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The Annals of Pharmacotherapy Oct 2022A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit. (Review)
Review
OBJECTIVE
A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit.
DATA SOURCES
Articles were gathered from MEDLINE, Cochrane Reviews, and PubMed databases (1980-2021). Abstracts from scientific meetings were considered. Search terms included ischemic stroke, aspirin, clopidogrel, dipyridamole, ticagrelor, cilostazol, prasugrel, glycoprotein IIb/IIIa inhibitors.
STUDY SELECTION AND DATA EXTRACTION
English-language original and review articles were evaluated. Guidelines from multiple countries were reviewed. Articles were evaluated independently by 2 authors.
DATA SYNTHESIS
An abundance of evidence supports aspirin and clopidogrel use for secondary stroke prevention. In the acute phase (first 21 days postinitial stroke), these medications have higher efficacy for preventing further stroke when combined, but long-term combination therapy is associated with higher hemorrhage rates. Antiplatelet treatment failure is influenced by poor adherence and genetic polymorphisms. Antiplatelet agents such as cilostazol may provide extra benefit over clopidogrel and aspirin, in certain racial groups, but further research in more diverse ethnic populations is needed.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
This review presents the data available on the use of different antiplatelet agents poststroke. Dual therapy, recurrence after initiation of secondary preventative therapy, and areas for future research are discussed.
CONCLUSIONS
Although good evidence exists for the use of certain antiplatelet agents postischemic stroke, there are considerable opportunities for future research to investigate personalized therapies. These include screening patients for platelet polymorphisms that confer antiplatelet resistance and for randomized trials including more racially diverse populations.
Topics: Aspirin; Cilostazol; Clopidogrel; Drug Therapy, Combination; Humans; Ischemic Stroke; Platelet Aggregation Inhibitors; Stroke
PubMed: 35094598
DOI: 10.1177/10600280211073009 -
Cell Nov 2019Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease...
Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.
Topics: Antigens, CD; Apyrase; B-Lymphocytes; Cell Death; Cellular Microenvironment; Child; Cohort Studies; Colon; Dendritic Cells; Dipyridamole; Endothelial Cells; Epithelial Cells; Fibroblasts; Gene Expression Regulation; Genetic Predisposition to Disease; Homeostasis; Humans; Immunoglobulin G; Immunologic Memory; Inflammation; Inflammatory Bowel Diseases; Interferon Type I; Intestinal Mucosa; Macrophages; Methylprednisolone; Myeloid Cells
PubMed: 31730855
DOI: 10.1016/j.cell.2019.10.027 -
Journal of Thrombosis and Haemostasis :... Apr 2023Antiphospholipid syndrome (APS) is a systemic autoimmune disease, where persistent presence of antiphospholipid antibodies (aPL) leads to thrombotic and obstetric... (Review)
Review
Antiphospholipid syndrome (APS) is a systemic autoimmune disease, where persistent presence of antiphospholipid antibodies (aPL) leads to thrombotic and obstetric complications. APS is a paradigmatic thromboinflammatory disease. Thromboinflammation is a pathophysiological mechanism coupling inflammation and thrombosis, which contributes to the pathophysiology of cardiovascular disease. APS can serve as a model to unravel mechanisms of thromboinflammation and the relationship between innate immune cells and thrombosis. Monocytes are activated by aPL into a proinflammatory and procoagulant phenotype, producing proinflammatory cytokines such as tumor necrosis factor α, interleukin 6, as well as tissue factor. Important cellular signaling pathways involved are the NF-κB-pathway, mammalian target of rapamycin (mTOR) signaling, and the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome. All of these may serve as future therapeutic targets. Neutrophils produce neutrophil extracellular traps in response to aPL, and this leads to thrombosis. Thrombosis in APS also stems from increased interaction of neutrophils with endothelial cells through P-selectin glycoprotein ligand-1. NETosis can be targeted not only with several experimental therapeutics, such as DNase, but also through the redirection of current therapies such as defibrotide and the antiplatelet agent dipyridamole. Activation of platelets by aPL leads to a procoagulant phenotype. Platelet-leukocyte interactions are increased, possibly mediated by increased levels of soluble P-selectin and soluble CD40-ligand. Platelet-directed future treatment options involve the inhibition of several platelet receptors activated by aPL, as well as mTOR inhibition. This review discusses mechanisms underlying thromboinflammation in APS that present targetable therapeutic options, some of which may be generalizable to other thromboinflammatory diseases.
Topics: Female; Pregnancy; Humans; Antiphospholipid Syndrome; Thromboinflammation; Endothelial Cells; Inflammation; Thrombosis; TOR Serine-Threonine Kinases
PubMed: 36696191
DOI: 10.1016/j.jtha.2022.12.002 -
Frontiers in Pharmacology 2017PDRN is a proprietary and registered drug that possesses several activities: tissue repairing, anti-ischemic, and anti-inflammatory. These therapeutic properties suggest... (Review)
Review
PDRN is a proprietary and registered drug that possesses several activities: tissue repairing, anti-ischemic, and anti-inflammatory. These therapeutic properties suggest its use in regenerative medicine and in diabetic foot ulcers. PDRN holds a mixture of deoxyribonucleotides with molecular weights ranging between 50 and 1,500 KDa, it is derived from a controlled purification and sterilization process of (Salmon Trout) or (Chum Salmon) sperm DNA. The procedure guarantees the absence of active protein and peptides that may cause immune reactions. and experiments have suggested that PDRN most relevant mechanism of action is the engagement of adenosine A receptors. Besides engaging the A receptor, PDRN offers nucleosides and nucleotides for the so called "salvage pathway." The binding to adenosine A receptors is a unique property of PDRN and seems to be linked to DNA origin, molecular weight and manufacturing process. In this context, PDRN represents a new advancement in the pharmacotherapy. In fact adenosine and dipyridamole are non-selective activators of adenosine receptors and they may cause unwanted side effects; while regadenoson, the only other A receptor agonist available, has been approved by the FDA as a pharmacological stress agent in myocardial perfusion imaging. Finally, defibrotide, another drug composed by a mixture of oligonucleotides, has different molecular weight, a DNA of different origin and does not share the same wound healing stimulating effects of PDRN. The present review analyses the more relevant experimental and clinical evidences carried out to characterize PDRN therapeutic effects.
PubMed: 28491036
DOI: 10.3389/fphar.2017.00224 -
Journal of Thrombosis and Haemostasis :... Nov 2018Despite the development of catheter-based interventions for ischemic and valvular heart disease, hundreds of thousands of people undergo open heart surgery annually for... (Review)
Review
Despite the development of catheter-based interventions for ischemic and valvular heart disease, hundreds of thousands of people undergo open heart surgery annually for coronary artery bypass graft (CABG), valve replacement or cardiac assist device implantation. Cardiac surgery patients are unique because therapeutic anticoagulation is required during cardiopulmonary bypass. Developmental hemostasis and altered drug metabolism affect management in children. This narrative review summarizes the current evidence-based and consensus guidelines regarding perioperative, intraoperative and postoperative antithrombotic therapy in patients undergoing cardiac surgery. Anticoagulation preoperatively is required in the setting of cardiac arrhythmias, prior valve replacement or history of venous thromboembolism. In patients with ischemic heart disease, aspirin is continued in the perioperative period, whereas oral P2Y antagonists are withheld for 5-7 days to reduce the risk of perioperative bleeding. Intraoperative management of cardiopulmonary bypass in adults and children includes anticoagulation with unfractionated heparin. Variability in dose-response to heparin and influence of other medical conditions on dosing and reversal of heparin make intraoperative anticoagulation challenging. Vitamin K antagonist therapy is the standard anticoagulant after mechanical heart valve or left ventricular assist device (LVAD) implantation. Longer duration of dual antiplatelet therapy is recommended after CABG if patients undergo surgery because of acute coronary syndrome. Antiplatelet therapy after LVAD implantation includes aspirin, dipyridamole and/or clopidogrel in children and aspirin in adults. A coordinated approach between hematology, cardiology, anesthesiology, critical care and cardiothoracic surgery can assist to balance the risk of thrombosis and bleeding in patients undergoing cardiac surgery.
Topics: Adolescent; Adult; Anticoagulants; Aspirin; Blood Coagulation; Cardiac Surgical Procedures; Cardiology; Child; Coronary Artery Bypass; Drug Administration Schedule; Evidence-Based Medicine; Fibrinolytic Agents; Heart Valve Diseases; Heart-Assist Devices; Hemorrhage; Hemostasis; Heparin; Humans; Inflammation; Intraoperative Period; Perioperative Period; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Protamines; Risk; Thrombolytic Therapy; Thrombosis; Vitamin K
PubMed: 30153372
DOI: 10.1111/jth.14276 -
JAMA Neurology Jun 2019Extracranial carotid and vertebral artery dissection is an important cause of stroke, particularly in younger individuals. In some but not all observational studies, it... (Comparative Study)
Comparative Study Randomized Controlled Trial
Antiplatelet Therapy vs Anticoagulation Therapy in Cervical Artery Dissection: The Cervical Artery Dissection in Stroke Study (CADISS) Randomized Clinical Trial Final Results.
IMPORTANCE
Extracranial carotid and vertebral artery dissection is an important cause of stroke, particularly in younger individuals. In some but not all observational studies, it has been associated with a high risk of recurrent stroke. Both antiplatelet agents (APs) and anticoagulants (ACs) are used to reduce stroke risk, but whether 1 treatment strategy is more effective is unknown.
OBJECTIVE
To determine whether AP or AC therapy is more effective in preventing stroke in cervical dissection and the risk of recurrent stroke in a randomized clinical trial setting. A secondary outcome was to determine the effect on arterial imaging outcomes.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, prospective, open-label international multicenter parallel design study with central blinded review of both clinical and imaging end points. Recruitment was conducted in 39 stroke and neurology secondary care centers in the United Kingdom and 7 centers in Australia between February 24, 2006, and June 17, 2013. One-year follow-up and analysis was conducted in 2018. Two hundred fifty participants with extracranial carotid and vertebral dissection with symptom onset within the last 7 days were recruited. Follow-up data at 1 year were available for all participants.
INTERVENTIONS
Randomization to AP or AC (heparin followed by warfarin) for 3 months, after which the choice of AP and AC agents was decided by the local clinician.
MAIN OUTCOMES AND MEASURES
The primary end point was ipsilateral stroke and death. A planned per protocol (PP) analysis was performed in patients meeting the inclusion criteria following central review of imaging to confirm the diagnosis of dissection. A secondary end point was angiographic recanalization in those with imaging confirmed dissection.
RESULTS
Two hundred fifty patients were randomized (118 carotid and 132 vertebral), 126 to AP and 124 to AC. Mean (SD) age was 49 (12) years. Mean (SD) time to randomization was 3.65 (1.91) days. The recurrent stroke rate at 1 year was 6 of 250 (2.4%) on ITT analysis and 5 of 197 (2.5%) on PP analysis. There were no significant differences between treatment groups for any outcome. Of the 181 patients with confirmed dissection and complete imaging at baseline and 3 months, there was no difference in the presence of residual narrowing or occlusion between those receiving AP (n = 56 of 92) vs those receiving AC (n = 53 of 89) (P = .97).
CONCLUSIONS AND RELEVANCE
During 12 months of follow-up, the number of recurrent strokes was low. There was no difference between treatment groups in outcome events or the rate of recanalization.
TRIAL REGISTRATION
ISRCTN.com Identifier: CTN44555237.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Carotid Artery, Internal, Dissection; Clopidogrel; Dipyridamole; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Mortality; Platelet Aggregation Inhibitors; Recurrence; Secondary Prevention; Stroke; Treatment Outcome; Vertebral Artery Dissection; Warfarin; Young Adult
PubMed: 30801621
DOI: 10.1001/jamaneurol.2019.0072 -
Stroke and Vascular Neurology Oct 2022Antiplatelet therapy is one of the mainstays for secondary stroke prevention. This narrative review aimed to highlight the current evidence and recommendations of... (Meta-Analysis)
Meta-Analysis
Antiplatelet therapy is one of the mainstays for secondary stroke prevention. This narrative review aimed to highlight the current evidence and recommendations of antiplatelet therapy for stroke prevention.We conducted advanced literature search for antiplatelet therapy. Landmark studies and randomised controlled trials evaluating antiplatelet therapy for secondary stroke prevention are reviewed. Results from Cochrane systematic review, pooled data analysis and meta-analysis are discussed.Single-antiplatelet therapy (SAPT) with aspirin, aspirin/extended-release dipyridamole or clopidogrel reduces the risk of recurrent ischaemic stroke in patients with non-cardioembolic ischaemic stroke or transient ischaemic attack (TIA). Dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel or ticagrelor for 21-30 days is more effective than SAPT in patients with minor acute noncardioembolic ischaemic stroke or high-risk TIA. Prolonged use of DAPT is associated with higher risk of haemorrhage without reduction in stroke recurrence than SAPT. Compared with placebo, aspirin reduces the relative risk of recurrent stroke by approximately 22%. Aspirin/dipyridamole and cilostazol are superior to aspirin but associated with significant side effects. Cilostazol or ticagrelor might be more effective than aspirin or clopidogrel in patients with intracranial stenosis.SAPT is indicated for secondary stroke prevention in patients with non-cardioembolic ischaemic stroke or TIA. DAPT with aspirin and clopidogrel or ticagrelor for 21-30 days followed by SAPT is recommended for patients with minor acute noncardioembolic stroke or high-risk TIA. Selection of appropriate antiplatelet therapy should also be based on compliance, drug tolerance or resistance.
Topics: Humans; Aspirin; Brain Ischemia; Cilostazol; Clopidogrel; Dipyridamole; Ischemic Attack, Transient; Ischemic Stroke; Platelet Aggregation Inhibitors; Stroke; Ticagrelor
PubMed: 35393359
DOI: 10.1136/svn-2021-001166