Anticoagulation with Otamixaban and Ischemic Events in Non–ST-Segment Elevation Acute Coronary Syndromes: the TAO Randomized Clinical Trial

Supplementary Online Content

Steg PG. Mehta SR, Pollak CV Jr et al; the TAO Investigators. Anticoagulation With Otamixaban and Ischemic Events in Non–ST-Segment Elevation Acute Coronary Syndromes: the TAO Randomized Clinical Trial. JAMA. doi:10.1001/JAMA.2013.277165

eAppendix. Trial Organization, Committees, and Investigators

eFigure 1. Study Design

eFigure 2. Kaplan-Meier Analyses of the Primary Efficacy Outcome Up to Day 30 for Otamixaban 0.100 mg/kg per hour vs Control

eFigure 3. Additional Subgroup Analyses (Defined Post Randomization) of the Primary (top panel) Efficacy and (bottom panel) Safety Outcomes at Day 7 in the Otamixaban 0.140 mg/kg per hour Group vs Control

eFigure 4. Subgroup Analysis of the Primary Safety Outcome for the Otamixaban 0.140 mg/kg per Hour Group Versus Control (logarithmic scale).

eFigure 5. Effect of Otamixaban on the Primary Efficacy Outcome: SEPIA-ACS1 Versus TAO

eTable 1 Main Inclusion and Exclusion Criteria

eTable 2. Thrombotic Procedural Complications During Percutaneous Coronary Intervention

eTable 3. Efficacy and Safety Outcomes at 7 days and at 30 days After Randomization (enrollment in the 0.100 dose arm of otamixaban was stopped at the time of the interim analysis)

eTable 4. Bleeding Assessment at Day 7 using Additional Bleeding Categorizations, and Adjudicated Bleedingsa

eTable 5. Treatment-Emergent Adverse Events Excluding Bleedings and Liver Function Abnormalities up to Day 7 in the Safety Population References

References

This supplementary material has been provided by the authors to give readers additional information about their work.

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Appendix. Trial organization, committees and investigators

Executive Committee: Ph. G. Steg (Chair), C. Bode, S. R. Mehta, C. V. Pollack, M. S. Sabatine, S. D. Wiviott (Ex officio).

Steering Committee: J. L. Navarro Estrada (Argentina); K. Huber (Austria); N. Mitkovskaya (Belarus); P. Sinnaeve (Belgium); J. C. Nicolau (Brazil); I. Petrov (Bulgaria); S. Mehta (Canada); R. Corbalan (Chile); C. Jaramillo (Colombia); P. Widimsky (Czech Republic); A. Mowafy (Egypt); P. Laanmets (Estonia); F. Schiele (France); C. Bode (Germany); P. S. Konstantinidis (Greece); R. Kiss (Hungary); P. Kerkar (India); H. Hod (Israel); C. Cavallini (Italy); M. Ho Jeong (South Korea ); J.-H. Kim (South Korea); A. Erglis (Latvia); S. Kabbani (Lebanon); B. Petrauskiene (Lithuania); K. H. Sim (Malaysia); G. A. Ramos (Mexico); W. Jukema (Netherlands); J. E. Nordrehaug (Norway); J. A. Aguero Rodriguez (Peru); W. Ruzyllo (Poland); L. Providencia (Portugal); M. Dorobantu (Romania); M Ruda (Russia); S. Dodic (Serbia); F Kovar (Slovakia); I Ebrahim (South Africa); M. Sabaté (Spain); J. M. Ruiz Nodar (Spain); T. Moccetti (Switzerland); C. Wu (Taiwan); H. Haouala (Tunisia); M. Sezer (Turkey); S. Guneri (Turkey); A. Parkomenko (Ukraine); A. H. Gershlick (UK); M. Cohen (USA); J. Hoekstra (USA); S. Rao (USA); W. French (USA); D. Faxon (USA); L. Nguyen (Vietnam).

Data Monitoring Committee: R. A. Harrington (Chair); K. Lee; L. Wallentin; M. E. Bertrand; H. R. Buller. Independent DMC statistician: S. Ellis, Duke University, Durham NC, USA

Independent Statistical Group (TIMI Study Group): Elaine B. Hoffman and Amarachi Umez-Eronini, TIMI study group, Brigham and Women’s Hospital, Boston, MA, USA.

Clinical Events Committee: S. D. Wiviott (Chair); C. Lowe (Project Director), E. Awtry; C. J. Berger; M. Bonaca; K. Croce; A. Desai; E. Gelfand; R. P. Giugliano; C. Ho; D. E. Leeman; M. S. Link; J. L. Mega; D. A. Morrow; A. Pande; F. Ruberg; C. Ruff; B. M. Scirica; J. A. Vita.

TAO Investigators: Argentina: Stella Macin, Manuel Sanjurjo Pyzcek, Jose Luis Navarro, Aníbal Damonte, Jacqueline Petrucci, Miguel Hominal, Alvaro Sosa Liprandi, Aldo Prado, Miguel Ballarino, Carlos Alberto Rapallo, Diego Gonzalia, Luis Cartasegna, Orlando Caruso, Nestor Vita, Horacio Enrique Fernandez, Ariel Tercelan, Rodolfo Andres Ahuad Guerrero, Juan Pablo Albisu Di Gennaro, Diego Grinfeld, Carlos Lorente, Marcelo Trivi, Sergio Muryan, Sebastian Nani, Javier Alberto Mariani, Oscar Octavio Carlevaro, Ernesto Duronto, Daniel Paolantonio, Alberto Licheri, Juan Medrano, Cesar Federico Vigo, Adrian Lescano, Pablo Comignani, Fernando Jose Sokn. Australia: Peter Stewart, James Alexander Shaw, Romulo Ernesto Oqueli Flores, Matthew Ian Worthley, David Bernard Brieger, John Kerswell French, Philip Roberts-Thomson. Austria: Kurt Huber, Rudolf Berger. Belarus: Valeriy Stelmashok, Natalya Mitkovskaya, Andrei Prystrom, Anzhalika Darahakupets . Belgium: John Roosen, José Castro Rodriguez, Antoine De Meester, Patrick Coussement, Peter Sinnaeve. Brazil: Paulo Caramori, Lilia Maia, Pedro Pimentel Filho, Luciano Baracioli , Roberto Botelho, Carisi Polanczyk, Lucia Belem, Rogério Tumelero, Benito Garbelini Junior, Raul D'aurea Mora Junior, Elizabete Santos, Alexandre Quadros, Mauro Hernandes, Fabio Dos Santos, Luiz Abreu, Fabio Vilas-Boas Pinto, Joao Batista Moraes Jr. Bulgaria: Todor Draganov, Ivo Petrov, Nora Tsvetkova, Elena Velcheva, Zdravka Koleva, Nikolay Penkov, Boicho Boichev, Hristo Popov, Boris Zehirov, Borislav Artzev, Petar Lazov. Canada: Gerald Barbeau, Asim Cheema, Francois Lemire, Claude Levesque, Shamir Mehta, Michel Nguyen, Sohrab Lutchmedial. Chile: Christofff Linnartz, Bernhard Westerberg, Maria Jofre, Raul Romero, Pablo Sepulveda, Francisco Albornoz, Manuel Mendez, Leonardo Nahuelpan, Gaston Dussaillant, Manuel Rodriguez, Arnoldo Aguirre, Luis Perez, Mario Yañez, Christian Pincetti, Oneglio Pedemonte, Salvador Villablanca, Rodrigo Riofrio. Colombia: Carlos Uribe , Boris Vesga, Carlos Francisco Jaramillo Muñoz, Jaime Cabrales, Jorge Edgar Villegas, Julian Ochoa, Carlos Cotes. Croatia: Pejo Samardzic, Boris Starcevic , Goran Milicevic, Maja Strozzi. Czech Republic: Tomas Budesinsky, Pavel Cervinka, Ondrej Aschermann, Petr Kala, Zdenek Coufal, Jiri Vejvoda, Jiri Ostransky, Leos Pleva, Stanislav Simek, Rostislav Polasek, Jan Vojacek. Egypt: Adel Mohammed Kamal El-Etriby, Ahmad Hossam Eldeen Mowafi, Hany Ragy, Mahmoud Ali El Badry. Estonia: Andres Reinold , Peep Laanmets. France: François Schiele, Michel Mansour, Yves Cottin, Christophe Tron, Gabriel Steg, Jean-Noël Labeque, Nicolas Delarche, Simon Cattan, Jean-Louis Georges, Patrick Ohlmann, Laurent Jacquemin. Germany: Sabine Genth-Zotz, Karl-Friedrich Appel, Ekkehard Schmidt, Nicole Toursarkissian, Stefan Kaab, Christoph Kadel, Evangelos Giannitsis, Hans-Georg Olbrich, Christoph Nienaber, Hans-Friedrich Vöhringer, Heyder Omran, Wilhelm Haverkamp, Constantin Von Zur Mühlen, Hans Krankenberg, Arnold Schmidt, Juergen Vom Dahl. Greece: Ioannis Kallikazaros, Dimitrios Alexopoulos, Dimitris Sionis, Antonis Manolis, Sotiris Patsilinakos, Ioannis Zarifis, Athanassios Kartalis, Filippos Triposkiadis, Stavros Konstantinides, Ioannis Kanakakis. Hong Kong: Shu Kin Li. Hungary: Béla Herczeg, Béla Merkely, János Tomcsányi, Róbert Gábor Kiss, Lajos Nagy, Géza Lupkovics, Ebrahim Noori, Zsolt Piróth,

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Imre Ungi. India: Jitendra Sawhney, Ajay Pandey, Tejas Patel, Keyur Parikh, Arun Srinivas, Nikhil Parikh, Prafulla Kerkar, Mukund Kumbla, Sameer Dani, Harinder Bali, Brian Pinto, Udaykumar Mahorkar, Aziz Khan, Rajendra Premchand, Upendra Kaul, Vinod Sharma, Sanjeev Chaudhary, Pravin Kahale, Narayan Gadkar, Ravindra Kulkarni, Sushan Mukhopadhyay, Mahesh Fulwani, Manojkumar Chopda, Rony Mathew, Sivakumar Rathnavel, Shailender Singh, Praveen Maddirala, Gautam Paladugu. Indonesia: Yahia Berkahanto Juwana, Teguh Santoso, Sunarya Soerianata, Pintoko Tedjokusumo, Muhammad Yamin. Israel: Shlomi Matetzky, Mady Moriel, Amos Katz, Uri Rosenschein, Yoav Turgeman, Alon Marmor, Ariel Finkelstein, Arthur Kerner, Yoseph Rozenman, Simcha Meisel, Zvi Vered, Arthur Pollak. Italy: Claudio Cavallini, Giuseppe Musumeci, Livio Dei Cas, Stefano Tondi, Leonardo Paloscia, Enrico Magagnini, Francesco Bonecci, Giancarlo Marenzi, Corrado Tamburino, Maurizio Tespili, Antonio Manari, Massimo Volpe, Angelo Branzi, Matteo Cassin, Patrizia Presbitero, Sergio Berti, Marcello Galvani, Zoran Olivari, Pietro Delise, Loris Roncon, Claudio Cuccia, Angelo Anzuini, Antonio Fiscella, Luigi Marzio Biasucci, Gianni Mobilia , Maurizio Nervi, Paolo Calabrò. Jordan: Qasem Moh'd Al Shamaileh. Korea, Republic of: Chong-Jin Kim, Seung-Ho Hur, Seung-Woon Rha, Young- Kwon Kim, Moo-Hyun Kim, Dong-Soo Kim, In-Ho Chae, Ki-Bae Seung, Young-Hak Kim, Jae-Hyung Kim, Myeong-Ki Hong, Seung-Jea Tahk, Jong Seon Park, Jung-Han Yoon, Myung-Ho Jeong, In-Whan Seong, Soon- Kil Kim. Latvia: Andrejs Erglis, Iveta Sime, Artis Kalnins,Galina Dormidontova . Lebanon: Samer Kabbani, Rabih Azar. Lithuania: Ausra Dambrauskaite, Marija Ruta Babarskiene, Birute Petrauskiene. Macedonia: Sasko Kedev. Malaysia: Tiong Kiam Ong . Mexico: Joel Dorantes, Luis Delgado-Leal, Jorge Carrillo-Calvillo, Enrique Lopez-Rosas, Luis Virgen-Carrillo, Marco Alcocer-Gamba, Sergio Villarreal, Juan-Carlos Perez-Alva, Gabriel-Arturo Ramos-Lopez, Eduardo Salcido-Vazquez, Guillermo Llamas-Esperon, Mariano-Salvador Ledesma-Velasco, Jose Luis Arenas-Leon, Carlos-Rodolfo Martinez-Sanchez. Montenegro: Aneta Boskovic. Netherlands: Pieter Smits, Johannes De Swart, Jurrien Ten Berg, Frank Willems, Robert Breedveld. New Zealand: Gerard Devlin, Nicholas Fisher, Hitesh Patel. Norway:Vegard Tuseth , Dennis W.T. Nilsen, Michael Uchto. Panama: Mario Lombana. Peru: Jose Aguero Ramirez, Marcos Pariona-Javier, William Cornelio- Fuster, Jorge Casana Bejarano, Luis Mejia-Vargas-Machuca, Walter Mogrovejo Ramos, Henry Anchante Hernandez, Felix Revilla. Poland: Witold Ruzyllo, Leszek Bryniarski, Bozena Wrzosek, Romuald Krynicki, Wlodzimierz Musial, Barbara Kusnierz, Robert Gil, Krystyna Loboz-Grudzien, Dariusz Karwowski, Wladyslaw Sinkiewicz, Teresa Nowak, Andrzej Kleinrok, Krystyna Jaworska, Andrzej Rynkiewicz, Maciej Dalkowski, Leszek Kolakowski, Jaroslaw Kasprzak, Jerzy Kopaczewski, Leszek Bystryk, Wojciech Kreis, Piotr Berkowski, Grzegorz Smolka, Slawomir Dobrzycki, Jakub Ostrowski, Andrzej Wysokinski, Jadwiga Nessler, Wojciech Wojakowski, Piotr Achremczyk. Portugal: Pedro Monteiro, Antonio Leitao Marques, Maria De Lurdes Ferreira, Ricardo Santos, Helder Pereira, Lino Manuel Patrício, Dinis Martins. Romania: Maria Dorobantu, Florin Ortan, Imre Benedek, Doina Ruxandra Dimulescu. Russian Federation: Mikhail Ruda, Sergey Gromov, Ivan Gordeev, Sergey Chernov, Victor Kostenko, Mikhail Karpenko, Nadezda Alexeeva, Olga Barbarash, Valentin Markov, Dmitry Duplyakov, Elena Kosmacheva, Elena Fokina, Evgeny Baranov, Oleg Khrustalev, Alexey Duda, Alexey Yakovlev, Abram Syrkin, Kirill Linev, Vitaly Ivanenko, Svetlana Boldueva. Serbia: Vladimir Miloradovic, Slobodan Dodic, Milan Pavlovic, Biljana Putnikovic Tosic, Petar Otasevic, Mirjana Krotin. Singapore: Soo Teik Lim, Jeremy Chow . Slovakia: Marian Hranai, Frantisek Kovar, Roman Margoczy. South Africa: Andrzej Michael Okreglicki, Jan Andries Saaiman, Iftikhar Osman Ebrahim, Tjaart Petrus Venter, Clive Henry Corbett, Mbuyu Bushidi. Spain: Juan Miguel Ruiz Nodar, Victoria Martin-Yuste, Francisco Javier Goicolea, Jose Javier Zueco, Francisco Bosa, Javier Fernandez Portales, Eugenio Herrero, Diego Lopez Otero, Javier Botas, Josepa Mauri, Jose Maria Hernandez, Ramon Lopez, Antonio Serra, Faustino Miranda, Martí Puigfel Pont, Vicent Bodi, Gerard Martí, Rafael Carrasco, Agustin Albarran, Angel Cequier, Antonio Fernandez Ortiz, Fernando Jara, Francisco Marin. Switzerland: Tiziano Moccetti, Roberto Corti. Taiwan, Province Of China: Jia-Yin Hou, Chiung-Jen Wu, I-Chang Hsieh, Tsung Lin, Ping-Han Lo, Yu-Wei Chiu, Tzung-Dau Wang. Thailand: Suphot Srimahachota, Chaiyasith Wongvipaporn, Nattawut Wongpraparut, Chumpol Piamsomboon, Dilok Piyayotai, Sarana Boonbaichaiyapruck, Srun Kuanprasert. Tunisia: Habib Haouala, Sondos Kraiem, Habib Gamra, Faouzi Maatouk. Turkey: Sema Guneri, Murat Yesil, Mehmet Aksoy, Fuat Gundogdu, Hasan Ari, Hüseyin Yilmaz, Mustafa Demirtas, Oguz Yavuzgil, Ibrahim Ozdogru, Ertan Ural, Kurtulus Ozdemir, Cevat Kirma, Murat Ersanli, Ahmet Camsari, Alparslan Birdane, Ozcan Yilmaz, Ali Aydinlar, Cagdas Ozdol, Hasan Pekdemir, Mehmet Yilmaz , Murat Sezer, Mustafa Erol, Meryem Aktoz, Omer Goktekin. Ukraine: Igor Kraiz, Olexandr Nykonenko, Svitlana Zhurba, Andriy Faynyk. United Kingdom: Andrew Moriarty, Simon Thackray, Robert Gerber, Andrew Docherty, Douglas Fraser, Steven Lindsay, Terry Levy. United States: Mark Izzo, Rakesh Prashad, David Drenning, David Schreibman, Ernesto Rivera, Suresh Chadrasekaran, Arnold Ghitis, Ravi Bhagwat, William David, Imran Virk, Gil Vardi, Deepak Parashara, Abul Nasser Khan, Steven J. Diamantis, Emmanouil Brilakis, Ajit Raisinghani, Jonathan Tobis, Mukesh K Sharma, Jeffrey Garrett, Ameer Kabour, Kyle Smith, Steven Bailey, Michael Bosak, Harinder S. Gogia, Santosh Gill, Roberto Secaira, Samir Turk, Eric Hockstad, Robert L. Feldman, Stavros Maragos, Michael Brodsky, Devang Desai, Venkata Chilakapati, Steven Hahn, Henry Cusnir, Evelyne Goudreau, Naeem Tahirkheli, Javed Ashraf, Paul Truong, Nima Amjadi, Sandeep Nathan, Ken Fujise, Sandeep Das, Paul Nager, Paul Gibson, Michael

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Pecora, Hooman Madyoon, Ralph Vicari, Charles Lambert, Jeffrey Chambers, Eric Carlson, Abedelrahim As4, John Heitner, Steven Guidera, William Suddath, Sandy Sundram, Bradley Bart, Barry Bertolet, David Roth, Liwa Younis, Scott Martin, Robert Duerr, Patrice Delafontaine, Naseem Jaffrani, Zoran Lasic , Aylmer Tang, Christopher Rogers, Charles Landau, Ion Jovin, George Revtyak, Andre Desire, William French, Bruce Graham, John Hunter, Jason Call, J. Tift Mann, Thomas Tu, Mehrdad Saririan, Majed Chane, William Henry Matthai, Manish Chauhan, Tayo Addo, Robert Iwaoka, Glenn J. Barquet, Amir Malik, John Marshall, Joseph E. Burchenal, Charles E. Olson, Wayne Leimbach, Vibhuti Singh, Mehrdad Ariani, Imran Dotani, George Chrysant, Harish Chandna, Aref Rahman, Ujjaval Patel. Vietnam: Quang Binh Truong, Quang Huan Do, Vo Than-Nhan, Manh Hung Pham.

Sanofi operations: Marie-France Bregeault, Judith Murphy and Kastytis Sestakauskas (clinical study directors), Noemie Charpentier and Candice Brecq (SAS programmers), Barbara Kittner (Pharmacovigilance), Sebastien Paoli, Annie Toulot and Marie Thirion (data managers), Corinne Festino (project leader), Sophie Ribadeau- Dumas, Timo Scheller, Mailys Testemale, Valerie Nicol Chedia Mahdi, Julie Diaz and Camelia Akhoundi (clinical trial operations managers), Elise Poulmaire (DPU Operations Manager), and Cecile Le-Breton (Industrial Supply Chain).

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Abbreviations: ADP, adenosine diphosphate; MI, myocardial infarction; NSTE-ACS, non-ST-elevation acute coronary syndrome; UFH, unfractionated heparin.

Interim analysis One interim analysis was planned when 35% of the patients for the 2 arms taken into account into the final analysis had completed 7 days of follow-up. The interim analysis would be performed by an independent data monitoring committee (DMC) statistician and reviewed by the DMC.

1. Futility Futility would be assessed, if the observed relative risk (RR) for the primary efficacy endpoint from randomization to day 7 of otamixaban versus UFH plus eptifibatide was ≥1.0 (otamixaban versus UFH plus eptifibatide) for both doses. If 1 (and only one) dose exhibited a RR ≥1 at interim analysis this dose would be automatically dropped and the trial proceed with the other dose. This corresponded to a conditional power based on the original hypothesis (RR = 0.75) <0.8%.

2. Dose selection If the 2 otamixaban doses were not assessed as futile, the DMC would decide which otamixaban dose to maintain. The decision would be based on evaluation of a composite of the 3 following adjudicated endpoints (benefit/risk assessment):  Primary efficacy endpoint: all-cause death + myocardial infarction from randomization to day 7  TIMI major bleedings from randomization to day 7  Thrombotic complications of the index PCI (based on patients who underwent a percutaneous coronary intervention) The proposed rule was to evaluate the RR of the higher dose (bolus plus infusion of 0.140 mg/kg per hour) versus the initial otamixaban dose (bolus plus infusion of 0.100 mg/kg per hour) on this composite endpoint and to decide that the initial dose would be maintained until the end of the study for final analysis unless the observed RR was ≥15% in favor of the higher dose at the interim analysis stage.

Since this decision would be based on unblinded data, the DMC (independent of the sponsor) would be responsible for reviewing these data and recommending the dose to be continued, based on the prespecified rules and the analysis made by the independent DMC statistician. The DMC would also be aware of descriptive data related to the 2 otamixaban doses, including components of the composite taken separately and other safety information available in the database.

3. Overwhelming efficacy It has to be noted that, to protect the global type 1 error in case the decision was taken to overrule the futility rule, nonbinding boundaries would be used adding a very conservative boundary for efficacy. Overwhelming efficacy would be assessed on the adjudicated primary efficacy endpoint using the gamma (-10) alpha spending function, in comparing the observed one-sided P-value with .00004 during this interim analysis. With such conservative alpha spending function, the global alpha level of the study would be maintained at .05 (2-sided).

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eFigure 2. Kaplan-Meier Analyses of the Primary Efficacy Outcome Up to Day 30 for Otamixaban 0.100 mg/kg per hour Versus Control.

Dotted line denotes day 7. Abbreviation: UFH, unfractionated heparin.

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TIMI 0-2, low risk of death or ischemic events; TIMI 3-4, intermediate risk; TIMI 5, high risk. GRACE score <113, low risk for hospital death; GRACE 113-139, intermediate risk; GRACE 140, high risk. n corresponds to the number of events and N to the number of patients in the subgroup. The x-axis is on a logarithmic scale. Abbreviations: GRACE, Global Registry of Acute Coronary Events; TIMI, Thrombolysis In Myocardial Infarction

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eFigure 4. Subgroup Analysis of the Primary Safety Outcome for the Otamixaban 0.140 mg/kg per hour Group Versus Control (logarithmic scale).

Otamixaban UFH/Eptifibatide Relative risk P Value for Subgroup (95% CI) 0.140 mg/kg/h (n/N) Interaction (n/N)

Overall 159/5106 80/5466 2,13 (1,63-2,78) Age (years) 0.47 <6 5 78/3019 32/3205 2.59 (1.72-3.89) ≥65 - <75 43/1325 25/1428 1.85 (1.14-3.02) ≥75 38/762 23/833 1.81 (1.09-3.00) Sex 0.49 Male 89/3561 41/3825 2.33 (1.62-3.37) Female 70/ 1545 39/1641 1.91 (1.30-2.80) Weight (kg) 0.27 <6 0 16 / 4 16 14/448 1.23 (0.61-2.49) ≥60 - <100 126/3997 59/4342 2.32 (1.71-3.15) ≥10 0 17/687 7/ 670 2.37 (0.99-5.67) Geographic region 0.86 Asia 13/428 5/490 2.98 (1.07-8.28) East ern Europe 48/1713 24/1828 2.13 (1.31-3.47) West ern Euro p e 28/1014 17/1042 1.69 (0.93-3.07) Nort h A merica 29/663 16 / 717 1.96 (1.07-3.58) Other 41/1288 18/1389 2.46 (1.42-4.25) Creat inine clearance (ml/ min) 0.55 <50 27/439 18 / 4 75 1.62 (0.91-2.90) ≥50 - <8 0 60/1510 31/1628 2.09 (1.36-3.20) >8 0 72/ 3115 31/3321 2.48 (1.63-3.76) Diabet es mellit us hist ory 0.23 Yes 54/1427 22/1581 2.72 (1.67-4.44) No 105/3679 58/3885 1.91 (1.39-2.63) TIA/stroke history 0.08 Yes 17/267 3/282 5.99 (1.77-20.19) No 142/4837 77/ 5181 1.98 (1.50-2.60) Prior aspirin 0.59 Yes 70/2059 39/2259 1.97 (1.34-2.90) No 89/3047 41/3207 2.28 (1.58-3.30) AAnt nt icoagulant icoagulant ≤ ≤24h24h before before randomization rando 0.17 Yes 102/3201 44/3420 2.48 (1.75-3.52) No 57/ 1905 36/2046 1.70 (1.13-2.57) Pat ient manag ement a 0.02 With index PCI 71/3328 50/ 3554 1.52 (1.06-2.17) With index CABG 45/251 20/295 2.64 (1.61-4.36) Without index PCI or index CABG 38/1475 10 / 158 3 4.08 (2.04-8.16) Access site of index PCIa 0.12 Femoral 116/2381 54/2654 2.39 (1.74-3.29) Non-femoral 38/2673 26/2776 1.52 (0.92-2.49) TimeTime fromfrom onsetonset ofto ischemicrando event to randomization 0.47 <12h 62/1856 36/2053 1.91 (1.27-2.86) ≥12 h 97/3246 44/3409 2.32 (1.63-3.30) Duration of study druga 0.10 <5h 65/3149 42/3321 1.63 (1.11-2.40) ≥5 - <12h 27/734 13 / 75 2 2.13 (1.11-4.09) ≥12 - <2 4 h 39/807 16/869 2.62 (1.48-4.66) ≥24h 28/373 8/481 4.51 (2.08-9.79)

0.5 1 248

Otamixaban better UFH/Eptifibatide better

n corresponds to the number of events and N to the number of patients in the subgroup. The x-axis is on a logarithmic scale. aDefined post randomization. Abbreviations: CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; TIA, transient ischemic attack

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eFigure 5. Effect of Otamixaban on the Primary Efficacy Outcome: SEPIA-ACS1 Versus TAO

n corresponds to the number of events and N to the number of patients in the subgroup. The x-axis is on a logarithmic scale. Abbreviations: CI, confidence interval; UFH, unfractionated heparin.

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eTable 1. Main Inclusion and Exclusion Criteria

Inclusion criteria Patients had to have ischemic symptoms (chest pain or equivalent) at rest for ≥10 minutes within 24 hours of randomization At least one of the 2 following criteria: (1) New ST-segment depression ≥0.1 mV (≥1 mm) or transient (<30 minutes) ST-segment elevation ≥0.1 mV (≥1 mm) in at least 2 contiguous leads on the ECG, or (2) Elevation of cardiac biomarkers, defined as elevated troponin T, troponin I, or CK-MB level above the upper limit of normal, within 24 hours of randomization All patients were scheduled to have a coronary angiography (followed, when indicated, by PCI) after at least 2 hours of treatment with study drug and within 36 hours (at the latest on day 3, if justified) All patients had to provide written informed consent Main exclusion criteria High likelihood of being unavailable for follow-up Age <18 years (or country’s legal age of majority) Pregnancy/breastfeeding Treatment with other investigational agents (including placebo) or devices within 30 days prior to randomization Revascularization procedure already performed for the qualifying event Acute ST-segment elevation myocardial infarction Patient having received therapeutic dose of anticoagulant treatment (including UFH, low-molecular- weight heparin, or bivalirudin) for more than 24 hours prior to randomization, or been treated with abciximab Inability to discontinue current anticoagulation in order to transition to investigational agents Patients who can not be treated by aspirin and clopidogrel (or any other oral antiplatelet agent) according to their local labeling Patient who cannot be treated with eptifibatide according to the national labeling (when available). In countries where eptifibatide is not approved the reference label to be considered will be either the European labeling or the US labeling Patient who cannot be treated with unfractionated heparin according to the national labeling Allergy to otamixaban Abbreviations: CK-MB, creatine kinase-MB; ECG, electrocardiogram; PCI, percutaneous coronary intervention; UFH, unfractionated heparin

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eTable 2. Thrombotic Procedural Complications During Percutaneous Coronary Intervention

Outcome Otamixaban UFH plus Relative risk (95% 0.080 mg/kg bolus eptifibatide CI)a and 0.140 mg/kg per hour infusion (n=3554) (n=3328) Any, including stent thrombosis, No. (%) 134 (4.0) 163 (4.5) 0.88 (0.70-1.10) Abrupt or threatened closure 11 (0.3) 15 (0.4) 0.78 (0.36-1.70) Side branch closure 13 (0.4) 17 (0.5) 0.82 (0.40-1.68) Distal embolization 29 (0.9) 33 (0.9) 0.94 (0.57-1.54) No or slow reflow 57 (1.7) 54 (1.5) 1.13 (0.78-1.63) New intracoronary thrombus 16 (0.5) 27 (0.8) 0.63 (0.34-1.17) Catheter or guidewire thrombus 1 (<0.1) 9 (0.3) 0.12 (0.02-0.94) Stent thrombosis, No. (%) 44 (1.3) 58 (1.6) 0.81 (0.55-1.20) Definite 21 (0.6) 32 (0.9) 0.70 (0.40-1.21) Probable 15 (0.5) 17 (0.5) 0.94 (0.47-1.88) Possible 8 (0.2) 9 (0.3) 0.95 (0.37-2.46) Abbreviations: CI, confidence interval; UFH, unfractionated heparin. aVersus UFH/eptifibatide.

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eTable 3. Efficacy and Safety Outcomes at 7 days and at 30 days After Randomization (enrollment in the 0.100 dose arm of otamixaban was stopped at the time of the interim analysis)

Outcome Otamixaban UFH plus Relative risk 0.080 mg/kg bolus eptifibatide (95% CI)a and 0.100 mg/kg per (n=5466) hour infusion (n=2657) Efficacy outcomes (intent-to-treat population), No. (%) Primary outcome: all-cause death or 167 (6.3) 310 (5.7) 1.11 (0.92-1.33) MI at day 7 Components of primary outcome All-cause death 16 (0.6) 47 (0.9) 0.70 (0.40-1.23) MI 156 (5.9) 276 (5.0) 1.16 (0.96-1.41) Type of MI (universal definition1)b Type 1 21 (0.8) 31 (0.6) 1.39 (0.80-2.42) Type 2 2 (<0.1) 2 (<0.1) 2.06 (0.29-14.60) Type 3 0 0 Not estimable Type 4a 113 (4.3) 206 (3.8) 1.13 (0.90-1.41) Type 4b 2 (<0.1) 12 (0.2) 0.34 (0.08-1.53) Type 5 20 (0.8) 28 (0.5) 1.47 (0.83-2.60) Secondary outcomes, No. (%) All-cause death, MI, or stroke at day 170 (6.4) 324 (5.9) 1.08 (0.90-1.29) 7 Procedural thrombotic complications n=1774 n=3554 during index PCI Any 79 (4.5) 163 (4.6) 0.97 (0.75-1.26) Any, including stent thrombosis Abrupt or threatened closure 7 (0.4) 15 (0.4) 0.50 (0.20-1.22) Side branch closure 8 (0.5) 17 (0.5) 0.50 (0.22-1.16) Distal embolization 15 (0.8) 33 (0.9) 0.49 (0.26-0.89) No or slow reflow 36 (2.0) 54 (1.5) 0.71 (0.47-1.08) New intracoronary thrombus 16 (0.9) 27 (0.8) 0.63 (0.34-1.17) Catheter or guidewire thrombus 1 (<0.1) 9 (0.3) 0.12 (0.02-0.94) Stent thrombosis (ARC2) 18 (1.0) 58 (1.6) 0.62 (0.37-1.05) Definite 11 (0.6) 32 (0.9) 0.37 (0.19-0.73) Probable 7 (0.4) 17 (0.5) 0.44 (0.18-1.06) Possible 1 (<0.1) 9 (0.3) 0.12 (0.02-0.94) Stroke at day 7 5 (0.2) 16 (0.3) 0.64 (0.24-1.75) Efficacy outcomes (intent-to-treat population) at day 30, No. (%) All-cause death or MI 207 (7.8) 383 (7.0) 1.11 (0.95-1.31) Rehospitalization or prolonged 62 (2.3) 96 (1.8) 1.33 (0.97-1.82) hospitalization due to new ischemia/MI All-cause death 39 (1.5) 85 (1.6) 0.94 (0.65-1.38) Safety outcomesb, No. (%) Primary safety outcome (TIMI major or 61 (2.3) 80 (1.5) 1.57 (1.13-2.18) minor bleeding at day 7) TIMI major 33 (1.2) 41 (0.8) 1.66 (1.05-2.61) Non–CABG-related major 15 (0.6) 21 (0.4) 1.47 (0.76-2.85) CABG-related major 19 (0.7) 20 (0.4) 1.95 (1.04-3.66) TIMI minor 28 (1.1) 40 (0.4) 1.44 (0.89-2.33) Any clinically overt bleed 249 (9.4) 306 (5.6) 1.67 (1.43-1.97) TIMI requiring medical attention 144 (5.4) 169 (3.1) 1.75 (1.41-2.18) TIMI minimal 56 (2.1) 55 (1.0) 2.09 (1.45-3.03)

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Outcome Otamixaban UFH plus Relative risk 0.080 mg/kg bolus eptifibatide (95% CI)a and 0.100 mg/kg per (n=5466) hour infusion (n=2657) Intracranial bleeding 2 (<0.1) 1 (<0.1) 4.11 (0.37-45.35) GUSTO bleeding Any 249 (9.4) 306 (5.6) 1.67 (1.43-1.97) Severe 19 (0.7) 25 (0.5) 1.56 (0.86-2.83) CABG-related 11 (0.4) 8 (0.1) 2.83 (1.14-7.02) Non-CABG-related 229 (8.6) 278 (5.1) 1.69 (1.43-2.01) BARC bleeding3 Any BARC bleed 246 (9.3) 298 (5.5) 1.70 (1.44-2.00) BARC type 5 (fatal) 5 (0.2) 5 (<0.1) 2.06 (0.60-7.10) BARC type 4 (CABG-related) 15 (0.6) 19 (0.3) 1.62 (0.83-3.19) BARC type 3c 2 (<0.1) 1 (<0.1) 4.11 (0.37-45.35) BARC type 3b 13 (0.5) 23 (0.4) 1.16 (0.59-2.29) BARC type 3a 28 (1.1) 38 (0.7) 1.52 (0.93-2.46) BARC type 2 143 (5.4) 163 (3.0) 1.80 (1.45-2.25) BARC type 1 56 (2.1) 56 (1.0) 2.06 (1.42-2.97) CURRENT-OASIS bleeding4 Any severe or major 48 (1.8) 68 (1.2) 1.45 (1.01-2.10) Severe 39 (1.5) 56 (1.0) 1.43 (0.95-2.15) Other major 9 (0.3) 12 (0.2) 1.54 (0.65-3.66) Abbreviations: ARC, Academic Research Consortium; BARC, Bleeding Academic Research Consortium classification; CABG, coronary artery bypass graft; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction; UFH, unfractionated heparin. aVersus UFH/eptifibatide. bA patient can be counted in several categories: Type 1: Spontaneous MI. Type 2: MI secondary to ischemia. Type 3: Sudden unexpected cardiac death. Type 4a: MI associated with PCI. Type 4b: MI associated with stent thrombosis. Type 5: MI associated with CABG.

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eTable 4. Bleeding Assessment at Day 7 using Additional Bleeding Categorizations, and Adjudicated Bleedingsa

Outcome Otamixaban UFH plus Relative risk 0.080 mg/kg bolus and eptifibatide (95% CI)b 0.140 mg/kg per hour (n=5466) infusion (n=5106) GUSTO bleeding, No. (%) Any 607 (11.9) 306 (5.6) 2.12 (1.86-2.42) Severe 58 (1.1) 25 (0.5) 2.48 (1.56-3.96) CABG-related 20 (0.4) 8 (0.1) 2.68 (1.18-6.07) Non-CABG-related 554 (10.8) 278 (5.1) 2.13 (1.86-2.45) BARC bleeding3, No. (%) Any BARC bleed 592 (11.6) 298 (5.5) 2.13 (1.86-2.43) BARC type 5 (fatal) 15 (0.3) 5 (<0.1) BARC type 4 (CABG-related) 39 (0.8) 19 (0.3) 2.20 (1.27-3.80) BARC type 3c 5 (<0.1) 1 (<0.1) 5.35 (0.63-45.80) BARC type 3b 43 (0.8) 23 (0.4) 2.00 (1.21-3.32) BARC type 3a 74 (1.4) 38 (0.7) 2.08 (1.41-3.08) BARC type 2 346 (6.8 163 (3.0) 2.27 (1.89-2.73) BARC type 1 135 (2.6) 56 (1.0) 2.58 (1.89-3.52) CURRENT-OASIS bleeding4, No. (%) Any severe or major 131 (2.6) 68 (1.2) 2.06 (1.54-2.76) Severe 109 (2.1) 56 (1.0) 2.08 (1.51-2.87) Other major 24 (0.5) 12 (0.2) 2.14 (1.07-4.28) Adjudicated bleedings Transfusion 64 (1.9%) 50 (1.4%) - Thrombocytopenia 67 (1.3%) 48 (0.9%) - Access site bleeding (TIMI major or - minor) 71 (1.4%) 34 (0.6%) Nonaccess site (TIMI major or - minor) 88 (1.7%) 46 (0.8%) Any bleeding 607 (11.9%) 306 (5.6%) - Access site (any bleeding) 251 (4.9%) 126 (2.3%) - Nonaccess site (any bleeding) 412 (8.1%) 182 (3.3%) - Gastrointestinal 174 (3.4%) 61 (1.1%) - Epistaxis 60 (1.2%) 32 (0.6%) - Other pulmonary 15 (0.3%) 4 (<0.1%) - Renal and urinary 47 (0.9%) 25 (0.5%) - Genital 8 (0.2%) 2 (<0.1%) - Abbreviations: BARC, Bleeding Academic Research Consortium classification; CABG, coronary artery bypass graft; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; MI, myocardial infarction; NSTEMI, non–ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; TIMI, Thrombolysis In Myocardial Infarction. aA patient can be counted in several categories. bVersus UFH/eptifibatide.

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eTable 5. Treatment-Emergent Adverse Events Excluding Bleedings and Liver Function Abnormalities up to Day 7 in the Safety Population

Factor Otamixaban Otamixaban UFH plus 0.080 mg/kg bolus 0.080 mg/kg bolus eptifibatide and 0.100 mg/kg per and 0.140 mg/kg per (n=5424) hour infusion hour infusion (n=2639) (n=5065) Any adverse event, No. (%) 811 (30.7) 1452 (28.7) 1517 (28.0) Any serious adverse event, No. 110 (4.2) 247 (4.9) 257 (4.7) (%) Any adverse event leading to 17 (0.6) 45 (0.9) 51 (0.9) death, No. (%) Any adverse event leading to 25 (0.9) 32 (0.6) 41 (0.8) permanent discontinuation, No. (%) Liver function test abnormalities up to day 7, No. (%) ALT n=2050 n=4074 n=4349 >3 ULN 21 (1.0) 46 (1.1) 61 (1.4) >5 ULN 10 (0.5) 19 (0.5) 27 (0.6) >10 ULN 6 (0.3) 9 (0.2) 16 (0.4) >20 ULN 2 (<0.1) 6 (0.1) 7 (0.2) Aspartate aminotransferase n=2043 n=4053 n=4323 >3 ULN 39 (1.9) 101 (2.5) 121 (2.8) >5 ULN 18 (0.9) 36 (0.9) 47 (1.1) >10 ULN 5 (0.2) 16 (0.4) 17 (0.4) >20 ULN 4 (0.2) 6 (0.1) 10 (0.2) Alkaline phosphatase, n/No. (%) >1.5 ULN 13/1913 (0.7) 33/3832 (0.9) 39/4079 (1.0) Total bilirubin, n/No. (%) >1.5 ULN 47/1977 (2.4) 119/3957 (3.0) 107/4219 (2.5) >2 ULN 15/1977 (0.8) 32/3957 (0.8) 28/4219 (0.7) ALT and total bilirubin, n/No. (%) ALT >3 ULN and total bilirubin 3/1953 (0.2) 4/3921 (0.1) 3/4188 (<0.1) >2 ULN Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal.

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References 1. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation. 2007;116(22):2634-2653. 2. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344-2351. 3. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736-2747. 4. Mehta SR, Bassand JP, Chrolavicius S, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010;363(10):930-942.

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eTable 4. Bleeding Assessment at Day 7 using Additional Bleeding Categorizations, and Adjudicated Bleedingsa

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eTable 5. Treatment-Emergent Adverse Events Excluding Bleedings and Liver Function Abnormalities up to Day 7 in the Safety Population

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