Objectives: Patients on ticagrelor undergoing urgent cardiac surgery are at high risk for perioperative bleeding complications. We sought to determine whether intraoperative hemoadsorption could ...remove ticagrelor and lower circulating drug concentrations. Methods: The hemoadsorption device was incorporated in the cardiopulmonary bypass (CPB) circuit and remained active for the duration of the pump run. Blood samples were collected before and after CPB. The main objective of the current analysis was to compare mean total plasma ticagrelor levels (ng/mL) at baseline with ticagrelor levels obtained at the end of CPB. Plasma ticagrelor levels were measured at a certified outside laboratory (LabConnect). Data are presented as mean ± standard deviation. Results: A total of 11 patients undergoing urgent coronary artery bypass grafting at 3 institutions were included (mean age, 67.9 ± 9.9 years; 91% male; mean European System for Cardiac Operative Risk Evaluation II of 3.0 ± 3.3%; range, 0.7%-12.4%). Mean intraoperative hemoadsorption duration was 97.1 ± 43.4 minutes with a mean flow rate through the device of 422.9 ± 40.3 mL/min. Mean ticagrelor levels pre-CPB were 103.5 ± 63.8 ng/mL compared with mean post-CPB levels of 34.0 ± 17.5 ng/mL, representing a significant 67.1% reduction (P < .001). Intraoperative integration of the device was simple and safe without any device-related adverse events reported. Conclusions: This is the first in vivo report demonstrating that intraoperative hemoadsorption can efficiently remove ticagrelor and significantly reduce circulating drug levels. Whether active ticagrelor removal can reduce serious perioperative bleeding in patients undergoing urgent cardiac surgery is currently being evaluated in the double-blinded, randomized Safe and Timely Antithrombotic Removal–Ticagrelor (STAR-T) trial.
Abstract Background The prognostic value of time from symptom onset to reperfusion may be enhanced by the identification of Q waves on the presenting electrocardiogram (ECG) in patients with ...ST-segment elevation myocardial infarction (STEMI). We evaluated whether the relative prognostic utility of these 2 metrics was altered by sex. Methods Q waves in the distribution of the ST-segment elevation on the baseline ECG were evaluated by a blinded core laboratory in 2838 STEMI patients (2163 men and 675 women) from the PLATelet inhibition and patient Outcomes (PLATO) trial who underwent percutaneous coronary intervention (PCI) within 12 hours of symptom onset. Results Women were older (median 63 vs 57 years), more likely to be diabetic (24.1% vs 15.5%), hypertensive (69.2% vs 50.9%), and a higher Killip class > I (8.6% vs 5.9%), as compared with men. Whereas the Q waves frequency rose progressively over time to ECG in men, this relationship was attenuated in women ( P = .057). Q waves on the baseline ECG were associated with a higher excess hazard of 1-year vascular death in men (hazard ratio HR 2.03; 95% confidence interval CI, 1.13-3.72), and a similar trend existed in women (HR 1.97; 95% CI, 0.86-4.51). Women with baseline Q waves tended to have higher risk of 1-year vascular death than men as continuous time from symptom onset to PCI increased ( P interaction = .182). Conclusions These differences in the evolution of baseline Q waves and relationship between time from symptom onset and vascular death in women and men deserve recognition in future studies of STEMI.
Abstract Background We evaluated whether electrocardiogram (ECG) characteristics were aligned with clinical outcomes and the effect of ticagrelor within the diverse spectrum of non-ST-elevation acute ...coronary syndrome patients enrolled in the PLATelet inhibition and patient Outcomes (PLATO) trial. Methods There were 8884 PLATO patients who had baseline ECGs assessed by a core laboratory; of these, 4935 had an ECG at hospital discharge that also was assessed. Associations with study treatment on vascular death or myocardial infarction within 1 year were examined. Results At baseline, most patients had either no or ≤0.5 mm of ST-segment depression (57%); 26% had 1.0 mm, and 17% had more extensive depression (>1.0 mm). Across the baseline ST-segment depression strata, there was a consistent treatment benefit with ticagrelor versus clopidogrel on vascular death/myocardial infarction. The extent of residual ST-segment depression at discharge was similar in the treatment groups, and the treatment effect did not differ by the extent of discharge ST-segment depression. There was a progressive increase in vascular death/myocardial infarction with increasing extent of baseline ST-segment depression (1.0 mm vs no/0.5 mm: hazard ratio HR 1.22; 95% confidence interval CI, 1.03-1.45; >1.0 mm: HR 1.49; 95% CI, 1.24-1.78; P <.001) and at discharge (HR 1.28; 95% CI, 1.02-1.61; HR 2.13; 95% CI, 1.54-2.95; P <.001). Conclusion The treatment effect of ticagrelor among non-ST-segment-elevation acute coronary syndrome patients was consistently expressed across all baseline ST-segment depression strata. There was no indication of an anti-ischemic benefit of ticagrelor as reflected on the discharge ECG. Our data affirm the independent prognostic relationship of both baseline and hospital discharge ST-segment depression on outcomes within 1 year in non-ST-segment-elevation acute coronary syndrome patients.
Abstract Objectives The aim of this landmark exploratory analysis, ATLANTIC-H24 , was to evaluate the effects of pre-hospital ticagrelor during the first 24 h after primary percutaneous coronary ...intervention (PCI) in the ATLANTIC (Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial infarction to open the Coronary artery study). Background The ATLANTIC trial in patients with ongoing ST-segment elevation myocardial infarction showed that pre-hospital ticagrelor was safe but did not improve pre-PCI coronary reperfusion compared with in-hospital ticagrelor. We hypothesized that the effect of pre-hospital ticagrelor may not have manifested until after PCI due to the rapid transfer time (31 min). Methods The ATLANTIC-H24 analysis included 1,629 patients who underwent PCI, evaluating platelet reactivity, Thrombolysis In Myocardial Infarction grade 3 flow, ≥70% ST-segment elevation resolution, and clinical endpoints over the first 24 h. Results Following PCI, largest between-group differences in platelet reactivity occurred at 1 to 6 h; coronary reperfusion rates numerically favored pre-hospital ticagrelor, and the degree of ST-segment elevation resolution was significantly greater in the pre-hospital group (median, 75.0% vs. 71.4%, p = 0.049). At 24 h, the composite ischemic endpoint was lower with pre-hospital ticagrelor (10.4% vs. 13.7%, p = 0.039), as were individual endpoints of definite stent thrombosis (p = 0.0078) and myocardial infarction (p = 0.031). All endpoints except death (1.1% vs. 0.2%, p = 0.048) favored pre-hospital ticagrelor, with no differences in bleeding events. Conclusions The effects of pre-hospital ticagrelor became apparent after PCI, with numerical differences in platelet reactivity and immediate post-PCI reperfusion, associated with reductions in ischemic endpoints, over the first 24 h, whereas there was a small excess of mortality. (Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial infarction to open the Coronary artery ATLANTIC, NCT01347580 ).
Background To investigate if ticagrelor treatment and other clinical characteristics were associated with increased cystatin C concentrations and if a deterioration in estimated renal function was ...associated with worse outcome in patients with acute coronary syndromes (ACS). Methods Plasma cystatin C concentrations were determined within 24 hours of admission (baseline), at discharge, 1 month, and 6 months in the PLATO trial. The changes over time in relation to randomized treatment were analyzed by analysis of covariance. C-statistics and the relative Integrated Discrimination Improvement of the cystatin C concentrations regarding the primary outcome (cardiovascular death or myocardial infarction) was evaluated by multivariable analysis including background characteristics and biomarkers: N-terminal-pro-B-type natriuretic peptide and Troponin I. Results Mean cystatin C concentrations in 2133 ticagrelor- and 2162 clopidogrel-treated patients were at baseline (0.86 mg/L and 0.86 mg/L), discharge (1.01 mg/L and 0.98 mg/L) ( P < .0005), 1 month (1.00 mg/L and 0.98 mg/L) ( P = .12), and 6 months (1.00 mg/L and 0.99 mg/L) ( P = .17), respectively. Age, heart failure, and type of ACS were major determinants of the cystatin C concentration. c Statistics and the relative Integrated Discrimination Improvement of the primary outcome for the baseline cystatin C concentration were 0.687 and 5.2%, compared to 0.684 and 4.5% at discharge (n = 4034) and 0.693 and 5.1% at one month (n = 3096), respectively. Conclusions Mean cystatin C concentrations increased in ACS patients, most importantly determined by age. The initial greater increase in ticagrelor-treated patients was not sustained over time. Risk prediction did not improve with serial measurements of renal markers.
Objectives We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared to clopidogrel. Background Ticagrelor reduced ...cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. Methods PLATO randomized 18,624 subjects with acute coronary syndrome (ACS) to ticagrelor vs. clopidogrel. The primary efficacy endpoint was cardiovascular death/myocardial infarction/stroke and the primary safety endpoint was major bleeding. The use of GPI was at the physician’s discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours. Results A total of 4020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, male, and undergo multi-vessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety endpoints. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared to clopidogrel (p<0.05), whereas there was no such difference with GPI (p-interaction<0.05). Conclusions In patients with ACS undergoing early PCI the efficacy and safety of ticagrelor as compared with clopidogrel was not modified by GPI use according to the primary efficacy and safety endpoint of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs. with) GPI treatment.
Abstract Objectives The purpose of this study was to compare the effects of ticagrelor versus clopidogrel on health-related quality of life in the PLATelet inhibition and patient Outcomes (PLATO) ...trial. Background The PLATO trial showed that ticagrelor was superior to clopidogrel for the prevention of cardiovascular death, myocardial infarction, or stroke in a broad population of patients with acute coronary syndromes. Methods HRQOL in the PLATO study was measured at hospital discharge, 6-month visit, and end of treatment (anticipated at 12 months) by using the EuroQol five-dimensional (EQ-5D) questionnaire. All patients who had an EQ-5D questionnaire assessment at discharge from the index hospitalization (n = 15,212) were included in the study. Patients who died prior to the end-of-treatment visit were assigned an EQ-5D questionnaire value of 0. Results The EQ-5D questionnaire value at discharge among 7631 patients assigned to ticagrelor was 0.847 and among 7581 patients assigned to clopidogrel was 0.846 ( P = 0.71). At 12 months, the mean EQ-5D questionnaire value was 0.840 for ticagrelor and 0.832 for clopidogrel ( P = 0.046). Excluding patients who died resulted in mean EQ-5D questionnaire values of 0.864 among ticagrelor patients and 0.863 among clopidogrel patients ( P = 0.69). Conclusions In patients hospitalized with acute coronary syndromes with or without ST-segment elevation, treatment with ticagrelor was associated with a lower mortality but otherwise no difference in quality of life relative to treatment with clopidogrel. The improved survival and reduction in cardiovascular events with ticagrelor are therefore obtained with no loss in quality of life.
Objectives The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical ...bradycardic events in patients presenting with acute coronary syndromes. Background Ticagrelor, an oral reversibly binding P2Y12 inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes. Methods Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days). Results A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses ≥3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 5.8% vs. 51 3.6%; relative risk: 1.61; p = 0.006). At 1 month, pauses ≥3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest. Conclusions In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome PLATO; NCT00391872 )
Objectives The purpose of this study is to evaluate the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome undergoing coronary artery bypass graft surgery ...(CABG), as a post-randomization strategy. Background Ticagrelor is a novel, reversibly binding, oral, direct-acting P2Y12 -receptor antagonist. In the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized 18,624 patients with acute coronary syndromes, ticagrelor compared with clopidogrel significantly reduced the risk of the primary composite end point of cardiovascular (CV) death, myocardial infarction, or stroke (hazard ratio HR: 0.84; 95% confidence interval CI: 0.77 to 0.92; p < 0.001). This report investigated the outcomes of patients treated with CABG during the trial. Methods In total, 1,899 patients underwent CABG post-randomization. The protocol recommended ticagrelor/placebo to be withheld for 24 to 72 h and clopidogrel/placebo for 5 days preoperatively. In all, 1,261 patients underwent CABG and were receiving study drug treatment <7 days before surgery. The statistical analysis was based on events occurring from the CABG procedure until the end of the study, excluding 3 patients with CABG after study end. Results In the 1,261 patient cohort, the relative reduction of primary composite end point at 12 months (10.6% 66 of 629 with ticagrelor versus 13.1% 79 of 629 with clopidogrel; HR: 0.84; 95% CI: 0.60 to 1.16; p = 0.29) was consistent with the results of the whole trial. Total mortality was reduced from 9.7% (58 of 629) to 4.7% (29 of 629; HR: 0.49; 95% CI: 0.32 to 0.77; p < 0.01), CV death from 7.9% (47 of 629) to 4.1% (25 of 629; HR: 0.52; 95% CI: 0.32 to 0.85; p < 0.01), and non-CV death numerically from 2.0% to 0.7% (p = 0.07). There was no significant difference in CABG-related major bleeding between the randomized treatments. Conclusions In the subgroup of patients undergoing CABG within 7 days after the last study drug intake, ticagrelor compared with clopidogrel was associated with a substantial reduction in total and CV mortality without excess risk of CABG-related bleeding.
Objectives The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy aimed to compare the antiplatelet effects of clopidogrel and ticagrelor in patients with acute coronary syndromes. ...Background The PLATO study demonstrated superiority of ticagrelor over clopidogrel in the prevention of ischemic events in patients with acute coronary syndromes. Methods Patients were randomized to receive either clopidogrel (300- to 600-mg loading dose LD, 75 mg/day) or ticagrelor (180-mg LD, 90 mg twice daily). The effects of maintenance therapy were studied in 69 patients pre- and 2 to 4 h post-dose after at least 28 days. The LD effect was studied in 24 clopidogrel-naive patients. Light transmittance aggregometry (adenosine diphosphate 5 to 20 μM), VerifyNow P2Y12, and VASP phosphorylation assays were performed. Results During maintenance therapy, ticagrelor achieved greater suppression of platelet reactivity compared with clopidogrel. The mean maximum light transmittance aggregometry responses (adenosine diphosphate 20 μM) post-maintenance dose were 44 ± 15% for clopidogrel and 28 ± 10% for ticagrelor (p < 0.001). High platelet reactivity was seen more frequently in the clopidogrel group. Proton pump inhibitor use was associated with higher platelet reactivity with clopidogrel but not ticagrelor. The ticagrelor LD also achieved greater inhibition of platelet aggregation compared with the clopidogrel LD. Conclusions Ticagrelor achieves greater antiplatelet effect than clopidogrel in patients with acute coronary syndromes, both in the first hours of treatment and during maintenance therapy.
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