Dirk Sibbing1, Dániel Aradi2, Claudius Jacobshagen3, Lisa Gross4, Dietmar Trenk5, Tobias Geisler6, Martin Orban4, Martin Hadamitzky7, Béla Merkely8, Róbert Gábor Kiss9, András Komócsi10, Csaba A Dézsi11, Lesca Holdt12, Stephan B Felix13, Radoslaw Parma14, Mariusz Klopotowski15, Robert H G Schwinger16, Johannes Rieber17, Kurt Huber18, Franz-Josef Neumann5, Lukasz Koltowski19, Julinda Mehilli20, Zenon Huczek19, Steffen Massberg20. 1. Department of Cardiology, LMU München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. Electronic address: dirk.sibbing@med.uni-muenchen.de. 2. Heart Centre Balatonfüred and Heart and Vascular Centre, Semmelweis University, Budapest, Hungary. 3. Department of Cardiology und Pneumology, Heart Centre/Georg-August-University Göttingen, Göttingen, Germany. 4. Department of Cardiology, LMU München, Munich, Germany. 5. Department of Cardiology and Angiology II, University Heart Centre Freiburg, Bad Krozingen, Germany. 6. University Hospital Tübingen, Department of Cardiology and Cardiovascular Disease, Tübingen, Germany. 7. Department of Radiology, Deutsches Herzzentrum, München, Germany. 8. Heart and Vascular Centre, University of Semmelweis, Budapest, Hungary. 9. Department of Cardiology, Military Hospital, Budapest, Hungary. 10. Department of Interventional Cardiology, Heart Institute, University of Pécs, Pécs, Hungary. 11. Department of Cardiology, Petz Aladár County Teaching Hospital, Győr, Hungary. 12. Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany. 13. Department of Internal Medicine B, University Medicine Greifswald, Germany and DZHK, Greifswald, Germany. 14. 3rd Department of Cardiology, Medical University of Silesia, Katowice, Poland. 15. Department of Interventional Cardiology and Angiology, Institute of Cardiology, Warsaw, Poland. 16. Medizinische Klinik II, Klinikum Weiden, Kliniken Nordoberpfalz AG, Weiden, Germany. 17. Heart Centre Munich-Bogenhausen, Department of Cardiology and Intensive Care Medicine, Munich, Germany. 18. 3rd Medical Department, Cardiology and Intensive Care Medicine, and Sigmund Freud Private University, Medical School, Wien, Austria. 19. 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland. 20. Department of Cardiology, LMU München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany.
Abstract
BACKGROUND: Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). METHODS: In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. FINDINGS: Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority=0·0004; hazard ratio [HR] 0·81 [95% CI 0·62-1·06], psuperiority=0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority=0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59-1·13]; p=0·23). INTERPRETATION: Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. FUNDING: Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.
RCT Entities:
BACKGROUND: Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). METHODS: In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. FINDINGS: Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority=0·0004; hazard ratio [HR] 0·81 [95% CI 0·62-1·06], psuperiority=0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority=0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59-1·13]; p=0·23). INTERPRETATION: Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. FUNDING: Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.
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