Optimal duration and combination of antiplatelet therapies following percutaneous coronary intervention: a meta-analysis.

Abstract Introduction The ideal duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) is still unknown. In this meta-analysis, we aimed to compare very short-term (1–3 months), short-term (6 months), standard-term (12 months) and long-term (>12 months) DAPT durations for efficacy and safety. Methods Overall DAPT comparisons were classified as "any shorter-term"/"any longer-term" DAPT. The primary outcome was a composite of major adverse cardiovascular events (MACE: non-fatal myocardial infarction, non-fatal stroke and cardiovascular death). The primary safety outcome was major bleeding. Results Twenty-six studies comprising 103.394 patients were included. Compared with standard-term DAPT duration, very short-term DAPT duration with subsequent drop of aspirin (RR 1.06, 95% CI, 0.95–1.18, p = 0.26) or drop of the P2Y12 inhibitor (RR 0.92, 95% CI, 0.72-1.16, p = 0.47) was not associated with a higher risk of MACE. Any longer-term compared with any shorter-term DAPT durations led to a significantly lower risk of MACE (RR 0.88, 95% CI, 0.81–0.96, p = 0.002), but a significantly higher risk of BARC 3-5 major bleeding events (RR 1.63, 95% CI, 1.22–2.17, p = 0.001). In the ACS subgroup receiving prasugrel or ticagrelor but not clopidogrel, any longer-term DAPT duration was associated with a significantly lower risk of MACE compared to any shorter-term DAPT duration (RR 0.84, 95% CI, 0.77–0.92, p = 0.0001). Conclusion DAPT may be shortened to 1-3 months in patients with low ischemic but high bleeding risk followed by aspirin or P2Y12 monotherapy. Prasugrel or ticagrelor based DAPT may be extended to >12 months in case of high ischemic and low bleeding risk. PROSPERO registration no CRD42020163719

The role of acetylsalicylic acid and circulating microRNAs in primary prevention of cardiovascular events in patients with Diabetes Mellitus Type 2 - a review

Introduction. Type 2 diabetes mellitus (T2DM) is a common metabolic disorder, which carries a risk for atherosclerosis and cardiovascular impairment. The purpose of this review is to demonstrate the role of acetylsalicylic acid (ASA) in primary cardiovascular prevention in T2DM patients, as well as present an outline of microRNAs (miRNA) relevant to ASA therapy and should be evaluated as targets to improve treatment. Brief description of state of knowledge. Although the etiology of hypercoagulable state in T2DM is considered multifactorial, attention mainly focuses on platelet disturbances. Platelets in T2DM not only demonstrate intensified adhesion, activation, aggregation, and thrombin generation, but are likely to deliver miRNAs at specific sites of action in the cardiovascular system, hence contributing to the pathogenesis of cardiovascular events. Objective. Since cardiovascular disease (CVD) is currently the leading cause of mortality among T2DM patients, appropriate risk stratification and management is necessary to reduce morbidity and mortality in this group. A large number of T2DM patients show inadequate response to antiplatelet therapy, which currently revolves around ASA, despite compliance with treatment regimens proposed by the guidelines. Conclusions. The review shows that the use of ASA for primary prevention is beneficial in patients at high cardiovascular risk. However, it is important to select patients in whom ASA therapy will bring the most beneficial outcome with minimal risk for adverse effects. This can be potentially achieved with the use of unique biomarkers. The biologically diverse characteristics of miRNA make them a promising novel biomarker and potential tool for better risk stratification, as well as antiplatelet therapy optimization

Ticagrelor – toward more efficient platelet inhibition and beyond

Michał J Kubisa,1 Mateusz P Jezewski,1 Aleksandra Gasecka,2,3 Jolanta M Siller-Matula,4 Marek Postuła1 1Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CEPT), 21st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland; 3Vesicle Observation Centre, Laboratory of Experimental Clinical Chemistry, Academic Medical Centre, University of Amsterdam, the Netherlands; 4Department of Cardiology, Medical University of Vienna, Vienna, Austria Abstract: Novel antiplatelet drugs, including ticagrelor, are being successively introduced into the therapy of atherothrombotic conditions due to their superiority over a standard combination of clopidogrel with acetylsalicylic acid in patients with acute coronary syndromes (ACS). A P2Y12 receptor antagonist, ticagrelor, is unique among antiplatelet drugs, because ticagrelor inhibits the platelet P2Y12 receptor in a reversible manner, and because it demonstrates a wide palette of advantageous pleiotropic effects associated with the increased concentration of adenosine. The pleiotropic effects of ticagrelor comprise cardioprotection, restoration of the myocardium after an ischemic event, promotion of the release of anticoagulative factors and, eventually, anti-inflammatory effects. Beyond the advantageous effects, the increased concentration of adenosine is responsible for some of ticagrelor’s adverse effects, including dyspnea and bradycardia. Large-scale clinical trials demonstrated that both standard 12-month therapy and long-term use of ticagrelor reduce the risk of cardiovascular events in patients with ACS, but at the expense of a higher risk of major bleeding. Further trials focused on the use of ticagrelor in conditions other than ACS, including ischemic stroke, peripheral artery disease and status after coronary artery bypass grafting. The results of these trials suggest comparable efficacy and safety of ticagrelor and clopidogrel in extra-coronary indications, but firm conclusions are anticipated from currently ongoing studies. Here, we summarize current evidence on the superiority of ticagrelor over other P2Y12 antagonists in ACS, discuss the mechanism underlying the drug–drug interactions and pleiotropic effects of ticagrelor, and present future perspectives of non-coronary indications for ticagrelor. Keywords: ticagrelor, P2Y12, antiplatelet drugs, myocardial infarction, acute coronary syndromes, pleiotropis

Expression Patterns of MiR-125a and MiR-223 and Their Association with Diabetes Mellitus and Survival in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome

Background: MicroRNAs (miRNA, miR) are small, non-coding RNAs which have become increasingly relevant as diagnostic and prognostic biomarkers. The objective of this study was the investigation of blood-derived miRNAs and their link to long-term all-cause mortality in patients who suffered from non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods: This study was an observational prospective study, which included 109 patients with NSTE-ACS. Analysis of the expression of miR-125a and miR-223 was conducted by polymerase chain reaction (PCR). The follow-up period comprised a median of 7.5 years. Long-term all-cause mortality was considered as the primary endpoint. Adjusted Cox-regression analysis was performed for prediction of events. Results: Increased expression of miR-223 (>7.1) at the time point of the event was related to improved long-term all-cause survival (adjusted (adj.) hazard ratio (HR) = 0.09, 95% confidence interval (95%CI): 0.01–0.75; p = 0.026). The receiver operating characteristic (ROC) analysis provided sufficient c-statistics (area under the curve (AUC) = 0.73, 95%CI: 0.58–0.86; p = 0.034; negative predictive value of 98%) for miR-223 to predict long-term all-cause survival. The Kaplan–Meier time to event analysis showed a separation of the survival curves between the groups at an early stage (log rank p = 0.015). Higher plasma miR-125a levels were found in patients with diabetes mellitus vs. in those without (p = 0.010). Furthermore, increased miR-125a expression was associated with an elevated HbA1c concentration. Conclusions: In this hypothesis-generating study, higher values of miR-223 were related to improved long-term survival in patients after NSTE-ACS. Larger studies are required in order to evaluate whether miR-223 can be used as a suitable predictor for long-term all-cause mortality

Switching between P2Y 12 antagonists – From bench to bedside

Platelet P2Y 12 receptors play a key role in platelet activation and thrombus formation. Accordingly, P2Y 12 receptor antagonists are the cornerstone of secondary prevention of atherothrombotic events in patients undergoing percutaneous coronary intervention (PCI). The availability of different oral P2Y 12 antagonists (clopidogrel, prasugrel, ticagrelor) along with the introduction of the first intravenous P2Y 12 antagonist cangrelor offer an opportunity to individualize antiplatelet therapy according to the changing clinical setting. The recent International Expert Consensus provided the first recommendations on switching between the P2Y 12 antagonists. While the consensus greatly helps to guide switching between P2Y 12 antagonists, a number of controversial clinical scenarios remain where the evidence regarding the optimal switch strategy is scarce. In such clinical scenarios, understanding of the (i) pharmacological properties of P2Y 12 antagonists, (ii) recent evidence from pharmacodynamics studies, clinical trials and registries, and (iii) factors affecting the efficacy and safety of the P2Y 12 antagonists, all summarized below, are crucial to choose the optimal switch strategy

Bioresorbable Vascular Scaffolds—Dead End or Still a Rough Diamond?

Percutaneous coronary interventions with stent-based restorations of vessel patency have become the gold standard in the treatment of acute coronary states. Bioresorbable vascular scaffolds (BVS) have been designed to combine the efficiency of drug-eluting stents (DES) at the time of implantation and the advantages of a lack of foreign body afterwards. Complete resolution of the scaffold was intended to enable the restoration of vasomotor function and reduce the risk of device thrombosis. While early reports demonstrated superiority of BVS over DES, larger-scale application and longer observation exposed major concerns about their use, including lower radial strength and higher risk of thrombosis resulting in higher rate of major adverse cardiac events. Further focus on procedural details and research on the second generation of BVS with novel properties did not allow to unequivocally challenge position of DES. Nevertheless, BVS still have a chance to present superiority in distinctive indications. This review presents an outlook on the available first and second generation BVS and a summary of results of clinical trials on their use. It discusses explanations for unfavorable outcomes, proposed enhancement techniques and a potential niche for the use of BVS

Inflammatory state does not affect the antiplatelet efficacy of potent P2Y12 inhibitors in ACS

Inflammation leads to atherosclerosis and acute coronary syndromes (ACS). We performed a prospective, observational study to assess association between the concentrations of inflammatory markers (high sensitivity C-reactive protein, hsCRP; high sensitivity interleukin6, hsIL-6; soluble CD40 ligand, sCD40 L) and platelet reactivity in 338 patients with ACS treated with ticagrelor and prasugrel. We also assessed whether hsCRP, hsIL-6, and sCD40 L are associated with standard inflammatory markers (white blood cell [WBC] and fibrinogen), and whether they differ according to patient diabetic status and pre-treatment with statins. Concentrations of hsCRP and concentrations of hsIL-6 and sCD40 L were assessed using turbidimetric assay and enzyme-linked immunosorbent assay, respectively. Platelet reactivity was measured using multiple electrode aggregometry. There was only a weak inverse correlation between hsIL-6 and platelet reactivity (r≤-0.125). In contrast, concentration of hsIL6 and hsCRP positively correlated with WBC and fibrinogen (r ≥ 0.199). Insulin-dependent diabetes mellitus (IDDM) was associated with higher concentration of hsIL-6 (p = .014), whereas pre-treatment with statins – with lower concentration of hsIL-6 (p = .035). In conclusion, inflammatory state does not affect the antiplatelet efficacy of potent P2Y12 inhibitors in the acute phase of ACS, confirming the safety and efficacy of potent P2Y12 inhibitors in patients with a high inflammatory burden

Ticagrelor attenuates the increase of extracellular vesicle concentrations in plasma after acute myocardial infarction compared to clopidogrel

Background: Platelet P2Y12 antagonist ticagrelor reduces mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets, leukocytes, and endothelial cells release proinflammatory and prothrombotic extracellular vesicles (EVs), we hypothesized that the release of EVs is more efficiently inhibited by ticagrelor compared to clopidogrel. Objectives: We compared EV concentrations and EV procoagulant activity in plasma of patients after AMI treated with ticagrelor or clopidogrel. Methods: After percutaneous coronary intervention, 60 patients with first AMI were randomized to ticagrelor or clopidogrel. Flow cytometry was used to determine concentrations of EVs from activated platelets (CD61+, CD62p+), fibrinogen+, phosphatidylserine (PS+), leukocytes (CD45+), endothelial cells (CD31+, 146+), and erythrocytes (CD235a+) in plasma at randomization, after 72 hours and 6 months of treatment. A fibrin generation test was used to determine EV procoagulant activity. Results: Concentrations of platelet, fibrinogen+, PS+, leukocyte, and erythrocyte EVs increased 6 months after AMI compared to the acute phase of AMI (P ≤.03). Concentrations of platelet EVs were lower on ticagrelor compared to clopidogrel after 6 months (P =.03). Concentrations of fibrinogen+, PS+, and leukocyte EVs were lower on ticagrelor compared to clopidogrel both after 72 hours and 6 months (P ≤.03). Concentrations of endothelial EVs and EV procoagulant activity did not differ between patient groups and over time (P ≥.17). Conclusions: Ticagrelor attenuates the increase of EV concentrations in plasma after acute myocardial infarction compared to clopidogrel. The ongoing release of EVs despite antiplatelet therapy might explain recurrent thrombotic events after AMI and worse clinical outcomes on clopidogrel compared to ticagrelor