Supplementary Appendix

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

Supplement to: Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or
PCI in atrial fibrillation. N Engl J Med 2019;380:1509-24. DOI: 10.1056/NEJMoa1817083
 1
 

Supplementary Appendix

Table of Contents
Executive Committee .............................................................................................................................. 2 
Operations Committee ............................................................................................................................ 2 
International Steering Committee ........................................................................................................ 3 
Data Safety Monitoring Board .............................................................................................................. 3 
Clinical Endpoints Committee .............................................................................................................. 3 
Investigators .............................................................................................................................................. 4 
Bleeding Definitions ................................................................................................................................ 7 
Figure S1A. Time to first ISTH major or clinically relevant nonmajor bleeding event in
various subgroups: Apixaban vs. VKA .............................................................................................. 8 
Figure S1B. Time to first ISTH major or clinically relevant nonmajor bleeding event in
various subgroups: Aspirin vs. Aspirin Placebo........................................................................... 10 
Figure S2A. Time to death or hospitalization in various subgroups: Apixaban vs. VKA ... 12 
Figure S2B: Time to death or hospitalization in various subgroups: Aspirin vs. Aspirin
Placebo ..................................................................................................................................................... 14 
Figure S3A. Time to death or ischemic events in various subgroups: Apixaban vs. VKA 16 
Figure S3B. Time to death or ischemic events: Aspirin vs. Aspirin Placebo ........................ 18 
Table S1. CHA2DS2-VASc and HAS-BLED score calculators ..................................................... 20 
Table S2. Time in therapeutic range among patients assigned to VKA .................................. 21 
Table S3. Randomization factors (oral anticoagulant and aspirin) interaction parameters
for the primary and secondary outcomes ....................................................................................... 22 
Table S4A. Primary bleeding outcome rates by both factors as treated ................................ 23 
Table S4B. Secondary outcome rates by both factors as treated ............................................ 24 
 2
 

Executive Committee
John Alexander (Chair)
Renato Lopes (Principal Investigator)
Ronald Aronson (Bristol-Myers Squibb)
Harald Darius (Germany)
Shaun Goodman (Canada)
Roxana Mehran (USA)
Stephan Windecker (Switzerland)

Operations Committee
Duke Clinical Research Institute
Renato Lopes (Principal Investigator)
John Alexander (Executive Committee Chair)
Gretchen Heizer (Principal Biostatistician)
Jerry Kirchner (Clinical Operations Project Lead)
Tyler Massaro (Biostatistician)
Amit Vora (Cardiology Fellow)

Bristol-Myers Squibb
Ronald Aronson (Clinical Study Lead)
Biren Amin (Field Medical Science Liaison)
Charlotte Jones-Burton (Global Clinical Program Lead)
Christoph Koenen (Head of Cardiovascular Development)
Jia Li (Associate Director, Statistics)
Beth Metzheiser (Senior Clinical Operations Lead)
Patricia Palmisano (Senior Protocol Manager)

Pfizer
Patricia McNamee (Field Medical Director)
James Revkin (Global Product Development)

PPD
Jean-David Bienvenu (Associate Director, Project Management)
Kathan Griscik (Senior Project Manager)
 3
 

Karen Ingersoll (Clinical Data Manager)

Paula Menchichi (Senior Clinical Team Manager)
Martha Simpkins (Oversight Director)

International Steering Committee

Argentina: M. Cecilia Bahit, Fernando Cura; Australia: David Brieger; Austria: Kurt Huber;
Belgium: Peter Sinnaeve; Brazil: Otavio Berwanger; Bulgaria: Dimitar Raev; Canada: Robert
Welsh, Shaun Goodman; Colombia: Pedro Martinez-Clark; Croatia: Davor Milicic; Czech
Republic: Michael Aschermann; Denmark: Thomas Engstrøm; France: Nicolas Meneveau;
Germany: Holger Thiele, Suzanne de Waha; Hungary: Bela Merkely; India: Denis Xavier;
Israel: Basil Lewis; Korea: Hyun-Jae Kang; Mexico: Jose Luis Leiva-Pons; Netherlands:
Robbert de Winter; Norway: Sigrun Halvorsen; Peru: German Malaga; Poland: Andrzej Budaj;
Portugal: João Morais; Romania: Dragos Vinereanu; Russian Federation: Oleg Averkov;
Serbia: Tajana Potpara; Slovakia: Viliam Fridrich; Spain: Manel Sabaté; Sweden: Ziad Hijazi;
Switzerland: Stephan Windecker; Ukraine: Alexander Parkhomenko; United Kingdom:
Robert Storey; United States: Roxana Mehran, Renato Lopes

Data Safety Monitoring Board

Lars Wallentin (Chair)
Stuart J. Pocock (Medical Statistician)
Robert Harrington

Clinical Endpoints Committee

Duke Clinical Research Institute
W. Schuyler Jones (CEC Principal Investigator)
Nikieia Hayden (Project Lead)
Olivia Wolf (Project Coordinator)

CEC Reviewers
Duke Clinical Research Institute
Adam DeVore, Keith Dombrowski, Alexander Fanaroff, Marat Fudim, Sarah Goldstein, Jorge
Gutierrez, Taku Inohara, Ajar Kochar, Brad Kolls, David Kong, Aditya Mandawat, Rajendra
Mehta, Chiara Melloni, Ann Marie Navar, Kishan Parikh, Chetan Patel, Matthew Roe, Jay
Shavadia, Monique Starks, Pierluigi Tricoci, Amit Vora
 4
 

Brazilian Clinical Research Institute

Pedro Gabriel Melo de Barros e Silva, Patricia O. Guimarães

Investigators
Argentina: A.D. Hrabar, A. Caccavo, A. Licheri, A.F. Alvarisqueta, A.M. Abud, C. Estrada, C.P.
Sueldo, E. Montenegro, E.A. Duronto, F.L. Blanco, F.C. Berra, F.A. Ferré Pácora, G.M. Lopez,
G. Calvo, G.M. Azize, H.A. Luquez, H. Ramos, H.R. Colombo, J.N. Guetta, J.H. Resk, J.C.
Medrano, J.P. Costabel, J. Carbajales, L.B. Schiavi, L.I. Saggia, M.A. Oliva, M. Casas, M.
Snitman, M.R. Litvak Bruno, N. Cluigt, N.A. Vita, P.N. Guzman, P.D. Zangroniz, R.A. Villarreal,
R.R. Bonato, S. Nani, S.A. Sassone, S.M. Macin, V.E. Arias. Australia: C. Alexopoulos, D.
Brieger, D. Colquhoun, W.F. Heddle. Austria: A. Podczeck-Schweighofer, C. Ebner, D. Scherr,
I.M. Lang, K. Huber. Belgium: A. Guedes, C. Convens, F. Cools, J. Vercammen, J. Bartunek,
P. Sinnaeve, T. Rossenbacker. Brazil: A.H. Pereira, A.M. Kormann, A.F. Freitas, A.G.T.
Fonseca, A. de Quadros, B.L. Janella, C.A.A. Kalil, C.S. Rodrigues, D.B. Precoma, E.
Ramacciotti, E.S. Resende, E.L. Figueiredo, E.R. Manenti, F.A. da Costa, G. Feitosa, H.J.L.
Reis, H.B. Ribeiro, J.B.M.X. de Moraes, Jr., J.M.M. Dantas, J.C. Nicolau, J.F.K. Saraiva, J.
Reolão, L.S. Piegas, L.F.A. Oliveira, L.E.F. Ritt, M.C.V.B. Braile, M.A. Dracoulakis, M.O.N de
Santos, P.E. Leães, P.P. Filho, R.L. Rech, R. Ueda, T.L. Silvestrini, Y.L. Michalaros. Bulgaria:
A. Manolova, A.K. Mihov, B. Yatseva, C. Velikov, D.H. Raev, D. Markov, D. Vassilev, E.
Georgiev, H.O. Benov, I. Daskalov, I.P. Petrov, M. Milanova, N.S. Shehova-Yankova, P.V.
Lazov, S. Beleva, S.T. Marchev, V.L. Gelev. Canada: B. Tyrrell, B. Wong, D. Dion, D.
LaFlamme, D.W. Rupka, D. Shukla, E. Sabbah, I.J. Nadra, I. Bata, J.M. Cherry, O. Toleva, P.
Dehghani, R. Vijayaraghavan, R. Welsh, R. Bagur, R.E. Labonte, S. Vizel, S. Fort, T. Huynh,
V.H. Quan, Y. Pesant. Colombia: D. Isaza, J.L. Accini Mendoza, J.E. Gomez, N.I. Jaramillo
Gomez. Croatia: A. Knezevic, A. Ruzic, D. Horvat, D. Milicic, K.S. Relatic, K. Pesek, M.K.
Pravecek, M. Kovacic, S. Manola, V. Persic. Czech Republic: D. Alan, J. Belohlavek.
Denmark: C.T. Larsen, J. Brønnum-Schou, K.T. Veien, L.S. Christensen, M. Maeng, R.
Steffensen. France: D. Angoulvant, F. Beygui, G. Range, G. Cayla, J.F. Aupetit, M. Elbaz, N.
Delarche, N. Meneveau. Germany: A. Ghanem, A. Hagendorff, A. Wilke, A. Hummel, C.
Axthelm, C. Kadel, C. Langer, C. Stellbrink, C. Jacobshagen, C.M. Gross, E.E.B. Blessing, H.H.
Minden, H. Darius, H. Bogossian, H. Wienbergen, H. Ebelt, H. Dreger, H. Thiele, H. Ince, I.
Akin, I. Eitel, I. Kreis, K.F. Appel, L. Maier, M. Bergmann, M. Moser, N. Toursarkissian, N.
Menck, O. Ritter, P. Bernhardt, P. Nordbeck, R. Stöhring, R. Schwinger, R.C. Braun-Dullaeus,
S.K.G. Maier, S. Schellong, S. Steiner, T. Rudolph, T.J. Dengler, T. Geisler, U. Rauch-Kröhnert,
 5
 

W. Jung, W. Jungmair. Hungary: A. Komócsi, A. Papp, A. Vértes, A. Mohácsi, B. Herczeg, B.

Merkely, C.A. Dézsi, E. Kis, F. Lakatos, G. Kerecsen, G.A. Piros, J. Takács, J. Tomcsányi, K.
Keltai, Z. Kovács. India: A. Mathur, H.A. Baxi, J. Narendra, J. Gupta, M. Kumbla, N.K. Jamwal,
P. Arora. Israel: A. Katz, A. Shotan, E. Schiff, N.A. Freedberg, O. Amir, O. Hussein, O.H.
Kracoff, R. Alcalai, S.Y. Adawi, S. Viskin, T. Hayek, Y. Hasin, Y. Rozenman. Korea: C.W. Nam,
C.W. Lee, D.J. Choi, D.S. Jeon, H.W. Park, J.W. Son, J.O. Jeong, K.S. Cha, S. Oh, S.W. Rha,
Y.H. Park, Y.K. On. Mexico: A.E. Bazzoni Ruiz, A.R. Valdespino, B.E. Castro Montes, G.A.
Ramos Lopez, G.A. Llamas Esperón, G. Solache, J.S. Macías García, J.L. Leiva-Pons, M.O. De
Los Rios Ibarra. Netherlands: F.F. Willems, H.P. Beyerbacht, R. van de Wal. Norway: J.
Hysing, K.T. Lappegard, L.E. Vinge, S. Halvorsen, V. Pönitz. Peru: C.A. Chavez Ayala, F.A.
Medina Palomino, J.C. Garcia Matheus. Poland: A. Włodarczak, A. Budaj, A. Lubinski, D.
Czarnecka, D. Wojciechowski, G. Skonieczny, J.D. Kasprzak, J.K. Wranicz, J. Szachniewicz,
K.K. Kincel, K. Zmudka, M. Lesiak, M. Piekarski, M. Wujkowski, M. Lica-Gorzynska, P. Miekus,
P. Feusette, R. Bartkowiak, R. Korzeniak, W. Sinkiewicz, W. Musial, Z. Krolikowski. Portugal:
A. Gaspar, F. Pinto, F. Almeida, J. Martinez, L. Brandão, L.M. Santos, P. Mateus, P. Monteiro,
S. Pernencar. Romania: C. Mornoş, D.M. Olinic, D. Vinereanu, D.T. Zdrenghea, F.O. Ortan, M.
Cinteza, M. Popescu, O. Voicu, S.B.F. Todea, V. Babes. Russian Federation: A.Y.
Vishnevskiy, A.D. Kuimov, D.V. Duplyakov, E. Kosmacheva, E. Pokushalov, I.G. Gordeev, K.N.
Zrazhevskiy, L.A. Sorokin, L.G. Ermoshkina, M.V. Zykov, M.Y. Ruda, O. Bulashova, O.G.
Smolenskaya, O.V. Orlikova, S.L. Grishaev, S.V. Shalaev, S.A. Boldueva, V. Kuznetsov, V.
Makukhin, V. Kostenko, Y. Shvarts, Z.D. Kobalava. Serbia: A. Selakovic, B.P. Tosic, D.B.
Sakac, M. Pavlovic, M. Dekleva, N.M. Tasic, S. Hinic, T. Jozic, T. Potpara. Slovakia (Slovak
Republic): A. Dzupina, D. Pella, I. Majercak, I. Striezova, J. Fedacko, J. Gonsorcik, J. Fecik, J.
Selecky, L. Antalik, M. Hranai, M. Gocar, M. Kokles, R. Oriesek. Spain: A. Regueiro, B. Ibánez,
D.P. Djurovic, E. Gutierrez Ibañes, F. Ridocci-Soriano, J. Diaz Fernandez, J.J. Artaecheverria
Zuazo, J.M. Escudier Villa, J. Nuñez Villota, M. Sanmartin Fernandez, P.A. Chinchurreta
Capote, R. Muñoz Aguilera, T. Vera Ripoll, V. Mainar Tello. Sweden: F. Björklund, J. Jensen, J.
Andersson, J. Lauermann, M. Hamid, O. Angerås, Z. Hijazi. Switzerland: S. Windecker, T.A.
Fischer. Ukraine: A.V. Yagensky, B.I. Goloborodko, I.I. Kyrychenko, I.P. Vakaliuk, I. Kovalskyy,
M.V. Rishko, N. Sydor, O.I. Karpenko, O.M. Parkhomenko, O.A. Koval, O. Godlevska, S.
Zhurba, V.Y. Maslovskyi, V.Z. Netiazhenko, V.K. Tashchuk, V.P. Shcherbak, V.I. Tseluyko.
United Kingdom: A. Cooke, B. Wrigley, C.M. Francis, C. Barr, D.A. Gorog, G.Y.H Lip, J. Irving,
J. Mills, R.F. Storey, T. Levy. United States: A.A. Cheema, A.S. Salacata, A.N. Tenaglia, A.W.
Meholick, A.R. Vedere, A.J. Patrello, A. Spaedy, A.C. Martin, B.H. Holland, B.K. Duffy, B.
 6
 

Schuler, C.B. Treasure, C. Paraboschi, C.A. Pickett, C.J. Rowan, C.R. Longnecker, C.N. Hess,
D.A. Hinchman, D.J. Schneider, D.K. Murdock, D.E. Baldwin, E.A. Flores, E.J. Sirulnick, F.
Ahmad, G. Aggarwala, G. Dhar, G.M. Kichura, G. Turitto, G.C. Sampognaro, G.K. Sharma, H.
Chandna, H.T.D. Truong, J. Poock, J.S. Walia, J.T. Zelenka, J.K. Amin, J. Foucauld, J.
Chambers, J.D. Abbott, J.S. Strobel, J.R. Dy, K.A. Nour, L.E. Sullenberger, L.T. Younis, L.
Gonzales, M. Chane, M.T. Foster, M.Y-M. King, M.A. Grabarczyk, M.R. Izzo, M.A. Leesar, M.A.
Bernabei, M.D. Cavender, M.J. Janik, M. Buchbinder, M. Arcarese, M. Yeh, M.J. Sheth, M.C.
Sinno, M.F. Shoukfeh, M. Alhaddad, N.V. Ranadive, N.A. Jaffrani, N.K. Little, N. Shammas,
N.A. Assi, O. Almousalli, P. Chan, P.A. Horwitz, P.A. Rozeman, P. Singh, R. Aggarwal, R.
Gopinathannair, R. Manshadi, R. Korabathina, R.M. Gilmore, R.B. Feldman, R.N. Schnitzler,
R.W. Harrison, S.N. Gandhi, S. Graham, S.K. Krueger, S.E. Jones, S.K. Rowe, S.B. Bazaz,
T.M. Haddad, T.J. Povsic, U.A. Badami, W.B. Abernethy, Z.A. Mirza.
 7
 

Bleeding Definitions

GUSTO Bleeding
Severe of life-threatening
Intracerebral hemorrhage
Resulting in substantial hemodynamic compromise requiring
treatment

Moderate
Requiring blood transfusion but not resulting in hemodynamic
compromise

Mild
Bleeding that does not meet above criteria
GUSTO, Global Strategies for Opening Occluded Coronary Arteries.

TIMI Bleeding (Non-CABG related bleeding)

Major
Any intracranial bleeding (excluding microhemorrhages 10 mm evident only on gradient-echo MRI
Clinically over signs of hemorrhage associated with a drop in hemoglobin of 5 g/dL
Fatal bleeding (bleeding that directly results in death within 7 days)

Minor
Clinically overt (including imaging), resulting in hemoglobin drop of 3 to 5 g/dL

Requiring medical attention

Any overt sign of hemorrhage that meets one of the following criteria and does not meet criteria for a
major or minor bleeding event, as defined above
Requiring intervention (medical practitioner-guided medical or surgical treatment to stop or treat
bleeding, including temporarily or permanently discontinuing or changing the dose of a medication or
study drug)
Leading to or prolonging hospitalization
Prompting evaluation (leading to an unscheduled visit to a healthcare professional and diagnostic
testing, either laboratory or imaging)

Minimal
Any overt bleeding event that does not meet the criteria above
TIMI, Thrombolysis in Myocardial Infarction.

1. 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;123:2736–47.

   
 8
 

Figure S1A. Time to first ISTH major or clinically relevant nonmajor bleeding event in

various subgroups: Apixaban vs. VKA

 
   
 9
 

 
 

   
 10
 

Figure S1B. Time to first ISTH major or clinically relevant nonmajor bleeding event in

various subgroups: Aspirin vs. Aspirin Placebo

 
   
 11
 

 
 12
 

Figure S2A. Time to death or hospitalization in various subgroups: Apixaban vs. VKA

 
   
 13
 

 
   
 14
 

Figure S2B: Time to death or hospitalization in various subgroups: Aspirin vs. Aspirin

Placebo

 
   
 15
 

 
   
 16
 

Figure S3A. Time to death or ischemic events in various subgroups: Apixaban vs. VKA

 
   
 17
 

 
   
 18
 

Figure S3B. Time to death or ischemic events: Aspirin vs. Aspirin Placebo

 
   
 19
 

 
 20
 

Table S1. CHA2DS2-VASc and HAS-BLED score calculators

Risk Factors Score

CHA2DS2-VASc risk factors
Congestive heart failure or left ventricular dysfunction 1
Hypertension 1
Age ≥ 75 years 2
Age 65-74 years 1
Diabetes mellitus 1
Prior stroke, transient ischemic attack 2
Vascular disease (prior myocardial infarction, prior PCI, prior CABG, aortic plaque) 1
Female 1

HAS-BLED
Hypertension (systolic blood pressure > 160mmHg) 1
Abnormal renal function (dialysis, renal transplant, serum Cr ≥ 2.6 mg/dL 1
Abnormal liver functions (chronic hepatic disease, bilirubin >2x ULN, AST, ALT, and ALP >3x 1
ULN)
History of stroke 1
History of bleeding 1
Labile INR (INR <2 or >3 in warfarin patients) 1
Age > 65 years 1
Use of antiplatelet drugs, NSAIDs, or other anti-inflammatory drugs 1
Drug or alcohol abuse 1
ALP indicates alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; CABG, coronary
artery bypass grafting; INR, international normalized ratio; NSAIDs, non-steroidal anti-inflammatory drugs; PCI,
percutaneous coronary intervention; ULN, upper limit of normal.

 
1. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and
thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart
Survey on Atrial Fibrillation. Chest 2010;137:263-72.
2. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year
risk of major bleeding in atrial fibrillation patients: the Euro Heart Survey. Chest 2010;138:1093-
100.
   
 21
 

Table S2. Time in therapeutic range among patients assigned to VKA

Time in target INR range (Rosendaal Method)

n 1977
Median (25th, 75th) 58.57% (33.31%, 81.03%)
Mean (SD) 55.95% (30.586%)
Min, Max 0.0%, 100.0%

Time below INR range 2.0

n 1977
Median (25th, 75th) 22.86% (4.82%, 50.29%)
Mean (SD) 32.03% (31.273%)
Min, Max 0.0%, 100.0%

Time above INR range 3.0

n 1977
Median (25th, 75th) 2.96% (0.00%, 17.55%)
Mean (SD) 12.02% (18.819%)
Min, Max 0.0%, 100.0%
INR indicates international normalized ratio; SD, standard deviation.
 22
 

Table S3. Randomization factors (oral anticoagulant and aspirin) interaction parameters

for the primary and secondary outcomes

2-Sided p-Value
for Superiority
Coefficient Std. Error HR (95% CI)* Test
ISTH major or CRNM bleeding
Interaction: Apixaban/VKA and 0.08 0.18 1.09 (0.77, 1.54) 0.64
Aspirin

Death or hospitalization
Interaction: Apixaban/VKA and 0.15 0.12 1.16 (0.92, 1.46) 0.21
Aspirin

Death or ischemic events

Interaction: Apixaban/VKA and 0.24 0.23 1.28 (0.82, 1.99) 0.28
Aspirin
*Cox Proportional Hazards Model for time to first event stratified by enrollment indication.
CI indicates confidence interval; CRNM, clinically relevant nonmajor; HR, hazard ratio; ISTH, International Society on
Thrombosis and Haemostasis.
 23
 

Table S4A. Primary bleeding outcome rates by both factors as treated

Apixaban and Apixaban and

ASA Placebo VKA and ASA VKA and Placebo
N=1145 N=1143 N=1123 N=1126

ISTH major or CRNM 158/1145 (13.8%) 84/1143 (7.3%) 210/1123 (18.7%) 123/1126 (10.9%)
bleeding
Event rate per 100 33.6 16.8 49.1 26.7
patient-years

ISTH major bleeding 48/1145 (4.2%) 23/1143 (2.0%) 62/1123 (5.5%) 44/1126 (3.9%)
Event rate per 100 9.7 4.5 13.3 9.2
patient-years

ISTH CRNM bleeding 118/1145 (10.3%) 62/1143 (5.4%) 158/1123 (14.1%) 88/1126 (7.8%)
Event rate per 100 24.9 12.3 36.4 19.0
patient-years
ASA indicates aspirin; CRNM, clinically relevant nonmajor; ISTH, International Society on Thrombosis and Haemostasis; VKA,
vitamin K antagonist.
   
 24
 

Table S4B. Secondary outcome rates by both factors as treated

Apixaban and Apixaban and

ASA Placebo VKA and ASA VKA and Placebo
N=1153 N=1153 N=1154 N=1154

All-cause death or 287/1153 (24.9%) 254/1153 (22.0%) 317/1154 (27.5%) 315/1154 (27.3%)
hospitalization
Event rate per 100 62.0 52.7 69.5 68.9
patient-years

Hospitalization 278/1153 (24.1%) 240/1153 (20.8%) 307/1154 (26.6%) 300/1154 (26.0%)

Event rate per 100 60.0 49.8 67.3 65.6
patient-years

Death 38/1153 (3.3%) 39/1153 (3.4%) 34/1154 (2.9%) 40/1154 (3.5%)

Event rate per 100 6.9 7.1 6.2 7.3
patient-years

All-cause death or ischemic 71/1153 (6.2%) 72/1153 (6.2%) 66/1154 (5.7%) 84/1154 (7.3%)
events
Event rate per 100 13.2 13.3 12.3 15.7
patient-years
ASA indicates aspirin; VKA, vitamin K antagonist.