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Background: The ISAR-REACT 5 trial compared the efficacy and safety of ticagrelor and prasugrel in patients with ACS managed invasively. The present study sought to investigate the impact of ticagrelor and prasugrel on the incidence and pattern of urgent revascularization in acute coronary syndromes (ACS) patients undergoing percutaneous coronary intervention (PCI)., Methods and Results: This post-hoc analysis of the ISAR-REACT 5 trial included all ACS patients who underwent PCI. The primary endpoint for this analysis was the incidence of urgent revascularization at 12-month follow-up. Secondary outcome was the pattern of urgent revascularization procedures (namely, urgent target vessel/non-target vessel revascularization - TVR/NTVR). Among 3,377 ACS patients who underwent PCI, 1,676 were assigned to ticagrelor and 1,701 to prasugrel before PCI. After 12 months, the incidence of urgent revascularization was higher among patients assigned to ticagrelor as compared to prasugrel (6.8% vs. 5.2%; hazard ratio [HR] = 1.32, 95% confidence interval [CI] 1.00-1.75; p = 0.051), mostly attributable to significantly more urgent NTVR in the ticagrelor group (3.8% vs. 2.4%; HR = 1.62 [1.09-2.41]; p = 0.017). The risk of urgent TVR did not differ between treatment groups (3.3% vs. 3.0%; HR = 1.13 [0.77-1.65]; p = 0.546)., Conclusions: In ACS patients treated with PCI, the cumulative rate of urgent revascularizations after 12 months is higher with ticagrelor compared to prasugrel, due to a significant increase in urgent revascularizations involving remote coronary vessels., (© 2024. The Author(s).)

Objectives: To assess the efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndrome (ACS) presenting during off- and on-hours., Background: The efficacy and safety of ticagrelor versus prasugrel in patients with ACS according to time of hospital presentation remain unknown., Methods: This post hoc analysis of the ISAR-REACT 5 trial included 1565 patients with ACS presenting off-hours and 2453 patients presenting on-hours, randomized to ticagrelor or prasugrel. The primary endpoint was a composite of death, myocardial infarction, or stroke; the safety endpoint was Bleeding Academic Research Consortium (BARC) type 3-5 bleeding, both at 12 months., Results: The primary endpoint occurred in 80 patients (10.4%) in the ticagrelor group and 57 patients (7.3%) in the prasugrel group in patients presenting off-hours (hazard ratio [HR] = 1.45; 95% confidence interval [CI] 1.03-2.03; P = 0.033), and 104 patients (8.5%) in the ticagrelor group and 80 patients (6.7%) in the prasugrel group in patients presenting on-hours (HR = 1.29 [0.97-1.73]; P = 0.085), without significant treatment arm-by-presentation time interaction (P int  = 0.62). BARC type 3 to 5 bleeding occurred in 35 patients (5.1%) in the ticagrelor group and 37 patients (5.3%) in the prasugrel group (P = 0.84) in patients presenting off-hours, and 60 patients (5.9%) in the ticagrelor group and 43 patients (4.6%) in the prasugrel group in patients presenting on-hours (P = 0.17)., Conclusions: In patients with ACS planned to undergo an invasive treatment strategy, time of presentation (off-hours vs. on-hours) does not interact significantly with the relative efficacy and safety of ticagrelor vs. prasugrel., Clinical Trial Registration: NCT01944800., (© 2022. The Author(s).)

Background: Immature or reticulated platelets are associated with impaired efficacy of antiplatelet drugs and adverse events in cardiovascular patients. Their role as a predictive biomarker in patients with acute coronary syndrome treated with potent P2Y 12 receptor inhibitors is not fully understood. We aimed to prospectively evaluate reticulated platelets as a predictor of the primary end point of the ISAR-REACT 5 trial consisting of death, myocardial infarction, or stroke at 1 year in patients with acute coronary syndrome randomized to prasugrel or ticagrelor., Methods: Immature platelet fraction (IPF) was assessed within 48 hours after randomization. Patients were divided based on the IPF median values: the IPF high group included patients with IPF>median and the IPF low group included patients with IPF≤median. Platelet aggregation was assessed using the Multiplate Analyzer and was correlated to IPF., Results: Five hundred seventy-seven patients were included in the study. IPF values in % (median [interquartile range]) within the first 48 hours did not differ between the two study groups: 3.6 (2.5-5.2)% in the prasugrel group and 3.6 (2.5-5.4)% in the ticagrelor group ( P =0.882). The incidence of the primary end point was significantly higher in the IPF high (IPF>3.6%) group compared with the IPF low (IPF ≤ 3.6%) group: 13.0% versus 7.2% (HR adj , 1.74 [1.02-3.00]; P =0.044), independently from the assigned drug ( P int =0.159). No significant association between IPF and BARC 3 to 5 bleeding was observed. ADP-induced platelet aggregation correlated significantly with IPF in patients treated with prasugrel ( r =0.22; P =0.005) while no correlation was detected in patients treated with ticagrelor ( r =0.09; P =0.257)., Conclusions: Independently from drug treatment, IPF was associated with the primary end point and therefore is a promising biomarker for the prediction of adverse cardiovascular events in patients with acute coronary syndrome treated with prasugrel or ticagrelor., Registration: https://www., Clinicaltrials: gov; Unique identifier: NCT01944800.

Aims: To assess whether the efficacy and safety of ticagrelor vs. prasugrel in patients with acute coronary syndromes (ACSs) are influenced by pre-admission treatment with aspirin and/or clopidogrel., Methods and Results: Patients (n = 4018) were categorized into two groups: pre-admission aspirin and/or clopidogrel group (n = 1455) and no pre-admission aspirin or clopidogrel group (n = 2563). The primary endpoint was the composite of all-cause death, myocardial infarction, or stroke; the secondary safety endpoint was Bleeding Academic Research Consortium (BARC) type 3-5 bleeding, both at 1 year. Patients in the pre-admission aspirin and/or clopidogrel group had a higher risk of ischaemic events, but a similar risk of bleeding to patients in the no pre-admission aspirin or clopidogrel group (cumulative incidences 10.5% vs. 6.7%, and 5.7% vs. 5.7%, respectively). The primary endpoint occurred in 81/717 patients assigned to ticagrelor and 69/738 patients assigned to prasugrel in the pre-admission aspirin and/or clopidogrel group [11.5% vs. 9.5%; hazard ratio (HR) = 1.23; 95% confidence interval (CI) 0.89-1.69], and in 103/1295 patients assigned to ticagrelor and 68/1268 patients assigned to prasugrel in the no pre-admission aspirin or clopidogrel group [8.0% vs. 5.4%; HR = 1.50 (1.10-2.03); Pint = 0.38]. BARC type 3-5 bleeding events did not differ between ticagrelor and prasugrel in patients in the pre-admission aspirin and/or clopidogrel (6.2% vs. 4.5%) or no pre-admission aspirin or clopidogrel (5.3% vs. 5.1%) group (Pint = 0.54)., Conclusion: In patients with ACS, pre-admission therapy with aspirin and/or clopidogrel has no influence on the relative efficacy and safety of ticagrelor and prasugrel., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction and Objectives: The efficacy and safety of ticagrelor vs prasugrel in patients with acute coronary syndromes (ACS) according to body mass index (BMI) remain unstudied. We assessed the efficacy and safety of ticagrelor vs prasugrel in patients with ACS according to BMI., Methods: Patients (n=3987) were grouped into 3 categories: normal weight (BMI <25kg/m 2 ; n=1084), overweight (BMI ≥ 25 to <30kg/m 2 ; n=1890), and obesity (BMI ≥ 30kg/m 2 ; n=1013). The primary efficacy endpoint was the 1 year incidence of all-cause death, myocardial infarction, or stroke. The secondary safety endpoint was the 1 year incidence of Bleeding Academic Research Consortium type 3 to 5 bleeding., Results: The primary endpoint occurred in 63 patients assigned to ticagrelor and 39 patients assigned to prasugrel in the normal weight group (11.7% vs 7.5%; HR, 1.62; 95%CI, 1.09-2.42; P=.018), 78 patients assigned to ticagrelor and 58 patients assigned to prasugrel in the overweight group (8.3% vs 6.2%; HR, 1.36; 95%CI, 0.97-1.91; P=.076), and 43 patients assigned to ticagrelor and 37 patients assigned to prasugrel in the obesity group (8.6% vs 7.3%; HR, 1.18; 95%CI, 0.76-1.84; P=.451). The 1-year incidence of bleeding events did not differ between ticagrelor and prasugrel in patients with normal weight (6.5% vs 6.6%; P=.990), overweight (5.6% vs 5.0%; P=.566) or obesity (4.4% vs 2.8%; P=.219). There was no significant treatment arm-by-BMI interaction regarding the primary endpoint (P int =.578) or secondary endpoint (P int =.596)., Conclusions: In patients with ACS, BMI did not significantly impact the treatment effect of ticagrelor vs prasugrel in terms of efficacy or safety., Clinical Trial Registration: NCT01944800., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Whether the access site influences the comparative efficacy and safety of ticagrelor and prasugrel in patients with acute coronary syndrome (ACS) undergoing invasive treatment strategy remains unstudied., Methods: This post-hoc analysis included ACS patients undergoing invasive treatment via radial or femoral access and randomized to either ticagrelor or prasugrel in the ISAR-REACT 5 trial. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke, safety endpoint was BARC 3 to 5 bleeding. Outcomes were assessed out to 12 months after randomization., Results: Out of 4018 patients, 3984 underwent invasive treatment via radial or femoral access. 1479 had coronary angiography via radial access (ticagrelor, N = 748; prasugrel, N = 731) and 2505 via femoral access (ticagrelor, N = 1245; prasugrel, N = 1260). There was no interaction between access route and assignment to either ticagrelor or prasugrel regarding the primary efficacy or safety endpoints (P for interaction≥0.616). In the radial group, the primary efficacy endpoint (7.6% versus 5.8%, HR: 1.32 [0.88-1.97], P = 0.151) and the safety endpoint (4.3% versus 3.0%, HR: 1.36, [0.73-1.31], P = 0.300) were not statistically different in patients receiving either ticagrelor or prasugrel. In the femoral group, the primary efficacy endpoint occurred more frequently in patients assigned to ticagrelor as compared to prasugrel (10.3% versus 7.3%, HR: 1.44 [1.10-1.88], P = 0.006) without significant difference in terms of safety endpoint (6.4% versus 5.8%, HR: 1.14, [0.81-1.60], P = 0.470)., Conclusions: In patients with ACS undergoing an invasive treatment strategy, the access route does not influence the comparative efficacy and safety of ticagrelor and prasugrel., Clinical Trial Registration: NCT01944800., (Copyright © 2021. Published by Elsevier Inc.)

Aim: Sex-specific analyses of direct head-to-head comparisons between newer P2Y 12 inhibitors are limited. This study was conducted to assess the efficacy and safety of ticagrelor versus prasugrel in women and men with acute coronary syndromes (ACS) planned for an invasive strategy., Methods: This pre-specified analysis of the ISAR-REACT 5 trial included 956 women and 3,062 men with ACS randomly assigned to either ticagrelor or prasugrel. The primary endpoint was the 12-month incidence of death, myocardial infarction, or stroke; the safety endpoint was the 12-month incidence of bleeding (type 3-5 according to the Bleeding Academic Research Consortium [BARC])., Results: The primary endpoint occurred in 42 women (8.9%) in the ticagrelor group and 39 women (8.3%) in the prasugrel group (hazard ratio [HR]=1.10, 95% confidence interval [CI] 0.71-1.70, P=0.657) and in 142 men (9.4%) in the ticagrelor group and 98 men (6.5%) in the prasugrel group (HR=1.47 [1.13-1.90], P=0.004; P for interaction [P int ]=0.275). BARC type 3-5 bleeding occurred in 36 women (9.7%) in the ticagrelor group and 34 women (9.7%) in the prasugrel group (HR=1.04 [0.65-1.67], P=0.856) and in 59 men in the ticagrelor group (4.4%) and 46 men (3.6%) in the prasugrel group (HR=1.24 [0.85-1.83], P=0.266; P int =0.571)., Conclusions: Although there was no significant interaction between sex and treatment effect of study drugs, the superior efficacy of prasugrel was more evident among men. No difference in bleeding between the two study groups was seen for both women and men.

Aims: Complex percutaneous coronary intervention (PCI) is associated with a higher risk of ischaemic events. However, no study has analysed the effect of PCI complexity on outcomes in a contemporary cohort of acute coronary syndrome (ACS) patients treated with a dual anti-platelet therapy regimen based on potent P2Y12-inhibitors. Therefore, we performed the current analysis., Methods and Results: This analysis included all ACS patients treated with PCI in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial. Complex PCI was defined as at least one of: multi-vessel PCI, ≥3 stents implanted, ≥3 lesions treated, and total stented length >60 mm. The primary endpoint was the composite of all-cause death, myocardial infarction (MI), or stroke at 12 months; the safety endpoint was Bleeding Academic Research Consortium types 3-5 bleeding at 12 months. Overall, 3377 patients were included in this analysis (complex PCI, n = 1429; non-complex PCI, n = 1948). The primary endpoint occurred more frequently in the complex PCI group than the non-complex PCI group [10.1% vs. 7.2%, hazard ratio (HR): 1.44, 95% confidence interval (CI) (1.14-1.82), P = 0.002], driven primarily by a higher risk of MI [HR: 1.62, (1.17-2.26), P = 0.004]. The safety endpoint was not statistically different between patients undergoing complex vs. non-complex PCI, although it was numerically higher in the complex PCI group [6.7% vs. 5.3%, HR: 1.28, (0.97-1.70), P = 0.08]., Conclusions: Acute coronary syndrome patients undergoing complex PCI have an increased incidence of ischaemic events compared with ACS patients undergoing non-complex PCI., Clinical Trial Registration: NCT01944800, Prospective, Randomized Trial of Ticagrelor Vs. Prasugrel in Patients With Acute Coronary Syndrome-Full-Text View-ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01944800., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

BACKGROUND Whether there are differences in the risk profile and treatment effect in patients recruited in a low recruitment center (LRC) versus patients recruited in a high recruitment center (HRC) in a randomized multicenter trial remains unknown. METHODS AND RESULTS This study included 4018 patients with acute coronary syndrome recruited in the ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) trial. The primary end point was a composite of all-cause death, myocardial infarction, or stroke. Overall, 3011 patients (75%) were recruited in the HRCs (7 centers recruiting 258 to 628 patients; median, 413 patients) and 1007 patients (25%) were recruited in the LRCs (16 centers recruiting 5 to 201 patients; median, 52 patients). Patients recruited in the LRCs had more favorable cardiovascular risk profiles than patients recruited in the HRCs. The primary end point occurred in 72 patients in the LRCs and 249 patients in the HRCs (cumulative incidence, 7.3% and 8.4%; P =0.267). All-cause mortality was lower among patients recruited in the LRCs (n=29) than among patients recruited in the HRCs (n=134; cumulative incidence 2.9% versus 4.5%; P =0.031). There was no significant interaction between the treatment effect of ticagrelor versus prasugrel and patient recruitment category (LRC versus HRC) regarding the primary efficacy end point (LRC: hazard ratio [HR], 1.42 [95% CI, 0.89-2.28]; HRC: HR, 1.33 [95% CI, 1.04-1.72]; P for interaction=0.800). CONCLUSIONS Patients with acute coronary syndrome recruited in a LRC appear to have more favorable cardiovascular risk profiles and lower 1-year mortality rates compared with patients recruited in a HRC. The recruitment volume did not interact with the treatment effect of ticagrelor versus prasugrel. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT01944800.

Importance: It is unclear whether ticagrelor or prasugrel hydrochloride is superior for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI)., Objective: To assess the safety and efficacy of ticagrelor vs prasugrel for patients with ACS treated with PCI., Design, Setting, and Participants: A prespecified analysis was performed of a postrandomization subgroup of 3377 patients who presented with ACS and were treated with PCI in the investigator-initiated, multicenter, phase 4, open-label Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 randomized clinical trial, conducted from September 1, 2013, to February 28, 2018. Statistical analysis was performed from September 1, 2020, to January 30, 2021. Analysis was performed according to the intention-to-treat principle., Interventions: Patients were randomly assigned to a ticagrelor-based or prasugrel-based strategy. This analysis focuses on the subgroup of patients who underwent PCI that was formed after randomization., Main Outcomes and Measures: The primary end point was a composite consisting of all-cause death, myocardial infarction, or stroke at 12 months. The safety end point was Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding., Results: The ticagrelor group comprised 1676 patients (1323 men [78.9%]; mean [SD] age, 64.4 [12.0] years), and the prasugrel group comprised 1701 patients (1341 men [78.8%]; mean [SD] age, 64.7 [12.0] years). The primary end point occurred for 162 patients (9.8%) in the ticagrelor group and 120 patients (7.1%) in the prasugrel group (hazard ratio [HR], 1.41; 95% CI, 1.11-1.78; P = .005). Myocardial infarction occurred in 88 patients (5.3%) in the ticagrelor group compared with 55 patients (3.8%) in the prasugrel group (HR, 1.67; 95% CI, 1.19-2.34; P = .003). The safety end point, BARC type 3 to 5 bleeding, occurred in 84 of 1672 patients (5.3%) in the ticagrelor group and 78 of 1680 patients (4.9%) in the prasugrel group (HR; 1.10; 95% CI, 0.81-1.50; P = .54)., Conclusions and Relevance: Among patients presenting with ACS who were treated with PCI, the incidence of the primary composite end point occurred less frequently for patients who received prasugrel compared with those who received ticagrelor. The incidence of bleeding events was comparable between the 2 groups. These results suggest that, for patients presenting with ACS who undergo PCI, a prasugrel-based strategy is superior to a ticagrelor-based strategy. However, because these observations are based on a postrandomization subgroup, these findings should be regarded as hypothesis generating and dedicated randomized clinical trials may be warranted to confirm these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT01944800.

Objectives: The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs)., Background: The outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined., Methods: Patients (n = 4,012) were categorized into 3 groups: low eGFR (<60 mL/min/1.73 m 2 ), intermediate eGFR (≥60 and <90 mL/min/1.73 m 2 ), and high eGFR (≥90 mL/min/1.73 m 2 ). The primary endpoint was a composite of all-cause death, myocardial infarction, and stroke; the secondary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding, both at 1 year., Results: Patients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted HR: 1.89; 95% CI: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding., Conclusions: These results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800)., Competing Interests: Funding Support and Author Disclosures This research was supported by a grant (FKZ 81X1600501) from the German Center for Cardiovascular Research and Deutsches Herzzentrum München. Dr Angiolillo has received grants and personal fees from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Janssen, Merck, Sanofi, and CeloNova; has received personal fees from Haemonetics, PhaseBio, PLx Pharma, Pfizer, The Medicines Company, and St. Jude Medical; and has received grants from CSL Behring, Eisai, Gilead, Idorsia Pharmaceuticals, Matsutani Chemical Industry, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr Hochholzer has received personal fees from Bayer Vital, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Novartis, AstraZeneca, and The Medicines Company. Dr Kufner has received personal fees from Bristol Myers Squibb, AstraZeneca, and Translumina. Dr Sager has received grants from the European Research Council, Else-Kröner-Fresenius-Stiftung, Deutsche Herzstiftung, and Deutsche Forschungsgemeinschaft. Dr Neumann has received personal fees from Amgen, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, and Ferrer; has received grants and personal fees from Pfizer, Biotronik, Edwards Lifesciences, Bayer Healthcare, and Boston Scientific; and has received grants from Medtronic and GlaxoSmithKline outside the submitted work. Dr Schüpke has received the Else Kröner memorial grant from Else Kröner-Fresenius Stiftung; has received financial support from the German Center for Cardiovascular Research; has received consulting fees from Bayer Vital; and has received lecture fees from Daiichi-Sankyo and Biopas Laboratories. Dr Sibbing has received personal fees from Daichi-Sankyo, Sanofi, AstraZeneca, Bayer, Pfizer, and Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with acute coronary syndromes (ACS) are not known. We assessed the efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with ACS undergoing invasive management., Methods: This pre-specified analysis of the ISAR-REACT 5 trial included 1349 smokers and 2652 nonsmokers randomized to receive ticagrelor or prasugrel. The primary endpoint was the incidence of death, myocardial infarction, or stroke; the secondary endpoint was the incidence of Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding (both endpoints assessed at 12 months)., Results: There was no significant treatment arm-by-smoking status interaction regarding the efficacy outcome. The primary endpoint occurred in 47 patients (7.0%) in the ticagrelor group and 41 patients (6.2%) in the prasugrel group in smokers (hazard ratio [HR] = 1.15; 95% confidence interval [CI] 0.76-1.75; P = 0.510) and in 133 patients (10.2%) in the ticagrelor group and 94 patients (7.2%) in the prasugrel group in nonsmokers (HR = 1.44 [1.10-1.87]; P = 0.007; P for interaction = 0.378). The secondary endpoint occurred in 27 patients (4.6%) in the ticagrelor group and 33 patients (5.6%) in the prasugrel group in smokers (HR = 0.81 [0.49-1.35]; P = 0.412) and in 66 patients (6.0%) in the ticagrelor group and 46 patients (4.4%) in the prasugrel group in nonsmokers (HR = 1.38 [0.94-2.01]; P = 0.097)., Conclusions: In patients with ACS undergoing an invasive management strategy, the smoking status did not significantly interact with the relative treatment effect of ticagrelor vs. prasugrel., Clinical Trial Registration: NCT01944800., (Copyright © 2021 Elsevier B.V. All rights reserved.)

[Figure: see text].

Background: Current guidelines recommend intensified platelet inhibition by prasugrel or ticagrelor in patients with unstable angina (UA) or non-ST-segment elevation (NSTE) myocardial infarction (MI)., Objectives: This study sought to investigate the benefits and risks of ticagrelor as compared with prasugrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and planned invasive management., Methods: This post hoc analysis combines the pre-specified subgroups of UA and NSTEMI of the randomized ISAR-REACT 5 trial. It included 1,179 patients assigned to ticagrelor and 1,186 assigned to prasugrel. Ticagrelor was started immediately after randomization and prasugrel after coronary angiography. The primary endpoint was a composite of death, MI, or stroke during 1-year follow-up, and the safety endpoint was Bleeding Academic Research Consortium class 3-5., Results: The primary endpoint was reached in 101 (8.7%) patients in the ticagrelor and in 73 (6.3%) patients in the prasugrel group (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.04 to 1.90). The HR for all-cause death was 1.43 (95% CI: 0.93 to 2.21) and that for MI 1.43 (95% CI: 0.94 to 2.19). The safety endpoint occurred in 49 (5.2%) patients in the ticagrelor and in 41 (4.7%) patients in the prasugrel group (HR: 1.09; 95% CI: 0.72 to 1.65). Landmark analysis revealed persistence of the efficacy advantage with prasugrel after the first month., Conclusions: In patients with NSTE-ACS, we found that prasugrel was superior to ticagrelor in reducing the combined 1-year risk of death, MI, and stroke without increasing the risk of bleeding. Due to the post hoc nature of the analysis, these findings need confirmation by further studies. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome; NCT01944800)., Competing Interests: Author Relationship With Industry Dr. Neumann has received lecture fees, paid to his institution, from Amgen, Daiichi-Sankyo, Novartis, and Ferrer; has received lecture fees, paid to his institution, and consulting fees, paid to his institution, from AstraZeneca and Boehringer Ingelheim; has received grant support and lecture fees, paid to his institution, from Pfizer, Biotronic, Edwards Lifesciences, Bayer HealthCare, and GlaxoSmithKline; and has received grant support from Medtronic, Abbott Vascular, and Boston Scientific. Dr. Sibbing has received personal fees from Bayer AG, Sanofi, AstraZeneca, Pfizer, Ferrer, and Daiichi-Sankyo; and has received grants and personal fees from Roche Diagnostics. Dr. Angiolillo has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has received payments for participation in review activities from CeloNova and St. Jude Medical; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr. Liebetrau has received consulting fees or honoraria from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Pfizer, and Thermo Fisher; and has received research grants from Deutsche Herzstiftung, Kerckhoff-Stiftung, and Kühl-Stiftung outside the submitted work. Dr. Liebetrau’s institution has received payments for participation in clinical study programs from Abbott, AstraZeneca, Bayer, Biosensors, Boston Scientific, Daiichi-Sankyo, and Neovasc. Dr. Hamm has received Advisory Board and speaker fees from AstraZeneca and Daiichi-Sankyo. Dr. Sager has received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (STRATO), the Else-Kröner-Fresenius-Stiftung, the Deutsche Herzstiftung, and the Deutsche Forschungsgemeinschaft. Dr. Joner has received personal fees from Biotronik, Orbus Neich, Boston Scientific, Edwards, AstraZeneca, and Recor; and has received grants from Boston Scientific, Edwards, and Amgen. Dr. Trenk has received consulting fees or honoraria from Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Ferrer, Pfizer, and Sanofi; and has received research grants from Deutsche Herzstiftung and PharmCompNet Baden-Wuerttemberg: Kompetenznetzwerk Pharmakologie Baden-Wuerttemberg outside the submitted work. Dr. Trenk’s institution has received payments for participation in clinical study programs from Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Doasense, Esperion, Idorsia, and Otsuka. Dr. Schunkert has received personal fees from Merck Sharp & Dohme, Amgen, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Servier, Brahms, Bristol Myers Squibb, Medtronic, Sanofi, Synlab, Pfizer, and Vifor; and has received grants and personal fees from AstraZeneca. Dr. Schüpke has received grants from the DZHK (German Center for Cardiovascular Research) and the Else Kröner-Fresenius-Stiftung; has received consulting fees from Bayer Vital GmbH; and has received lecture fees from Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: The aim of this study was to assess the efficacy and safety of ticagrelor versus prasugrel in patients with diabetes mellitus (DM) presenting with acute coronary syndromes (ACS) in whom invasive therapy was planned., Background: The efficacy and safety of ticagrelor versus prasugrel in patients with ACS with DM undergoing invasive treatment remain unknown., Methods: This pre-specified analysis of the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) 5 trial included 892 patients with ACS with DM and 3,124 patients with ACS without DM randomized to prasugrel or ticagrelor. The primary endpoint was a composite of death, myocardial infarction, or stroke; the safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding (both assessed 12 months after randomization)., Results: The primary endpoint occurred in 51 patients (11.2%) in the ticagrelor group and 55 patients (13.0%) in the prasugrel group in the DM cohort (hazard ratio: 0.84; 95% confidence interval: 0.58 to 1.24; p = 0.383) and in 132 patients (8.6%) in the ticagrelor group and 81 patients (5.2%) in the prasugrel group in the non-DM cohort (hazard ratio: 1.70; 95% confidence interval: 1.29 to 2.24; p < 0.001). There was a significant treatment arm-by-diabetic status interaction (p int  = 0.0035). Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 27 patients (6.9%) in the ticagrelor group and 19 patients (5.5%) in the prasugrel group (p = 0.425) in the DM cohort and in 68 patients (5.2%) in the ticagrelor group and 60 patients (4.6%) in the prasugrel group in the non-DM cohort (p = 0.500)., Conclusions: DM seems to affect the efficacy of ticagrelor and prasugrel in patients with ACS. In patients with DM, the efficacy of ticagrelor was comparable with that of prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800)., (Copyright © 2020. Published by Elsevier Inc.)

Background: The efficacy and safety of a reduced dose of prasugrel versus a standard dose of ticagrelor in elderly patients or those with a low body weight presenting with an acute coronary syndrome (ACS) are unknown., Objective: To investigate the effect of an age- and weight-adapted dose of prasugrel versus a standard dose of ticagrelor in patients with ACS. (ClinicalTrials.gov: NCT01944800)., Design: Prespecified analysis of the multicenter, randomized ISAR-REACT 5 trial., Setting: 23 centers in Germany and Italy., Patients: 3997 patients with ACS planned for invasive management., Intervention: Participants were randomly assigned to receive a standard dose of ticagrelor or prasugrel (reduced dose in the elderly or low-weight group and standard dose in the neither elderly nor low-weight group)., Measurements: The efficacy end point was a composite of death, myocardial infarction, or stroke, and the safety end point was bleeding, both at 12 months., Results: In the elderly or low-weight group, the efficacy end point occurred in 12.7% of patients assigned to receive prasugrel and 14.6% of those assigned to receive ticagrelor (hazard ratio [HR], 0.82 [95% CI, 0.60 to 1.14]); in the neither elderly nor low-weight group, the efficacy end point occurred in 4.8% of patients assigned to receive prasugrel and 7.3% of those assigned to receive ticagrelor (HR, 0.65 [CI, 0.48 to 0.88]; P for interaction > 0.2). In the elderly or low-weight group, Bleeding Academic Research Consortium type 3 to 5 bleeding occurred in 8.1% of patients assigned to receive prasugrel and 10.6% of those assigned to receive ticagrelor (HR, 0.72 [0.46 to 1.12]), and in 3.7% and 3.8%, respectively, of patients in the neither elderly nor low-weight group (HR, 0.98 [CI, 0.65 to 1.47]; P for interaction > 0.2)., Limitation: The study is a subgroup analysis., Conclusion: In elderly or low-weight patients with ACS, a reduced dose of prasugrel compared with the standard dose of ticagrelor is associated with maintained anti-ischemic efficacy while protecting these patients against the excess risk for bleeding., Primary Funding Source: German Center for Cardiovascular Research and Deutsches Herzzentrum München.

Background: The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain., Methods: In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary end point (the safety end point) was bleeding., Results: A total of 4018 patients underwent randomization. A primary end-point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006). The respective incidences of the individual components of the primary end point in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, and definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46)., Conclusions: Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups. (Funded by the German Center for Cardiovascular Research and Deutsches Herzzentrum München; ISAR-REACT 5 ClinicalTrials.gov number, NCT01944800.)., (Copyright © 2019 Massachusetts Medical Society.)

In patients presenting with acute coronary syndrome (ACS) the optimal duration of dual-antiplatelet therapy after drug-eluting stent (DES) implantation remains unclear. At 6 months after intervention, patients receiving clopidogrel were randomly assigned to either a further 6-month period of placebo or clopidogrel. The primary composite endpoint was death, myocardial infarction, stent thrombosis, stroke, or major bleeding 9 months after randomization. The ISAR-SAFE trial was terminated early due to low event rates and slow recruitment. 1601/4000 (40.0%) patients presented with ACS and were randomized to 6 (n = 794) or 12 months (n = 807) clopidogrel. The primary endpoint occurred in 14 patients (1.8%) receiving 6 months of clopidogrel and 17 patients (2.2%) receiving 12 months; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.41-1.68, P = 0.60. There were 2 (0.3%) cases of stent thrombosis in each group; HR 1.00, 95% CI 0.14-7.09, P = >0.99. Major bleeding occurred in 3 patients (0.4%) receiving 6 months clopidogrel and 5 (0.6%) receiving 12 months; HR 0.60, 95% CI 0.15-2.49, P = 0.49. There was no significant difference in net clinical outcomes after DES implantation in ACS patients treated with 6 versus 12 months clopidogrel. Ischaemic and bleeding events were low beyond 6-months.

Aims: The influence of reticulated platelets (RPs) on platelet inhibition by ticagrelor when compared with prasugrel is unknown. We aimed to determine the influence of RPs on adenosine diphosphate- (ADP-) induced platelet aggregation in patients with acute coronary syndrome who were randomly assigned to receive either ticagrelor or prasugrel for P2Y12 receptor inhibition., Methods and Results: One hundred and twenty-four patients were prospectively enrolled. The immature platelet fraction (IPF) was measured by an automated haematoanalyzer and platelet aggregation was assessed by multiple electrode aggregometry. In a subgroup of patients (n = 28) ADP-induced P-selectin expression was measured in dependence of the time point of study drug intake in RPs that were discriminated from mature platelets by thiazole-orange (TO) staining. The primary endpoint was the correlation of platelet aggregation and IPF in ticagrelor- vs. prasugrel-treated patients. Platelet aggregation significantly correlated with IPF in patients who received prasugrel (r = 0.41, P < 0.001). In contrast, no correlation between IPF and platelet aggregation was observed in ticagrelor-treated patients (r = 0.08, P = 0.51, P for difference of correlation coefficients P = 0.05). Within the TO-positive RP fraction, P-selectin expression was significantly higher in prasugrel when compared with ticagrelor-treated individuals (prasugrel 18.6 ± 16.0% vs. ticagrelor 11.5 ± 6.0%, P = 0.047). A time-dependent P-selectin expression was observed in prasugrel but not in ticagrelor-treated patients (prasugrel early 11.9 ± 9.4% vs. late 26.3 ± 19.0%, P = 0.031, ticagrelor early 9.6 ± 4.9% vs. late 13.5 ± 6.6%, P = 0.127)., Conclusion: Reticulated platelets show a greater impact on platelet reactivity in response to prasugrel when compared with ticagrelor., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)