Left atrial appendage closure: therapeutic option or solution?

Atrial fibrillation (AF) is the most common type of arrhythmia. AF increases the risk of thromboembolic complications including stroke. Stroke in patients with AF is more severe compared with patients with sinus rhythm. Long-term oral anticoagulant therapy (OAT) is widely used in a large population of patients with AF to prevent arterial thromboembolic events, such as stroke and systemic embolism. However, it is well established that OAT significantly increases the risk of bleeding. Percutaneous left atrial appendage closure (LAAC) is an option for stroke prophylaxis in patients with nonvalvular AF and high risk of bleeding. This paper provides an overview of recent studies that address the effectiveness and safety of LAAC using the Amplatzer Cardiac Plaque and Watchman Left Atrial Appendage System. LAAC provides a superior choice of treatment in patients with absolute contraindication of systemic OAT, in cases of refusal of systemic OAT by a patient, and as a complementary treatment to anticoagulation in patients with embolic events despite adequate OAT. LAAC should be also considered as a therapeutic option for patients with high thromboembolic risk and very high bleeding risk on the basis of individual risk/benefit evaluation for OAT vs. alternative methods of treatment. In general, LAAC becomes more attractive with increasing thromboembolic risk. There is a need for further studies to address the question of whether LAAC is actually the best method for preventing thromboembolism for patients with moderate/high thromboembolic risk and relatively low bleeding risk, to determine the optimum antithrombotic or antiplatelet therapy in patients who underwent LAAC, as well as to conduct direct comparative analysis of LAAC and the use of new oral anticoagulant drugs (NOAC)

A systematic review on the role of bivalirudin in patients undergoing percutaneous coronary interventions: primus inter pares or a falling star?

Intracoronary thrombosis triggered by ruptured or eroded atherosclerotic plaques constitutes the predominant underlying cause of acute coronary syndromes (ACS). Thrombin is considered a central enzyme in hemostasis and thrombosis, and a well-established target for anticoagulant therapies. Bivalirudin was introduced in the clinical practice as a promising, reversible, direct thrombin inhibitor with a predictable anticoagulant effect. Initial randomized clinical trials demonstrated that bivalirudin compared with heparin on top of a glycoprotein IIb/IIIa inhibitor was associated with a significant reduction of major bleeding and favorable net clinical outcomes in patients undergoing percutaneous coronary interventions (PCI). The HORIZON-AMI trial even indicated mortality benefit in bivalirudin-treated patients. Thereby, the 2011 and 2012 European Society of Cardiology Guidelines on the management of non-ST-segment elevation ACS and ST-segment elevation myocardial infarction positioned bivalirudin as the anticoagulant of choice in the PCI setting. Further randomized studies, better reflecting routine clinical practice, revealed significantly increased rates of stent thrombosis and myocardial infarction in the bivalirudin arm. Additionally, these findings were corroborated in the subsequent meta-analyses. Speculations that excessive occurrence of stent thrombosis and myocardial infarction may be caused by too short duration of post PCI bivalirudin infusion did not find confirmation in the latest MATRIX trial. In this systematic review, we aim to assess the efficacy and safety of bivalirudin therapy in patients undergoing PCI and to formulate recommendations on the bivalirudin use for clinicians. In our opinion, the research evidence and pharmacoeconomic considerations strongly support the use of bivalirudin in PCI patients at high risk of bleeding complications, while in other situations old and inexpensive UFH or enoxaparin remain the first line antithrombotic drugs

Impact of health education on adherence to clopidogrel and clinical effectiveness of antiplatelet treatment in patients after myocardial infarction

Non-adherence rates to antiplatelet drugs in patients with acute myocardial infarction (AMI) range from 13% to 60%. We aimed to evaluate whether individual health education can improve adherence to treatment with clopidogrel in patients after AMI. This was a prospective, single-center, randomized clinical trial with a 12-month follow-up. Patients with AMI treated with percutaneous coronary intervention (PCI) were enrolled. The primary endpoint was defined as non-adherence to clopidogrel during follow-up (drug availability ≤ 80%). Secondary endpoints included platelet function assessment, adverse cardiovascular (CV) events (CV death, PCI for ACS, unscheduled CV hospitalization). There were 191 patients enrolled in the study and divided into two groups: the individual education (IE) group (100 patients) and the standard treatment (ST) group (91 patients). Adherence to the treatment with clopidogrel based on the data from the National Health Fund did not differ significantly between the IE and ST groups [76.7% (30.7–99.7%) v. 84.4% (46.5–99.7%); p = 0.25]. There was a substantial difference in the prevalence of unscheduled CV hospitalizations between both groups, IE and ST respectively [22 (22.0%) v. 10 (11.0%); p = 0.042]. The rate of CV death and ACS treated with PCI during follow-up was low and did not differ between groups. In conclusion, the program of individual health education did not improve adherence to treatment with clopidogrel. The expected benefits of medication are not achievable at current levels of adherence. The self-reported adherence assessment is unreliable and cannot be used for effective treatment guidance

Variability of prasugrel antiplatelet effect in patients with acute coronary syndrome

Background. Many reports have demonstrated excessive variability in response to clopidogrel, the most commonly used P2Y12 receptor antagonist. Clopidogrel resistant patients are at increased risk of cardiovascular (CV) events. Prasugrel is a new P2Y12 inhibitor that provides greater and faster platelet inhibition and reduces CV events more effectively than clopidogrel. The aim of this study was to evaluate the variability and efficacy of prasugrel antiplatelet activity in patients presenting with acute coronary syndrome (ACS). Materials and methods. The study was designed as a prospective, single-center, non-randomized, observational trial. Platelet reactivity (PR) was assessed with the VeryfyNow assay three times during hospitalization in forty-two patients undergoing percutaneous coronary intervention (PCI) for ACS and treated with standard doses of prasugrel. Results. Platelet aggregation with prasugrel displayed relatively high variability. The platelet aggregation was lowest on the 3rd day of the treatment at 4 p.m. and was significantly different from the measurements obtained on the 3rd and 4th day in the morning (6.0 v. 8.5 U; p = 0.0005 and 6.0 v. 36.5 U; p < 0.00001, respectively), with the latter two differing significantly from each other (p = 0.002). All participants were successfully treated with prasugrel achieving PR < 208 PRU in each measurement, whereas 42.9–80.9% (depending on sampling point) of patients presented very low platelet activity. The subgroups of stable and persistent low PR included a higher percentage of active smokers (73.3 v. 40.7%; p = 0.04 and 80.0 v. 43.8%; p = 0.04, respectively). Conclusions. Prasugrel treatment is associated with high variability of PR. Nonetheless, prasugrel is a highly effective antiplatelet drug. Active smoking may predispose to strong and stable on-prasugrel platelet inhibition.

Mild therapeutic hypothermia for patients with acute coronary syndrome and cardiac arrest treated with percutaneous coronary intervention (UNICORN). The design and rationale for the prospective, observational, multicenter study

Introduction. Cardiac arrest constitutes the most frequent reason for sudden death in developed countries. Out-of-hospital cardiac arrest (OHCA) survivors are at high risk of death or neurologic deficits. The existing data regarding effectiveness and safety of mild therapeutic hypothermia (MTH) for treatment of OHCA survivors are inconsistent and ambiguous. Moreover, a uniform protocol of treatment by means of MTH is lacking. Methods. The UNICORN study is a phase IV, prospective, international, multi-centre, observational study designed to assess the effectiveness of MTH in patients after OHCA with shockable rhythm presenting with acute coronary syndrome (ACS). The trial is expected to include up to 500 patients. Depending on the availability of MTH in each study centre, besides the routine treatment of ACS in OHCA survivors, patients will either undergo MTH according to a uniform protocol or will not undergo MTH (250 patients per group). The primary end-point of the study is all cause mortality at 180 days after enrolment. Secondary end-points include: neurological outcome at discharge, stent thrombosis at 30 days, bleeding according to the BARC criteria, infectious complications at 180 days, and rhythm and conduction disorders at 180 days. Ethics and dissemination. The study received approval from the Local Ethics Committee to conduct the study (Komisja Bioetyczna Uniwersytetu Mikołaja Kopernika w Toruniu przy Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy; study approval reference number KB 615/2015). The study results will be disseminated through conference presentations and publications in peer-reviewed journals. Trial registration. ClinicalTrials.gov identifier: NCT02611934 (18 November 2015).

The impact of metabolic syndrome on the antiplatelet effect of clopidogrel and aspirin in patients with acute coronary syndrome

Aim. The aim of this study was to evaluate the impact of metabolic syndrome and features clustering in this syndrome on the antiplatelet effect of clopidogrel and aspirin in patients with myocardial infarction.Material and methods. The study population comprised 186 consecutive patients treated with primary percutaneous coronary intervention for acute myocardial infarction. Measurements of ADP induced platelet aggregation (ADP-PA) and arachidonic acid induced platelet aggregation (AA-PA) were performed using impedance aggregometry with a Multiplate Analyser. The following factors were analysed as potential determinants of responsiveness to clopidogrel and to aspirin: diagnosed metabolic syndrome, diabetes, hypertension, abdominal obesity, body mass index (BMI), and serum concentrations of triglycerides, HDL-cholesterol and high sensitivity C-reactive protein (hsCRP).Results. The ADP-PA was significantly higher in patients with metabolic syndrome and with diabetes.The AA-PA was significantly higher in subjects with increased levels of hsCRP and in subjects with BMI > 25 kg/m2. The hsCRP was found to be the only independent factor influencing APD-PA (p=0.034). Serum concentrations of hsCRP, HDL-cholesterol and abdominal obesity were independent factors influencing AA-PA (p=0.000004).Conclusion. Metabolic syndrome, diabetes mellitus, obesity and increased hsCRP are determinants of low responsiveness to aspirin and clopidogrel in patients with ACS treated with PCI

The influence of genetic polymorphisms of CYP2C19 and ABCB1 on ADP-induced platelet aggregation in clopidogrel-treated patients: A comparison between the index hospitalization for myocardial infarction and the 3-month follow-up visit

Background. Recent studies suggest that polymorphisms of genes involved in the clopidogrel metabolism may be associated with an impaired drug bioactivation and possibly with unfavourable clinical outcomes. The aim of this study was to assess the effect of selected genetic polymorphisms on adenosine diphosphate-induced platelet aggregation (ADP-PA) during the index hospitalization and after 3 months of clopidogrel therapy in patients presenting with myocardial infarction (MI). Materials and methods. The study was designed as a single-center cohort trial with the 3-month follow-up. Genotyping for CYP2C19*2, CYP2C19*17, ABCB1 alleles and platelet reactivity assessment using the Multiplate Analyzer were performed in 157 patients. Results. ADP-PA during the index hospitalization was significantly higher than at the 3-month follow-up visit regardless of the genotyp e [CYP2C19*1/*1 alleles (24.0 v. 15.5 U; p < 0.00001), CYP2C19*17 allele (CT: 25.0 v. 15.0 U; p = 0.000 2; TT: 35.0 v. 22.0 U; p = 0.02) and ABCB1 allele (CC: 27.0 v. 15.0 U; p < 0.0002; CT 24.0 v. 17.0 U; p < 0.0005)]. In univariate analysis we failed to demonstrate any impact of the analyzed genetic variants on both in-hospital and 3-month ADP-PA, except for CYP2C19*17/*17 homozygotes. Significantly higher values of ADP-PA were found in CYP2C19*17/*17 (TT homozygotes) allele carriers when compared with carriers of two wild alleles during the index hospitalization (CC: 20.0 U v. TT: 35.0 U; p = 0.02), but not at the 3-month follow-up visit. Multivariate regression analysis revealed increased mean platelet volume (β = 7.2), elevated platelet count (β = 0.2) and the presence of heart failure at discharge (β = 6.9), but not genetic polymorphisms, to be independent determinants of high ADP-PA during the index hospitalization. Similarly, elderly age (β = 3.3), high white blood cell count (β = 1.4), elevated platelet count (β = 0.4) and increased mean platelet volume (β = 0.1), but not genetic polymorphisms, were independently associated with the higher values of ADP-PA after 3 months of clopidogrel therapy. Conclusions. On-clopidogrel platelet reactivity significantly decreases beyond the acute phase of MI regardless of the genotype. Additionally, our study indicates that in clopidogrel-treated MI patients genetic polymorphisms are not the major determinants of the interindividual variability in platelet reactivity. However, due to a limited sample size, their minor contribution cannot be excluded

Early administration of LEvosimendan in Patients witH decompensAted chroNic hearT failure (ELEPHANT) study. Rationale and protocol of the study

Dobutamine and levosimendan are both indicated for inotropic support in acute decompensated heart failure (HF). The study aimed to assess the impact of early administration of levosimendan (first iv therapeutic approach) versus dobutamine (first iv therapeutic approach) on in-hospital treatment expenses and clinical outcomes in patients with decompensated chronic HF. The ELEPHANT study was designed as a phase III, multicentre, randomized 1:1, double-blind, active-controlled trial that will include patients admitted to the hospital due to HF decompensation. Co-primary endpoints were defined as total in-hospital expenses/survivor and duration of hospitalization/survivor. Secondary efficacy endpoints: on the last day of hospitalization: occurrence of treatment side effects, body weight change during hospitalization, BNP change during hospitalization, in-hospital mortality, additional levosimendan administration due to the ineffectiveness of the initial treatment. Patients will be randomized 1:1 to the active group receiving continuous infusion 24 h of levosimendan 0.1 μg/kg/min or to the control group receiving continuous infusion 24 h of dobutamine 3 μg/kg/min. After the enrolment of 20 patients, results analysis will be performed (pilot phase — single centre). Based on this analysis conducted according to the intention-to-treat principle, the final population size will be defined. The multicentre phase of the study will be initiated after the pilot phase

The impact of the time of drug administration on the effectiveness of combined treatment of hypercholesterolemia with Rosuvastatin and Ezetimibe (RosEze): study protocol for a randomized controlled trial

Abstract Background Hypercholesterolemia is one of the main risk factors for cardiovascular disease. The first line treatment for hypercholesterolemia is statin therapy. When the expected low-density lipoprotein cholesterol (LDL-C) concentration is not achieved, the pharmacotherapy may be extended by combining the statin with the cholesterol absorption inhibitor ezetimibe. Methods/design The study is designed as a randomized, open-label, single-center, crossover study evaluating the effectiveness of combined therapy with rosuvastatin and ezetimibe for hypercholesterolemia. The study is planned to include 200 patients with hypercholesterolemia ineffectively treated with statins for at least 6 weeks. After enrollment participants are randomized into one of two arms receiving rosuvastatin and ezetimibe. In the first arm the study drug is administered in the morning (8:00 am) for 6 weeks and then in the evening for the next 6 weeks; in the second arm the study drug is administered at first in the evening (8:00 pm) for the first 6 weeks and then in the morning for the following 6 weeks. In order to minimize non-adherence to the treatment, all patients will receive the study drug free of charge. The primary outcome of the study is change in LDL-C at 6 and 12 weeks of the treatment, depending on the time of day of study drug administration. The secondary endpoints include change in total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins ApoB and Apo AI, non-HDL cholesterol, small, dense (sd)-LDL cholesterol, lipoprotein(a), glucose, glycated hemoglobin, high-sensitivity C-reactive protein, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, and creatine kinase at 6 and 12 weeks of the study drug treatment, as well as assessment of plasma fluorescence using stationary and time-resolved fluorescence spectroscopy at baseline and at 6 and 12 weeks of the therapy. Discussion The RosEze trial is expected to demonstrate whether there is a significant difference in the effectiveness of the lipid-lowering therapy in reducing the concentration of cholesterol when the medications are taken in the morning compared with the evening time of day. Trial registration ClinicalTrials.gov, NCT02772640 . Registered on 28 March 2016