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, Anne H.; Hermanides, Renicus S; Ottervanger, Jan Paul; Rasoul, Saman; Slingerland, Robbert J.; Tolsma, Rudolf T; Workum, S. van; Kedhi, Elvin; Hof, Arnoud W J van ‘t

doi:10.1007/s12471-019-1241-6

Cited by 9 publications

(5 citation statements)

References 33 publications

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“…The impact of intravenous acetaminophen on the level of platelet inhibition was assessed in the ON-TIME 3 (The Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation) trial. 65 This study did not report lower levels of platelet reactivity compared with intravenous fentanyl in STEMI patients, although plasma levels were significantly increased. Another trial, the LOCAL trial, investigated the use of intravenous lignocaine as an alternative to intravenous fentanyl and showed a significantly lower rate of HPR at 60minutes after administration in non-STEMI patients (lignocaine 6 vs. fentanyl 59%, p <0.001 measured with the VerifyNow assay).…”

Section: Other Approaches To Improve Suboptimal Early Platelet Inhibi...mentioning

confidence: 55%

Parenteral Antiplatelet Drugs in ST-Elevation Myocardial Infarction: Current Status and Future Directions

et al. 2022

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Oral inhibitors of the platelet P2Y12 receptor are indispensable in the treatment of ST-elevation myocardial infarction (STEMI), improving outcomes and even reducing mortality in some studies. However, these drugs are limited by delayed absorption and suboptimal platelet inhibition at the time of primary percutaneous coronary intervention. Despite efforts to achieve faster and more sustained platelet inhibition, strategies such as prehospital administration, higher loading doses, and crushed formulations have not led to improved coronary reperfusion. Parenteral glycoprotein IIb/IIIa inhibitors act sooner and are more potent than oral P2Y12 inhibitors, but their use has been limited by the increased risk of major bleeding and thrombocytopenia. Hence, there is a clinical need to refine drugs that deliver rapid, effective, yet safe platelet inhibition in the setting of STEMI. Novel parenteral antiplatelet drugs, such as cangrelor, selatogrel, and zalunfiban, have been recently developed to achieve rapid, potent antiplatelet effects while preserving hemostasis. We provide a description of currently available parenteral antiplatelet agents and of those in clinical development for prehospital administration in STEMI patients.

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Section: Other Approaches To Improve Suboptimal Early Platelet Inhibi...mentioning

confidence: 55%

Parenteral Antiplatelet Drugs in ST-Elevation Myocardial Infarction: Current Status and Future Directions

et al. 2022

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“…The inclusion and exclusion criteria have been published before ( 12 ). In brief, patients with signs or symptoms of STEMI and a pain score of 4 or higher on a 10-step numeric rating pain score who were planned to undergo a primary PCI and who were P2Y 12 naive, were enrolled.…”

Section: Methodsmentioning

confidence: 99%

Sex Differences in Platelet Reactivity in Patients With ST-Elevation Myocardial Infarction: A Sub-Analysis of the ON-TIME 3 Trial

Tavenier

Hermanides

Ottervanger

et al. 2021

Front. Cardiovasc. Med.

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Background: Fast and adequate platelet inhibition is one of the cornerstones in the treatment of patients with ST-elevation myocardial infarction (STEMI). The aim of this analysis is to examine sex differences in platelet inhibition in the acute treatment of STEMI patients.Methods: Platelet reactivity units (PRU) and ticagrelor plasma concentrations of all patients in the ON-TIME 3 were compared according to sex. All patients were pre-treated with crushed ticagrelor, aspirin and heparin. Both univariable and multivariable analyses were performed.Results: In this sub-analysis of the ON-TIME 3 trial, 195 STEMI patients, of which 58 female patients (29.7%) and 137 male patients (70.3%), were analyzed. PRU-values immediately post-PCI were not different in females [median 135 (IQR 47-228)] compared to males [160 (IQR 40-219), P = 0.92]. Ticagrelor plasma concentrations were higher in the females at the start of primary PCI [141 ng/mL (IQR 25-491) vs. 76 ng/mL (IQR 15-245), P = 0.049] and at 6 hours post-primary PCI [495 ng/mL (IQR 283-661) vs. 321 ng/mL (IQR 196-537), P = 0.001] compared to males. However, immediately post-primary PCI and at 1-hour post-primary PCI no significant differences in ticagrelor concentrations were seen between sexes. In multivariable analysis, sex was significantly associated with ticagrelor concentration (P = 0.04), but not with PRU (P = 0.93).Conclusion: Effective platelet inhibition reached by crushed ticagrelor in STEMI patients was similar in both sexes. Females had similar or even higher ticagrelor plasma concentrations up to 6 hours post-primary PCI compared with males.

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“…The trial design and rationale of this study have been published previously. 16 In brief, STEMI patients (defined as on-going chest pain >30 min and <12 h duration and ST-segment elevation >0.1 mV in at least two contiguous leads) as diagnosed by the paramedic team with a pain score of 4 or higher at a 10-step numeric rating pain score, were included. After verbal informed consent patients were randomized in a 1:1 fashion to either iv acetaminophen or iv fentanyl using an app-based randomization.…”

Section: Methodsmentioning

confidence: 99%

Impact of opioids on P2Y12 receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial

Tavenier¹,

Hermanides

Ottervanger

et al. 2020

European Heart Journal - Cardiovascular Pharmacotherapy

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Aim Platelet inhibition induced by P2Y12 receptor antagonists in patients with ST-elevation myocardial infarction (STEMI) can be affected by concomitant use of opioids. The aim of this trial was to examine the effect of intravenous (iv) acetaminophen compared with iv fentanyl on P2Y12 receptor inhibition in patients with STEMI. Methods and Results The ON-TIME 3 trial randomised 195 STEMI patients who were scheduled to undergo primary percutaneous coronary intervention (PCI) and were pre-treated with crushed ticagrelor to iv acetaminophen (N = 98) or iv fentanyl (N = 97) in the ambulance. The primary endpoint, consisting of the level of platelet reactivity units (PRU) measured immediately after primary PCI, was not significantly different between the study arms (median PRU 104 [IQR 37-215] vs. 175 [63-228], P = 0.18). However, systemic levels of ticagrelor were significantly higher in the acetaminophen arm at the start of primary PCI (151 ng/mL [32-509] vs. 60 ng/mL [13-206], P = 0.007), immediately after primary PCI (326 ng/mL [94-791] vs. 115 ng/mL [38-326], P = 0.002) and at one-hour after primary PCI (488 ng/mL [281-974]) vs. 372 ng/mL [95-635], P = 0.002). Acetaminophen resulted in the same extent of pain relief as compared to fentanyl (reduction of 3 points on 10-step-pain scale before primary PCI [IQR 1-5] in both study arms (P = 0.67) and immediately after PCI (reduction of 5 points [3-7]; P = 0.96). Conclusion Iv acetaminophen in comparison with iv fentanyl was not associated with significantly lower platelet reactivity in STEMI patients, but resulted in significantly higher ticagrelor plasma levels and was effective in pain relief.

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Cited by 9 publications

References 33 publications

Parenteral Antiplatelet Drugs in ST-Elevation Myocardial Infarction: Current Status and Future Directions

Parenteral Antiplatelet Drugs in ST-Elevation Myocardial Infarction: Current Status and Future Directions

Sex Differences in Platelet Reactivity in Patients With ST-Elevation Myocardial Infarction: A Sub-Analysis of the ON-TIME 3 Trial

Impact of opioids on P2Y12 receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial

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