Ticagrelor Monotherapy or Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation: Per-Protocol Analysis of the GLOBAL LEADERS Trial

Felice Gragnano, Marcel Zwahlen, Pascal Vranckx, Dik Heg, Kurt Schmidlin, Christian Hamm, Philippe Gabriel Steg, Giuseppe Gargiulo, Eugene P McFadden, Yoshinobu Onuma, Ply Chichareon, Edouard Benit, Helge Möllmann, Luc Janssens, Sergio Leonardi, Aleksander Zurakowski, Alessio Arrivi, Robert Jan Van Geuns, Kurt Huber, Ton Slagboom, Paolo Calabrò, Patrick W Serruys, Peter Jüni, Marco Valgimigli, Stephan Windecker, GLOBAL LEADERS Investigators [Link], Mohamed Abdellaoui, David Adlam, Ibrahim Akin, Agustin Albarran Gonzalez-Trevilla, Manuel Almeida, Pedro Alves Lemos Neto, Adel Aminian, Richard Anderson, Rick Andreae, Michael Angioi, Taku Asano, Emanuele Barbato, Peter Barlis, Pascal Barraud, Edouard Benit, Olivier Bertrand, Farzin Beygui, Leonardo Bolognese, Roberto Botelho, Coby Bouwman, Marco Bressers, Philippe Brunel, Pawel Buszman, Ian Buysschaert, Pedro Canas da Silva, Didier Carrie, Angel Cequier, Ply Chichareon, Chun Chin Chang, Saqib Chowdhary, Carlos Collet, Antonio Colombo, James Cotton, Rui Cruz Ferreira, Salvatore Curello, Nick Curzen, Judith de Bot, Tone de Vreede, Georg Delle Karth, Lynn Dijksma, Marcello Dominici, István Édes, Eric Eeckhout, Ingo Eitel, József Faluközy, Farzin Fath-Ordoubadi, Maurizio Ferrario, Geza Fontos, Jose Francisco Diaz, Edgard Freitas Quintella, Bernhard Frey, Guy Friedrich, Gavin Galasko, Grzegorz Galuszka, Vasco Gama Ribeiro, Scot Garg, Giuseppe Gargiulo, Tobias Geisler, Valeri Gelev, Art Ghandilyan, Javier Goicolea, Tommaso Gori, Felice Gragnano, Ana Guimarães, Christian Hamm, Michael Haude, Dik Heg, Pieter Heijke, Rosa Ana Hernández Antolin, David Hildick-Smith, Dorien Hillen, Ina Hoekman, Sjoerd Hofma, Lene Holmvang, Stephen Hoole, Iván Horváth, Kurt Huber, Annemarie Hugense, Karim Ibrahim, Andres Iñiguez, Karl Isaaz, Zoltán Jambrik, Luc Janssens, Pawel Jasionowicz, Judith Jonk, Werner Jung, Peter Jüni, Yuki Katagiri, Norihiro Kogame, Tian Hai Koh, René Koning, Mariana Konteva, Zsolt Kőszegi, Florian Krackhardt, Yvonne Kreuger, Neville Kukreja, Boudijn Ladan, Pierre Lantelme, Sergio Leandro, Gregor Leibundgut, Christoph Liebetrau, Wietze Lindeboom, Carlos Macaya Miguel, François Mach, Michael Magro, Luc Maillard, Negar Manavifar, Laura Mauri, Eugene McFadden, Bela Merkely, Yosuke Miyazaki, Adam Młodziankowski, Tiziano Moccetti, Rodrigo Modolo, Helge Möllman, Jean-François Morelle, Aris Moschovitis, Michael Munndt Ottesen, Martin Muurling, Christoph Kurt Naber, Franz-Josef Neumann, Keith Oldroyd, Paul Ong, Yoshinobu Onuma, Sanne Palsrok, Ivo Petrov, Sylvain Plante, Janusz Prokopczuk, Tessa Rademaker-Havinga, Christopher Raffel, Benno Rensing, Marco Roffi, Kees-Jan Royaards, Manel Sabate, Volker Schächinger, Tim Seidler, Antonio Serra Peñaranda, Patrick Serruys, Lali Sikarulidze, Ton Slagboom, Osama I Soliman, Amanda Sousa, Ernest Spitzer, Rod Stables, Gabriel Steg, Clemens Steinwender, Eduardas Subkovas, Harry Suryapranata, Kuniaki Takahashi, Suneel Talwar, Emmanuel Teiger, Addy Ter Weele, Eva Teurlings, Attila Thury, Jan Tijssen, Gincho Tonev, Diana Trendafilova-Lazarova, Carlo Tumscitz, Victor Umans, Imre Ungi, Veselin Valkov, Pim van der Harst, Robert Jan van Geuns, Cokky van Meijeren, Dobrin Vassilev, Vasil Velchev, Esther Velthuizen, Freek Verheugt, Natalia Vlcek, Jürgen Vom Dahl, Mathias Vrolix, Simon Walsh, Nikos Werner, Stephan Windecker, Maarten Witsenburg, Azfar Zaman, Krzysztof Żmudka, Bernhard Zrenner, Aleksander Zurakowski, Robert Zweiker, Felice Gragnano, Marcel Zwahlen, Pascal Vranckx, Dik Heg, Kurt Schmidlin, Christian Hamm, Philippe Gabriel Steg, Giuseppe Gargiulo, Eugene P McFadden, Yoshinobu Onuma, Ply Chichareon, Edouard Benit, Helge Möllmann, Luc Janssens, Sergio Leonardi, Aleksander Zurakowski, Alessio Arrivi, Robert Jan Van Geuns, Kurt Huber, Ton Slagboom, Paolo Calabrò, Patrick W Serruys, Peter Jüni, Marco Valgimigli, Stephan Windecker, GLOBAL LEADERS Investigators [Link], Mohamed Abdellaoui, David Adlam, Ibrahim Akin, Agustin Albarran Gonzalez-Trevilla, Manuel Almeida, Pedro Alves Lemos Neto, Adel Aminian, Richard Anderson, Rick Andreae, Michael Angioi, Taku Asano, Emanuele Barbato, Peter Barlis, Pascal Barraud, Edouard Benit, Olivier Bertrand, Farzin Beygui, Leonardo Bolognese, Roberto Botelho, Coby Bouwman, Marco Bressers, Philippe Brunel, Pawel Buszman, Ian Buysschaert, Pedro Canas da Silva, Didier Carrie, Angel Cequier, Ply Chichareon, Chun Chin Chang, Saqib Chowdhary, Carlos Collet, Antonio Colombo, James Cotton, Rui Cruz Ferreira, Salvatore Curello, Nick Curzen, Judith de Bot, Tone de Vreede, Georg Delle Karth, Lynn Dijksma, Marcello Dominici, István Édes, Eric Eeckhout, Ingo Eitel, József Faluközy, Farzin Fath-Ordoubadi, Maurizio Ferrario, Geza Fontos, Jose Francisco Diaz, Edgard Freitas Quintella, Bernhard Frey, Guy Friedrich, Gavin Galasko, Grzegorz Galuszka, Vasco Gama Ribeiro, Scot Garg, Giuseppe Gargiulo, Tobias Geisler, Valeri Gelev, Art Ghandilyan, Javier Goicolea, Tommaso Gori, Felice Gragnano, Ana Guimarães, Christian Hamm, Michael Haude, Dik Heg, Pieter Heijke, Rosa Ana Hernández Antolin, David Hildick-Smith, Dorien Hillen, Ina Hoekman, Sjoerd Hofma, Lene Holmvang, Stephen Hoole, Iván Horváth, Kurt Huber, Annemarie Hugense, Karim Ibrahim, Andres Iñiguez, Karl Isaaz, Zoltán Jambrik, Luc Janssens, Pawel Jasionowicz, Judith Jonk, Werner Jung, Peter Jüni, Yuki Katagiri, Norihiro Kogame, Tian Hai Koh, René Koning, Mariana Konteva, Zsolt Kőszegi, Florian Krackhardt, Yvonne Kreuger, Neville Kukreja, Boudijn Ladan, Pierre Lantelme, Sergio Leandro, Gregor Leibundgut, Christoph Liebetrau, Wietze Lindeboom, Carlos Macaya Miguel, François Mach, Michael Magro, Luc Maillard, Negar Manavifar, Laura Mauri, Eugene McFadden, Bela Merkely, Yosuke Miyazaki, Adam Młodziankowski, Tiziano Moccetti, Rodrigo Modolo, Helge Möllman, Jean-François Morelle, Aris Moschovitis, Michael Munndt Ottesen, Martin Muurling, Christoph Kurt Naber, Franz-Josef Neumann, Keith Oldroyd, Paul Ong, Yoshinobu Onuma, Sanne Palsrok, Ivo Petrov, Sylvain Plante, Janusz Prokopczuk, Tessa Rademaker-Havinga, Christopher Raffel, Benno Rensing, Marco Roffi, Kees-Jan Royaards, Manel Sabate, Volker Schächinger, Tim Seidler, Antonio Serra Peñaranda, Patrick Serruys, Lali Sikarulidze, Ton Slagboom, Osama I Soliman, Amanda Sousa, Ernest Spitzer, Rod Stables, Gabriel Steg, Clemens Steinwender, Eduardas Subkovas, Harry Suryapranata, Kuniaki Takahashi, Suneel Talwar, Emmanuel Teiger, Addy Ter Weele, Eva Teurlings, Attila Thury, Jan Tijssen, Gincho Tonev, Diana Trendafilova-Lazarova, Carlo Tumscitz, Victor Umans, Imre Ungi, Veselin Valkov, Pim van der Harst, Robert Jan van Geuns, Cokky van Meijeren, Dobrin Vassilev, Vasil Velchev, Esther Velthuizen, Freek Verheugt, Natalia Vlcek, Jürgen Vom Dahl, Mathias Vrolix, Simon Walsh, Nikos Werner, Stephan Windecker, Maarten Witsenburg, Azfar Zaman, Krzysztof Żmudka, Bernhard Zrenner, Aleksander Zurakowski, Robert Zweiker

Abstract

Background In the GLOBAL LEADERS trial, ticagrelor monotherapy beyond 1 month compared with standard antiplatelet regimens after coronary stent implantation did not improve outcomes at intention-to-treat analysis. Considerable differences in treatment adherence between the experimental and control groups may have affected the intention-to-treat results. In this reanalysis of the GLOBAL LEADERS trial, we compared the experimental and control treatment strategies in a per-protocol analysis of patients who did not deviate from the study protocol. Methods and Results Baseline and postrandomization information were used to classify whether and when patients were deviating from the study protocol. With logistic regressions, we derived time-varying inverse probabilities of nondeviation from protocol to reconstruct the trial population without protocol deviation. The primary end point was a composite of all-cause mortality or nonfatal Q-wave myocardial infarction at 2 years. At 2-year follow-up, 1103 (13.8%) of 7980 patients in the experimental group and 785 (9.8%) of 7988 patients in the control group qualified as protocol deviators. At per-protocol analysis, the rate ratio for the primary end point was 0.88 (95% CI, 0.75-1.03; P=0.10) on the basis of 274 versus 325 events in the experimental versus control group. The rate ratio for the key safety end point of major bleeding was 1.00 (95% CI, 0.79-1.26; P=0.99). The per-protocol and intention-to-treat effect estimates were overall consistent. Conclusions Among patients who complied with the study protocol in the GLOBAL LEADERS trial, ticagrelor plus aspirin for 1 month followed by ticagrelor monotherapy was not superior to 1-year standard dual antiplatelet therapy followed by aspirin alone at 2 years after coronary stenting. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01813435.

Keywords: DAPT; P2Y12 inhibitor monotherapy; intention‐to‐treat; per‐protocol; ticagrelor.

Figures

Figure 1. Distribution of protocol deviators and…
Figure 1. Distribution of protocol deviators and nondeviators in GLOBAL LEADERS at 2 years.
A, Design of the GLOBAL LEADERS trial. B, Time trend of protocol deviators (bar graphs), nondeviators (lines), and deaths (bar graphs) at 2 years stratified by treatment strategy. ACS indicates acute coronary syndrome; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; and R, randomization.
Figure 2. Per‐protocol and intention‐to‐treat effect of…
Figure 2. Per‐protocol and intention‐to‐treat effect of ticagrelor monotherapy from 1 month vs standard antiplatelet regimens after coronary stent implantation.
Among patients who complied with the study protocol in the GLOBAL LEADERS, ticagrelor plus aspirin for 1 month followed by ticagrelor monotherapy was not superior to 1‐year standard DAPT followed by aspirin alone 2 years after coronary stenting. The per‐protocol and intention‐to‐treat effect estimates were overall consistent. ACS indicates acute coronary syndrome; ASA, acetylsalicylic acid; bid, bis in die (twice daily); CCS, chronic coronary syndrome; and DAPT, dual antiplatelet therapy.
Figure 3. Cumulative incidence of all‐cause mortality…
Figure 3. Cumulative incidence of all‐cause mortality at 2 years in the per‐protocol population.
RR indicates rate ratio.

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