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

ACS network-based implementation of therapeutic hypothermia for the treatment of comatose out-of-hospital cardiac arrest survivors improves clinical outcomes: the first European experience

Background: There is a paucity of data regarding clinical outcomes associated with the integration of a mild therapeutic hypothermia (MTH) protocol into a regional network dedicated to treatment of patients with acute coronary syndromes (ACS). Additionally, a recent report suggests that the neurological benefits of MTH therapy in interventionally managed ACS patients resuscitated from out-of-hospital cardiac arrest (OHCA) may be potentially offset by the catastrophic occurrence of stent thrombosis. The goal of this study was to share our experience with the implementation of an MTH program using a previously established ACS network in consecutive comatose OHCA survivors undergoing interventional management due to an initial diagnosis of ACS and to assess the clinical effectiveness and safety of MTH. Methods: We conducted a retrospective historically controlled single centre study. Hospital survival with a favourable neurological outcome (Cerebral Performance Category of 1 or 2) and all-cause in-hospital mortality were the primary and secondary efficacy end points, respectively. Occurrence of definite stent thrombosis was the primary safety end point while the development of pneumonia, presence of positive blood cultures, occurrence of probable stent thrombosis, any bleeding complications, need for red blood cell transfusion and presence of rhythm and conductions disorders during hospitalisation constituted secondary safety end points. Results: Comatose OHCA survivors (n = 32) were referred to our Department based on ECG recording transmissions and/ or phone consultations or admitted from the Emergency Department. Compared with controls (n = 33), they were significantly more likely to be discharged from hospital with a favourable neurological outcome (59 vs. 27%; p < 0.05; number needed to treat [NNT] = 3.11) and experienced lower all-cause in-hospital mortality (13 vs. 55%; p < 0.05; NNT = 2.38). Rates of all safety end points were similar in patients treated with and without MTH. Conclusions: Our study indicates that a regional system of care for OHCA survivors may be successfully implemented based on an ACS network, leading to an improvement in neurological status and to a reduction of in-hospitalmortality in patients treated with MTH, without any excess of complications. However, our findings should be verified in large, prospective trials

Mild therapeutic hypothermia after sudden cardiac arrest

Wysoką śmiertelność wśród pacjentów, u których osiągnięto powrót spontanicznego krążenia po jego zatrzymaniu, można przypisać różnym procesom patofizjologicznym. Działająca wielokierunkowo łagodna hipotermia terapeutyczna (MTH) jest — jak dotąd — jedyną terapią, w odniesieniu do której udowodniono, że zwiększa przeżywalność pacjentów po zatrzymaniu krążenia. Europejskie Towarzystwo Kardiologiczne w 2012 roku przyznało hipotermii terapeutycznej stosowanej po nagłym zatrzymaniu krążenia najwyższą klasę wskazań I/B. Hipotermia, ze względu na swój skomplikowany mechanizm, wywiera zarówno pożądane, jak i niepożądane działania na organizm. Sposób jej stosowania i monitorowania są nadal kwestią sporną. Celem niniejszej pracy było podsumowanie obecnej wiedzy na temat stosowania MTH po nagłym zatrzymaniu krążenia.High mortality among survivors of sudden cardiac arrest results from multiple pathophysiological pathways. Acting in different directions, mild therapeutic hypothermia (MTH) constitutes the only available treatment method that has been proven to increase the survival after sudden cardiac arrest, and has found its place in the European Society of Cardiology guidelines in 2012. Hypothermia, due to its complex mechanism, exerts both desirable and undesirable effects. Therefore the mode of its application and monitoring are still a matter of question. The aim of this paper is to summarize the current knowledge on MTH after sudden cardiac arrest

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 &lt; 0.00001, respectively), with the latter two differing significantly from each other (p = 0.002). All participants were successfully treated with prasugrel achieving PR &lt; 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).

Efficacy of double vs. standard empagliflozin dose for METabolic syndromE tReatment (DEMETER — SIRIO 11) study. Rationale and protocol of the study

Complex metabolic disorders associated with obesity and diabetes pose a serious therapeutic challenge. The DEMETER-SIRIO 11 study is a phase III, multicenter, randomized, open-label, investigator-initiated clinical trial with a 6-month follow-up aimed at performing a comparative evaluation of the effect of two empagliflozin doses (10 mg vs. 20 mg) on selected metabolic parameters in patients with metabolic syndrome. The primary hypothesis of the study is that a higher dose of empagliflozin will result in a significant reduction of BMI and HbA1c in patients with obesity and MS receiving empagliflozin 20 mg as compared to 10 mg. Sample size and power calculation were based on a superiority assumption for the primary efficacy endpoint (the difference in decrease of body weight by &gt; 1.5 kg and HbA1c by &gt; 0.4%) for the higher vs. standard dose arm at 6-months of follow-up. Therefore, a sample size of 79 patients per arm is required to provide 80% power to detect a higher decrease in BMI, and 85 patients per arm is required to provide 80% power to detect a higher decrease in HbA1c in the 20 mg versus 10 mg arm with a type I error rate of 0.05. Summing up, enrollment of a total of 200 patients (100 in each arm) is planned to compensate for the potential drop-out rate from the study of up to 15%. Prespecified subanalyses will be performed according to: 1) diabetes mellitus; 2) chronic kidney disease (GFR &lt; 60 mL/min/1.73 m2); 3) gender; and 4) age. A greater comprehensive improvement in biochemical, functional, and anthropometric parameters reflecting favorable metabolic changes is expected at the higher dose of empagliflozin compared to the standard dose

Platelet reactivity during mild therapeutic hypothermia in patients with acute myocardial infarction treated with ticagrelor: study protocol of a single-centre study

In summary, the available data on the antiplatelet efficacy of P2Y12 receptor inhibitors suggest their less potent and/or delayed effect in patients undergoing mild therapeutic hypothermia (MTH). However, previous studies do not explain the mechanisms of the impact of MTH on platelet function. Moreover, there is a lack of evidence of any relationship between the increased prevalence of thrombotic complications in MTH patients and the anti-platelet effect of P2Y12 receptor inhibitors. We hypothesise that MTH may interfere with the absorption of ticagrelor and consequently results in significant changes in the pharmacokinetic and pharmacodynamic profile of this P2Y12 receptor inhibitor. It cannot be ruled out that the high initial level of platelet activation in MTH patients may additionally modify the pharmacodynamics of ticagrelor. Malabsorption may slow down the desired antiplatelet effect, while high levels of platelet activation may reduce the antiplatelet effect of ticagrelor. The aim of this study is to verify whether the use of MTH after resuscitation in out-of-hospital cardiac arrest (OHCA) patients with STEMI (ST-segment elevation myocardial infarction) treated with primary percutaneous coronary intervention (pPCI), affects the anti-platelet effect of ticagrelor. Moreover, we attempt to elucidate the mechanisms of impaired effect of ticagrelor in MTH patients based on pharmacodynamic and pharmacokinetic measurements. To achieve the aim of the study, we planned the following: 1) comparison of the pharmacokinetic and pharmacodynamic results obtained from the study population (MTH + pPCI + ticagrelor) with results obtained from a demographically and clinically comparable population of patients with STEMI treated with primary PCI and receiving ticagrelor (pPCI + ticagrelor); and 2) analysis of the pharmacodynamic results in relation to the pharmacokinetic measurements in the target population. Understanding the mechanisms standing behind the impact of MTH on the efficacy of platelet inhibition with P2Y12 inhibitors is pivotal in reducing the risk of thrombotic complications. The study is expected to provide information leading to improvement of the safety of MTH in STEMI patients with OHCA treated with pPCI and receiving ticagrelor