Is a ticagrelor-based or prasugrel hydrochloride–based strategy superior for patients with acute coronary syndrome treated with percutaneous coronary intervention?
In this prespecified subgroup analysis of a randomized clinical trial, among patients with acute coronary syndrome who underwent percutaneous coronary intervention, the composite end point of all-cause death, myocardial infarction, or stroke occurred less frequently for patients who received prasugrel compared with ticagrelor.
These results suggest that, for patients with acute coronary syndrome who undergo percutaneous coronary intervention, a prasugrel-based strategy is superior to a ticagrelor-based strategy.
It is unclear whether ticagrelor or prasugrel hydrochloride is superior for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI).
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.
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.
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.
ClinicalTrials.gov Identifier: NCT01944800
Percutaneous coronary intervention (PCI) is the recommended treatment for the majority of patients with acute coronary syndrome (ACS).1,2 The combination of anticoagulation, aspirin, and P2Y12 inhibition is the mainstay of pharmacotherapy for patients with ACS who are treated with PCI.1,2 Randomized clinical trials have demonstrated the superiority of prasugrel hydrochloride and ticagrelor compared with clopidogrel bisulfate3,4 and of prasugrel compared with ticagrelor in the treatment of ACS.5
These trials3-5 had important differences in study design, patient populations, and loading-dose strategies. One of the most important differences was the proportion of patients treated with PCI. TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel—Thrombolysis in Myocardial Infarction 38) was primarily a PCI study, with 99% of patients having undergone PCI at the time of randomization.3 In the PLATO (Platelet Inhibition and Patient Outcomes) trial, only 64.3% of patients had undergone PCI during the study period,4 whereas in the ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) trial, 84% of patients were treated with PCI.5
A detailed analysis of the large subset of patients with ACS who underwent a PCI procedure in the ISAR-REACT 5 trial may offer useful information regarding not only the comparison between the 2 study drugs, prasugrel and ticagrelor, but also the value of P2Y12 antagonist pretreatment in this category of patients. Therefore, we carried out this prespecified, in-depth, subanalysis of the ISAR-REACT 5 trial.
Study Population and Enrollment Criteria
This study was a prespecified analysis of the ISAR-REACT 5 trial,5 conducted from September 1, 2013, to February 28, 2018, and includes all patients in the trial who underwent PCI, a subgroup that was formed after randomization. The full trial design has previously been reported.5,6 The trial protocol and statistical analysis plan are available in Supplement 1. In brief, patients were eligible to be enrolled if they were hospitalized for an ACS and were planned to undergo an invasive treatment strategy. The full exclusion criteria for this trial have been described previously.5 This study conforms to the Declaration of Helsinki7 and the study protocol was approved by the ethics committee of each participating center (Deutsches Herzzentrum München, Munich, Germany; Department of Cardiology and Angiology II, University Heart Center Freiburg, Bad Krozingen, Germany; Medizinische Klinik und Poliklinik Innere Medizin I [Kardiologie, Angiologie, Pneumologie], Klinikum rechts der Isar, Munich, Germany; Ulm University Hospital, Cardiology, Ulm, Germany; Heart Center, Bad Segeberg, Germany; Heart Center, Campus Kerckhoff of Justus-Liebig-University, Giessen, Germany; Helios Amper-Klinikum Dachau, Cardiology & Pneumology, Dachau, Germany; University Clinic Mannheim, Cardiology, Mannheim, Germany; Klinikum Landkreis Erding, Cardiology, Erding, Germany; Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany; Department of Cardiology, Charité, University Medicine Berlin, Berlin, Germany; University Clinic Heidelberg, Cardiology, Heidelberg, Germany; Klinik der Universität München, Ludwig Maximilians University, Cardiology, Munich, Germany; Helios University Hospital, University of Witten/Herdecke, Department of Cardiology, Wuppertal, Germany; Schön Klinik Starnberger See, Berg, Germany; Städtisches Klinikum München GmbH—Klinikum Neuperlach, Cardiology and Pneumology, Munich, Germany; Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Cardiology, Mainz, Germany; Universitätsmedizin Göttingen, Heart Center, Göttingen, Germany; Klinikum Traunstein, Cardiology, Traunstein, Germany; Städtisches Klinikum Karlsruhe, Cardiology and Angiology, Karlsruhe, Germany; Klinikum Lippe-Detmold, Cardiology and Angiology, Lippe, Germany; Ospedale Fabrizio Spaziani, Cardiology, Frosinone, Italy; and Careggi University Hospital Firenze, Florence, Italy). All patients provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
The loading-dose strategy for the 2 trial drugs is shown in eFigure 1 in Supplement 2. In the ticagrelor group, patients received the loading dose of 180 mg as soon as possible after stratified randomization, followed by a twice-daily maintenance dose of 90 mg. In the prasugrel group, the timing of loading-dose administration depended on the clinical presentation. For patients with ST-elevation myocardial infarction (STEMI), patients received the loading dose of 60 mg of prasugrel hydrochloride as soon as possible. For patients with non–ST-elevation myocardial infarction (NSTEMI) or unstable angina, loading-dose administration with prasugrel was postponed until the coronary anatomy was known. There was no treatment before angiography and the loading dose was given before proceeding to PCI (ie, before the guide wire crossed the lesion). Thereafter, patients received a maintenance dose of 10 mg once daily. For patients older than 75 years or those below 60 kg body weight, a 5-mg reduced dose was recommended. All patients received aspirin therapy consisting of 150 to 300 mg as a loading dose followed by a maintenance dose of 75 to 100 mg daily.8
End Points and Definitions
In-depth descriptions of the study end point definitions have been published previously.5,6 The primary end point in this analysis was a composite of all-cause death, myocardial infarction (MI), or stroke at 12 months after randomization. The safety end point was the incidence of Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding at 12 months after randomization. Additional end points in this study included the individual components of the primary composite end point and definite stent thrombosis. We also performed a landmark analysis at 30 days for both the primary end point and the safety end point to assess for any heterogeneity of treatment effect. Finally, we collected data on discontinuation of the assigned study drugs in both groups.
In this study, patients were followed up at 30 (±10) days, 6 (±1) months, and 12 (±1) months. In case of potential end point–related adverse events, source data were solicited. Patients were either contacted by telephone, were sent a structured follow-up letter, or returned for hospital or outpatient visits.
Statistical analysis was performed from September 1, 2020, to January 30, 2021. This analysis of the patient cohort undergoing treatment with PCI was specified in the study protocol. The distribution of continuous data are presented as mean (SD) values or median values and interquartile ranges. Hypothesis tests for group differences were performed using either the t test or Wilcoxon rank sum test, as appropriate. Categorical data are presented as counts and proportions. Data distribution was tested for normality by using the Kolmogorov-Smirnov test for goodness of fit. Depending on the data distribution, the χ2 test or the Fisher exact test was used for hypothesis testing of respective group differences. The risk of adverse events was calculated using either Kaplan-Meier estimates or cumulative incidence functions in case of competing risks for events other than all-cause death. Hazard ratios (HRs) were calculated using a Cox proportional hazards regression model after checking for fulfilment of the proportional hazards assumption per the method of Grambsch and Therneau.9 The Cox proportional hazards regression model included the following factor variables as covariates: trial group, participating center, and clinical presentation. Similar models were used for subgroup analysis. These models additionally included the factor variables: age (<75 or ≥75 years), sex (male or female), smoking status (active or nonactive smoker), weight (<60 vs ≥60 kg), type 1 or 2 diabetes (yes or no), creatinine level (<0.94 or ≥0.94 mg/dL [to convert to micromoles per liter, multiply by 88.4]), cardiogenic shock (yes or no), clinical presentation (STEMI or NSTEMI or unstable angina), access site (femoral or radial or other), and PCI type (stent or percutaneous transluminal coronary angioplasty). The analysis of the outcomes of interest was performed mainly in the full analysis set according to the intention-to-treat principle. The analysis of the safety end point (BARC type 3-5 bleeding) was performed on a modified full analysis set, including patients who received at least 1 dose of the study drug. In the setting of this analysis, assessment of patients who discontinued the study drug was not extended beyond 1 week after discontinuation. Statistical analysis was performed using the R, version 3.6.0 statistical package (R Group for Statistical Computing). Hypothesis testing was performed at 2-tailed significance levels of P < .05.
Percutaneous coronary intervention was performed in 3377 of 4016 patients (84.1%) enrolled in the ISAR-REACT 5 trial, of whom 1676 were assigned to the ticagrelor group and 1701 to the prasugrel group. Characteristics and clinical outcomes of patients in the non-PCI cohort are shown in eTable 1 and eTable 2 in Supplement 2, according to randomly assigned therapy.
Baseline characteristics were similar for the 2 groups and are shown in Table 1. Of the 3377 patients enrolled in the study, 713 (21.1%) were women and 2664 (78.9%) were men. Mean (SD) patient age was 64.5 (12.0) years. Baseline characteristics for the non-PCI cohort are summarized in eTable 1 in Supplement 2.
Angiographic Data, Procedural Characteristics, and Discharge Therapy
Angiographic data and procedural characteristics are shown in eTable 3 and eTable 4 in Supplement 2 and were well matched between the 2 groups. Drug therapy at discharge is summarized in eTable 5 in Supplement 2.
At 12-month follow up, 218 of 1676 patients (13.0%) assigned to ticagrelor and 178 of 1701 patients (10.5%) assigned to prasugrel had discontinued the study drug (P = .02). The median time to discontinuation of the study drug in the ticagrelor group was 90 days (interquartile range, 27-183 days) and in the prasugrel group was 113 days (interquartile range, 38-219 days) (P = .05). Dyspnea resulted in study drug discontinuation in 40 of 1676 patients assigned to ticagrelor compared with 1 of 1701 patients assigned to prasugrel (P < .001).
The efficacy outcomes for both groups are summarized in Table 2. The primary end point (all-cause death, MI, or stroke at 1 year) occurred in 162 patients (9.8%) in the ticagrelor group and 120 patients (7.1%) in the prasugrel group (HR, 1.41; 95% CI, 1.11-1.78; P = .005) (Figure 1). With regard to the secondary end points, all-cause death occurred in 79 patients (4.8%) in the ticagrelor group compared with 64 patients (3.8%) in the prasugrel group (HR, 1.28; 95% CI, 0.92-1.77; P = .15). 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 breakdown of the various types of MI events in both groups is shown in Table 2. Stroke occurred in 16 patients (1.0%) in the ticagrelor group compared with 14 patients (0.8%) in the prasugrel group (HR, 1.20; 95% CI, 0.58-2.46; P = .62). Definite stent thrombosis occurred in 21 patients (1.3%) in the ticagrelor group compared with 12 patients (0.7%) in the prasugrel group (HR, 1.81; 95% CI, 0.89-3.68; P = .10).
The primary end point was analyzed by various subgroups according to age, sex, smoking status, body weight, type 1 or 2 diabetes, serum creatinine, cardiogenic shock, clinical presentation, access site, and PCI type. Diabetes was the only subgroup that demonstrated a significant interaction (P < .001 for interaction), as previously reported10 (eFigure 2 in Supplement 2). In patients with diabetes, the primary efficacy end point occurred in 40 of 376 patients assigned to ticagrelor and 50 of 367 patients assigned to prasugrel (10.7% vs 13.8%; HR, 0.77; 95% CI, 0.50-1.16). In patients without diabetes, the primary efficacy end point occurred in 121 of 1299 patients assigned to ticagrelor and in 69 of 1333 patients assigned to prasugrel (9.4% vs 5.2%; HR, 1.87; 95% CI, 1.39-2.52).
Bleeding outcomes are also shown in Table 2. The safety end point (BARC type 3-5 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) (Figure 2). The incidence of BARC type 0 to 2 bleeding was also comparable between the 2 groups (ticagrelor: 252 of 1676 [15.2%] vs prasugrel: 276 of 1701 [16.4%]; HR, 0.92; 95% CI, 0.77-1.09; P = .32). The breakdown of the various classes of BARC type 3 to 5 bleeding events in both groups is shown in Table 2.
Within the first 30 days, the primary efficacy end point occurred in 75 patients (4.5%) in the ticagrelor group and 60 patients (3.5%) in the prasugrel group (HR, 1.29; 95% CI, 0.92-1.82; P = .14) (Figure 3). From 30 days to 1 year, the primary efficacy end point occurred in 87 patients (5.2%) in the ticagrelor group and 60 patients (3.5%) in the prasugrel group (HR, 1.52; 95% CI, 1.09-2.11; P = .01). There was no difference in the occurrence of the primary safety end point between the 2 groups in the first 30 days or from 30 days to 1 year.
This analysis is, to our knowledge, the first study to directly compare outcomes between ticagrelor-based and prasugrel-based strategies in patients with ACS who are treated with PCI. The PCI procedure for these patients reflected contemporary practice with new-generation drug-eluting stents. This was not the case in the TRITON-TIMI 38 and PLATO trials, where most patients treated with PCI (50.5% in TRITON-TIMI 38; and 69.5% in PLATO) were treated with bare metal stents.3,4
For patients with ACS treated with PCI, prasugrel was superior to ticagrelor with regard to the primary outcome, a composite of all-cause death, MI, or stroke, at 12 months. This superiority was primarily driven by a reduction in the number of MIs in the prasugrel group. Landmark analysis demonstrated that the superiority of prasugrel compared with ticagrelor for this outcome was maintained after 30 days through to the end of the study period. The incidence of stent thrombosis was numerically lower in the prasugrel group, but this difference did not reach statistical significance. Outcomes between prasugrel and ticagrelor were comparable with respect to the incidence of bleeding events at 12 months. Prasugrel was better tolerated than ticagrelor, with a lower incidence of drug discontinuation at 12 months after PCI.
Differential Loading-Dose Strategies for Potent P2Y12 Inhibitors
This study compares not only 2 drugs but also 2 loading-dose strategies. In our analysis, the incidence of both PCI-related (type 4a) and stent thrombosis–related (type 4b) MI in the prasugrel group was almost half that observed in the ticagrelor group. The differential timing of P2Y12 inhibitor loading doses in our study is a mechanism that may have contributed to these observed differences in clinical outcomes. It has been suggested11 that an advantage associated with the ticagrelor-based strategy is that it does not need to be withheld until the coronary anatomy is known. However, recently published observational data suggest that pretreatment with P2Y12 inhibitors (including ticagrelor) is not associated with improved clinical outcomes but is associated with increased bleeding.12 The ACCOAST-PCI (A Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction) trial13 reported similar findings with prasugrel pretreatment in patients with non–ST-segment elevation (NSTE)–ACS. The randomized COMPARE CRUSH (Comparison of Pre-Hospital Crushed vs Uncrushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Interventions) trial also did not find any benefit in clinical outcomes with crushed prasugrel tablets compared with integral prasugrel tablets in patients with STEMI treated with primary PCI, despite an enhanced degree of platelet inhibition in the group receiving the crushed tablets.14 In addition, the DUBIUS (Downstream vs Upstream Administration of P2Y12 Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication) trial failed to show that a downstream P2Y12 inhibition strategy was superior to an upstream strategy in patients with NSTE-ACS.15 Taken together, these data suggest that platelet inhibition may not be as crucial in the period prior to and during PCI, a time when patients will also be receiving therapeutic anticoagulation. Instead, the benefit of P2Y12 inhibition may be more important in the period after PCI, once periprocedural anticoagulation has stopped. These data are acknowledged in the current guidelines in which it is not recommended to routinely administer pretreatment with a P2Y12 inhibitor in patients with NSTE-ACS in whom the coronary anatomy is not known and early invasive management is planned.2
The landmark analysis also demonstrated that the superiority associated with the prasugrel strategy was even more pronounced after the first 30 days through to 1 year after PCI. The incidence of both type 1 (spontaneous) MI and STEMI was higher in the ticagrelor group at 12 months. There are several reasons that prasugrel may have been superior to ticagrelor in the later phase after ACS treated with PCI. Several studies have highlighted concerns with respect to the efficacy of ticagrelor in comparison with clopidogrel in the real-world setting.16-18 Postulated hypotheses for these findings included the adverse effect profile of ticagrelor and issues with compliance. The consequences of noncompliance may be greater for patients taking ticagrelor than for patients taking prasugrel given that ticagrelor is a twice-daily medication that does not irreversibly inhibit the P2Y12 receptor.19,20 In our study, significantly more patients overall stopped ticagrelor compared with prasugrel and dyspnea was more common in the ticagrelor group. This is important, as adverse side effect profiles may lead to issues with compliance.21
Potent P2Y12 Inhibition in ACS Treated With PCI
Although a subgroup analysis of PLATO for patients managed with and without revascularization within 10 days of randomization has been published, a dedicated analysis of patients treated with PCI has not.22 However, data supplied to a French transparency committee23 indicated that, in 11 520 patients treated with PCI, the reduction in the primary composite end point was less impressive for those who received ticagrelor vs clopidogrel (HR, 0.88; 95% CI, 0.78-0.99; P = .04) than for 5216 patients treated medically (HR, 0.78; 95% CI, 0.67-0.90; P < .001). Similar data in the US Food and Drug Administration drug approval summary review24 reported an HR of 0.89 (95% CI, 0.78-1.00) in 11 855 patients treated with any PCI. These both compare unfavorably to the reduction in the composite end point observed with prasugrel vs clopidogrel in TRITON-TIMI 38 (HR, 0.81; 95% CI, 0.73-0.90; P < .001), where more than 99% of patients were treated with PCI. It may be speculated based on these data that the benefit of prasugrel vs ticagrelor in the treatment of ACS increases with the proportion of patients treated with PCI.
Postulated Mechanisms for the Superiority of Prasugrel vs Ticagrelor
These results suggest that for patients with ACS treated with PCI, a prasugrel-based strategy is superior to a ticagrelor-based strategy. There are several possible mechanisms underpinning this superiority. Although ticagrelor and prasugrel are both potent inhibitors of the P2Y12 receptor, their drug class and mechanism of action are different.19,20 In a pharmacodynamic analysis of ISAR-REACT 5,25 the prasugrel group demonstrated lower levels of adenosine diphosphate–induced platelet aggregation compared with ticagrelor. The incidence of the study end point increased across tertiles of platelet aggregation independently to the assigned study drug. Differential “off-target” effects may also have contributed to the observed differences between the ticagrelor and prasugrel groups, although contrasting results have previously been published in this regard. Although the HI-TECH (Hunting for the Off-Target Properties of Ticagrelor on Endothelial Function in Humans) study26 did not find that ticagrelor improved endothelial function or resulted in an increase in systemic adenosine levels compared with prasugrel or clopidogrel, Schnorbus et al27 subsequently reported that prasugrel was associated with improvements in endothelial function, higher levels of platelet inhibition, and lower levels of interleukin 6 in comparison with both ticagrelor and clopidogrel. Higher levels of interleukin 6 after ACS have been previously associated with adverse outcomes,28 which may offer another potential mechanistic explanation for the superiority observed with prasugrel vs ticagrelor in our analysis.
This study has some limitations. Although it was prespecified, it is a subgroup analysis of a randomized clinical trial. As such, it is liable to the usual potential limitations associated with subgroup analysis, and its results should be regarded as hypothesis generating. With regard to sample size, despite including 84% of the population from the ISAR REACT 5 trial, this analysis is slightly underpowered for the primary end point. The PCI subgroup was formed after randomization; therefore, there is the possibility that this may confound the observations with respect to treatment comparisons. Another limitation is that this was an open-label study, albeit with adjudication of clinical events carried out in a blinded manner.
Our results have demonstrated that, among patients with ACS treated with PCI, the incidence of the primary end point (a composite of all-cause death, MI, or stroke) occurred less frequently in patients who received prasugrel compared to with those who received ticagrelor. This difference was driven primarily by a reduction in the number of MIs in the prasugrel group. The incidence of bleeding was comparable in both groups. Overall, these data support the preference for a prasugrel-based strategy vs a ticagrelor-based strategy in patients presenting with ACS who are treated with PCI. 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.
Accepted for Publication: March 9, 2021.
Published Online: June 30, 2021. doi:10.1001/jamacardio.2021.2228
Corresponding Author: Adnan Kastrati, MD, Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse 36, 80636 Munich, Germany (email@example.com).
Author Contributions: Dr Kastrati had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Coughlan and Aytekin contributed equally to this work.
Concept and design: Coughlan, Menichelli, Mayer, Bernlochner, Joner, Richardt, Neumann, Schüpke, Kastrati.
Acquisition, analysis, or interpretation of data: Coughlan, Aytekin, Lahu, Ndrepepa, Mayer, Wöhrle, Bernlochner, Gewalt, Witzenbichler, Hochholzer, Sibbing, Cassese, Angiolillo, Hemetsberger, Valina, Müller, Kufner, Liebetrau, Xhepa, Hapfelmeier, Sager, Fusaro, Richardt, Laugwitz, Neumann, Schunkert, Schüpke, Kastrati.
Drafting of the manuscript: Coughlan, Aytekin, Mayer.
Critical revision of the manuscript for important intellectual content: Lahu, Ndrepepa, Menichelli, Mayer, Wöhrle, Bernlochner, Gewalt, Witzenbichler, Hochholzer, Sibbing, Cassese, Angiolillo, Hemetsberger, Valina, Müller, Kufner, Liebetrau, Xhepa, Hapfelmeier, Sager, Joner, Fusaro, Richardt, Laugwitz, Neumann, Schunkert, Schüpke, Kastrati.
Statistical analysis: Coughlan, Aytekin, Ndrepepa, Hapfelmeier, Laugwitz, Schüpke.
Obtained funding: Schüpke.
Administrative, technical, or material support: Lahu, Wöhrle, Witzenbichler, Hochholzer, Sibbing, Hemetsberger, Valina, Müller, Liebetrau, Xhepa, Sager, Joner, Fusaro, Laugwitz, Schunkert, Schüpke, Kastrati.
Supervision: Menichelli, Sibbing, Cassese, Angiolillo, Xhepa, Richardt, Neumann, Schüpke, Kastrati.
Conflict of Interest Disclosures: Dr Bernlochner reported receiving personal fees from Sysmex Europe GmbH outside the submitted work. Dr Witzenbichler reported receiving grants from ISAReasarch Center during the conduct of the study. Dr Hochholzer reported receiving personal fees from Bayer Vital, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AstraZeneca, and The Medicines Company outside the submitted work. Dr Sibbing reported receiving personal fees from Sanofi, Bayer, Daiichi Sankyo, AstraZeneca, and Pfizer during the conduct of the study. Dr Angiolillo reported receiving 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; and receiving payments for participation in review activities from CeloNova and St Jude Medical outside the present work; his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr Kufner reported personal fees from Bristol Myers Squibb, personal fees from AstraZeneca, and personal fees from Translumia outside the submitted work. Dr Joner reported receiving personal fees from Biotronik, Orbus Neich, Boston Scientific, Edwards, Recor, AstraZeneca, and Abbott; and grants from Boston Scientific, Edwards, and Amgen, outside the submitted work. Dr Neumann reported receiving grants from Abbott Vascular, Medtronic, GlaxoSmithKline, Boston Scientific, Pfizer, Biotronic, and Bayer Healthcare; personal fees to institution from Amgen, Daiichi Sankyo, Pfizer, Biotronic, Edwards Lifesciences, and Boston Scientific; personal fees and consultancy fees to institution from Boehringer Ingelheim, Novartis, and Ferrer; and personal fees from Bayer Healthcare outside the submitted work. Dr Schunkert reported receiving personal fees from MSD Sharp & Dohme, Amgen, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Servier, Brahms, Bristol Myers Squibb, Medtronic, Sanofi Aventis, Synlab, Pfizer, and Vifor; and grants from AstraZeneca outside the submitted work. Dr Schüpke reported receiving grants from DZHK (German Center for Cardiovascular Research) during the conduct of the study; and grants from Else Kröner-Fresenius-Stiftung (Else Kröner-Memorial grant); personal fees from Bayer Vital GmbH, Daiichi Sankyo, and Biopas Laboratoires outside the submitted work. No other disclosures were reported.
Data Sharing Statement: See Supplement 3.
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