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A randomised, investigator-initiated, clinical trial of the effects of fentanyl on P2Y12-receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: rationale and design of the Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial.

ABSTRACT: BACKGROUND:Fast and accurate platelet inhibition is an important therapeutic goal in the acute treatment of patients with ST-elevation myocardial infarction (STEMI). Platelet inhibitory effects induced by oral P2Y12-receptor antagonists are delayed in STEMI patients undergoing primary percutaneous coronary intervention (PCI) due to haemodynamic changes and delayed gastro-intestinal absorption. Concomitant use of opioids, although recommended in the American College of Cardiology/American Heart Association and European Society of Cardiology STEMI guidelines, further delays gastro-intestinal absorption. To date, trials investigating alternative analgesics in STEMI patients have been scarce. This trial aims to assess the feasibility of a novel drug strategy for treatment of STEMI patients with crushed ticagrelor in combination with paracetamol (acetaminophen) instead of opioids. HYPOTHESIS:STEMI patients who are pre-treated with crushed ticagrelor and paracetamol have a higher level of platelet inhibition after primary PCI than patients pre-treated with crushed ticagrelor and fentanyl. STUDY DESIGN:The Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial is a randomised controlled trial designed to examine whether administration of paracetamol instead of fentanyl can optimise platelet inhibition in STEMI patients who are pre-treated with crushed ticagrelor in the ambulance. One hundred and ninety patients with STEMI will be randomised (1:1 fashion) to intravenous (IV) fentanyl or IV paracetamol. The primary endpoint is the level of platelet reactivity units measured immediately after primary PCI. The ON-TIME 3 trial (NCT03400267) aims to achieve optimal platelet inhibition and pain relief in STEMI patients receiving crushed ticagrelor in the ambulance by investigating IV fentanyl and IV paracetamol as analgesics.

SUBMITTER: Tavenier AH

PROVIDER: S-EPMC6439041 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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A randomised, investigator-initiated, clinical trial of the effects of fentanyl on P2Y12-receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: rationale and design of the Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial.

Tavenier A H AH Hermanides R S RS Ottervanger J P JP Rasoul S S Slingerland R J RJ Tolsma R R van Workum S S Kedhi E E van 't Hof A W J AWJ

Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 20190401 4

<h4>Background</h4>Fast and accurate platelet inhibition is an important therapeutic goal in the acute treatment of patients with ST-elevation myocardial infarction (STEMI). Platelet inhibitory effects induced by oral P2Y12-receptor antagonists are delayed in STEMI patients undergoing primary percutaneous coronary intervention (PCI) due to haemodynamic changes and delayed gastro-intestinal absorption. Concomitant use of opioids, although recommended in the American College of Cardiology/American ...[more]

PMID: 30767166

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Project description:BackgroundData are lacking on the effects of the alternation of P2Y12 receptor antagonists (P2Y12) on bleeding and outcome in patients with myocardial infarction (MI) with cardiogenic shock (CS). We compared the effects of different P2Y12 and alternation of P2Y12 (combination) on bleeding and outcome in patients with MI and CS.MethodsData from 247 patients divided into four groups: clopidogrel, ticagrelor, prasugrel, and the combination group, were analyzed. The association between P2Y12 and bleeding as well as 30-day and one-year mortality was examined.ResultsThe highest bleeding rate was observed in patients in the combination group, followed by the clopidogrel, ticagrelor, and prasugrel groups [12(50%) patients, 22(28.2%), 21(18.3%) and 4(13.3%), respectively; p = 0.003]. Bleeding occurred with a similar frequency in the combination and clopidogrel groups (p = 0.081), but more frequently than in the ticagrelor and prasugrel groups (p = 0.002 and p = 0.006, respectively). Bleeding rates were similar in patients receiving P2Y12 alone (p = 0.13). Compared to clopidogrel, both ticagrelor and prasugrel had a lower bleeding risk (aOR: 0.40; 95% CI: 0.18-0.92; p = 0.032 and aOR: 0.20; 95% CI: 0.05-0.85; p = 0.029, respectively) and the combination had a similar bleeding risk (aOR: 2.31; 95% CI: 0.71-7.48; p = 0.16). The ticagrelor and prasugrel groups had more than an 80% and 90% lower bleeding risk than the combination group (aOR: 0.17; 95% CI: 0.06-0.55; p = 0.003 and aOR: 0.09; 95% CI: 0.02-0.44; p = 0.003, respectively). The unadjusted 30-day and one-year mortality were highest in the clopidogrel group, followed by the ticagrelor, prasugrel, and combination groups (44(56.4%) and 55(70.5%) patients died in the clopidogrel group, 53(46.1%) and 56(48.7%) in the ticagrelor group, 12(40%) and 14(46.7%) patients died in the prasugrel, and 6(25%) and 9(37.5%) patients died in the combination group; p = 0.045 and p < 0.0001. After adjustment for confounders, the P2Y12 groups were not independently associated with either 30-day (p = 0.23) or one-year (p = 0.17) mortality risk.ConclusionOur results suggest that the choice of P2Y12 was not associated with treatment outcome. The combination of P2Y12 increased bleeding risk compared with ticagrelor and prasugrel and was comparable to clopidogrel in patients with MI and CS. However, these higher bleeding rates did not result in worse treatment outcomes.

Project description:IntroductionAmong patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI), intravenous fentanyl does not enhance ticagrelor-induced platelet inhibition within 2 h compared to morphine. The impact of the total dose of fentanyl and morphine received on ticagrelor pharmacodynamic and pharmacokinetic responses in patients with STEMI remains however undetermined.Materials and methodsWe performed a post-hoc subanalysis of the prospective, open-label, single-center, randomized PERSEUS trial (NCT02531165) that compared treatment with intravenous fentanyl vs. morphine among symptomatic patients with STEMI treated with primary PCI after ticagrelor pretreatment. Patients from the same population as PERSEUS were further stratified according to the total dose of intravenous opioids received. The primary outcome was platelet reactivity using P2Y12 reaction units (PRU) at 2 h following administration of a loading dose (LD) of ticagrelor. Secondary outcomes were platelet reactivity and peak plasma levels of ticagrelor and AR-C124910XX, its active metabolite, at up to 12 h after ticagrelor LD administration. Generalized linear models for repeated measures were built to determine the relationship between raw and weight-weighted doses of fentanyl and morphine.Results38 patients with STEMI were included between December 18, 2015, and June 22, 2017. Baseline clinical and procedural characteristics were similar between low- and high-dose opioid subgroups. At 2 h, there was a significant correlation between PRU and both raw [regression coefficient (B), 0.51; 95% confidence interval (CI), 0.02-0.99; p = 0.043] and weight-weighted (B, 0.54; 95% CI, 0.49-0.59; p < 0.001) doses of fentanyl, but not morphine. Median PRU at 2 h was significantly lower in patients receiving low, as compared to high, doses of fentanyl [147; interquartile range (IQR), 63-202; vs. 255; IQR, 183-274; p = 0.028], whereas no significant difference was found in those receiving morphine (217; IQR, 165-266; vs. 237; IQR, 165-269; p = 0.09). At 2 h, weight-weighted doses of fentanyl and morphine were significantly correlated to plasma levels of ticagrelor and AR-C124910XX.ConclusionIn symptomatic patients with STEMI who underwent primary PCI after ticagrelor pretreatment and who received intravenous opioids, we found a dose-dependent relationship between the administration of intravenous fentanyl, but not morphine, and ticagrelor-induced platelet inhibition.

Project description:Importance:The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain. Objective:To evaluate the short-term safety of ticagrelor when compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy. Design, Setting and Participants:We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%. Interventions:Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel. Main Outcomes and Measures:The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days. Results:The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, -0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, -0.18%; 95% CI, -0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57). Conclusions and Relevance:In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days. Trial Registration:clinicaltrials.gov Identifier: NCT02298088.

Project description:Background Ticagrelor reduced cardiovascular death, myocardial infarction (MI), or stroke in patients with prior MI in PEGASUS-TIMI 54 (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin). MI can occur in diverse settings and with varying severity; therefore, understanding the types and sizes of MI events prevented is of clinical importance. Methods and Results MIs were adjudicated by a blinded clinical events committee and categorized by subtype and fold elevation of peak cardiac troponin over the upper limit of normal. A total of 1042 MIs occurred in 898 of the 21 162 randomized patients over a median follow-up of 33 months. The majority of the MIs (76%) were spontaneous (Type 1), with demand MI (Type 2) and stent thrombosis (Type 4b) accounting for 13% and 9%, respectively; sudden death (Type 3), percutaneous coronary intervention-related (Type 4a) and coronary artery bypass graft-related (Type 5) each accounted for <1%. Half of MIs (520, 50%) had a peak troponin ≥10x upper limit of normal and 21% of MIs (220) had a peak troponin ≥100× upper limit of normal. A total of 21% (224) were ST-segment-elevation MI STEMI. Overall ticagrelor reduced MI (4.47% versus 5.25%, hazard ratio 0.83, 95% confidence interval 0.72-0.95, P=0.0055). The benefit was consistent among the subtypes, including a 31% reduction in MIs with a peak troponin ≥100× upper limit of normal (hazard ratio 0.69, 95% confidence interval 0.53-0.92, P=0.0096) and a 40% reduction in ST-segment elevation MI (hazard ratio 0.60, 95% confidence interval 0.46-0.78, P=0.0002). Conclusions In stable outpatients with prior MI, the majority of recurrent MIs are spontaneous and associated with a high biomarker elevation. Ticagrelor reduces the MI consistently among subtypes and sizes including large MIs and ST-segment elevation MI. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01225562.

Project description:Importance:Dual anti-platelet therapy represents standard care for treating patients with ST-segment elevation myocardial infarction (STEMI). Ticagrelor is a direct-acting P2Y12 inhibitor and, unlike clopidogrel and prasugrel, does not require metabolic activation. Objective:To evaluate whether chewing a loading dose (LD) of ticagrelor, 180 mg, vs traditional oral administration of an equal dose enhances platelet inhibition at 30 minutes and 1 hour after LD administration in patients with STEMI. Design, Setting, and Participants:A randomized clinical trial was conducted in adults aged 30 to 87 years from May to October 2016 in a large tertiary care center. Analyses were intention-to-treat. Interventions:Fifty patients with STEMI were randomized to either chewing an LD of ticagrelor, 180 mg, or standard oral administration of an equal dose. Main Outcomes and Measures:P2Y12 reaction units were evaluated using VerifyNow (Accumentrics) at baseline, 30 minutes, 1 hour, and 4 hours after LD. Results:Baseline characteristics were similar in both groups. The mean (SD) of P2Y12 reaction units in the chewing group compared with the standard group at baseline, 30 minutes, 1 hour, and 4 hours after ticagrelor LD were 224 (33) vs 219 (44) (95% CI, -16.77 to 27.73; P?=?.26), 168 (78) vs 230 (69) (95% CI, -103.77 to -19.75; P?=?.003), 106 (90) vs 181 (89) (95% CI, -125.15 to -26.29; P?=?.005), and 43 (41) vs 51 (61) (95% CI, -36.34 to 21.14; P?=?.30), respectively. Platelet reactivity in the chewing group was significantly reduced by 24% at 30 minutes after LD (95% CI, 19.75 to 103.77; P?=?.001). The relative inhibition of platelet aggregation in the chewing vs the standard group were 51% vs 10% (95% CI, 13.69 to 67.67; P?=?.005) at 1 hour and 81% vs 76% (95% CI, -12.32 to 16.79; P?=?.24) at 4 hours, respectively. Major adverse cardiac and cardiovascular event rate at 30 days was low (4%) and occurred in 1 patient in each group (95% CI, 0.06 to 16.93; P?>?.99). Conclusions and Relevance:Chewing an LD of ticagrelor, 180 mg, in patients with STEMI is feasible and facilitates better early platelet inhibition compared with a standard oral LD. Larger studies are warranted to see if our preliminary findings translate into clinical outcomes. Trial Registration:clinicaltrials.gov Identifier: NCT02725099.

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