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Randomized Comparison of Ticagrelor versus Prasugrel in Patients with Acute Coronary Syndrome and Planned Invasive Strategy—Design and Rationale of the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 Trial

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Abstract

In acute coronary syndromes (ACS), a dual antiplatelet regimen with an adenosine diphosphate (ADP) receptor antagonist plus aspirin has become the cornerstone of treatment. The third-generation thienopyridine prasugrel and the cyclopentyl-triazolo-pyrimidine ticagrelor provide a greater, more rapid and consistent platelet inhibition compared to their predecessor clopidogrel. Based on their advantages over clopidogrel in two landmark studies, both drugs received a class I recommendation for their use in ACS patients with and without ST segment elevation. Due to differences in ACS populations and conditions investigated, the relative merits of ticagrelor versus prasugrel in the treatment of ACS patients with planned invasive strategy cannot be reliably estimated from independent trials. To date, no direct head-to-head comparison of ticagrelor and prasugrel in terms of clinical outcome exists. The aim of this multicenter, randomized, open-label trial is to assess whether ticagrelor is superior to prasugrel in ACS patients with planned invasive strategy.

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Abbreviations

ACS:

Acute coronary syndrome

ADP:

Adenosine diphosphate

ASA:

Acetylsalicylic acid

CABG:

Coronary artery bypass graft

ISAR-REACT:

Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment

LBBB:

Left bundle branch block

MRI:

Magnetic resonance imaging

NSTE–ACS:

Non-ST segment elevation acute coronary syndrome

NSTEMI:

Non-ST segment elevation myocardial infarction

PCI:

Percutaneous coronary intervention

STEMI:

ST segment elevation myocardial infarction

URL:

Upper reference limit

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Funding

Currently there is no extramural funding for the trial.

Conflict of interest

Dominick J. Angiolillo reports receiving payment (a) as consulting fee or honorarium from Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular and PLx Pharma; (b) for participation in review activities from Johnson & Johnson, St. Jude, and Sunovion; institutional payments for grants from Bristol Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Evolva; and for other financial relationships with Esther and King Biomedical Research Grant. David Antoniucci reports receiving consulting fee or honorarium from AstraZeneca and Eli Lilly, payment for lectures including service on speakers bureaus for Bayer, and travel/accommodations/meeting expenses unrelated to activities listed from Terumo. Adnan Kastrati reports receiving lecture fees from Abbott, Biotronik and The Medicines; from advisory board meetings for AstraZeneca, MSD, and St. Jude Medical; and from event adjudication for Biosensors. Franz-Josef Neumann reports consultancy, grants/grant pending, and payment for lectures including service on speakers bureaus from Eli Lilly, Daiichi Sankyo, and AstraZeneca. Helmut Schühlen reports consultancy and payment for lectures including service on speakers bureaus from Lilly and Daiichi Sankyo and grants/grants pending from AstraZeneca. The other coauthors have reported no conflicts of interest.

Author information

Authors and Affiliations

  1. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany

    Stefanie Schulz, Katharina Mayer, Barbara von Merzljak, Tanja Morath, Judith Ruf, Gisela Schömig, Heribert Schunkert & Adnan Kastrati

  2. University of Florida College of Medicine, Jacksonville, FL, USA

    Dominick J. Angiolillo

  3. Careggi Hospital Firenze, Florence, Italy

    David Antoniucci

  4. 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Isabell Bernlochner, Juliane Jaitner & Karl-Ludwig Laugwitz

  5. Kerckhoff Klinik, Bad Nauheim, Germany

    Christian Hamm

  6. Herzzentrum Bad Krozingen, Bad Krozingen, Germany

    Franz-Josef Neumann

  7. Herzzentrum der Segeberger Kliniken, Bad Segeberg, Germany

    Gert Richardt

  8. Vivantes, Auguste-Viktoria-Klinikum, Berlin, Germany

    Helmut Schühlen

  9. DZHK, Partner Site Munich Heart Alliance, Munich, Germany

    Karl-Ludwig Laugwitz, Heribert Schunkert & Adnan Kastrati

  10. DZHK, Partner Site Rhine-Main, Frankfurt, Germany

    Christian Hamm

  11. ISAResearch Center, Deutsches Herzzentrum München, Lazarettstr. 36, 80636, Munich, Germany

    Stefanie Schulz

Authors
  1. Stefanie Schulz
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  2. Dominick J. Angiolillo
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  4. Isabell Bernlochner
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  5. Christian Hamm
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  6. Juliane Jaitner
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  7. Karl-Ludwig Laugwitz
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  8. Katharina Mayer
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  9. Barbara von Merzljak
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  10. Tanja Morath
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  11. Franz-Josef Neumann
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  12. Gert Richardt
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  13. Judith Ruf
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  14. Gisela Schömig
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  15. Helmut Schühlen
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  16. Heribert Schunkert
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Consortia

Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 Trial Investigators

Corresponding author

Correspondence to Stefanie Schulz.

Additional information

Associate Editor Emanuele Barbato oversaw the review of this article

Author list includes all members of the Steering and Operations Committees in alphabetic order except the principal investigator and study chair.

Clinical trial registration information: URL www.clinicaltrials.gov

Unique identifier NCT01944800

Appendices

Appendix 1: Endpoint Definitions

Death

The primary endpoint includes death from any cause. In addition, the cause of death will be adjudicated. All deaths will be assumed cardiovascular in nature unless a noncardiovascular cause can be clearly provided (e.g., malignancy, trauma, and infection). If an autopsy has been performed, autopsy reports should be solicited for determination of cause of death [1].

Myocardial infarction

The definition of myocardial infarction used in this trial is adapted from the Third Universal Definition of Myocardial Infarction [32]. Cardiac troponin will be used as the preferred biomarker. Creatine kinase-myocardial band (CK-MB) and CK values will be assessed concurrently and used in the case that troponin values are not available.

Spontaneous myocardial infarction (not related to PCI or CABG)

Detection of a rise and/or fall in cardiac biomarkers (preferably cardiac troponin) with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following:

  • symptoms of ischemia

  • development of pathological Q waves in the ECG

  • new or presumed new ST segment–T wave changes (ST–T changes) or new left bundle branch block (LBBB)

  • imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

Myocardial infarction after randomization and before PCI

Recurrent symptoms of cardiac ischemia or hemodynamic instability plus one of the following criteria:

  • new or presumed new ST segment elevation or new LBBB (distinct from the last ECG)

  • in patients with normal biomarkers and not presenting with STEMI on admission: detection of a rise and/or fall in cardiac biomarkers (preferably cardiac troponin) with at least one value above the 99th percentile URL

  • if the baseline troponin values are elevated and are stable or falling, then a rise of >20 % is required

  • development of new pathological Q waves in the ECG distinct from the coronary territory identified on admission

  • imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

PCI-related myocardial infarction (within 48 h after PCI)

Cardiac enzymes (troponin T or I, CK, and CK-MB) will be determined on admission, in patients with nonurgent PCI again at 4–6 h after admission (before angiography) and from blood drawn from the arterial sheath in the cath lab immediately after sheath insertion and before PCI.

The biomarker course will be used for redefinition of baseline status in patients with NSTE–ACS, i.e., to differentiate unstable angina pectoris from NSTEMI and to better describe biomarker course in NSTEMI patients.

Based on the mandatory two sets of biomarkers (on admission and in the cath lab), the baseline status will be redefined:

  • If biomarkers on admission have been normal (initial diagnosis of unstable angina) and biomarkers are rising >99th percentile URL in the second sample (before catheterization or from the arterial sheath) without recurrent symptoms of ischemia, then the initial diagnosis of unstable angina is revised to ongoing NSTEMI on admission.

  • If biomarkers on admission have been elevated (NSTEMI), then it will be documented whether biomarker values are stable, rising, or falling.

Unstable angina at baseline

In patients undergoing PCI with normal (<99th percentile URL) baseline troponin concentrations, PCI related myocardial infarction requires elevation of troponin >5 × 99th percentile URL occurring within 48 h of the procedure, plus either one of the following:

  • evidence of prolonged ischemia (>20 min) as demonstrated by prolonged chest pain or

  • ischemic ST-changes or new pathological Q waves, or

  • angiographic evidence of a flow-limiting complication, such as of loss of patency of a side branch, persistent slow flow or no reflow, embolization, or

  • imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

In patients with recent symptoms (<6 h) before admission, no second blood sample before catheterization, a short interval from biomarker assessment on admission and in the cath lab, and normal values in both samples, it will be challenging to differentiate an ongoing myocardial infarction from post-PCI myocardial infarction.

In this case, the diagnosis of myocardial infarction requires criteria as defined in the following “NSTEMI with rising biomarkers or STEMI” section for patients with rising biomarkers.

NSTEMI with documented stable or falling biomarkers

If baseline troponin values are elevated on admission and are stable or falling, then a rise of >20 % is required for the diagnosis of reinfarction. In addition, either of the following is required:

  • symptoms suggestive of myocardial ischemia or hemodynamic instability, or

  • new ischemic ECG changes or new LBBB, or

  • angiographic loss of patency of a major coronary artery or a side branch or persistent slow or no flow or embolization, or

  • imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality.

NSTEMI with rising biomarkers or STEMI

  • new symptoms suggestive of myocardial ischemia or hemodynamic instability plus

  • new ischaemic ECG changes or new LBBB plus

  • angiographic loss of patency of a major coronary artery or a side branch or persistent slow or no flow or embolization

Myocardial infarction related to CABG

Myocardial infarction associated with CABG is defined by elevation of cardiac biomarker values >10 × 99th percentile URL in patients with normal baseline troponin values (<99th percentile URL) in addition to either of the following:

  • new pathological Q waves or new left bundle branch block, or

  • angiographic documented new graft or new native coronary artery occlusion, or

  • imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Stroke

Stroke is defined as the new onset of focal or global neurological deficit caused by ischemia or hemorrhage within or around the brain and lasting for more than 24 h or leading to death. The diagnosis of stroke requires confirmation by CT, MRI, or autopsy.

Appendix 2: Study Organizational Structure

Steering Committee: A. Kastrati (Chairman), S. Schulz (Coordinating investigator), D. J. Angiolillo, D. Antoniucci, C. Hamm, K.-L. Laugwitz, F.-J. Neumann, G. Richardt, H. Schühlen, H. Schunkert

Operations Committee: A. Kastrati, S. Schulz, I. Bernlochner, J. Jaitner, K. Mayer, B. von Merzljak, T. Morath, J. Ruf, G. Schömig

Data Coordinating Center: ISAResearch Center Munich: K. Hoesl, H. Holle, J. Neudecker, I. Zenullahi, H. Paul, N. Rifatov, J. Vogel

Data and Safety Monitoring Board: A. Schömig (Chair), F. Hofmann, K. Ulm (Statistician), B. Höfling

Trial Statistician: I. C. Rondak

Event Adjudication Committee: K. Tiroch (Chair), C. Volmer, D. Keta

Angiographic Core Laboratory: R.A. Byrne, S. Pinieck, S. Hurt

ECG Core Laboratory: S. Kufner

MRI Core Laboratory: M. Hadamitzky, S. Cassese

Platelet Function Core Labs: S. Braun, G. Mößmer

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Schulz, S., Angiolillo, D.J., Antoniucci, D. et al. Randomized Comparison of Ticagrelor versus Prasugrel in Patients with Acute Coronary Syndrome and Planned Invasive Strategy—Design and Rationale of the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 Trial. J. of Cardiovasc. Trans. Res. 7, 91–100 (2014). https://doi.org/10.1007/s12265-013-9527-3

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