripheral artery disease (PAD) have a high risk of cardiovascular and limb symptoms and complications, which affects...
Patients with widespread atherosclerosis such as peripheral artery disease (PAD) have a high risk of cardiovascular and limb symptoms and complications, which affects their quality of life and longevity. Over the past 2 decades there have been substantial advances in diagnostics, pharmacotherapy, and interventions including endovascular and open surgical to aid in the management of PAD patients. To summarize the evidence regarding approaches to diagnosis, risk stratification, medical and intervention treatments for patients with PAD, guided by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework, evidence was synthesized, and assessed for quality, and recommendations provided-categorized as weak or strong for each prespecified research question. Fifty-six recommendations were made, with 27% (15/56) graded as strong recommendations with high-quality evidence, 14% (8/56) were designated as strong recommendations with moderate-quality evidence, and 20% (11/56) were strong recommendations with low quality of evidence. Conversely 39% (22/56) were classified as weak recommendations. For PAD patients, strong recommendations on the basis of high-quality evidence, include smoking cessation interventions, structured exercise programs for claudication, lipid-modifying therapy, antithrombotic therapy with a single antiplatelet agent or dual pathway inhibition with low-dose rivaroxaban and aspirin; treatment of hypertension with an angiotensin converting enzyme or angiotensin receptor blocker; and for those with diabetes, a sodium-glucose cotransporter 2 inhibitor should be considered. Furthermore, autogenous grafts are more effective than prosthetic grafts for surgical bypasses for claudication or chronic limb-threatening ischemia involving the popliteal or distal arteries. Other recommendations indicated that new endovascular techniques and hybrid procedures be considered in patients with favourable anatomy and patient factors, and finally, the evidence for perioperative risk stratification for PAD patients who undergo surgery remains weak.
Topics: Canada; Humans; Intermittent Claudication; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Quality of Life; Risk Factors
PubMed: 35537813
DOI: 10.1016/j.cjca.2022.02.029 -
Cardiovascular Intervention and... Jan 2022Primary Percutaneous Coronary Intervention (PCI) has significantly contributed to reducing the mortality of patients with ST-segment elevation myocardial infarction... (Review)
Review
Primary Percutaneous Coronary Intervention (PCI) has significantly contributed to reducing the mortality of patients with ST-segment elevation myocardial infarction (STEMI) even in cardiogenic shock and is now the standard of care in most of Japanese institutions. The Task Force on Primary PCI of the Japanese Association of Cardiovascular Interventional and Therapeutics (CVIT) society proposed an expert consensus document for the management of acute myocardial infarction (AMI) focusing on procedural aspects of primary PCI in 2018. Updated guidelines for the management of AMI were published by the European Society of Cardiology (ESC) in 2017 and 2020. Major changes in the guidelines for STEMI patients included: (1) radial access and drug-eluting stents (DES) over bare-metal stents (BMS) were recommended as a Class I indication, (2) complete revascularization before hospital discharge (either immediate or staged) is now considered as Class IIa recommendation. In 2020, updated guidelines for Non-ST-Elevation Myocardial Infarction (NSTEMI) patients, the followings were changed: (1) an early invasive strategy within 24 h is recommended in patients with NSTEMI as a Class I indication, (2) complete revascularization in NSTEMI patients without cardiogenic shock is considered as Class IIa recommendation, and (3) in patients with atrial fibrillation following a short period of triple antithrombotic therapy, dual antithrombotic therapy (e.g., DOAC and single oral antiplatelet agent preferably clopidogrel) is recommended, with discontinuation of the antiplatelet agent after 6 to 12 months. Furthermore, an aspirin-free strategy after PCI has been investigated in several trials those have started to show the safety and efficacy. The Task Force on Primary PCI of the CVIT group has now proposed the updated expert consensus document for the management of AMI focusing on procedural aspects of primary PCI in 2022 version.
Topics: Consensus; Drug-Eluting Stents; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; ST Elevation Myocardial Infarction; Treatment Outcome
PubMed: 35018605
DOI: 10.1007/s12928-021-00829-9 -
The Cochrane Database of Systematic... Oct 2019Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a vasoconstrictor and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, low-dose aspirin in particular, might prevent or delay development of pre-eclampsia.
OBJECTIVES
To assess the effectiveness and safety of antiplatelet agents, such as aspirin and dipyridamole, when given to women at risk of developing pre-eclampsia.
SEARCH METHODS
For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (30 March 2018), and reference lists of retrieved studies. We updated the search in September 2019 and added the results to the awaiting classification section of the review.
SELECTION CRITERIA
All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent were included. Studies only published in abstract format were eligible for inclusion if sufficient information was available. We would have included cluster-randomised trials in the analyses along with individually-randomised trials, if any had been identified in our search strategy. Quasi-random studies were excluded. Participants were pregnant women at risk of developing pre-eclampsia. Interventions were administration of an antiplatelet agent (such as low-dose aspirin or dipyridamole), comparisons were either placebo or no antiplatelet.
DATA COLLECTION AND ANALYSIS
Two review authors assessed trials for inclusion and extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For this update we incorporated individual participant data (IPD) from trials with this available, alongside aggregate data (AD) from trials where it was not, in order to enable reliable subgroup analyses and inclusion of two key new outcomes. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE.
MAIN RESULTS
Seventy-seven trials (40,249 women, and their babies) were included, although three trials (relating to 233 women) did not contribute data to the meta-analysis. Nine of the trials contributing data were large (> 1000 women recruited), accounting for 80% of women recruited. Although the trials took place in a wide range of countries, all of the nine large trials involved only women in high-income and/or upper middle-income countries. IPD were available for 36 trials (34,514 women), including all but one of the large trials. Low-dose aspirin alone was the intervention in all the large trials, and most trials overall. Dose in the large trials was 50 mg (1 trial, 1106 women), 60 mg (5 trials, 22,322 women), 75mg (1 trial, 3697 women) 100 mg (1 trial, 3294 women) and 150 mg (1 trial, 1776 women). Most studies were either low risk of bias or unclear risk of bias; and the large trials were all low risk of bas. Antiplatelet agents versus placebo/no treatment The use of antiplatelet agents reduced the risk of proteinuric pre-eclampsia by 18% (36,716 women, 60 trials, RR 0.82, 95% CI 0.77 to 0.88; high-quality evidence), number needed to treat for one women to benefit (NNTB) 61 (95% CI 45 to 92). There was a small (9%) reduction in the RR for preterm birth <37 weeks (35,212 women, 47 trials; RR 0.91, 95% CI 0.87 to 0.95, high-quality evidence), NNTB 61 (95% CI 42 to 114), and a 14% reduction infetal deaths, neonatal deaths or death before hospital discharge (35,391 babies, 52 trials; RR 0.85, 95% CI 0.76 to 0.95; high-quality evidence), NNTB 197 (95% CI 115 to 681). Antiplatelet agents slightly reduced the risk of small-for-gestational age babies (35,761 babies, 50 trials; RR 0.84, 95% CI 0.76 to 0.92; high-quality evidence), NNTB 146 (95% CI 90 to 386), and pregnancies with serious adverse outcome (a composite outcome including maternal death, baby death, pre-eclampsia, small-for-gestational age, and preterm birth) (RR 0.90, 95% CI 0.85 to 0.96; 17,382 women; 13 trials, high-quality evidence), NNTB 54 (95% CI 34 to 132). Antiplatelet agents probably slightly increase postpartum haemorrhage > 500 mL (23,769 women, 19 trials; RR 1.06, 95% CI 1.00 to 1.12; moderate-quality evidence due to clinical heterogeneity), and they probably marginally increase the risk of placental abruption, although for this outcome the evidence was downgraded due to a wide confidence interval including the possibility of no effect (30,775 women; 29 trials; RR 1.21, 95% CI 0.95 to 1.54; moderate-quality evidence). Data from two large trials which assessed children at aged 18 months (including results from over 5000 children), did not identify clear differences in development between the two groups.
AUTHORS' CONCLUSIONS
Administering low-dose aspirin to pregnant women led to small-to-moderate benefits, including reductions in pre-eclampsia (16 fewer per 1000 women treated), preterm birth (16 fewer per 1000 treated), the baby being born small-for-gestational age (seven fewer per 1000 treated) and fetal or neonatal death (five fewer per 1000 treated). Overall, administering antiplatelet agents to 1000 women led to 20 fewer pregnancies with serious adverse outcomes. The quality of evidence for all these outcomes was high. Aspirin probably slightly increased the risk of postpartum haemorrhage of more than 500 mL, however, the quality of evidence for this outcome was downgraded to moderate, due to concerns of clinical heterogeneity in measurements of blood loss. Antiplatelet agents probably marginally increase placental abruption, but the quality of the evidence was downgraded to moderate due to low event numbers and thus wide 95% CI. Overall, antiplatelet agents improved outcomes, and at these doses appear to be safe. Identifying women who are most likely to respond to low-dose aspirin would improve targeting of treatment. As almost all the women in this review were recruited to the trials after 12 weeks' gestation, it is unclear whether starting treatment before 12 weeks' would have additional benefits without any increase in adverse effects. While there was some indication that higher doses of aspirin would be more effective, further studies would be warranted to examine this.
Topics: Aspirin; Female; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Maternal Mortality; Platelet Aggregation Inhibitors; Pre-Eclampsia; Pregnancy; Premature Birth; Prenatal Care; Randomized Controlled Trials as Topic
PubMed: 31684684
DOI: 10.1002/14651858.CD004659.pub3 -
Profiles of Drug Substances,... 2015A comprehensive profile of prasugrel HCl is reported herein with 158 references. A full description including nomenclature, formulae, elemental analysis, and appearance... (Review)
Review
A comprehensive profile of prasugrel HCl is reported herein with 158 references. A full description including nomenclature, formulae, elemental analysis, and appearance is included. Methods of preparation for prasugrel HCl, its intermediates, and derivatives are fully discussed. In addition, the physical properties, analytical methods, stability, uses and applications, and pharmacology of prasugrel HCl are also discussed.
Topics: Animals; Chemistry, Pharmaceutical; Drug Stability; Humans; Molecular Structure; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Technology, Pharmaceutical; Thiophenes
PubMed: 26051687
DOI: 10.1016/bs.podrm.2015.01.002 -
Anticoagulation management in haemodialysis patients with atrial fibrillation: evidence and opinion.Nephrology, Dialysis, Transplantation :... Oct 2022In the absence of robust evidence to guide clinical decision-making, the optimal approach to prevent stroke and systemic embolism in haemodialysis (HD) patients with...
In the absence of robust evidence to guide clinical decision-making, the optimal approach to prevent stroke and systemic embolism in haemodialysis (HD) patients with atrial fibrillation (AF) remains moot. In this position paper, studies on oral anticoagulation (OAC) in HD patients with AF are highlighted, followed by an evidence-based conclusion, a critical analysis to identify sources of bias and practical opinion-based suggestions on how to manage anticoagulation in this specific population. It remains unclear whether AF is a true risk factor for embolic stroke in HD. The currently employed cut-off values for the CHA2DS2-VASc score do not adequately discriminate dialysis patients deriving a net benefit from those suffering a net harm from OAC. Anticoagulation initiation should probably be more restrictive than currently advocated by official guidelines. Recent evidence reveals that the superior benefit-risk profile of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) observed in the general population and in moderate chronic kidney disease can be extended to the HD population. VKA may be especially harmful in dialysis patients and should therefore be avoided, in particular in patients with a high bleeding risk and labile international normalized ratio. Dose-finding studies of DOACs suggest that rivaroxaban 10 mg daily and apixaban 2.5 mg twice daily are appropriate choices in dialysis patients. Combined treatment with oral anticoagulants and antiplatelet agents should be reserved for strong indications and limited in time. Left atrial appendage occlusion is a potential attractive solution to reduce the risk of stroke without increasing bleeding propensity, but it has not been properly studied in dialysis patients.
Topics: Humans; Atrial Fibrillation; Rivaroxaban; Platelet Aggregation Inhibitors; Administration, Oral; Renal Dialysis; Anticoagulants; Stroke; Hemorrhage; Risk Factors; Vitamin K
PubMed: 33647941
DOI: 10.1093/ndt/gfab060 -
European Heart Journal Oct 2021The aim of this collaborative document is to provide an update for clinicians on best antithrombotic strategies in patients with aortic and/or peripheral arterial...
Antithrombotic therapies in aortic and peripheral arterial diseases in 2021: a consensus document from the ESC working group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy.
The aim of this collaborative document is to provide an update for clinicians on best antithrombotic strategies in patients with aortic and/or peripheral arterial diseases. Antithrombotic therapy is a pillar of optimal medical treatment for these patients at very high cardiovascular risk. While the number of trials on antithrombotic therapies in patients with aortic or peripheral arterial diseases is substantially smaller than for those with coronary artery disease, recent evidence deserves to be incorporated into clinical practice. In the absence of specific indications for chronic oral anticoagulation due to concomitant cardiovascular disease, a single antiplatelet agent is the basis for long-term antithrombotic treatment in patients with aortic or peripheral arterial diseases. Its association with another antiplatelet agent or low-dose anticoagulants will be discussed, based on patient's ischaemic and bleeding risk as well therapeutic paths (e.g. endovascular therapy). This consensus document aims to provide a guidance for antithrombotic therapy according to arterial disease localizations and clinical presentation. However, it cannot substitute multidisciplinary team discussions, which are particularly important in patients with uncertain ischaemic/bleeding balance. Importantly, since this balance evolves over time in an individual patient, a regular reassessment of the antithrombotic therapy is of paramount importance.
Topics: Anticoagulants; Aorta; Consensus; Fibrinolytic Agents; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Thrombosis
PubMed: 34279602
DOI: 10.1093/eurheartj/ehab390 -
Interventional Neuroradiology : Journal... Feb 2022The use of antiplatelets is widespread in clinical practice. However, for neurointerventional procedures, protocols for antiplatelet use are scarce and practice varies... (Review)
Review
The use of antiplatelets is widespread in clinical practice. However, for neurointerventional procedures, protocols for antiplatelet use are scarce and practice varies between individuals and institutions. This is further complicated by the quantity of antiplatelet agents which differ in route of administration, dosage, onset of action, efficacy and ischemic and hemorrhagic complications. Clarifying the individual characteristics for each antiplatelet agent, and their associated risks, will increasingly become relevant as the practice of mechanical thrombectomy, stenting, coiling and flow diversion procedures grows. The aim of this review is to summarize the existing literature for the use of P2Y12 inhibitors in neurointerventional procedures, examine the quality of the evidence, and highlight areas in need of further research.
Topics: Endovascular Procedures; Humans; Platelet Aggregation Inhibitors; Stents
PubMed: 33947251
DOI: 10.1177/15910199211015042 -
Biochemical Pharmacology Dec 2022Platelets are the main effectors of the thrombotic events occurring at a ruptured atherosclerotic plaque and therefore antiplatelet agents are the mainstay of... (Review)
Review
Platelets are the main effectors of the thrombotic events occurring at a ruptured atherosclerotic plaque and therefore antiplatelet agents are the mainstay of antithrombotic treatment for the prevention of myocardial infarction, atherotrombotic ischemic stroke and critical limb ischemia due to the thrombotic occlusion of the peripheral arteries. Despite great progress in antiplatelet agents over the last two decades, a number of important unmet medical needs still remain, like insufficient efficacy and a high incidence of hemorrhagic complications. Advances in the knowledge of the molecular mechanisms regulating platelet participation in hemostasis and in thrombosis and progress in pharmaceutical design have allowed to identify new drugs for established antiplatelet targets and novel targets for the development of new agents. Among the latter, several innovative approaches have already proceeded to clinical testing, like GPVI antagonism, PAR4 antagonism, PI3K inhibition, and some preliminary results seem promising. Here we review the pharmacologic approaches to platelet inhibition currently available and in development for their effects on platelet activation in vitro and on thrombosis in animal models and in humans. An ideal antithrombotic agent should selectively target events crucial for pathological thrombus formation without affecting hemostasis, an objective so far not achieved: if one or more of the novel agents in development will reach this goal this will represent a great step forward in the prevention of ischemic cardiovascular events.
Topics: Animals; Humans; Platelet Aggregation Inhibitors; Platelet Activation; Blood Platelets; Thrombosis; Fibrinolytic Agents
PubMed: 36243098
DOI: 10.1016/j.bcp.2022.115297