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BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden. The ERIC-PPCI trial was funded by a British Heart Foundation clinical study grant (grant number CS/14/3/31002) and a University College London Hospitals/University College London Biomedical Research Centre clinical research grant. The CONDI-2 trial was funded by Danish Innovation Foundation grants (grant numbers 11-108354 and 11-115818), Novo Nordisk Foundation (grant number NNF13OC0007447), and TrygFonden (grant number 109624). DJH was supported by the British Heart Foundation (grant number FS/10/039/28270), the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the Duke-National University Singapore Medical School, the Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (grant number NMRC/CSA-SI/0011/2017) and its Collaborative Centre Grant scheme (grant number NMRC/CGAug16C006), and the Singapore Ministry of Education Academic Research Fund Tier 2 (grant number MOE2016-T2-2-021). HEB was supported by the Novo Nordisk Foundation (grant numbers NNF14OC0013337, NNF15OC0016674). RKK is supported by the Oxford NIHR Biomedical Centre. The research was also supported by the NIHR infrastructure at Leeds. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. This article is based on the work of COST Action EU-CARDIOPROTECTION (CA16225) and supported by COST (European Cooperation in Science and Technology). We thank all study personnel for their invaluable assistance. Sí

Background Oral P2Y12 inhibitors take more than 2 hours to achieve full effect in healthy subjects and this action is further delayed in patients with acute myocardial infarction. Intravenous P2Y12 inhibition might lead to more timely and potent anti-platelet effect in the context of emergency primary angioplasty, improving myocardial recovery. Objectives This article compares the efficacy of intravenous cangrelor versus ticagrelor in a ST-elevation myocardial infarction (STEMI) population treated with primary percutaneous coronary intervention (PPCI). Materials and Methods In an open-label, prospective, randomized controlled trial, 100 subjects with STEMI were assigned 1:1 to intravenous cangrelor or oral ticagrelor. The co-primary endpoints were platelet P2Y12 inhibition at infarct vessel balloon inflation time, 4 and 24 hours. Secondary endpoints included indices of coronary microcirculatory function: index of microvascular resistance (IMR), initial infarct size (troponin at 24 hours) and final infarct size at 12 weeks (cardiac magnetic resonance). Secondary endpoints included indices of coronary microcirculatory function (index of microvascular resistance [IMR]), initial infarct size (troponin at 24 hours), final infarct size at 12 weeks (cardiac magnetic resonance), corrected thrombolysis in myocardial infarction (TIMI) frame count, TIMI flow grade, myocardial perfusion grade, and ST-segment resolution (ClinicalTrials.gov NCT02733341). Results P2Y12 inhibition at first balloon inflation time was significantly greater in cangrelor-treated patients (cangrelor P2Y12 reaction unit [PRU] 145.2 ± 50.6 vs. ticagrelor 248.3 ± 55.1). There was no difference in mean PRU at 4 and 24 to 36 hours post-dosing. IMR, final infarct size, angiographic and electrocardiographic measures of reperfusion were all similar between groups. Conclusion Cangrelor produces more potent P2Y12 inhibition at the time of first coronary balloon inflation time compared with ticagrelor. Despite this enhanced P2Y12 inhibition, coronary microvascular function and final infarct size did not differ between groups.

Introduction Mechanical coronary reperfusion with primary percutaneous coronary intervention (PPCI) and concomitant oral dual antiplatelet therapy, is the preferred strategy in patients presenting with ST elevation myocardial infarction (STEMI). Currently, guidelines regarding the choice of oral P2Y12 inhibitor are conflicting. We sought to determine the impact of clopidogrel, prasugrel and ticagrelor in a real-world STEMI population on the incidence of in-hospital, 30 day and 1 year mortality, in addition to their effects on the incidence of in-hospital major bleeding episodes. Methods A retrospective observational analysis of 2200 STEMI patients managed by PPCI between November 2011 and November 2015 was undertaken. During this period our clinical protocol changed sequentially from prescribing clopidogrel to prasugrel to ticagrelor for patients undergoing PPCI. All data were collected and verified by review of the patient clinical records. Mortality data were obtained via the Office of National Statistics. Bleeding information was taken from the clinical records and review of haematology database. Statistical analysis was two fold: standard multi-logistic regression and a second propensity score (PS) based analysis. Results The study population n=2200 (24% female) were treated with either clopidogrel (n=570), prasugrel (n=1058) or ticagrelor (n=592). Refer to table 1 for baseline characteristics. Figures 1 and 2 demonstrate that ticagrelor treated patients had improved in-hospital (PS, p=0.001), 30 day (PS, p Conclusion This is the first clinical analysis of the three major oral P2Y12 inhibitors in STEMI patients treated with PPCI. There appear to be advantages associated with the use of ticagrelor when compared to prasugrel, in terms of mortality at all time points, and when compared to clopidogrel at 1 year.

Introduction Ticagrelor, an orally administered, direct acting, reversible P2Y12 receptor inhibitor, provides faster onset and greater levels of platelet inhibition when compared to clopidogrel. Current data indicates a reduced antiplatelet effect in STEMI. We sought to determine the early pharmacokinetic (PK) and pharmacodynamic (PD) effect of ticagrelor loading doses administered to patients undergoing PCI for STEMI and NSTEMI. Methods This is a single centre non-randomised study. P2Y12 naive patients presenting with STEMI or NSTEMI were considered for inclusion. All patients gave informed consent. Enrolled patients were administered a loading dose of aspirin 300 mg and ticagrelor 180 mg prior to PCI. Blood was sampled at 20 min, coronary balloon time, 1 hour and 4 hours after loading. PD results are expressed as P2Y12 reaction units (PRU) and were assessed using VerifyNow. A PRU>208 indicates a sub-optimal antiplatelet response. PK properties were assessed by measuring plasma concentration of ticagrelor parent compound (T-PC) and active metabolite (T-AM) using liquid chromatography in tandem with mass spectrometry. The lower limits of quantification of T-PC and its active metabolite, AR-C124910XX (T-AM) are 1 ng/ml and 2.5 ng/ml respectively. PRU and plasma concentrations over time were tested between the two groups using 2-way ANOVA. p Results 30 patients (15 STEMI/15 NSTEMI) were recruited. Baseline characteristics are described in Table 1. PD analysis In STEMI patients high residual platelet reactivity is seen at 20 min following administration of ticagrelor 180 mg (256±13.1), an attenuated effect is also observed at 4 hours. However, in our NSTEMI patients, a marked and rapid antiplatelet effect is seen at all time points (figure 1). PK analysis Low plasma concentrations of T-PC are observed in STEMI vs NSTEMI patients; (9.0±4.1) vs (22.8±10.3), p=0.225 and this trend continues until 4 hours. A similar trend is noted for T-AM concentrations (figure 2). Conclusion Ticagrelor, in STEMI does not provide adequate P2Y12 inhibition at the point of reperfusion. In contrast platelet inhibition is significantly more rapid in patients with NSTEMI. Although a directly acting P2Y12 inhibitor that can exert an antiplatelet effect independent of metabolic biotransformation, ticagrelor is still reliant upon absorption via the gastrointestinal (GI) tract. The sub-therapeutic PRU and plasma concentrations of both T-PC and T-AM indicate that GI absorption is an important determinant of the onset of action and clinical efficacy of ticagrelor during the acute phase of a STEMI. GI absorption may be further impaired by co-administration of morphine. Modification of formulation e.g administration of chewed/orodispersible tablets or an intravenous agent (cangrelor) could help to overcome delayed GI absorption and provide adequate levels of platelet inhibition during the acute phase of presentation in STEMI patients.

Background Oral P2Y12 inhibitors have a delayed onset of action in ST-segment elevation myocardial infarction (STEMI) patients. We describe the first randomised controlled trial comparing Cangrelor with Ticagrelor in the context of primary percutaneous coronary intervention (PPCI). Methods 100 subjects with first acute STEMI were randomised on arrival to Ticagrelor (180 mg then 90 mg bd) or Cangrelor (bolus then infusion). Cangrelor treated subjects received Ticagrelor 30 min prior to infusion end. All patients received Aspirin 300 mg. Platelet P2Y12 inhibition was assessed using VerifyNow at first coronary balloon inflation, 4 and 24 hours post drug initiation. Coronary microcirculation was assessed after PPCI by calculating the index of microvascular resistance (IMR). ST-segment resolution at 90 min was measured and the corrected TIMI frame count, flow grade and myocardial perfusion grade were calculated. Peak Troponin level at 24 hours and infarct size at 12 weeks were measured by cardiac magnetic resonance imaging (CMRI) (ClinicalTrials.gov NCT02733341). Results P2Y12 inhibition was markedly greater in the Cangrelor group (PRU 145.2 vs 248.3 p Conclusion Early, more potent P2Y12 inhibition with Cangrelor does not translate into improved measures of microcirculatory function or infarct size.

Despite advances in ST-segment elevation myocardial infarction (STEMI) treatment, a sizeable minority of patients suffer poor outcomes even when treated with timely primary percutaneous intervention (PPCI). More potent P2Y12 inhibition improves clinical outcomes, however, oral agents have a slow

Despite advances in ST-segment elevation myocardial infarction (STEMI) treatment, a sizeable minority of patients suffer poor outcomes even when treated with timely primary percutaneous coronary intervention (PPCI). More potent P2Y12 inhibition improves clinical outcomes, however oral agents have

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Introduction Oral P2Y12 inhibitors have proven clinical efficacy in a variety of cardiological settings. The degree and time course of platelet inhibition using common P2Y12 inhibitors during the acute phase of a myocardial infarction is an under explored area. We aimed to determine the effect of clopidogrel, prasugrel and ticagrelor in the first four hours following loading in patients admitted with STEMI undergoing primary percutaneous coronary intervention (PPCI). Methods A single centre non-randomised study in patients presenting with STEMI. All patients gave informed consent. Enrolled patients were administered a loading dose of aspirin 300mg and then either clopidogrel 600mg, prasugrel 60mg or ticagrelor 180mg prior to percutaneous coronary intervention. Platelet reactivity was measured using a Verify Now assay at 20 minutes post loading, first balloon inflation, 1 and 4 hours post loading. Results are expressed a P2Y12 reaction units (PRU). PRU ≥ 208 indicates poor antiplatelet response. The effect of the three drugs over time were assessed using 2 way ANOVA. P Results A total of 43 STEMI patients were recruited to the study. Refer to Table 1 for baseline characteristics. PRU results for the 3 drugs at 20 minutes, balloon time, 60 minutes and 240 minutes were determined. Mean dose to balloon time was 26.8 + 12.7. At balloon time, 20 minutes and 60 minutes none of the agents achieved a PRU Conclusion Clopidogrel in the context of STEMI does not provide adequate platelet inhibition as evidenced by PRU > 208 at all data collection time points, Both prasugrel and ticagrelor are superior to clopidogrel resulting in a significant reduction in the degree of platelet reactivity. Although Prasugrel and ticagrelor are comparable in terms of inhibition of platelet activity at 20 minutes, balloon inflation, 1 hour and 4 hours, they still do not achieve the desired levels of platelet inhibition necessary during PPCI as demonstrated by PRU > 208. It is possible that fast acting intravenous antiplatelet agents may have a role to play in achieving adequate platelet inhibition in the context of PPCI.

Introduction Current pharmacodynamic (PD) data suggest reduced antiplatelet effect in ST-Elevation myocardial infarction (STEMI) of prasugrel and ticagrelor. We sought to investigate the early PD effect of prasugrel and ticagrelor administered in two patient groups: those admitted with STEMI and a cohort admitted with NSTEMI/unstable angina (UA). Methods P2Y12 inhibitor naive patients presenting with STEMI or NSTEMI/UA were assessed for inclusion. All patients provided informed consent. All received aspirin (300mg) and loading dose of either prasugrel (60mg) or ticagrelor (180mg) in a non-randomised fashion. Platelet reactivity was measured using VerifyNow assay at 20 min, 1 and 4 h post loading. Results are expressed a P2Y12 reaction units (PRU). PRU≥208 indicates a sub optimal antiplatelet response. PRU over time was tested between groups using 2 way ANOVA, P Results A total of 58 patients were enrolled (30 STEMI, and 28 NSTEMI/UA Table 1). Results are shown in Fig 1. In the STEMI patients there was little effect of either agent at 20 min post loading (prasugrel PRU 247 + 48.8, ticagrelor PRU 256 + 50.8) with a limited effect at 1 h and persisting attenuated results at 4 h. In the NSTEMI group however there was a marked and rapid antiplatelet effect of both agents at all time points. Over time there was a significant difference between the effect of both prasugrel ( P Conclusion Prasugrel and ticagrelor in the context of STEMI do not provide adequate P2Y12 inhibition at reperfusion and the first hour post loading when compared to patients with NSTEMI/UA.