ticagrelor and Atherosclerosis

The aim of this study was to evaluate the efficacy and safety of antithrombotic regimens and their combinations in preventing thrombotic incidents in patients with stable atherosclerotic cardiovascular disease (S-ASCVD).. A systematic literature search was conducted in the PubMed, Embase, Cochrane Library, Scopus, and Google Scholar databases. The primary comprehensive endpoint was a major adverse cardiovascular event (MACE) composite of cardiovascular death, stroke, or myocardial infarction, while the secondary endpoints were cardiovascular death, all-cause stroke, ischemic stroke, myocardial infarction, and all-cause death. The safety endpoint was major bleeding. Bayesian network meta-regression analysis in R software was used to calculate the final effect size and to correct for the effect of follow-up time on the outcome effect size.. Twelve studies reporting 122,190 patients with eight antithrombotic regimens were included in this systematic review. For the primary composite endpoint, low-dose aspirin plus clopidogrel 75 mg (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.33-0.87) and low-dose aspirin plus rivaroxaban 2.5 mg twice daily (HR 0.53, 95% CI 0.34-0.82) showed significantly better efficacy than clopidogrel monotherapy, and the efficacy was comparable among the first two regimens. Unfortunately, none of the active regimens significantly decreased all-cause death, cardiovascular death branch, and all-cause stroke as part of the secondary endpoints. Low-dose aspirin plus ticagrelor 90 mg twice daily (HR 0.81, 95% CI 0.69-0.94) and low-dose aspirin plus ticagrelor 60 mg twice daily (HR 0.84, 95% CI 0.74-0.95) had a significant advantage in myocardial infarction compared with low-dose aspirin monotherapy, while low-dose aspirin plus 2.5 mg rivaroxaban twice daily (HR 0.62, 95% CI 0.41-0.94) was better than low-dose aspirin in the treatment of ischemic stroke. In the major bleeding branch, low-dose aspirin plus ticagrelor 90 mg twice daily (HR 2.2, 95% CI 1.70-2.90), low-dose aspirin plus ticagrelor 60 mg twice daily (HR 2.1, 95% CI 1.70-2.60), low-dose aspirin plus rivaroxaban 2.5 mg twice daily (HR 1.7, 95% CI 1.30-2.00), and rivaroxaban 5 mg twice daily (HR 1.5, 95% CI 1.20-1.90) showed higher major bleeding risk compared with low-dose aspirin.. Considering MACEs, myocardial infarction, all kinds of stroke, ischemic stroke, and major bleeding, low-dose aspirin plus rivaroxaban 2.5 mg twice daily should be considered the preferred regimen for S-ASCVD patients with low bleeding risk.

Topics: Aspirin; Atherosclerosis; Bayes Theorem; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Ischemic Stroke; Myocardial Infarction; Network Meta-Analysis; Platelet Aggregation Inhibitors; Regression Analysis; Rivaroxaban; Stroke; Ticagrelor

Randomized trials did not consistently support superiority of ticagrelor, as monotherapy or in combination with aspirin, in terms of efficacy or safety, in patients with atherosclerotic artery disease.. Medline, EMBASE, the Cochrane Central Register of Controlled Trials, and scientific session abstracts were searched for trials of patients with coronary or peripheral artery disease (with >1,000 participants and a follow-up ≥3 months) randomly assigned to ticagrelor-based or conventional antiplatelet therapies. Trial-level hazard ratios (HRs) were pooled using a fixed- or random-effect model (in case of significant heterogeneity) with the inverse variance weighting. The primary outcome was all-cause mortality. Other outcomes were myocardial infarction (MI), stroke, and major bleeding.. Overall 77,489 patients received either ticagrelor-based (n = 38,721) or conventional antiplatelet regimens (n = 38,768) in 6 trials. The primary outcome occurred in 4.5% of patients treated with experimental therapy and 4.9% of patients treated with control therapy (HR = 0.91, 95% CI 0.81-1.01; P = .07). Overall, patients treated with ticagrelor-based versus conventional antiplatelet regimens showed no significant difference in terms of all-cause death, MI, stroke, or major bleeding after 20 months. However, in trials of patients with coronary artery disease as primary diagnosis, the risk for all-cause death (HR = 0.84 [0.77-0.91], P < .001) and MI (HR = 0.87 [0.80-0.94], P = .007) was significantly reduced by experimental therapy.. In patients with atherosclerotic artery disease, the benefit of ticagrelor-based therapies was confined to patients treated for coronary artery disease. The drug significantly reduced the risk for all-cause death and MI without excess risk of bleeding in these patients. In consideration of limitations of subgroup analyses, these results need further validation.

Topics: Atherosclerosis; Cause of Death; Coronary Artery Disease; Hemorrhage; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Stroke; Ticagrelor

Antiplatelet therapy is recommended among patients with established atherosclerosis. We compared monotherapy with a P2Y. In this systematic review and meta-analysis, all randomised trials comparing P2Y. A total of nine randomised trials were identified and included in this study, and 42 108 patients randomly allocated to a P2Y. Compared with aspirin monotherapy, P2Y. Italian Ministry of Education.

Topics: Aged; Aspirin; Atherosclerosis; Cerebrovascular Disorders; Clopidogrel; Coronary Disease; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Assessment; Secondary Prevention; Stroke; Ticagrelor; Ticlopidine

More potent antithrombotic strategies have significantly reduced the rate of recurrent ischemic events in cardiovascular disease. Ticagrelor, in particular, has significantly improved the outcome in patients with acute coronary syndromes, offering potential benefits also in terms of survival. In addition, more recent data have suggested that the advantages of ticagrelor could be extended also to non-coronary atherothrombotic disease, although with contrasting results, especially for mortality reduction. The aim of the present meta-analysis was to investigate the safety and effectiveness of a newer antiplatelet strategy with ticagrelor as compared to traditional antiplatelet regimens in patients with coronary or non-coronary atherothrombotic disease.. Literature and main scientific session abstracts were searched for studies comparing a ticagrelor-based antiplatelet regimen vs. different antiplatelet agents in the secondary prevention of cardiac, cerebral or vascular atherothrombotic events. The primary efficacy endpoint was mortality, primary safety endpoint was the occurrence of major bleedings. Secondary endpoints were myocardial infarction and stroke.. We included 10 randomized clinical trials, for a total population of 73,121 patients, 54.9% randomized to ticagrelor. At a mean follow-up of 13.4 ± 12.6 months, a newer antiplatelet strategy based on ticagrelor was associated with a significant reduction in mortality as compared to a traditional therapy (OR[95%CI] = 0.92[0.86,0.99], p=0.02; phet = 0.14), however, such benefits were more evident in patients with coronary artery disease, while not in non-coronary trials, with a significant interaction between patients' setting and the prognostic impact of ticagrelor (p int = 0.03). A similar result was achieved for cardiovascular mortality, recurrent myocardial infarction, while for the risk of stroke, the largest advantages were observed in patients with a previous cerebrovascular accident. Major bleeding events were increased in ticagrelor treated patients (OR [95%CI] = 1.11 [1.02, 1.20], p=0.01; phet = 0.0003), although not affecting overall mortality, as confirmed by meta-regression analysis.. Based on the current meta-analysis, a newer antiplatelet strategy based on ticagrelor is associated with a significant reduction in mortality and recurrent cardiovascular events, as compared to a traditional treatment, among patients treated for coronary disease but not among those with non-coronary atherothrombotic disease. However, ticagrelor therapy was associated with a significant increase in major bleeding complications.

Topics: Atherosclerosis; Coronary Artery Disease; Coronary Thrombosis; Humans; Randomized Controlled Trials as Topic; Thrombosis; Ticagrelor

Ticagrelor is a cornerstone of modern antithrombotic therapy alongside aspirin in patients with acute coronary syndrome and after percutaneous coronary intervention. Adverse effects such as bleeding and dyspnea have been associated with premature ticagrelor discontinuation, which may limit any potential advantage of ticagrelor over clopidogrel. The randomized trials of ticagrelor captured adverse events, offering the opportunity to more precisely quantify these effects across studies. Therefore, a meta-analysis of 4 randomized clinical trials of ticagrelor conducted between January 2007 and June 2017 was performed to quantify the incidence and causes of premature ticagrelor discontinuation. Among 66,870 patients followed for a median 18 months, premature ticagrelor discontinuation was seen in 25%; bleeding was the most common cause of discontinuation followed by dyspnea. Versus the comparators, the relative risk of dyspnea-related discontinuation during follow-up was 6.4-fold higher, the relative risk of bleeding was 3.2-fold higher, and the relative risk of discontinuation due to any adverse event was 59% higher for patients receiving ticagrelor. Understanding these potential barriers to adherence to ticagrelor is crucial for informed patient-physician decision making and can inform future efforts to improve ticagrelor adherence. This review discusses the incidence, causes, and biological mechanisms of ticagrelor-related adverse effects and offers strategies to improve adherence to ticagrelor.

Topics: Acute Coronary Syndrome; Atherosclerosis; Humans; Medication Adherence; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Secondary Prevention; Ticagrelor

To provide an overview of selected randomized studies reported over the last 2 years evaluating antiplatelet therapies in patients with either acute or stable manifestations of atherosclerosis.. From large outcome trials included evidence for reduced risk of ischemic events associated with use of ticagrelor and aspirin versus aspirin alone, albeit with an increased bleeding risk in patients with stable coronary artery disease and history of myocardial infarction. No benefit regarding ischemic outcomes could be demonstrated for ticagrelor monotherapy compared with aspirin or clopidogrel in patients with stroke or peripheral vascular disease, respectively. Results from pharmacokinetic/pharmacodynamic studies suggest that switching from prasugrel to ticagrelor is safe, regardless of the use of a loading dose, and that loading with prasugrel or ticagrelor compared with clopidogrel leads to more prompt and potent platelet inhibition in patients undergoing ad hoc percoutaneous coronary intervention. No evidence could be demonstrated for the prognostic value of routine platelet function monitoring to adjust antiplatelet therapy.. Large outcome trials demonstrated various effects of antithrombotic strategies including ticagrelor on clinical outcomes across patient populations. Pharmacokinetic/pharmacodynamic studies confirmed a more prompt and potent platelet inhibition after loading with the new P2Y12 inhibitors versus clopidogrel, and suggested the safety of switching from prasugrel to ticagrelor.

Topics: Acute Coronary Syndrome; Adenosine; Aspirin; Atherosclerosis; Blood Platelets; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Ticagrelor; Ticlopidine

Although the rate of cardiovascular disease (CVD)-related mortality has declined over the last decade, it is still the leading cause of mortality in the USA, accounting for over 1.4 million deaths annually. In addition, total direct (primarily hospital admissions) and indirect costs of CVD in the US is over $316 billion annually and is expected to grow to over $918 billion by 2030. Much of the etiology of CVD is due to atherosclerosis and its thrombotic complications, and central to this is the role of platelets. Atherosclerosis is a systemic disease, with meaningful morbidity and mortality when present in the coronary, cerebral, or major peripheral arteries. The recommended antiplatelet therapy differs based on the vascular bed impacted, with the optimal antiplatelet therapy yet to be defined. The PARTHENON program is a series of completed and ongoing phase III clinical trials investigating the efficacy and safety of ticagrelor in atherosclerotic CVD in comparison with established antiplatelet therapy or placebo. The overall aim of the program is to determine if more potent antiplatelet therapy, with different pharmacology, may reduce cardiovascular events in patients with atherosclerotic disease.

Topics: Adenosine; Atherosclerosis; Cardiovascular Diseases; Humans; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor

The effect and clinical benefit of P2Y12 receptor antagonists may not be limited to platelet inhibition and the prevention of arterial thrombus formation. Potential additional effects include reduction of the pro-inflammatory role of activated platelets and effects related to P2Y12 receptor inhibition on other cells apart from platelets. P2Y12 receptor antagonists, thienopyridines and ticagrelor, differ in their mode of action being prodrugs instead of direct acting and irreversibly instead of reversibly binding to P2Y12 . These key differences may provide different potential when it comes to additional effects. In addition to P2Y12 receptor blockade, ticagrelor is unique in having the only well-documented additional target of inhibition, the equilibrative nucleoside transporter 1. The current review will address the effects of P2Y12 receptor antagonists beyond platelets and the protection against arterial thrombosis. The discussion will include the potential for thienopyridines and ticagrelor to mediate anti-inflammatory effects, to conserve vascular function, to affect atherosclerosis, to provide cardioprotection and to induce dyspnea.

Topics: Adenosine; Animals; Atherosclerosis; Blood Platelets; Cardiotonic Agents; Cardiovascular Physiological Phenomena; Equilibrative Nucleoside Transporter 1; Humans; Inflammation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thienopyridines; Ticagrelor

Ticagrelor (P2Y12 receptor antagonist) is presently indicated for preventing atherothrombotic events in patients with acute coronary syndrome and patients with a history of myocardial infarction. The PARTHENON clinical development program comprises five randomized, controlled, cardiovascular, indication-seeking outcome studies, aiming to evaluate ticagrelor across the spectrum of patients with atherothrombotic disease. Results of two large-scale trials support a benefit for ticagrelor in patients with acute coronary syndrome (PLATO; ClinicalTrials.gov: NCT00391872) and in patients with a history of myocardial infarction (PEGASUS-TIMI 54; ClinicalTrials.gov: NCT01225562). Ongoing trials will provide information on the efficacy and safety of ticagrelor in patients with acute ischemic stroke or transient ischemic attack (SOCRATES; ClinicalTrials.gov: NCT01994720), peripheral artery disease (EUCLID; ClinicalTrials.gov: NCT01732822) and coronary artery disease in patients with Type 2 diabetes mellitus (THEMIS: ClinicalTrials.gov: NCT01991795).

Topics: Acute Coronary Syndrome; Adenosine; Atherosclerosis; Diabetes Mellitus, Type 2; Humans; Myocardial Infarction; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Ticagrelor; Treatment Outcome

Platelets play a key role in the initiation of hemostatic mechanisms during vascular injury. When contemplating prescription of antiplatelet agents (APAs) for patients as primary prevention for cardiovascular events, the physician should carefully weigh the potential benefits of cardiovascular risk reduction with the likelihood of harm, related mostly to hemorrhagic complications. The role of APAs in secondary prevention of atherosclerosis and coronary artery disease is well established, however, optimal duration of therapy and intensity of patient treatment are not settled and probably need to be individualized per patient. We describe the data emerging from contemporary trials on the efficacy and safety of the use of oral APAs in various patient subpopulations. We also discuss the advantages and potential roles of new APAs during and following acute coronary syndromes, percutaneous coronary interventions, and symptomatic atherosclerosis. We propose certain strategies and directions for future research to enhance the safety and efficacy prevention by optimizing the beneficial effects of APAs along with other contemporary treatment modalities of primary and secondary prevention.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Aspirin; Atherosclerosis; Clopidogrel; Coronary Artery Disease; Female; Humans; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Risk Factors; Thiophenes; Ticagrelor; Ticlopidine

Acute coronary syndromes (ACS) remain life-threatening disorders associated with high morbidity and mortality, despite advances in treatment over the last decade. Adenosine diphosphate-induced platelet activation via P2Y(12) receptors plays a pivotal role in the pathophysiology of ACS. The current standard of treatment involves dual antiplatelet therapy with aspirin (acetylsalicylic acid) and the thienopyridine clopidogrel. Numerous studies and wide use in clinical practice have established the value of this approach in the treatment of ACS. However, clopidogrel treatment has a number of limitations, including a delayed onset of action due to the need for metabolic activation, variable and reduced antiplatelet effects in patients with certain genotypes, and prolonged recovery of platelet function due to irreversible P2Y(12) receptor binding. Prasugrel, a new thienopyridine, has demonstrated more consistent inhibition of platelet aggregation (IPA) than clopidogrel, although this thienopyridine also requires metabolic activation and treatment is associated with a significantly increased risk of life-threatening and fatal bleeding. The recently approved oral antiplatelet agent ticagrelor has the potential to overcome some of the limitations of current therapy due to its unique pharmacokinetic and pharmacodynamic profiles. It is a member of a new chemical class, the cyclopentyltriazolopyrimidines, and is a potent P2Y(12) receptor antagonist. Ticagrelor is rapidly absorbed, with a median time to maximum concentration of 1.3-2.0 hours. Ticagrelor does not require metabolic activation to an active form and binds rapidly and reversibly to the P2Y(12) receptor. As well as exerting effects via platelet P2Y(12) receptors, ticagrelor may confer additional benefits via inhibition of non-platelet P2Y(12) receptors. The pharmacokinetic profile of ticagrelor is not significantly affected by age, gender or administration with food, nor by prior treatment with, or responsiveness to, clopidogrel. Ticagrelor is primarily metabolized via the cytochrome P450 (CYP) 3A4 enzyme, rapidly produces plasma concentration-dependent IPA that is greater and more consistent than that observed with clopidogrel, and can also enhance platelet inhibition and overcome non-responsiveness in patients previously treated with clopidogrel. Importantly, the pharmacodynamic characteristics of ticagrelor are not influenced by CYP2C19 and ABCB1 genotypes. This article summarizes our current knowledge r

Topics: Acute Coronary Syndrome; Adenosine; Administration, Oral; Animals; Atherosclerosis; Coronary Artery Disease; Drug Interactions; Humans; Pharmacogenetics; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Ticagrelor

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y(12) receptor antagonist that blocks ADP-induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y(12) receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate greater separation between antithrombotic effects and bleeding effects with ticagrelor than with thienopyridines. Unlike the thienopyridines, ticagrelor does not require metabolic activation. It is quickly absorbed and exhibits a rapid antiplatelet effect, with higher and more consistent levels of inhibition of platelet aggregation (IPA) being maintained across the dosing interval than with clopidogrel. IPA levels decline with plasma drug levels after discontinuation of dosing. In the phase II DISPERSE-2 trial of 990 patients with non-ST-elevation acute coronary syndromes (ACS), ticagrelor treatment with 90 mg and 180 mg twice daily showed comparable rates of major and minor bleeding compared with clopidogrel 75 mg while there were numerically fewer myocardial infarctions. Ticagrelor resulted in greater IPA in clopidogrel-naïve patients and produced substantial additional reductions in platelet aggregation activity in patients pretreated with clopidogrel. Ticagrelor treatment was well tolerated in DISPERSE-2, and discontinuation rates were comparable to those observed for clopidogrel. An increased risk of mild to moderate dyspnea and mostly asymptomatic ventricular pauses were observed in phase II studies. The mechanisms for these effects are currently being investigated. The efficacy and safety of ticagrelor are being further evaluated in the phase III PLATO trial, involving approximately 18,000 patients with ACS, including both ST-elevation and non-ST-elevation ACS.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Diphosphate; Animals; Atherosclerosis; Clinical Trials as Topic; Clopidogrel; Humans; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Ticlopidine; Vasoconstriction

Topics: Acute Coronary Syndrome; Aged; Atherosclerosis; Case-Control Studies; Clopidogrel; Cysteine Endopeptidases; Cysteine Proteases; Death; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Risk Factors; Stroke; Ticagrelor; Treatment Outcome

Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown.. TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials.. The rate of VTE in patients with atherosclerosis is ≈0.3% per year while on treatment with ≥1 antiplatelet agent, with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk, and they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01225562.

Topics: Aged; Aspirin; Atherosclerosis; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Risk Factors; Ticagrelor; Venous Thromboembolism

Ticagrelor is an effective antiplatelet therapy among patients with atherosclerotic disease and, therefore, could be more effective than aspirin in preventing recurrent stroke and cardiovascular events among patients with embolic stroke of unknown source (ESUS), which includes patients with ipsilateral stenosis <50% and aortic arch atherosclerosis.. We randomized 13 199 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90) within 24 hours of symptom onset. In all patients, investigators informed on the presence of ipsilateral stenosis ≥50%, small deep infarct <15 mm, and on cardiac source of embolism detected after enrollment or rare causes, which allowed to construct an ESUS category in all other patients with documented brain infarction. The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days.. In this post hoc, exploratory analysis, we found no treatment-by-ESUS category interaction. ESUS subgroups have heterogeneous response to treatment (Funded by AstraZeneca).. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720.

Topics: Adenosine; Aged; Aortic Diseases; Aspirin; Atherosclerosis; Carotid Stenosis; Female; Humans; Intracranial Embolism; Ischemic Attack, Transient; Male; Middle Aged; Mortality; Myocardial Infarction; Platelet Aggregation Inhibitors; Recurrence; Stroke; Ticagrelor; Treatment Outcome

Ticagrelor is an effective antiplatelet therapy for patients with coronary atherosclerotic disease and might be more effective than aspirin in preventing recurrent stroke and cardiovascular events in patients with acute cerebral ischaemia of atherosclerotic origin. Our aim was to test for a treatment-by-ipsilateral atherosclerotic stenosis interaction in a subgroup analysis of patients in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial.. SOCRATES was a randomised, double-blind, controlled trial of ticagrelor versus aspirin in patients aged 40 years or older with a non-cardioembolic, non-severe acute ischaemic stroke, or high-risk transient ischaemic attack from 674 hospitals in 33 countries. We randomly allocated patients (1:1) to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-90, given orally) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90, given orally) within 24 h of symptom onset. Investigators classified all patients into atherosclerotic and non-atherosclerotic groups for the prespecified, exploratory analysis reported in this study. The primary endpoint was the time to occurrence of stroke, myocardial infarction, or death within 90 days. Efficacy analysis was by intention to treat. The SOCRATES trial is registered with ClinicalTrials.gov, number NCT01994720.. Between Jan 7, 2014, and Oct 29, 2015, we randomly allocated 13 199 patients (6589 [50%] to ticagrelor and 6610 [50%] to aspirin). Potentially symptomatic ipsilateral atherosclerotic stenosis was reported in 3081 (23%) of 13 199 patients. We found a treatment-by-atherosclerotic stenosis interaction (p=0·017). 103 (6·7%) of 1542 patients with ipsilateral stenosis in the ticagrelor group and 147 (9·6%) of 1539 patients with ipsilateral stenosis in the aspirin group had an occurrence of stroke, myocardial infarction, or death within 90 days (hazard ratio 0·68 [95% CI 0·53-0·88]; p=0·003). In 10 118 patients with no ipsilateral stenosis, 339 (6·7%) of 5047 patients in the ticagrelor group had an occurrence of stroke, myocardial infarction, or death within 90 days compared with 350 (6·9%) of 5071 in the aspirin group (0·97 [0·84-1·13]; p=0·72). There were no significant differences in the proportion of life-threatening bleeding or major or minor bleeding events in patients with ipsilateral stenosis in the ticagrelor group compared with the aspirin group.. In this prespecified exploratory analysis, ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. An understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatments for early stroke prevention.. AstraZeneca.

Topics: Adenosine; Adult; Aged; Aspirin; Atherosclerosis; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fibrinolytic Agents; Humans; International Cooperation; Ischemic Attack, Transient; Male; Middle Aged; Proportional Hazards Models; Stroke; Ticagrelor; Treatment Outcome

The aim of this health economic analysis was to compare the cost-effectiveness of ticagrelor versus clopidogrel within the German health care system. A two-part decision model was adapted to compare treatment with ticagrelor or clopidogrel in a low-dose acetylsalicylic acid (ASA) cohort (≤150 mg) for all ACS patients and subtypes NSTEMI/IA and STEMI. A decision-tree approach was chosen for the first year after initial hospitalization based on trial observations from a subgroup of the PLATO study. Subsequent years were estimated by a Markov model. Following a macro-costing approach, costs were based on official tariffs and published literature. Extensive sensitivity analyses were performed to test the robustness of the model. One-year treatment with ticagrelor is associated with an estimated 0.1796 life-years gained (LYG) and gained 0.1570 quality-adjusted life-years (QALY), respectively, over the lifetime horizon. Overall average cost with ticagrelor is estimated to be EUR 11,815 vs. EUR 11,387 with generic clopidogrel over a lifetime horizon. The incremental cost-effectiveness ratio (ICER) was EUR 2,385 per LYG (EUR 2,728 per QALY). Comparing ticagrelor with Plavix(®) or the lowest priced generic clopidogrel, ICER ranges from dominant to EUR 3,118 per LYG (EUR 3,567 per QALY). These findings are robust under various additional sensitivity analyses. Hence, 12 months of ACS treatment using ticagrelor/ASA instead of clopidogrel/ASA may offer a cost-effective therapeutic option, even when the generic price for clopidogrel is employed.

Topics: Acute Coronary Syndrome; Adenosine; Adult; Atherosclerosis; Clopidogrel; Cost-Benefit Analysis; Decision Trees; Double-Blind Method; Drugs, Generic; Follow-Up Studies; Germany; Humans; Markov Chains; Models, Economic; Myocardial Infarction; Platelet Aggregation Inhibitors; Prospective Studies; Quality-Adjusted Life Years; Thrombosis; Ticagrelor; Ticlopidine; Time Factors

The platelet P2Y(12) receptor is the target of clopidogrel therapy, which has been shown to reduce thromboembolic complications of atherosclerotic disease but has limitations in terms of variability of response and irreversibility of effect. This receptor is also a target for ticagrelor (AZD6140), the first reversibly binding oral P2Y(12) receptor antagonist that does not require metabolic activation and yields more consistent inhibition of platelet aggregation than clopidogrel therapy. Single nucleotide polymorphisms (SNPs) have been described in the gene for this receptor (P2RY12), some of which have been associated with variability in platelet reactivity. SNPs in P2RY1 and ITGB3 have also been reported by some groups to affect platelet reactivity to adenosine diphosphate (ADP). We assessed whether SNPs in these genes influenced the pharmacodynamic response to ticagrelor in patients enrolled in both the DISPERSE study (stable atherosclerotic disease) and the DISPERSE2 study (non-ST-segment elevation acute coronary syndromes). Platelet aggregation data (at baseline and 4 weeks) and DNA samples from clopidogrel-naive Caucasian patients treated with ticagrelor were available for 151 patients. Seventy four SNPs within three genes were genotyped. After adjustment for multiple comparisons, none of these SNPs were found to significantly influence inhibition of ADP-induced platelet aggregation by ticagrelor.

Topics: Adenosine; Adenosine Diphosphate; Area Under Curve; Atherosclerosis; Clopidogrel; Dose-Response Relationship, Drug; Humans; Integrin beta3; Pharmacogenetics; Platelet Aggregation; Polymorphism, Single Nucleotide; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y12; Ticagrelor; Ticlopidine

This double-blind, parallel-group study was conducted to assess the pharmacodynamics, pharmacokinetics, and safety of AZD6140, the first oral, reversible adenosine diphosphate (ADP) receptor antagonist.. Patients (n = 200) with atherosclerosis were randomized to receive AZD6140 50, 100, or 200 mg twice daily (bid) or 400 mg daily (qd) or clopidogrel 75 mg qd for 28 days. All groups received aspirin 75-100 mg qd. AZD6140 (100 and 200 mg bid, 400 mg qd) rapidly and nearly completely inhibited ADP-induced platelet aggregation after initial dosing (day 1) and at day 28. On day 1, peak final-extent inhibition of platelet aggregation (IPA) was observed 2-4 h post-dose with AZD6140, whereas clopidogrel minimally inhibited platelet aggregation (mean percentage IPA < 20%, all time points). Four hour post-dose at steady state, the three higher doses of AZD6140 produced comparable final-extent mean percentage IPA (approximately 90-95%), which exceeded that with AZD6140 50 mg bid or clopidogrel (approximately 60%). AZD6140 was generally well tolerated. All bleeding events, except one in a patient receiving 400 mg qd, were minor and of mild-to-moderate severity.. AZD6140 100 and 200 mg bid were well tolerated and were superior to AZD6140 50 mg bid and clopidogrel 75 mg qd with regard to antiplatelet efficacy.

Topics: Adenosine; Administration, Oral; Adult; Aged; Aged, 80 and over; Aspirin; Atherosclerosis; Bleeding Time; Clopidogrel; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Postmenopause; Ticagrelor; Ticlopidine

It is unclear whether patients with different stroke/transient ischemic attack etiologies benefit differently from gene-directed dual antiplatelet therapy. This study explored the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in transient ischemic attack or minor stroke with different causes in the CHANCE-2 trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events-II).. This was a prespecified analysis of the CHANCE-2 trial, which enrolled 6412 patients with minor stroke or transient ischemic attack who carried. A total of 6336 patients were included in this study. In patients administered ticagrelor-aspirin and clopidogrel-aspirin, respectively, stroke recurred in 85 (9.8%) and 88 (10.7%) patients with large-artery atherosclerosis (hazard ratio, 0.86 [95% CI, 0.63-1.18];. In this prespecified analysis of the CHANCE-2 trial, the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in preventing new stroke were consistent in patients with different causes. The influence of stroke cause on benefit of gene-guided antiplatelet therapy should be explored by further trials.. URL: https://www.. gov; Unique identifier: NCT04078737.

Topics: Aspirin; Atherosclerosis; Clopidogrel; Drug Therapy, Combination; Hemorrhage; Humans; Ischemic Attack, Transient; Platelet Aggregation Inhibitors; Stroke; Ticagrelor; Treatment Outcome

Nanoprodrugs with responsive release properties integrate the advantages of stimuli-responsive prodrugs and nanotechnology. They would provide ultimate opportunity in fighting atherosclerosis. In this study, we synthesized a redox-responsive nanoprodrug of simvastatin (TPTS) by conjugating α-tocopherol polyethylene glycol derivative to the pharmacophore of simvastatin with a thioketal linker. TPTS formed nanoparticles and released parent simvastatin in the presence of hydrogen peroxide. Moreover, by taking advantage of the self-assembly behavior of TPTS, we developed a fibronectin-targeted delivery system (TPTS/C/T) to codelivery simvastatin prodrug and ticagrelor. In vitro and in vivo experiments indicated that TPTS and TPTS/C/T had good stability, which could reduce off-target leakage of drugs. They greatly inhibited the M1-type polarization of macrophages; reduced intracellular reactive oxygen species level and inflammatory cytokine; and TNF-α, MCP-1, and IL-1β were secreted by macrophage cells, thus providing enhanced anti-inflammatory and antioxidant effects compared with free simvastatin. TPTS/C/T realized targeted drug release to plaques and synergistic therapeutic effects of simvastatin and ticagrelor on atherosclerosis treatment in an ApoE-/- mouse model, resulting in excellent atherosclerosis therapeutic efficacy and a promising biosafety profile. Therefore, this study provides a new method for manufacturing statin nanodrugs and a new design idea for related responsive drug release nanosystems for atherosclerosis.

Topics: Animals; Atherosclerosis; Drug Liberation; Fibronectins; Mice; Nanoparticles; Prodrugs; Reactive Oxygen Species; Simvastatin; Ticagrelor

Although ticagrelor has been demonstrated to possess an anti‑atherosclerosis (AS) effect, its underlying mechanism remains unclear. In the present study, it was investigated whether ticagrelor reduces oxidized low‑density lipoprotein (ox‑LDL)‑induced endothelial cell apoptosis, an initial step for the development of AS, and alleviates AS in apolipoprotein‑E‑deficient (ApoE‑/‑) mice by inhibiting the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9). The human endothelial cell line EAhy926 was treated with ox‑LDL, ox‑LDL + ticagrelor (40 µmol/l) and ox‑LDL + ticagrelor (60 µmol/l) for 24 h. Cell apoptosis was detected using Annexin V‑fluorescein isothiocyanate/propidium iodide staining. The expression levels of PCSK9, apoptosis‑associated proteins and signaling pathways were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting. ApoE‑/‑ mice fed a high‑fat diet were used to induce an AS model. After 20 weeks, ApoE‑/‑ mice were randomly assigned to receive saline or ticagrelor intragastrically for 10 days. The formation of atherosclerotic plaques was detected by hematoxylin and eosin staining. The expression of PCSK9 in the arterial tissues was measured by immunohistochemistry. The results demonstrated that treatment with ticagrelor was able to decrease ox‑LDL‑induced apoptosis in a concentration‑dependent manner (40 µmol/l vs. ox‑LDL, 17.58±2.66 vs. 27.25±5.54%; 60 µmol/l vs. ox‑LDL, 12.26±1.54 vs. 27.25±5.54%). The mRNA and protein expression level of PCSK9 significantly decreased following treatment with ticagrelor, accompanied with upregulation of B‑cell lymphoma (Bcl) 2 and downregulation of Bcl‑2 associated X, apoptosis regulator, caspase‑3, p38, phosphorylated‑(p) p38, p‑c‑Jun N‑terminal kinases (JNK), p‑extracellular signal‑regulated kinases and the ratio of p‑JNK to JNK. Histological analysis of arterial tissues revealed ticagrelor markedly decreased the atherosclerotic plaque area and inhibited the expression of PCSK9. The present results suggested that ticagrelor may alleviate AS via downregulation of PCSK9‑mediated endothelial cell apoptosis, which may be JNK‑dependent.

Topics: Animals; Apolipoproteins E; Apoptosis; Atherosclerosis; bcl-2-Associated X Protein; Diet, High-Fat; Endothelial Cells; Gene Expression Regulation; Humans; JNK Mitogen-Activated Protein Kinases; Lipoproteins, LDL; Mice; Mice, Knockout; Proprotein Convertase 9; Ticagrelor

Ticagrelor (TIC), a P2Y purinoceptor 12 (P2Y12)-receptor antagonist, has been widely used to treat patients with acute coronary syndrome. Although animal studies suggest that TIC protects against atherosclerosis, it remains unknown whether it does so through its potent platelet inhibition or through other pathways. Here, we placed hypercholesterolemic Ldlr-/-Apobec1-/- mice on a high-fat diet and treated them with either 25 mg/kg/day of clopidogrel (CLO) or 180 mg/kg/day of TIC for 16 weeks and evaluated the extent of atherosclerosis. Both treatments equally inhibited platelets as determined by ex vivo platelet aggregation assays. The extent of atherosclerosis, however, was significantly less in the TIC group than in the CLO group. Immunohistochemical staining and ELISA showed that TIC treatment was associated with less macrophage infiltration to the atherosclerotic intima and lower serum levels of CCL4, CXCL10, and TNFα, respectively, than CLO treatment. Treatment with TIC, but not CLO, was associated with higher serum activity and tissue level of paraoxonase-1 (PON1), an anti-atherosclerotic molecule, suggesting that TIC might exert greater anti-atherosclerotic activity, compared with CLO, through its unique ability to induce PON1. Although further studies are needed, TIC may prove to be a viable strategy in the prevention and treatment of chronic stable human atherosclerosis.

Topics: Acute Coronary Syndrome; Animals; Aryldialkylphosphatase; Atherosclerosis; Blood Platelets; Clopidogrel; Cross-Sectional Studies; Hypercholesterolemia; Male; Mice; Mice, Inbred C57BL; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Receptors, LDL; Ticagrelor

Ticagrelor reduces cardiovascular events in patients with acute coronary syndrome (ACS). Recent studies demonstrated the expression of P2Y12 on vascular cells including endothelial cells, as well as platelets, and suggested its contribution to atherogenesis. We investigated whether ticagrelor attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein E-deficient (apoe. Ticagrelor treatment for 20 weeks attenuated atherosclerotic lesion progression in the aortic arch compared with control (p < 0.05). Ticagrelor administration for 8 weeks attenuated endothelial dysfunction (p < 0.01). Ticagrelor reduced the expression of inflammatory molecules such as vascular cell adhesion molecule-1, macrophage accumulation, and lipid deposition. Ticagrelor decreased the phosphorylation of JNK in the aorta compared with control (p < 0.05). Ticagrelor and a JNK inhibitor ameliorated impairment of endothelium-dependent vasodilation by adenosine diphosphate (ADP) in wild-type mouse aortic segments. Furthermore, ticagrelor inhibited the expression of inflammatory molecules which were promoted by ADP in HUVEC (p < 0.001). Ticagrelor also inhibited ADP-induced JNK activation in HUVEC (p < 0.05).. Ticagrelor attenuated vascular dysfunction and atherogenesis through the inhibition of inflammatory activation of endothelial cells. These effects might be a potential mechanism by which ticagrelor decreases cardiovascular events in patients with ACS.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Atherosclerosis; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Inflammation Mediators; JNK Mitogen-Activated Protein Kinases; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Phosphorylation; Plaque, Atherosclerotic; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Vasodilation

There is increasing evidence supporting the role of platelets in atherosclerotic vascular disease. The G-protein-coupled receptor P2Y12 is a central mediator of platelet activation and aggregation but has also been linked to platelet-independent vascular disease. Ticagrelor is an oral P2Y12 antagonist that is used as a standard treatment in patients after acute myocardial infarction. However, the effects of ticagrelor on advanced atherosclerosis have not been investigated.. Twenty-week-old apolipoprotein-E-deficient mice received standard chow or standard chow supplemented with 0.15% ticagrelor (approximately 270 mg/kg/day) for 25 weeks. The lesion area was evaluated in the aortic sinus by Movat's pentachrome staining and lesion composition, thickness of the fibrous cap, and size of the necrotic core evaluated by morphometry. RAW 264.7 macrophages were serum starved and treated with ticagrelor in vitro for the detection and quantification of apoptosis. In addition, oxLDL uptake in RAW 264.7 macrophages was evaluated.. A trend toward the reduction of total lesion size was detected. However, data did not reach the levels of significance (control, n=11, 565,881 μm(2) [interquartile range {IQR} 454,778-603,925 μm(2)] versus ticagrelor, n=13, 462,595 μm(2) [IQR 379,740-546,037 μm(2)]; P=0.1). A significant reduction in the relative area of the necrotic core (control, n=11, 0.46 [IQR 0.4-0.51] versus ticagrelor, n=13, 0.34 [IQR 0.31-0.39]; P=0.008), and a significant increase in fibrous caps thickness (control, n=11, 3.7 μm [IQR 3.4-4.2 μm] versus ticagrelor, n=13, 4.7 [IQR 4.3-5.5 μm], P=0.04) were seen in ticagrelor-treated mice. In vitro studies demonstrated a reduction in apoptotic RAW 264.7 macrophages (control 0.07±0.03 versus ticagrelor 0.03±0.03; P=0.0002) when incubated with ticagrelor. Uptake of oxLDL in RAW 264.7 was significantly reduced when treated with ticagrelor (control 9.2 [IQR 5.3-12.9] versus ticagrelor 6.4 [IQR 2.5-9.5], P=0.02).. The present study demonstrates for the first time a plaque-stabilizing effect of ticagrelor in a model of advanced vascular disease, potentially induced by a reduction of oxLDL uptake or an inhibition of apoptosis as seen in vitro.

Topics: Adenosine; Administration, Oral; Animals; Apolipoproteins E; Apoptosis; Atherosclerosis; Disease Models, Animal; Dose-Response Relationship, Drug; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Structure-Activity Relationship; Ticagrelor

Abnormal expression of thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR) was found in patients with acute coronary syndrome. Ticagrelor, an oral platelet ADP P2Y12 receptor antagonist, is widely used in these patients. The aim of this study was to verify whether different doses of ticagrelor regulated plaque progression and platelet activity by modulating TSLP/TSLPR. Seventy-five ApoE-/- mice were randomly divided into five groups: (1) high-cholesterol diet (HCD, n = 15); (2) HCD plus ticagrelor 25 mg/kg/d (T1, n = 15); (3) HCD plus ticagrelor 50 mg/kg/d (T2, n = 15); (4) HCD plus ticagrelor 100 mg/kg/d (T3, n = 15); and (5) a normal diet group (ND, n = 15). At day 0 and at week 16, blood lipids and serum TSLP levels, expression of TSLPR, CD62, and CD63, platelet aggregation, platelet ATP release, PI3K/Akt signaling pathway, and plaque morphology were assessed. HCD increased TSLPR expression and atherosclerosis progression but high-dose ticagrelor (100 mg/kg) moderated this trend. TSLPR was positively correlated with Akt1, platelet aggregation, corrected plaque area, and vulnerability index in the T3 group (P<0.01). In conclusion, low-dose ticagrelor only inhibited platelet activity. Besides this inhibition, high-dose ticagrelor modulated platelet activity and atherosclerosis mediated by TSLPR, potentially through the PI3K/Akt signal pathway.

Topics: Adenosine; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Cholesterol, Dietary; Cytokines; Dose-Response Relationship, Drug; Hyperlipoproteinemia Type II; Immunoglobulins; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; P-Selectin; Phosphatidylinositol 3-Kinases; Platelet Aggregation; Platelet Aggregation Inhibitors; Proto-Oncogene Proteins c-akt; Purinergic P2Y Receptor Antagonists; Random Allocation; Receptors, Cytokine; Signal Transduction; Tetraspanin 30; Thymic Stromal Lymphopoietin; Ticagrelor

Platelets have a fundamental role in atherothrombosis, but their role in early atherogenesis is unclear. The P2Y12 receptor is responsible for amplifying and sustaining platelet activation and P2Y12 inhibition is crucial in modulating the vessel wall response to injury. We therefore examined the role of platelet vs. vessel wall P2Y12 in early atherogenesis and considered the use of P2Y12 antagonists ticagrelor and clopidogrel in modulating this process.. ApoE(-/-) and ApoE(-/-)P2Y12 (-/-) male mice underwent bone marrow transplantation and were fed a western diet for 4 weeks before assessing atherosclerotic burden. Compared with ApoE(-/-) controls, platelet P2Y12 deficiency profoundly reduced platelet reactivity but had no effect on atheroma formation, whereas vessel wall P2Y12 deficiency significantly attenuated atheroma in the aortic sinus and brachiocephalic artery (both P < 0.001). ApoE(-/-) and ApoE(-/-)P2Y12 (-/-) male mice fed western diet plus either twice-daily doses of ticagrelor (100 mg/kg) or daily clopidogrel (20 mg/kg) for 4 weeks exhibited no significant reduction in atheroma compared with control mice fed mannitol. Attenuated P-selectin expression confirmed platelet P2Y12 inhibition in drug-treated mice.. Despite its major contribution to platelet reactivity, platelet P2Y12 has no effect on early atheroma formation, whereas vessel wall P2Y12 is important in this process. Ticagrelor and clopidogrel effectively reduced platelet reactivity but were unable to inhibit early atherogenesis, demonstrating that these P2Y12 inhibitors may not be effective in preventing early disease.

Topics: Adenosine; Animals; Apolipoproteins E; Atherosclerosis; Blood Platelets; Blood Vessels; Clopidogrel; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; P-Selectin; Receptors, Purinergic P2Y12; Ticagrelor; Ticlopidine

Topics: Acute Coronary Syndrome; Adenosine; Adult; Atherosclerosis; Humans; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor

The P2Y12 receptor has proven to be a key target in the prevention of complications associated with atherosclerotic vascular disease especially in the context of acute coronary syndrome and percutaneous coronary intervention in addition to aspirin. Three generations of thienopyridines, ticlopidine, clopidogrel, and prasugrel have proven efficacy in the prevention of ischemic vascular events but with increased bleeding. The concept of individualized tailored therapy has recently emerged with the discovery of the diminished effect of some thienopyridine among carriers of the loss-of-function cytochrome (CYP) P4502C19*2 variant. Non-thienopyridine P2Y12 antagonists have also recently demonstrated that these benefits are not limited to one class of agents or may be generalizable to reversible antagonists of this receptor. Future rational use of these agents will require attention to disease and patient features to strike the optimal balance of benefit to risk.

Topics: Acute Coronary Syndrome; Adenosine; Angioplasty, Balloon, Coronary; Aspirin; Atherosclerosis; Coronary Artery Bypass; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Postoperative Complications; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Stroke; Thiophenes; Ticagrelor

Topics: Adenosine; Atherosclerosis; Humans; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Ticagrelor