Mattia Galli1,2, Stefano Benenati3, Francesco Franchi1, Fabiana Rollini1, Davide Capodanno4, Giuseppe Biondi-Zoccai5,6, Giovanni Maria Vescovo7, Larisa H Cavallari8, Behnood Bikdeli9,10,11, Jurrien Ten Berg12, Roxana Mehran13, Charles Michael Gibson14, Filippo Crea2, Naveen L Pereira15, Dirk Sibbing16,17,18, Dominick J Angiolillo1. 1. Division of Cardiology, University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA. 2. Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Largo Francesco Vito, 1, Rome 00168, Italy. 3. Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Policlinico San Martino IRCCS, University of Genoa, Largo Rosanna Benzi, 10, Genoa 16132, Italy. 4. Division of Cardiology, Azienda Ospedaliero Universitaria Policlinico "G. Rodolico-San Marco", University of Catania, Via Santa Sofia, 78, Catania 95123, Italy. 5. Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University, Latina, Piazzale Aldo Moro, 5, Rome 00185, Italy. 6. Mediterranea Cardiocentro, Via Orazio, 2, Napoli 80122, Italy. 7. Interventional Cardiology, Department of Cardiothoracic and Vascular Science, Ospedale dell'Angelo, Via Paccagnella, 11, Venice 30174, Italy. 8. Department of Pharmacotherapy & Translational Research, Center for Pharmacogenomics & Precision Medicine, University of Florida, Gainesville, FL 32611, USA. 9. Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA. 10. Center for Outcomes Research and Evaluation (CORE), Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510, USA. 11. Clinical Trials Center, Cardiovascular Research Foundation, 1700 Broadway, New York, NY 10019, USA. 12. Department of Cardiology and Center for Platelet Function Research, St Antonius Hospital, The Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, Maastricht 6229, the Netherlands. 13. Icahn School of Medicine at Mount Sinai, Cardiovascular Institute, 1 Gustave L. Levy Pl, New York, NY 10029, USA. 14. Department of Medicine, Beth Israel Deaconess Medical Center, 169 Pilgrim Rd, Boston, MA 02215, USA. 15. Department of Cardiovascular Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA. 16. Privatklinik Lauterbacher Mühle am Ostersee, Unterlauterbach 1, Seeshaupt 82402, Germany. 17. Department of Cardiology, Ludwig-Maximilians-Universität München (LMU Munich), Geschwister-Scholl-Platz 1, Munich 80539, Germany. 18. DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Greifswald 17475, Germany.
Abstract
AIMS: Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS. METHODS AND RESULTS: We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65-0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96-1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments. CONCLUSION: In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS. STUDY REGISTRATION NUMBER: This study is registered in PROSPERO (CRD42021258603). KEY QUESTION: A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored. KEY FINDING: In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality. TAKE HOME MESSAGE: A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS. METHODS AND RESULTS: We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65-0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96-1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments. CONCLUSION: In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS. STUDY REGISTRATION NUMBER: This study is registered in PROSPERO (CRD42021258603). KEY QUESTION: A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored. KEY FINDING: In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality. TAKE HOME MESSAGE: A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome. Published on behalf of the European Society of Cardiology. All rights reserved.
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