Supplementary Appendix of HOPE 3 Trial

Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without
cardiovascular disease. N Engl J Med. DOI: 10.1056/NEJMoa1600176
SUPPLEMENTARY APPENDIX
This appendix has been provided by the authors to give readers additional information for
the following 3 papers:
1. Lonn E, Bosch J, Lopez-Jaramillo P, et al., for the HOPE-3 Investigators. Blood
pressure lowering in intermediate risk people without vascular disease. NEJM 2016.
2. Yusuf, S., Bosch, J., Dagenais, G., et al. for the HOPE-3 Investigators. Rosuvastatin
in intermediate-risk people without cardiovascular disease. NEJM 2016.
3. Yusuf, S., Lonn, E., Pais, P. et al. for the HOPE-3 Investigators. Blood pressure and
cholesterol lowering in people without cardiovascular disease. NEJM 2016.
THE HEART OUTCOMES PREVENTION EVALUATION (HOPE)-3 TRIAL

Supplementary Appendix
Table of Contents
HOPE-3 Investigators and Committees .......................................................................... 7
Blood Pressure Measurement Protocol ......................................................................... 11
Collection and Measurement of Lipids and High Sensitivity C-Reactive Protein (hs-CRP)
....................................................................................................................................... 12
Definitions of Outcome Events ..................................................................................... 14
Safety Monitoring and Reporting ................................................................................. 22
Adjustment For Multiple Testing In HOPE-3 .............................................................. 24
Figure S1: CONSORT Diagram for the Candesartan/HCTZ versus Placebo Comparison
....................................................................................................................................... 25
Figure S2: CONSORT Diagram for the Rosuvastatin versus Placebo Comparison .... 26
Figure S3: CONSORT Diagram for the Double Active versus Double Placebo
Comparison ................................................................................................................... 27
Figure S4: Diastolic Blood Pressure Over the Course of the Trial in the
Candesartan/HCTZ and Placebo Groups ...................................................................... 28
Figure S5: Cumulative Incidence of Co-Primary Outcome 1 for the Candesartan/HCTZ
versus Placebo Comparison .......................................................................................... 29
Figure S6: Cumulative Incidence of the Secondary Outcome 1 for the Candesartan/HCTZ
Figure S7: Cumulative Incidence of Co-Primary Outcome 1 for the Rosuvastatin versus
Placebo Comparison ..................................................................................................... 31
Figure S8: Cumulative Incidence of the Secondary Outcome for the Rosuvastatin versus
Figure S9: Cumulative Incidence of Co-Primary Outcome 1 in the
Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, Candesartan-HCTZ Alone and
Double Placebo Groups ................................................................................................ 33
Figure S10: Cumulative Incidence of the Secondary Outcome for the
Figure S11A: Secondary Outcome 1 by Tertiles of Baseline Systolic Blood Pressure for
the Candesartan/HCTZ versus Placebo Comparison .................................................... 35
Figure S11B: Secondary Outcome 2 by Tertiles of Baseline Systolic Blood Pressure for
the Candesartan/HCTZ versus Placebo Comparison .................................................... 36
Figure S12: Selected Subgroup Analysis for Co-Primary Outcome 1: Candesartan/HCTZ
Figure S13: Selected Subgroup Analysis for Co-Primary Outcome 2: Candesartan/HCTZ
versus ............................................................................................................................ 38
Figure S14: Selected Subgroup Analysis for Co-Primary Outcome 1: Rosuvastatin versus
Placebo Comparison* ................................................................................................... 39
Figure S15: Selected Subgroup Analysis for Co-Primary Outcome 2: Rosuvastatin versus
Figure S16: Selected Subgroup Analysis for Co-Primary Outcome 1:
Candesartan/HCTZ+Rosuvastatin, versus Double Placebo Comparisons.................... 41
Candesartan/HCTZ+Rosuvastatin, versus Double Placebo Comparisons.................... 42
Figure S18: HOPE-3 Results* in the Context Major Vascular Event Reduction versus
LDL Cholesterol in mg/dl Lowering in Randomized Controlled Trials....................... 43
Table S1: The Heart Outcomes Prevention Evaluation (HOPE) - 3 Trial Design........ 44
Table S2: HOPE-3 Eligibility Criteria ......................................................................... 45
Table S3: Adherence to Study Drug and Open Label Use of ARBs, ACE-Is and Thiazides
in the Candesartan/HCTZ and Placebo Groups ............................................................ 46
Table S4: Adherence to Study Drug and Open Label Use of Statins and Other Lipid
Lowering Drugs in the Rosuvastatin and Placebo Groups ........................................... 47
Table S5: Adherence to Study Drug and Open Label Use of ARBs, ACE-Is, Thiazides
and Statins in the Candesartan/HCTZ+Rosuvastatin and the Double Placebo Groups 48
Table S6: Predefined Safety Outcomes in Candesartan/HCTZ and Placebo Groups .. 49
Table S7: Reasons for Hospitalization in the Candesartan/HCTZ and Placebo Groups50
Table S8: Causes of Death in the Candesartan/HCTZ and Placebo Groups* .............. 52
Table S9: Adverse Events Leading to Permanent Study Drug Discontinuations in the
Table S10: Adverse Events Leading to Temporary Study Drug Discontinuations in the
Table S11: Reported Serious Unexpected Suspected Adverse Reactions (SUSARS) in the
Candesartan/HCTZ and Placebo Groups* .................................................................... 55
Table S12: Causes of Death in the Rosuvastatin and Placebo Groups* ....................... 56
Table S13: Predefined Safety Outcomes in the Rosuvastatin and Placebo Groups .... 57
Table S14: Reasons for Hospitalization in the Rosuvastatin and Placebo Groups ....... 58
Rosuvastatin and Placebo Groups ................................................................................. 60
Rosuvastatin and Placebo Groups ................................................................................. 61
Rosuvastatin and Placebo Groups* ............................................................................... 62
Table S18: Causes of Death in the Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone,
Candesartan/HCTZ Alone and Double Placebo Broups* ............................................. 63
Table S19: Predefined Safety Outcomes in the Candesartan/HCTZ+Rosuvastatin,
Rosuvastatin Alone, Candesartan/HCTZ Alone and Double Placebo Groups ............. 64
Table S20: Reasons for Hospitalization in the Candesartan/HCTZ+Rosuvastatin,
Table S21A: Adverse Events Leading to Permanent Study Drug Discontinuation of
Candesartan/HCTZ or Candesartan/HCTZ Placebo ONLY in the
Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, Candesartan/HCTZ Alone and
Table S21B: Adverse Events Leading to Permanent Study Drug Discontinuation of
Rosuvastatin or Rosuvastatin Placebo ONLY in the Candesartan/HCTZ+Rosuvastatin,
Table S21C: Adverse Events Leading to Permanent Study Drug Discontinuation of Both
Candesartan/HCTZ and Rosuvastatin or Their Placebos in the
Table S22A: Adverse Events Leading to Temporary Study Drug Discontinuation of
Candesartan/HCTZ or Candesartan/HCTZ Placebo ONLY in the

Table S22B: Adverse Events Leading to Temporary Study Drug Discontinuation of
Rosuvastatin or Rosuvastatin Placebo ONLY in the Candesartan/HCTZ+Rosuvastatin,
Table S22C: Adverse Events Leading to Temporary Study Drug Discontinuation of Both
Candesartan/HCTZ and Rosuvastatin or Their Placebos in the
Double Placebo Groups* .............................................................................................. 73
HOPE-3 Investigators and Committees

Steering Committee: S. Yusuf (Chair and Principal Investigator), E. Lonn (Co-Principal
Investigator), A. Avezum, J. Bosch, I. Chazova, A. Dans, R. Diaz, G. Fodor, C. Held, P.
Jansky, M. Keltai, K. Keltai, K. Khunti, J. Kim, L.A. Leiter, B.S. Lewis, L. Loss, L.S. Liu,
P. Lopez-Jaramillo, P. Pais, A. Parkhomenko, R.J.G. Peters, L.S. Piegas, J. Pogue*, C.M.
Reid, K. Sliwa, W.D. Toff, J. Varigos, D. Xavier, K. Yusoff, J. Zhu.
Event Adjudication Committee: G. Dagenais (Chair), R. McKelvie (Co-Chair), N.
Anderson, P. Magloire, M. Naufal, C. Morillo, L. Morillo, V. Pavlova, M. Rokoss, D.
Sahlas, J Silva, B. Tsang, N. Yakubovich, P. Bogaty, Z. Punthakee, J. Wilkinson, Y. Liang,
A. Avezum, P. Hildebrandt, M. Keltai, D. Halon, K. Yusoff, R.J.G. Peters, G. Fodor, C.
Held, M. Corson, J. Mann, R. Hart, M. Sharma.
Data and Safety Monitoring Board: D. Sackett (Chair)*, D. DeMets (Chair), C. Baigent,
C. Hennekens, J. Mancini.
Study Statisticians & Programmers: J. Pogue*, H. Jung, P. Gao, G. Wong, K.
Balasubramanian, B. Swaminathan, R. Khatun, L. Dyal, C. Tang, A. Casanova.
Project Office Study Staff: J. Bosch, J. Wilkinson, A. Rathe, J. Castelli, J. Miller, A.
Whate, K. Brettell, A. Rogge, C. Choppick, A. Kuptsova, S. Owens, S. MacRae, A. Mead,
J. Gibson, N. Barkhordari, S. Chang, M. Hogge.
Central Laboratory Staff: M. McQueen, K. Hall, Hamilton, ON Canada; D. Prabhakaran,
R. Gupta, Haryana, India; X.Y. Wang, Beijing, China.
National Leader Office Coordination and Monitoring by Country: Argentina: R. Diaz,
M. Cabezon, B. Dellavedova, A. Pascual Australia: C.M. Reid, J. Varigos, L. Shiel Brazil:
L.S. Piegas, A. Avezum, G.B.F. Oliveira, M.S. Marroni Tavares, D.C. Vila Nova, L.P.
Tanabe Batista, M.Y. Nakashima Konishi Canada: E. Lonn, L.A. Leiter, L. Baetz, S.
Kulkarni, T. Newman China: L.S. Liu, J. Zhu, Y. Liang, L. Ma, H.Q. Tan, Y. Ge
Colombia & Ecuador: P. Lopez-Jaramillo, M. Lopez-Pico Czech Republic: P. Jansky, J.
Vanova Hungary: M. Keltai, K. Keltai India: P. Pais, D. Xavier, A. Sigamani, D. Kamath,
F. Xavier, S. Alban Israel: B.S. Lewis, Y. Marmor*, R. Yuval Korea: J. Kim Malaysia:
K. Yusoff, S. Muhamad Yunus Netherlands: R.J.G. Peters, N. Bruinsma, Y.K. Chan, P.
Ebbinkhuijsen Philippines: A. Dans, J. Sanchez, E. Villarruz-Sulit Russia: I. Chazova, A.
Aksenova, N. Blinova, E. Helis Slovakia: G. Fodor S. Africa: K. Sliwa Sweden: C. Held,
G. Lindstrom, E. Svensson, G. Alsj UK: K. Khunti, W.D. Toff, S. Leji Ukraine: A.
Parkhomenko, L. Parkhomenko, O. Skarzhevskyi.
Site Principal and Co-Investigators:

Argentina (1459**): M. Alzogaray, M. Aparici, M. Berli, M. Bevacqua, M. Bustamante
Labarta, B. Bustos, A. Caccavo, A. Candiello, M. Carignano, N. Carrillo, N. Carro, L.
Cartasegna, W. Casali, A. Cassettari, M. Centeno, J. Cuello, S. Cusimano, C. Cuneo, R.
Garcia Duran, C. Damonte, M. De Landaluc, E. De Martino, R .Diez, R. Duran, A.
Fernandez, A. Ferrari, L. Forti, M. Galello, C. Garcia, F. Giachello, M. Garrido, M.
Gonzalez, F. Guerlloy, R. Guerrero, A. Hrabar, H. Imposti, M. Hominal, G. Liniado, P.
Lanchiotti, C. Laugle, G. Liniado, M.R. Litvak, A. Longhi, H. Luciardi, I. Mackinnon, J.
Marino, R. Manzano, B. Merlo, R. Milesi, D.I. Molina de Salazar, C. Mulazzi, S. Nemi, S.
Orio, M. Pelaggage, S. Raimondi, L. Rodino, A. Rodriguez, C. Rodriguez, D. Rodriguez, L.
Sago, J. Sala, A. Sanchez, R. Sanchez, D. Santos, P. Schygiel, V. Sernia, T. Smith, F. Sokn,
L. Soso, M. Trivi, M. Vico, O. Gomez Vilamajo, A. Villamil, D. Vogel, C. Zaidman
Australia (45**): W. Abhayaratna, J. Canalese, H. Krum*, A. Patel Brazil (551**): A.R.
Alves Jr, C.B. Alves, J.C.A. Ayoub, L.C.C. Bergoli, M.G. Blacher, L.C. Bodanese, J.C.F.
Braga, C.K.O.L. Brasil, M.K.M. Costa, O.M.C. Costa, D.G. de Faria, M.I. Del Monaco, L.
Fabian Restelatto, F. Filho, R.J.S. Franco, M.V. Furtado, P.E. Leaes, L.N. Maia, J.A.
MarinNeto, A.P.D. Martins, E.T.B. Mattar, C.M. Melo, F.S. Mothe, G.B.F. Oliveira, L.F.A.
Oliveira, E. Pelloso, C.A. Polanczyk, P.R. Rosa, S.O.C. Sales, J.F.K. Saraiva, A. Schmidt,
V.S. Silva, A.C.S. Sousa, A. P. Valle, M. Wiehe Canada (1156**): B. Abramson, S.
Anand, J. Aw, W. Baxter, J. Berlingieri, J. Cha, R. Chaulk, T. Chetty, G. Dagenais, D.
Dattani, F. Delage, D. Dion, M. Dominguez, R. Gallo, K. Glendinning, H. Goldman, G.
Gosselin, A. Greenspoon, Q. Hungly, M. Juneau, P. Keegan, A. Kelly, D. Kilby, M. Lavoie,
L.A. Leiter, E. Lonn, P. Magloire, P. Mehta, N. Mercante, H. Miscescu, G. Moran, S.
Nawaz, A. Nigam, P. Pang, E. Papp, R. Petrella, C. Poirier, R. Rabasa-Lhoret, Q. Rizvi, D.
Saulnier, M. Sharma, P. Sohal, S. Stern, S. Tobe, P. Walsh, R .Ward, A. Weeks, V. Woo, J.
Yellin, P. Zuliani China (3677**): X.J. Bai, L.G. Dong, J.Z. Feng, P. Fu, P. Gao, M.M.
Gao, H. Ge, S.P. Hu, Q. Hua, D.J Li, Z.D. Liu, Y.J. Liu, X.L Liu, L.H. Liu, F.Y. Liu, F.H.
Lu, T. Lv, H. Ma, S.P. Ma, R.H. Man, Y. Shen, J.F. Shi, X.D. Sun, B. Wang, S.Y. Wang,
Y.N. Wang, Y.Q. Wang, Y.J. Wei, H.S. Yang, X.C. Yang, J.H. Yu, K. Yu, L.T. Yu, B.
Zhang, F. Zhang, H.Y. Zhang, L. Zhang, W. Zhang, J.G. Zhao, Y. Zhao, B.X. Zhong
Colombia (1463**): J. Accini, G. Aroca, E. Arcos, M. Accini-Valencia, M. Casanova, C.
Celemin, B.J. Coronel, C. Cotes, C. Cure, A. Duarte, D. Escobar, M. Figueredo, H. Garcia,
L. Garcia, M. Grisales, Z. Hernandez, D. I. Molina de Salazar, K. Martinez, B. Nino
Castellanos, M. Diego-Olite, N. Ospina Rendon, I. Posada, A. Quintero, F. Quiros, G.
Sanchez, A. Sotomayor, M. Suarez, M. Urina Czech Republic (70**): V. Adamkova, R.
Cifkova, R. Ferkl, M. Galovcova, J. Hartman, M. Jozifova, K. Linhart, T. Linhart, D.
Moravcikova, B. Nussbaumerova, M. Plachy, H. Rosolova, B. Seifert, M. Soucek Ecuador
(397**): Y. Duarte Vera, M.Espinel, M. Lopez-Jaramillo, J. McDermont, E. Penaherrera, F.
Plascencia, F. Pow-Chon-Long, D. Tettamanti
Hungary (263**): L. Bajnok, E. Baranyi, E. Bartfai, E. Bod, B. Bodis, I. Czuriga, E.

Huber, E. Mezosi, F. Poor, E. Somos, Z. Tarjanyi, T. Tatrai, J. Tomcsanyi, A. Vertes, A.
Zsary India (1824**): D.K. Aggarwal, K.G. Alexander, S. D. Aman, Arun, V. Ayyar, Y.
Balaji, E. Balasubramanian, G. Bantwal, Y. Bhalvishiya, B. Bosco, N. Chidambaram, A.
Dabra, S. Daniel, N. Deshpande, H.R. Devendra, D. Ghoshroy, S. Gnanasekaran, R. Gupta,
M.Z. Gutti, P. Jayakumar, G. S. Joshi, S. Joshi, S.P. Kalantri, A. Kapoor, A. Khan, R. S.
Khedar, J. Kishore, A. Kumar, S. Kumar, Kumaravel, A.R. Manjunath, K. Mehta, V.
Mohan, S. Murthy, A. Nambiar, J. Narendra, S.K. Paul, M.A. Qureshi, S. Rajasekaran, M.
Ramu, R.L. Ranka, K. Rangadham, S. Roy, M.R. Sathyanarayan, K. Selvam, J.P.
Sethuraman, D. Shabhasane, K. Shivaraj, M. Shunmugvavelu, G. Sidhu, B. Singh, R. Singh,
A. Srinivas, J. Srinivas, B. Srinivasulu, N. Thomas, R. Umarani, K. Varghese, S. Varma, S.
Yelvatkar Israel (81**): A. Biton, A. Goldhaber, S. Ivri, I. Shapiro, E. Shveydel, N.
Shveydel, D. Tsalihin, S. Vinker, H. Yosefy
Korea (14**): S. Kil Kim, K.H. Choe Malaysia (87**): D. Ambigga, M.A. Aris, K.A.
Ghapar, C. Krishnan, P. Mahadasa, M. Maizatullifah, Y. Mazapuspavina, L. Ramanathan,
A. Shah Mohd Shah, K. Yusoff Netherlands (117**): J.H. Bonarius, A. De Jong, Z.
DeRuiter, R. DeVos, H.A. Dirkse, E. Drenth, H. Ferguson, R. Jansen, H. Mevissen, H. Rol,
A. Schilder, I. Spelt, P. VanLeeuwen Philippines (571**): M. Abola, H. Co, A. Loyola, J.
Mercado, D. Morales, L. Padua, L. Palileo, A. Patanao, G. Rogelio, A. Roxas, D. Sulit, A.
Tang-Manga, B. Tumanan-Mendoza Russia (190**): S. Boytsov, I. Chukaeva, Y. Karpov,
O. Kisliak, Z. Kobalava, A. Ledyacva, Y. Lopatin, S. Nedogoda, M. Solovieva, V. Tsoma,
T. Tyurina Slovakia (10**): M. Hranai South Africa (211**): A. Badat, T. Gerntholtz, K.
Sliwa Sweden (117**): F. Al-Khalili, B. Carlberg, A. Dotevall, P. Nilsson, A. Olsson, A.
Rosengren, S. Soderberg
UK (69**): K. Khunti, I. Loke, W.D. Toff Ukraine (333**): D. Artomov, T. Babanina, A.
Bagriy, G. Chobotko, S. Danyliuk, N. Doretska, O. Dorovska, N. Dovgan, G. Dzyak, L.
Glushko, I. Gorbas*, T. Ilashchuk, K Karapetyan, I. Karavanska, L. Khimion, A. Khorsun,
L. Kononenko, O. Kuryata, O. Kvasha, S. Lazareva, D. Loktyev, G. Lysenko, V.
Martynyuk, N. Miroshnchenko, O. Onyschenko, N. Petryk, S. Pivovarova, I. Rakytskay, L.
Sapozhnychenko, I. Smymova, O. Soya, V. Tashchuk, N. Turubarova-Leunova, L.
Vasilyeva, N. Velichko, A. Yagensky, S. Zborovskyy, S. Zhurba.
Site Coordinators: Brazil: A.S. Almeida, M.S. Almeida, A.L.D.S. Augusto, R.F. Batista,
A.P.D. Martins, D. Rodrigues, A.C. da Silva, L. Silva, N. Tamashiro, L.P. Tanabe Batista,
D.C. Vila Nova Canada:, B. Barnabe, C. Dihel, A. Dufour, L. Frenette, M. Gourgues, J.
Lalonde, P. Lavigne, A. Magi, N. Perkins, R. Raymond, B. Walsh, M. Wiebe Colombia: M.
Florez-Archila, M. Escobar-Vitola, M. Accini-Valencia, C. Saso-Polo, A. Sorchar-Gomez,
M. Moreno-Pico, J. Alzate-Alvarez, J. Yepez-Alvaran, S. Botero-Baena, M. Salazar-Molina,
G. Estefanny Marin-Hernandez, I. Mejia-Arias, L. Caicedo Gonzalez, C. Guervo-Astudillo,
A. Gerleim-Rojas, S. Betancourt-Sanchez, A. Guzman-Tocora, G. Cordoba-Avendario
Czech Republic: H. Elnerova, E. Habermannova, V. Zelenkova Ecuador: S. Caceres-
Vinueza Hungary: L. Matics, J. Roll India: R. N. Ahmed, S. Babu, S. Chavhan, A.C.

Leela, M. Mahajan, P. Mehta, K. Palaniappan, R. Parmaj, S. Poongothai, Y. Prathyusha, M.
Saha, K. Sankar, R. Sidhu, S. Singh, S. Sudha, J. Varsha Israel: M. Goldhaber, D. Kisos, S.
Meyuhas, S. Srour Malaysia: S. Yunus Philippines: M. Arbis, T.G. An, M. Cabral, R.
Dioquino, R. Flotildes, L. Gilo, F. Joaquin, K. Herrera, T. Mararac, S.Vasquez S. Africa:
C. Phuti Sweden: M. Andreasson, M. Backlund, A. Gustavsson, C. Hjerpe, M. Johansson,
P. Lof, P. Sandell, C. Sundholm, T. Tollefsen, K. Skoglund UK: S. Leji, V. Meynell
Ukraine: V. Ignatiuk, V. Martynyuk.
*deceased ** Number of participants randomized
10
Blood Pressure Measurement Protocol

Automatic Blood Pressure Measurement
Use the Omron automatic blood pressure monitor.
Ask the participant to remove tight-fitting clothing from his/her arm.
The participant must be sitting for >5 minutes.
Put the participants arm through the cuff loop making sure the bottom edge of the
cuff is approximately one-half inch (1.25cm) above the elbow and that the arrow on
the cuff is above the brachial artery.
The entire cuff should be evenly tight around the participants arm. Ask the
participant to remain still until the measurement is complete.
Press the ON/OFF button. After the heart symbol () appears on the digital panel,
press the START button.
After the measurement is complete, the monitor will display the systolic and
diastolic blood pressures and pulse. The cuff will automatically deflate.
Take 2 readings on the right arm at least 1-minute apart.
Record all readings.
Manual Blood Pressure Measurement

Use a mercury sphygmomanometer.
Ask the participant to remove tight-fitting clothing from his/her arm.
The participant must be sitting for >5 minutes.
Put the participants arm through the cuff loop making sure the bottom edge of the
cuff is approximately one-half inch (1.25cm) above the elbow crease and the bladder
of the cuff is centered over the brachial artery.
The entire cuff should be evenly tight around the participants arm. Ask the
participant to remain still until the measurement is complete.
Increase the pressure in the cuff rapidly to 30 mmHg above the level at which the
radial pulse is extinguished.
Place the bell (or diaphragm) of the stethoscope over the brachial artery. Open the
control valve of the sphygmomanometer and deflate the cuff at approximately 2
mmHg per heartbeat.
Read the systolic level (the first appearance of a clear tapping sound -- phase I
Korotkoff) and the diastolic level (the point at which the sound disappears -- phase V
Korotkoff).
Record the reading.
All analyses were done using the automated blood pressure measurements. At baseline
automated blood pressure measurements were not obtained in 72 participants. The manual
blood pressure measurement was used for statistical analyses in 70 of these participants, and
was missing in 2 participants. The mean difference between automated and manual baseline
blood pressure measurements was 1.46/0.34 mmHg.
11
Collection and Measurement of Lipids and High Sensitivity C-Reactive

Protein (hs-CRP)
A. Blood Sample Collection
Baseline blood samples were requested from all participants. Subsequent samples were
collected in a sample representative of different ethnicities and geographic distributions (not
all participants) at 1 year, 3 years and study end. Samples were collected from the largest
centers in these countries. The following tables provide the number of samples collected
overall and by ethnic group (ethnicity and geographic region are highly correlated)
Any Central LDL-Cholesterol Measurement
Randomized Baseline
1 year
3 years
Study End
N
N
N
N
N
Overall
11398
1531
1545
1701
European Descent
2546
2425
427
346
328
Latin American
3496
3308
299
277
250
Asian
6241
5309
604
773
1014
Black African
225
212
142
122
77
Other
194
144
59
27
32
Note: Geography and ethnicity are highly correlated so only ethnicity is presented.
Any Central hs-CRP Measurement
Randomized Baseline
1 year
3 years
Study End
N
N
N
N
N
Overall
11531
1544
1554
1718
European Descent
2546
2459
433
348
336
Latin American
3496
3364
303
282
252
Asian
6241
5347
605
774
1020
Black African
225
214
144
123
78
Other
194
147
59
27
32
Note: Geography and ethnicity are highly correlated so only ethnicity is presented.
All Serial Central Lipid or hs-CRP Measurement at All 4 Time Points (baseline, 1 year
1, 3 year1 and study end)
Lipid
CRP
N
N
Overall
975
994
European Descent
304
312
Latin American
190
197
Asian
396
398
Black African
63
65
Other
22
22
12
B. Analytical Methods
Quantitative determination of serum analytes was performed on the Beckman Coulter
UniCel DxC600 System using turbimetric methods for Apolipoproteins A1 and B (ApoA1
and ApoB), timed endpoint methods for Cholesterol (CHOL), High Density Lipoprotein
(HDL) and Triglycerides (TG), and a highly sensitive Near Infrared Particle Immunoassay
for C-Reactive Protein (CRP).
Measurements were made at three laboratories; the Core Laboratory at the Population
Health Research Institute in Hamilton, Canada, the Laboratory of Human Genetics, Beijing
Hypertension League in Beijing, China and the Laboratory of the Centre for Chronic
Conditions & Injuries of the Public Health Foundation of India, in Haryana, India. All
laboratories used the same assays/methods standardized at the Core Laboratory in Hamilton,
Canada, which provided also quality control.
13
Definitions of Outcome Events

CARDIOVASCULAR DEATH
Defined as a death with a cardiovascular cause or a death for which a definite noncardiovascular cause has not been identified. Uncertain causes of deaths are presumed to be
cardiovascular unless proven otherwise.
Unwitnessed unexpected death
Death due to presumed cardiovascular cause where the patient was well or stable prior to
death.
Sudden witnessed unexpected death
Defined as death that occurred suddenly and unexpectedly in a patient who was well or had
stable cardiovascular status prior to death. Death was witnessed, and due to the following:
An identified arrhythmia
Cardiac arrest or cardiovascular collapse
Patients resuscitated from a sudden cardiac arrest who later die due to sequelae
of the event or patients who die during attempted resuscitation
Non-sudden arrhythmic death
Death due to documented arrhythmia, when death is expected, not sudden and not
associated with evidence of myocardial ischemia.
Fatal myocardial infarction (MI)
Death occurring within 30 days of a documented MI, when there is no evidence of
another cause of death.
Autopsy evidence of a recent infarct with no other evidence of another cause of death.
Presence of suggestive criteria of MI preceding death, when the strict definition of an
MI may not be possible. The suggestive criteria are presentation of chest pain considered
to be due to myocardial infarction and one of the following:
ECG changes indicative of a myocardial injury (including new left bundle branch
block)
OR
Abnormal cardiac markers below the level of diagnostic myocardial necrosis:
CKMB > 1.0 but < 1.5 x upper limit of normal (ULN) or troponin increase not
reaching the level for diagnosis of MI or other markers above normal range but <
2.0 x ULN (e.g. when death occurred before a subsequent draw)
OR
Imaging evidence of new wall motion abnormality.
Heart failure death
Death due to heart failure, in the absence of ischemia or arrhythmia, including cardiogenic
shock.
14
Deaths occurring in patients with documented heart failure with systolic dysfunction who
die suddenly during an admission for worsening heart failure were considered as heart
failure deaths.
Death after invasive cardiovascular intervention
Death occurring within 30 days of cardiovascular surgery or limb amputation, or within 7
days of catheterization, arrhythmia ablation, angioplasty (with or without stent placement),
atherectomy (coronary, cerebral or peripheral artery disease), or other invasive coronary or
peripheral vascular interventions.
Death due to stroke
Death occurring within 30 days of signs/symptoms of stroke or autopsy evidence of a recent
stroke with no evidence of another cause of death.
Other cardiovascular causes of death
Other vascular events, including pulmonary embolism and ruptured abdominal aortic
aneurysm.
Presumed cardiovascular death
Death suspicious of cardiovascular death with supporting clinical evidence that may not
fulfill other criteria (e.g. presentation with chest pain typical for MI, but without ECG
tracing or cardiac biomarker documentation that fulfill MI criteria).
Death from unknown causes
Considered to be a cardiovascular death unless evidence of a non-cardiovascular cause
exists.
MYOCARDIAL INFARCTION
Definite Non-procedural MI
EITHER
Cardiac Ischemic Symptoms lasting > 20 minutes, determined by the site investigator to be
secondary to ischemia
OR
ECG or changes consistent with acute infarction or ischemia MI:
New diagnostic Q waves (Q wave in leads V2 and V3 0.02 sec or QS complex in
leads V2 and V3; Q wave 0.03 sec and 0.1 mV deep or QS complex in leads I,
II, aVL, aVF or V4-V6 in any two leads of a contiguous lead grouping (I and aVL;
V1-V6; II, III, aVF, R wave 0.04 sec in V1 and V2 and R/S 1 with a concordant
positive T wave)) in the absence of conduction abnormalities
15
New significant ST-segment- T-wave changes in two or more contiguous leads: ST

elevation at the J point 0.1 mV in all leads other than leads V2 and V3 where the
following cut points apply: 0.2 mV in men 40 years; 0.25 mV in men < 40 years,
or 0.15 mV in women. ST depression horizontal or downsloping 0.05 mV; or T
wave inversion 0,1mV with prominent R wave or R/S ratio 1.
Development of new left bundle branch block (LBBB)
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality
Intracoronary thrombus by angiography
AND
Elevated cardiac biomarkers (values according to each hospitals laboratory):
A rise and/or fall in cardiac biomarker values (preferably troponin, CKMB, AST, LDH or
myoglobin) with at least one value above the 99th percentile of the upper reference limit.
Probable Non-procedural MI
In cases of missing cardiac biomarkers:
Ischemic symptoms lasting 20 minutes considered to be of cardiac origin and
requiring hospitalization with ECG changes consistent with acute ischemia or with
thrombolysis or coronary revascularization within 12 hours.
In cases of missing information on symptoms and ECG report or tracing:
History of hospitalization for MI with cardiac enzymes showing a typical pattern of
MI as for definite MI. However, the local PI should find out if the participant had
chest pain or if the event occurred in a peri-operative period.
In cases of missing information on cardiac markers, ECG findings and duration of typical
symptoms:
History of hospitalization for MI with a documented finding compatible with recent
MI on follow-up ECG or on imaging (cardiac echocardiography, nuclear scan, MRI)
in a participant without previous MI or in a participant with previous MI having a
new ECG or imaging finding compatible with MI in comparison to a previous ECG
or imaging finding.
Procedural MI: PCI-related MI
An MI after a PCI is defined as:
EITHER
Cardiac ischemic symptoms as above
OR
ECG or imaging changes consistent with MI, as above, or angiographic findings consistent
with a procedural complication,
AND
Increased troponin values greater than 5 X 99th percentile URL in patients with normal
baseline values (less than 99th percentile URL), or a rise of troponin values greater than
20% if baseline values are elevated and are stable or falling.
CABG-related MI
An MI after CABG surgery is defined as:
16
ECG changes consistent with MI, including new pathological Q waves or new LBBB; or
angiographic documented new graft or new native coronary artery occlusion, or imaging
evidence of new loss of viable myocardium or new regional wall motion abnormality,
AND
Increased cardiac biomarker values (greater than 10 X 99th percentile URL) during the first
48 hours following CABG in patients with normal troponin values.
Procedural MI: MI related to other cardiac procedures
For cardiac catheterization same criteria as for Definite Non-procedural MI. For
transcatheter aortic valve implantation or mitral clip procedure same criteria as for as
CABG-related MI.
MI associated with non-cardiac procedures (within 48 to 72 hours of procedure)
Same criteria a as for Definite Non-procedural MI
Unrecognized (silent) MI
MI documented on ECG that may not have been clinically recognized. If the investigator
(based on review of the clinical status and ECGs) feels that this occurred, he/she should
submit information supporting the diagnosis of a clinically unrecognized MI. Such
documents could be an ECG showing new and significant Q-waves not attributed to
intraventricular conduction defect, left ventricular hypertrophy, pre-excitation syndrome,
idioventricular rhythm, or electronic pacer. In addition, confirmation may be achieved by
echocardiographic or other evidence of new regional wall motion or perfusion
abnormalities.
STROKE
Stroke is defined as the presence of an acute focal neurological deficit thought to be of
vascular origin. The duration of the neurological deficit should be > 24 hours if no imaging
is done or when there is no acute stroke on imaging. The duration of symptoms may be less
than 24 hours if a new stroke is documented on CT or MRI.
On the basis of clinical symptoms or signs, and CT or MRI imaging, strokes will be
classified as:
Definite Ischemic Stroke
Stroke with CT or MRI performed within 3 weeks that is either normal or shows infarction
in the clinically concordant area:
Lacunar infarct
Cerebral infarction with:
Consciousness and higher mental functions maintained.
One of the typical lacunar syndromes, such as pure motor stroke, pure
sensory stroke, mixed sensori-motor stroke or ataxic hemiparesis.
CT/MRI performed within 3 weeks that is either normal (for CT only) or
shows a small (< 2 cm) subcortical infarct in the basal ganglia, internal
capsule, brain stem or elsewhere.
17
Cardioembolic infarct
Cerebral infarction with:
Absence of lacunar syndrome and findings symptoms cortical involvement.
No definite evidence of large artery disease in the neck.
Major cardioembolic source present (e.g. atrial fibrillation, MI in the last 6
weeks, cardiomyopathy, endocarditis or prosthetic heart valve).
CT/MRI performed within 3 weeks that is either normal (CT only) or shows a >
2 cm or cortically-based infarct.
Large artery infarct
Absence of lacunar syndrome and symptoms suggesting cortical involvement.
No major cardioembolic source present.
Evidence of large ipsilateral artery disease in the neck (e.g. a bruit or duplex scan
evidence of arterial stenosis of more than 50%).
CT/MRI performed within 3 weeks that is either normal (CT only) or shows a >
2 cm cortically- or subcortically-based infarct but not in the classical lacunar
region.
Unclassified infarct
Cerebral infarction that is not lacunar, cardioembolic or large artery in origin. This category
also includes patients who have more than one potential cause for stroke (e.g. atrial
fibrillation and large artery disease) if it is not possible to determine which mechanism is the
cause of the stroke.
Definite hemorrhagic stroke (Intracerebral hemorrhage)
Definite stroke with CT/MRI evidence of cerebral hemorrhage. (Note: Does not include
hemorrhage secondary to cerebral infarct, post-traumatic intracerebral hemorrhage,
hemorrhage into a tumor and hemorrhage into a vascular malformation.)
Subarachnoid hemorrhage
Typical clinical syndrome of sudden onset headache, with or without focal signs*, and CT
or cerebrospinal fluid evidence of bleeding primarily in the subarachnoid space.
Non traumatic subarachnoid hemorrhage documented by imaging is considered a
hemorrhagic stroke.
Stroke, type uncertain or unknown
Definite stroke that does not meet the above criteria for cerebral infarction or hemorrhage
(CT scan or MRI not done).
HEART FAILURE
A diagnosis is made based on signs and symptoms. Heart Failure symptoms include dyspnea
(at rest or on exertion), orthopnea, paroxysmal nocturnal dyspnea; and signs: rales, edema,
elevated jugular venous pressure includes:
18
Hospitalization for Heart Failure

Defined as hospitalization for heart failure or attendance in an acute care setting for
administration of intravenous diuretic, escalation of diuretic doses and/or administration of
inotropes, and/or evidence of heart failure from chest X-rays or elevated B-type natriuretic
peptide (BNP) > 300 pg/ml or NT-pro B-type natriuretic peptide > 900 pg/ml.
Significant Heart Failure not requiring hospitalization
Defined as at least one symptom of heart failure, plus either one positive diagnostic test
(such as BNP > 300 pg/ml or NT-pro BNP > 900 pg/ml or chest X-ray showing pulmonary
congestion, edema or pleural effusion) OR needing intravenous diuretic or inotropic
therapy.
RESUSCITATED CARDIAC ARREST
Resuscitated cardiac arrest is defined as sudden cardiac arrest, with or without premonitory
symptoms of heart failure or MI, following which the patient is resuscitated by
defibrillation, medication and/or cardiopulmonary resuscitation. The patient should not be
dependent on respiratory mechanical assistance and should have a meaningful recovery of
consciousness. This definition excludes known transient losses of consciousness such as
seizure or vasovagal episodes that do not reflect significant cardiac dysfunction.
ANGINA
Definite new angina
Defined as new onset of typical angina with documented ischemia by stress testing (ECG,
echocardiography stress testing or nuclear) in a patient previously not known to have angina
at baseline. For ischemic ECG changes, the ST depression should be 2 mm in comparison
to the tracing at rest obtained in the same position.
New angina also includes:
angina occurring 6 months or more after CABG/PCI
angina occurring any time after CABG/PCI if the subject did not have angina before
the procedure
Probable new angina
Defined as new onset of typical angina without documented ischemia by stress test. In such
a case the local PI has to confirm the presence of typical ischemic pain symptoms
characterized by pressure, squeezing or burning in the retrosternal area, cervical
region or arm
occurring on exertion
relieved by rest and/or nitroglycerine
Worsening angina
Defined as known angina increasing in frequency, duration, and/or severity, and requiring
new or increased dosage of antianginal medication or coronary revascularization.
Definite unstable angina
Defined as ischemic symptoms at rest or accelerated ischemic symptoms that the
investigator determines is secondary to ischemia and requires hospitalization
19
AND
Ischemic ECG changes as compared to the most recent ECG or during the previous stable
phase:
> 0.5 mm transient ST segment depression in two contiguous limb or precordial
leads
> 1 mm transient ST elevation of two contiguous leads (or ST depression in V1 or
V2)
> 2 mm transient T wave change in two or more contiguous leads
OR
Cardiac Markers (CKMB and/or other enzymes or myoglobin) suggestive of myocardial
injury, > ULN but not sufficient to meet MI criteria.
Probable unstable angina
Defined as ischemic symptoms considered to be of cardiac origin and having required
hospitalization and treated as acute coronary syndrome but when data on cardiac biomarkers
and ECG are missing.
ARTERIAL REVASCULARIZATION
1. Percutaneous coronary intervention (with or without stenting)
2. Coronary artery bypass graft surgery
3. Carotid endarterectomy or carotid bypass
4. Other arterial angioplasty (with or without stenting).
5. Other arterial surgery: This includes aortic (thoracic or abdominal) aneurysm
repair including stent for aortic aneurysm, aortobifemoral bypass, femoropopliteal
bypass, femoral-tibial bypass and cerebral aneurysm.
NON-CARDIOVASCULAR DEATH
Defined as any death for which clear evidence of a non-cardiovascular cause exists.
Cancer death
Death due to cancer or as a consequence of cancer related treatment complications. These
were classified by the following sites:
Gastrointestinal malignancy (including pancreatic and liver cancer)
Lung malignancy
Breast malignancy
Prostate malignancy
Brain malignancy
Skin malignancy
Hematologic malignancy (e.g. leukemia or lymphoma, multiple myeloma)
Genito-urinary malignancy
Bone/connective tissue (e.g. sarcoma)
Unknown primary site
Other malignancy (specify)
20
Other non-cardiovascular deaths

Pulmonary
Gastrointestinal
Hepatobiliary
Infection
Accidental, trauma
Suicide
Drug overdose
Renal
Other (specify)
NEW DIAGNOSIS OF DIABETES MELLITUS
Clinical diagnosis of diabetes with either elevated fasting or plasma glucose to 7 mmol/L
( 126 mg/dL) or locally measured 2 hour glucose 11.1 mmol/L ( 200 mg/dL) following
a 75 gm oral glucose tolerance test (OGTT) or elevated HbA1c 6.5 % (if measured
according to the NGSP certified and standardized to the DCCT assay or 48 mmol/mol by
IFCC method) or HbA1c 110 % ULN of the local laboratory if any other methods are
used, or the initiation of insulin or oral hypoglycemic agents.
DEEP VEIN THROMBOSIS
As reported by sites with information on use of anticoagulants and modality of diagnosis
(leg venography, ultrasonography, autopsy or other)
PULMONARY EMBOLISM
Hospitalization for pulmonary embolism, death reports, autopsy
CATARACT SURGERY
Hospitalization for cataract surgery or as reported by sites if performed as outpatient
procedure
21
Safety Monitoring and Reporting

The HOPE-3 trial used approved drugs with large amounts of available safety information
on each, which enabled us to use a focused approach to adverse event reporting.
The pre-defined safety assessments included:
A. Pre-defined Safety Outcomes
B. Adverse Events
C. Suspected Unexpected Serious Adverse Reports (SUSAR)
In addition, all hospitalizations were reported and the reason for hospitalization
documented. Hospitalizations are both efficacy and safety outcomes.
A. Pre-defined Safety Outcomes
1. CANCER
Cancer was adjudicated according to the primary site, whether new or recurrent.
New Primary cancer:
Cancer that is diagnosed for the first time and is a new cancer six months after
randomization will be considered new cancer.
Recurrent cancer:
Recurrent cancer is a previously diagnosed cancer that was thought to be completely
eradicated (whether with surgery, radiation, chemotherapy or other treatment) but has
reccurred.
All cancers and cancer deaths were classified by organ systems.
2. MYOPATHY
Defined as muscle aches or pains accompanied by CK rise >10 ULN
3. RHABDOMYOLYSIS
Defined as muscle pain and/or weakness associated with CK rise >10 ULN and evidence of
acute renal dysfunction (with or without documented myoglobinuria), defined as creatinine
elevation to > laboratory ULN, or creatinine increase to above baseline that is also above
ULN, or acute renal insufficiency or acute renal failure.
4. HOSPITAL ADMISSIONS AND THE REASONS FOR HOSPITAL ADMISSION
Data on all hospital admissions was collected including discharge summaries and other
pertinent information and hospital admissions were classified by reasons for admission.
Detailed information on all deaths was collected and all deaths were classified by reason.
B. Adverse Events Reporting
Adverse events (AEs) were defined as changes in health status that required temporary or
permanent study drug discontinuation. This ensured that only those events the investigator
thought were associated with either medication, were reported as adverse events.
22
AEs were classified by MEDRA coding, by groupings according to organ class and by
special events of interest as defined by the Principal Investigators and the DSMB based on
the profile of the study drugs used and the study population evaluated.
C. Suspected Unexpected Serious Adverse Reports (SUSAR)
Investigators were instructed to complete a suspected unexpected serious adverse reaction
(SUSARs) form for those events they deemed to be serious (i.e. resulting in death,
hospitalization or persistent or significant disability, is life-threatening or considered
medically important), were not predefined cardiovascular outcomes, were unexpected (in
terms of drug labeling and the subjects history) and were unexpected in terms of study
medication and were thought to be causally associated with either of the study medications.
Investigators were encouraged to submit SUSAR forms even when they were not certain the
event met the HOPE-3 SUSAR criteria. These events were then adjudicated centrally and
sent to regulators when pre-specified criteria were met.
23
Adjustment For Multiple Testing In HOPE-3

Prespecified analyses in the HOPE-3 trial included the testing of both co-primary
outcomes in the two factorial comparisons (the BP-lowering comparison and the
cholesterol-lowering comparison), as well as in the comparison of dual active therapy versus
dual placebo. To preserve an overall type I error rate of 5%, the first co-primary outcome
was tested at a P value of 0.04 and the second at a P value of 0.02 for each of the factorial
comparisons (considering 80% overlap between the co-primary outcomes). If either coprimary outcome reached its prespecified level of significance for the analyses in the
factorial comparisons, then a nominal P value of <0.05 would be used to test both coprimary outcomes for the comparison of dual active therapy with dual placebo. If neither
analysis reached the prespecified thresholds in the factorial comparisons, then both coprimary outcomes would be tested at a P value of 0.0044 for the comparison of dual active
therapy with dual placebo. A nominal P<0.05 was used for all other analyses.
24
Figure S1: CONSORT Diagram for the Candesartan/HCTZ versus

Placebo Comparison
14,682 included in Run-In
1,977 (13.5%) Excluded

509 (3.5%) Side effects*
844 (5.7%) Compliance <80%
483 (3.3%) Unwilling to continue
141 (1.0%) Other reasons
12,705 Randomized (86.5 %)
6,356 assigned to Candesartan/HCTZ
6,349 assigned to Placebo
6,291 primary outcome status ascertained

52 were lost to follow-up
13 withdrew consent

10 withdrew consent
6,356 were included in analysis

0 were excluded from analysis

HCTZ=hydrochlorothiazide
Vital status was ascertained at the end of follow-up in 12,587 (99.1%) participants, 6,289 in
the Candesartan/HCTZ group and 6,298 in the Placebo group.
* The most common side effects resulting in run-in failure were hypotension, N=283 (1.9%)
and abnormal laboratory values, N=252 (1.7%). Note that participants could have more than
one side effect.
25
Figure S2: CONSORT Diagram for the Rosuvastatin versus Placebo

Comparison
14,682 included in Run-In
1,977 (13.5%) Excluded

844 (5.7%) Compliance <80%
12,705 Randomized (86.5 %)
6,361 assigned to Rosuvastatin
6,344 assigned to Placebo

8 withdrew consent

15 withdrew consent


Vital status was ascertained at the end of follow up in 12,587 (99.1%) participants,
6,306 in the Rosuvastatin group and 6,281 in the Placebo group.
* The most common side effects resulting in run-in failure were hypotension, N=283
(1.9%) and abnormal laboratory values, N=252 (1.7%). Note that participants could
have more than one side effect.
26
Figure S3: CONSORT Diagram for the Double Active versus Double
Placebo Comparison
14, 682 Participants screened for eligibility
1,977 (13.5%) Excluded

844 (5.7%) Compliance <80%
12,705 were randomized (86.5%)
3,180 assigned
Cand/HCTZ Active
Rosuvastatin Active
3,181 assigned
Rosuvastatin Active
Cand/HCTZ Placebo

27 were lost to follow up
4 withdrew consent
3,176 assigned
Cand/HCTZ Active
Rosuvastatin Placebo

9 withdrew consent

4 withdrew consent
3,180 Included in
analysis
3,181 Included in
analysis
3,168 assigned
Double Placebo

6 withdrew consent
3,176 Included in
analysis
3,168 Included in
analysis
Vital status was ascertained at the end of follow up in 12,587 (99.1%) participants,
3,149 in the Double Active group, 3,157 in the Rosuvastatin Active/ Candesartan/HCTZ
Placebo group, 3140 in the Candesartan/HCTZ Active/ Rosuvastatin Placebo group and
3,141 in the Double Placebo group
* The most common side effects resulting in run-in failure were hypotension, N=283
(1.9%) and abnormal laboratory values, N=252 (1.7%). Note that participants could
have more than one side effect.
27
75
80
Placebo
Candesartan/HCTZ
70
Diastolic Blood Pressure (mmHg)
85
Figure S4: Diastolic Blood Pressure Over the Course of the Trial in the
Candesartan/HCTZ and Placebo Groups
Cand/HCTZ
Placebo
6356
6347
5907
5879
5667
5623
5446
5442
Years
5213
5185
3862
3822
1437
1424
350
334
28
Figure S5: Cumulative Incidence of Co-Primary Outcome 1 for the

Candesartan/HCTZ versus Placebo Comparison
CV Death, MI,Stroke
1.0
0.10
HR (95% CI) = 0.93 (0.79-1.10)
0.08
Cumulative Hazard Rates
0.8
P-value: 0.40
0.06
0.6
Placebo
0.04
Candesartan/HCTZ
0.02
0.4
0.0
0
0.2
0.0
0
No. at Risk
Candesartan/HCTZ
Placebo
6005
6004
5008
5008
2099
2096
530
501
Years
6356
6349
6282
6278
6216
6217
6127
6126
29
Figure S6: Cumulative Incidence of the Secondary Outcome 1 for the

Candesartan/HCTZ versus Placebo Comparison
CV death, MI, Stroke, Revascularization, Heart Failure, Resuscitated

Cardiac
Arrest, Angina
A. Secondary
Outcome
1 with Evidence of Ischemia
1.0
0.10
0.8
0.6
0.08
HR (95% CI) = 0.92 (0.79-1.06)
0.06
P-value: 0.26
Placebo
0.04
Candesartan/HCTZ
0.02
0.4
0.0
0
0.2
0.0
0
No. at Risk
Candesartan/HCTZ 6356
Placebo
6349
5948
5940
4952
4944
2068
2062
522
484
Years
6266
6259
6189
6184
6086
6073
30
Figure S7: Cumulative Incidence of Co-Primary Outcome 1 for the

Rosuvastatin versus Placebo Comparison
CV Death,MI,Stroke
1.0
0.10
0.08
0.8
0.06
Placebo
0.6
0.04
Rosuvastatin
0.02
HR (95% CI) = 0.76 (0.64-0.91)
0.4
P-value: 0.0019
0.0
0
0.2
0.0
0
3019
2987
2524
2488
1056
1041
265
244
Years
No. at Risk
Rosuvastatin
Placebo
3168
3185
3137
3140
3112
3097
3079
3054
31

Rosuvastatin versus Placebo Comparison
CV Death,MI,Stroke,Resuscitated Cardiac Arrest,Revascularization,HF,Angina

1.0
0.10
0.08
0.8
0.06
Placebo
0.6
0.04
Rosuvastatin
0.02
HR (95% CI) = 0.77 (0.66-0.89)
0.4
P-value: 0.0006
0.0
0
0.2
0.0
0
5982
5906
4993
4903
2092
2038
519
487
Years
No. at Risk
Rosuvastatin
Placebo
6361
6344
6281
6244
6215
6158
6103
6056
32
Figure S9: Cumulative Incidence of Co-Primary Outcome 1 in the

Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, CandesartanHCTZ Alone and Double Placebo Groups
CV Death,MI,Stroke
1.0
0.10
0.08
0.8
Combination
Rosuvastatin
Candesartan/HCTZ
Double Placebo
0.06
0.6
0.04
0.02
HR (95% CI) = 0.71 (0.56-0.90)

P-value: 0.0054
0.4
0.0
0
0.2
0.0
No. at Risk
Combination
Rosuvastatin
Candesartan/HCTZ
Double Placebo
3180
3181
3176
3168
3151
3145
3131
3133
3125
3116
3091
3101
3077
3076
3050
3050
3014
3025
2991
2979
2526
2520
2482
2488
1068
1054
1031
1042
276
255
254
246
Years
Cumulative hazard curves are shown for those receiving rosuvastatin + BP lowering,
rosuvastatin alone, BP lowering alone, and double placebo. The hazard ratios (HR), 95%
confidence intervals (CI), and P values are presented for the comparison between dual active
therapy (rosuvastatin + BP lowering) and dual placebo.
Rosuvastatin refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
33

Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, CandesartanHCTZ Alone and Double Placebo Groups
CV Death,MI,Stroke,Resuscitated Cardiac Arrest,Revascularization,HF,Angina

0.12
1.0
0.10
0.8
0.08
Combination
Rosuvastatin
Candesartan/HCTZ
Double Placebo
0.06
0.6
0.04
0.02
0.4
HR (95% CI) = 0.71(0.57-0.87)

P-value: 0.0012
0.0
0
0.2
0.0
No. at Risk
Combination
Rosuvastatin
Candesartan/HCTZ
Double Placebo
3180
3181
3176
3168
3144
3137
3122
3122
3112
3103
3077
3081
3054
3049
3032
3024
2987
2995
2961
2945
2500
2493
2452
2451
1053
1039
1015
1023
272
247
250
237
Years
Cumulative hazard curves are shown for those receiving rosuvastatin + BP lowering,
rosuvastatin alone, BP lowering alone, and double placebo. The hazard ratios (HR), 95%
confidence intervals (CI), and P values are presented for the comparison between dual
active therapy (rosuvastatin + BP lowering) and dual placebo.
Rosuvastatin refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
34
Figure S11A: Secondary Outcome 1 by Tertiles of Baseline Systolic Blood Pressure for the Candesartan/HCTZ versus
Placebo Comparison
CV Death, MI, Stroke, Cardiac Arrest, Revascularization, Heart Failure, Angina

BP
(mmHg)
Candesartan
/HCTZ
Placebo
Hazard Ratio (95% CI)
P Trend
no. of events / total no.(%)
Overall
6.0/3.0
335/6356 (5.3)
364/6349 (5.7)
0.92 (0.79-1.06)
131.5 (Mean=122.2)
6.1/3.1
97/2080 (4.7)
83/2122 (3.9)
1.20 (0.89-1.60)
131.6-143.5 (Mean=137.6)
5.6/2.7
109/2120 (5.1)
109/2141 (5.1)
1.01 (0.77-1.31)
>143.5 (Mean=154.1)
5.8/3.0
129/2156 (6.0)
172/2084 (8.3)
0.72 (0.57-0.90)
SBP-mmHg
0.005
0.5
1.0
2.0
Candesartan/HCTZ Placebo
Better
Better
35
Figure S11B: Secondary Outcome 2 by Tertiles of Baseline Systolic Blood Pressure for the Candesartan/HCTZ versus
Placebo Comparison
Stroke
Overall
BP
(mmHg)
Placebo
Candesartan
/HCTZ
no. of events / total no.(%)
6.0/3.0
75/6356 (1.2)
94/6349 (1.5)
P Trend
0.80 (0.59-1.08)
SBP-mmHg
0.217
131.5 (Mean=122.2) 6.1/3.1
11/2080 (0.5)
15/2122 (0.7)
0.75 (0.35-1.64)
131.6-143.5 (Mean=137.6) 5.6/2.7
32/2120 (1.5)
26/2141 (1.2)
1.24 (0.74-2.08)
>143.5 (Mean=154.1) 5.8/3.0
32/2156 (1.5)
53/2084 (2.5)
0.58 (0.37-0.90)
0.5
1.0
2.0
Better
Better
36
Figure S12: Selected Subgroup Analysis for Co-Primary Outcome 1: Candesartan/HCTZ versus Placebo Comparison
BP
(mmHg)
no. of events / total no.
P Interaction
Overall
6.0/3.0
260/6356
279/6349
0.93 (0.79-1.10)
Rosuvastatin Active
5.8/2.8
6.1/3.1
113/3180
147/3176
122/3181
157/3168
0.92 (0.72-1.19)
0.93 (0.75-1.17)
0.951
Age 65 yrs (Mean=60.4)

Age >65 yrs (Mean=70.6)
6.0/3.2
6.0/2.8
85/3053
175/3303
81/3006
198/3342
1.03 (0.76-1.39)
0.90 (0.73-1.10)
0.464
Female
Male
5.1/2.4
6.8/3.5
95/2910
165/3446
115/2964
164/3385
0.83 (0.63-1.09)
0.99 (0.80-1.23)
0.322
DBP-mmHg
78 (Mean=71.8)
78.1-86 (Mean=82.2)
>86 (Mean=92.1)
5.5/2.7
5.7/2.8
6.6/3.2
84/2135
78/2157
98/2064
96/2181
98/2146
85/2020
0.89 (0.66-1.19)
0.78 (0.58-1.06)
1.13 (0.85-1.51)
0.245
INTERHEART Risk Score

Tertile 1 12(Mean=9.3)
Tertile 2 13-16(Mean=14.5)
Tertile 3 >16(Mean=20.4)
5.5/2.8
6.1/2.7
6.3/3.4
78/2344
67/1901
115/2111
66/2391
100/1938
113/2020
1.21 (0.87-1.67)
0.68 (0.50-0.93)
0.97 (0.75-1.26)
0.479
LDL-Cmg/dl
112.3 (Mean=89.1)
112.4-141.7 (Mean=126.8)
>141.7 (Mean=166.7)
6.0/2.9
6.7/3.3
6.3/3.5
85/1928
76/1888
80/1891
83/1834
90/1891
91/1966
0.98 (0.73-1.33)
0.84 (0.62-1.14)
0.91 (0.67-1.23)
0.731
8.7/4.5
7.2/3.7
2.2/1.1
6.0/2.5
10.8/5.7
5.4/2.5
44/1284
67/1739
56/1844
53/932
19/342
14/116
50/1262
84/1757
66/1847
42/922
21/354
13/109
0.87 (0.58-1.30)
0.80 (0.58-1.10)
0.85 (0.59-1.21)
1.27 (0.85-1.90)
0.92 (0.50-1.72)
1.02 (0.48-2.18)
0.483
Ethnicity*
European descent
Latin American
Chinese
South Asian
Other Asian
Black African
0.5
1.0
2.0
Better
Better
P for interaction provided for all subgroups except DBP, Risk Score and LDL-C, in which P for trend is provided
* 197 participants of Other ethnicity
BP blood pressure; yrs years; DBP diastolic blood pressure; LDL-C low density lipoprotein cholesterol

37
Figure S13: Selected Subgroup Analysis for Co-Primary Outcome 2: Candesartan/HCTZ versus
BP
(mmHg)
P Interaction
Overall
6.0/3.0
312/6356
328/6349
0.95 (0.81-1.11)
Rosuvastatin Active
5.8/2.8
6.1/3.1
136/3180
176/3176
141/3181
187/3168
0.96 (0.76-1.22)
0.94 (0.76-1.15)
0.873
Age 65 yrs(Mean=60.4)
Age >65 yrs (Mean=70.6)
6.0/3.2
6.0/2.8
106/3053
206/3303
101/3006
227/3342
1.03 (0.78-1.35)
0.92 (0.76-1.11)
0.507
Female
Male
5.1/2.4
6.8/3.5
109/2910
203/3446
129/2964
199/3385
0.85 (0.66-1.10)
1.01 (0.83-1.22)
0.310
DBP-mmHg
78 (Mean=71.8)
78.1-86 (Mean=82.2)
>86 (Mean=92.1)
5.5/2.7
5.7/2.8
6.6/3.2
102/2135
99/2157
111/2064
113/2181
115/2146
100/2020
0.92 (0.70-1.20)
0.85 (0.65-1.11)
1.09 (0.83-1.43)
0.372

5.5/2.8
6.1/2.7
6.3/3.4
95/2344
82/1901
135/2111
86/2391
112/1938
130/2020
1.12 (0.84-1.51)
0.75 (0.56-1.00)
0.99 (0.78-1.26)
0.660
LDL-Cmg/dl
112.3 (Mean=89.1)
112.4-141.7 (Mean=126.8)
>141.7 (Mean=166.7)
6.0/2.9
6.7/3.3
6.3/3.5
96/1928
94/1888
99/1891
95/1834
106/1891
107/1966
0.97 (0.73-1.29)
0.88 (0.67-1.17)
0.96 (0.73-1.26)
0.965
8.7/4.5
7.2/3.7
2.2/1.1
6.0/2.5
10.8/5.7
5.4/2.5
54/1284
88/1739
70/1844
58/932
20/342
15/116
69/1262
100/1757
73/1847
45/922
24/354
13/109
0.77 (0.54-1.09)
0.88 (0.66-1.17)
0.96 (0.69-1.33)
1.29 (0.88-1.91)
0.85 (0.47-1.54)
1.10 (0.52-2.31)
0.494
Ethnicity*
European Descent
Latin American
Chinese
South Asian
Other Asian
Black African
0.5
1.0
2.0
Better
Better

38
Figure S14: Selected Subgroup Analysis for Co-Primary Outcome 1: Rosuvastatin versus Placebo
Comparison*
Rosuvastatin
Placebo
P Interaction*

Overall
235/6361
304/6344
0.76 (0.64-0.91)
Candesartan Active
Candesartan Placebo
113/3180
122/3181
147/3176
157/3168
0.76 (0.59-0.97)
0.77 (0.61-0.97)
0.949
70/1888
71/1865
85/1952
98/1874
95/1914
86/1905
0.70 (0.52-0.96)
0.76 (0.56-1.03)
0.96 (0.71-1.29)
0.159

57/2341
76/1904
102/2116
87/2394
91/1935
126/2015
0.66 (0.47-0.92)
0.85 (0.63-1.15)
0.77 (0.59-0.99)
0.567
CRP 2.0 (Mean=1.1)

CRP >2.0 (Mean=6.2)
112/2871
115/2905
136/2902
146/2853
0.82 (0.64-1.06)
0.77 (0.60-0.98)
0.694
SBP <=131.5 (Mean=122.2)

SBP 131.6-143.5 (Mean=137.6)
SBP >143.5 (Mean=154.1)
53/2113
75/2129
107/2119
79/2089
93/2132
132/2121
0.64 (0.46-0.91)
0.80 (0.59-1.09)
0.81 (0.63-1.05)
0.347
Age 65.3 yr (Mean=60.6)

Age >65.3 yr (Mean=70.8)
80/3192
155/3168
101/3162
203/3182
0.78 (0.59-1.05)
0.75 (0.61-0.93)
0.828
Male
Female
139/3410
96/2951
190/3421
114/2923
0.72 (0.58-0.90)
0.83 (0.64-1.09)
0.427
36/1286
53 /1854
61/1268
69/1744
16/209
58/1260
69/1837
74/1282
82/1752
21/213
0.60 (0.40-0.92)
0.76 (0.53-1.08)
0.83 (0.59-1.16)
0.84 (0.61-1.15)
0.75 (0.39-1.43)
0.777
LDL 112.3 (Mean=89.1)

LDL 112.4-141.7 (Mean=126.8)
LDL >141.7 (Mean=166.7)
Ethnicity
European Descent
Chinese
Other Asian
Latin American
Other
0.5
Rosuvastatin Better
1.0
2.0
Placebo Better
39
Figure S15: Selected Subgroup Analysis for Co-Primary Outcome 2: Rosuvastatin versus Placebo
Comparison
Rosuvastatin
Placebo
P Interaction*

Overall
277/6361
363/6344
0.75 (0.64-0.88)
Candesartan Active
Candesartan Placebo
136/3180
141/3181
176/3176
187/3168
0.76 (0.61-0.95)
0.74 (0.60-0.93)
0.876
LDL 112.3 (Mean=89.1)

LDL 112.4-141.7 (Mean=126.8)
LDL >141.7 (Mean=166.7)
79/1888
85/1865
101/1952
112/1874
115/1914
105/1905
0.69 (0.52-0.92)
0.75 (0.57-1.00)
0.93 (0.71-1.22)
0.145

72/2341
86/1904
119/2116
109/2394
108/1935
146/2015
0.66 (0.49-0.89)
0.81 (0.61-1.07)
0.77 (0.60-0.98)
0.486
CRP 2.0 (Mean=1.1)

CRP >2.0 (Mean=6.2)
128/2871
140/2905
163/2902
174/2853
0.79 (0.62-0.99)
0.78 (0.63-0.98)
0.992
SBP 131.5 (Mean=122.2)

SBP 131.6-143.5 (Mean=137.6)
SBP >143.5 (Mean=154.1)
66/2113
87/2129
124/2119
98/2089
110/2132
155/2121
0.65 (0.47-0.88)
0.79 (0.60-1.05)
0.80 (0.63-1.01)
0.335
Age 65.3 yr (Mean=60.6)

Age >65.3 yr (Mean=70.8)
98/3192
179/3168
125/3162
238/3182
0.78 (0.60-1.01)
0.74 (0.61-0.90)
0.779
Male
Female
169/3410
108/2951
233/3421
130/2923
0.72 (0.59-0.87)
0.82 (0.64-1.06)
0.404
48/1286
61/1854
66/1268
85/1744
17/209
75/1260
82/1837
81/1282
103/1752
22/213
0.62 (0.43-0.89)
0.73 (0.52-1.02)
0.82 (0.59-1.13)
0.82 (0.61-1.09)
0.76 (0.40-1.42)
0.790
Ethnicity
European Descent
Chinese
Other Asian
Latin American
Other
0.5
Rosuvastatin Better
1.0
2.0
Placebo Better
* P for interaction provided for all subgroups except LDL, Risk Score and SBP, in which P for trend is provided
LDL low density lipoprotein cholesterol in mg/dl; CRP high sensitivity C-reactive protein; SBP systolic blood pressure; yr years
40

Candesartan/HCTZ+Rosuvastatin, versus Double Placebo Comparisons
SBP LDL-C Candesartan/HCTZ

(mmHg) (mg/dL) +Rosuvastatin
Double
Placebo
P Interaction*

Overall
6.2
25.2
113/3180
157/3168
0.71 (0.56-0.90)
SBP 131.5 (Mean=122.2)

SBP 131.6-143.5 (Mean=137.6)
SBP >143.5 (Mean=154.1)
5.9
5.7
6.4
23.8
24.5
26.4
24/1059
44/1050
45/1071
33/1068
50/1062
74/1036
0.71 (0.42-1.21)
0.89 (0.59-1.33)
0.59 (0.40-0.85)
0.386
LDL 112.3 (Mean=89.1)

LDL 112.4-141.7 (Mean=126.8)
LDL >141.7 (Mean=166.7)
6.1
6.9
6.6
20.2
24.8
32.5
36/992
34/917
40/950
49/938
53/943
46/964
0.69 (0.45-1.06)
0.65 (0.42-1.00)
0.87 (0.57-1.33)
0.444

5.9
5.8
6.4
26.5
29.5
17.6
31/1158
29/942
53/1080
40/1208
53/976
64/984
0.79 (0.50-1.27)
0.56 (0.36-0.88)
0.75 (0.52-1.08)
0.980
Age 65.3 yr (Mean=60.6)

Age >65.3 yr (Mean=70.8)
5.7
6.6
23.9
26.5
37/1604
76/1576
46/1567
111/1601
0.78 (0.51-1.21)
0.68 (0.51-0.92)
0.614
Male
Female
7.2
5.0
26.7
23.3
67/1715
46/1465
92/1690
65/1478
0.71 (0.52-0.97)
0.70 (0.48-1.03)
0.980
Ethnicity
European descent
Chinese
Other Asian
Latin American
Other
8.9
2.4
7.3
6.9
9.0
49.5
14.5
0.4
25.1
39.7
16/651
23/922
31/634
32/864
11/109
30/627
36/915
33/642
47/877
11/107
0.51 (0.28-0.93)
0.63 (0.37-1.06)
0.95 (0.58-1.55)
0.68 (0.43-1.06)
0.97 (0.42-2.23)
0.514
0.5
1.0
Double Active Better
* P for interaction provided for all subgroups except SBP, LDL, and Risk Score in which P for trend is provided
SBP systolic blood pressure; LDL-C low density lipoprotein cholesterol; yr - years

2.0
Double Placebo Better
41

Candesartan/HCTZ+Rosuvastatin, versus Double Placebo Comparisons
SBP LDL-C Candesartan/HCTZ Double

(mmHg) (mg/dL) +Rosuvastatin
Placebo
P Interaction*

Overall
6.2
25.2
136/3180
187/3168
0.72 (0.57-0.89)
SBP 131.5 (Mean=122.2)

SBP 131.6-143.5 (Mean=137.6)
SBP >143.5 (Mean=154.1)
5.9
5.7
6.4
23.8
24.5
26.4
31/1059
51/1050
54/1071
39/1068
62/1062
86/1036
0.78 (0.49-1.25)
0.83 (0.57-1.20)
0.60 (0.43-0.84)
0.298
LDL 112.3 (Mean=89.1)

LDL 112.4-141.7 (Mean=126.8)
LDL >141.7 (Mean=166.7)
6.1
6.9
6.6
20.2
24.8
32.5
41/992
43/917
49/950
57/938
64/943
55/964
0.67 (0.45-1.00)
0.68 (0.46-1.00)
0.89 (0.61-1.31)
0.319

5.9
5.8
6.4
26.5
29.5
17.6
39/1158
34/942
63/1080
53/1208
60/976
74/984
0.75 (0.50-1.14)
0.58 (0.38-0.89)
0.77 (0.55-1.08)
0.821
Age 65.3 yr (Mean=60.6)

Age >65.3 yr (Mean=70.8)
5.7
6.6
23.9
26.5
46/1604
90/1576
57/1567
130/1601
0.79 (0.53-1.16)
0.69 (0.53-0.90)
0.591
Male
Female
7.2
5.0
26.7
23.3
85/1715
51/1465
115/1690
72/1478
0.72 (0.54-0.95)
0.71 (0.49-1.01)
0.936
Ethnicity
European descent
Chinese
Other Asian
Latin American
Other
8.9
2.4
7.3
6.9
9.0
49.5
14.5
0.4
25.1
39.7
20/651
30/922
34/634
41/864
11/109
41/627
42/915
37/642
56/877
11/107
0.46 (0.27-0.79)
0.70 (0.44-1.12)
0.93 (0.58-1.48)
0.73 (0.49-1.09)
0.96 (0.42-2.22)
0.374
0.5
1.0
2.0
Double Active Better Double Placebo Better
* P for interaction provided for all subgroups except SBP, LDL, and Risk Score in which P for trend is provided
SBP systolic blood pressure; LDL-C low density lipoprotein cholesterol in mg/dl; yr - years
42
Figure S18: HOPE-3 Results* in the Context Major Vascular Event Reduction versus LDL
Cholesterol in mg/dl Lowering in Randomized Controlled Trials
HOPE-3
*Co-Primary Outcome 2
HOPE-3 results plotted on the graphs created by CTT Collaboration based on individual patient data (Lancet 2005;
366:1267-78. Lancet 2010; 376: 1670-81).
43
Table S1: The Heart Outcomes Prevention Evaluation (HOPE) - 3 Trial Design
(N=12,705)
Candesartan/HCTZ
Active
Placebo
Rosuvastatin
Active
Placebo
Candesartan/HCTZ
Margins
Rosuvastatin Active/
Candesartan/HCTZ
Active
n=3,180
Rosuvastatin Active/
Candesartan/HCTZ
Placebo
n=3,181
Rosuvastatin Placebo/
Candesartan/HCTZ
Active
n=3,176
Candesartan/HCTZ
Active
n=6,356
Rosuvastatin Placebo/
Candesartan/HCTZ
Placebo
n=3,168
Candesartan/HCTZ
Placebo
n=6,349
Rosuvastatin
Margins
Rosuvastatin
Active
n=6,361
Rosuvastatin
Placebo
n=6,344
HCTZ=hydrochlorothiazide
44
Table S2: HOPE-3 Eligibility Criteria

Inclusion Criteria
Women aged 65 years* and men aged 55 years
At least one of the following additional CV risk factors:
Waist/hip ratio 0.85 in women and 0.90 in men
History of current or recent smoking (regular tobacco use within 5 years)
Low HDL-C ( HDL-C < 1.0 mmol/L in men and <1.3 mmol/L in women)
Dysglycemia (impaired fasting glucose, impaired glucose tolerance or uncomplicated diabetes treated with diet only)
Early renal dysfunction
Family history of premature coronary heart disease in first degree relatives (men < 55 years or women <65 years)
Provision of informed consent
Exclusion Criteria
Documented clinically manifest atherothrombotic CVD
Indication for statin and/or ARB, ACE inhibitor or thiazide diuretics
Contraindications for statin and/or ARB or thiazide diuretics1
Symptomatic hypotension
Chronic liver disease (cirrhosis or persistent hepatitis) or abnormal liver function (ALT or AST > 3 x ULN)
Inflammatory muscle disease (such as dermatomyositis or polymyositis) or creatine kinase (CK > 3 x ULN)
Moderate renal dysfunction defined as serum creatinine > 2.0 mg/dL (180mol/L) or eGFR <45ml/min/1.73m
Treatment with cyclosporine or fibrates
Other serious condition(s) likely to interfere with study participation or with the ability to complete the trial
Concurrent use of any experimental pharmacological agent
* women 60 years with at least two additional risk factors were also eligible
An early protocol version allowed the use of one oral hypoglycemic drug; the trial was amended in October 2008 to include those with diabetes treated
only by diet
microalbuminuria or estimated GFR<60ml/min/1.73m or creatinine >1.4mg/dL (124mol/L), unless the participant has proteinuria or BP
>130/80mmHg
Subjects with persistently elevated BP and who are considered by the recruiting /local physician to require antihypertensive therapy can be entered in
the trial after BP control is attained with lifestyle interventions or with non-study drugs such as beta-blockers, calcium channel blockers or alpha
blockers. Subjects on lipid lowering therapy other than a statin or a fibrate can also be considered for the trial.
45
Table S3: Adherence to Study Drug and Open Label Use of ARBs, ACE-Is and Thiazides in the
A. Candesartan
Candesartan/HCTZ
On Open Label
On Study Drug
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
Cand/HCTZ
N (%)
ARB
N (%)
ACE-I
N (%)
Thiazide
N (%)
6314
6267
6205
6101
4854
5990
5567(88.2)
5374(85.8)
5189(83.6)
4967(81.4)
3639(75.0)
4599(76.8)
14(0.2)
28(0.4)
45(0.7)
52(0.9)
60(1.2)
93(1.6)
24(0.4)
41(0.7)
48(0.8)
59(1.0)
66(1.4)
100 (1.7)
1(0)
10(0.2)
15(0.2)
30(0.5)
30(0.6)
47(0.8)
Other BP Lowering
Drug(s)*
N (%)
1011(16.5)
1068(18.2)
B. Placebo
Placebo
Visit
Eligible
6306
6262
6188
6089
4818
5985
On Study Drug
Cand/HCTZ
Placebo
N (%)
5545(87.9)
5359(85.6)
5161(83.4)
4953(81.3)
3588 (74.5)
4530(75.7)
On Open Label
ARB
N (%)
ACE-I
N (%)
Thiazide
N (%)
30(0.5)
66(1.1)
76(1.2)
106(1.7)
104(2.2)
146(2.4)
48(0.8)
67(1.1)
82(1.3)
102(1.7)
110(2.3)
137(2.3)
9(0.1)
27(0.4)
45(0.7)
57(0.9)
57(1.2)
79 (1.3)
Other BP Lowering
Drug(s)*
N (%)
1514(24.7)
1688(28.8)
* measured only at 2 years and end of study
46
Table S4: Adherence to Study Drug and Open Label Use of Statins and Other Lipid Lowering Drugs
in the Rosuvastatin and Placebo Groups
A. Rosuvastatin
On Drug
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
Rosuvastatin
N (%)
6327
6286
6223
6118
4870
6014
5565 (88.0)
5384 (85.7)
5196 (83.5)
4961 (81.1)
3678 (75.5)
4649 (77.3)
Rosuvastatin
On Open Label
Other Lipid Lowering
Statin
Drugs
N (%)
N (%)
35 (0.6)
17 (0.3)
62 (1.0)
17 (0.3)
103 (1.7)
20 (0.3)
124 (2.0)
31 (0.5)
120 (2.5)
33 (0.7)
163 (2.7)
32 (0.5)
B. Placebo
Placebo
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
6293
6243
6170
6072
4802
5961
On Drug
Rosuvastatin
Placebo
N (%)
5528 (87.8)
5312 (85.1)
5121 (83.0)
4879 (80.4)
3515 (73.2)
4457 (74.8)
Statin
N (%)
76 (1.2)
152 (2.4)
203 (3.3)
265 (4.4)
270 (5.6)
370 (6.2)
On Open Label
Other Lipid Lowering
Drugs
N (%)
20 (0.3)
45 (0.7)
64 (1.0)
87 (1.4)
70 (1.5)
76 (1.3)
47
Table S5: Adherence to Study Drug and Open Label Use of ARBs, ACE-Is, Thiazides and Statins in
the Candesartan/HCTZ+Rosuvastatin and the Double Placebo Groups
A. Candesartan/HCTZ + Rosuvastatin (Double Active)
On Open Label
N (%)
On Study Drug
N (%)
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
3164
3144
3114
3056
2438
3008
Both
Candesartan/HCTZ
and Rosuvastatin
2728 (86.2)
2627 (83.6)
2519 (80.9)
2400 (78.5)
1762 (72.3)
2245 (74.6)
Only
Candesartan/HCTZ
Only
Rosuvastatin
ARB
ACE-I
Thiazide
Other BP*
Statin
47 (1.5)
44 (1.4)
50 (1.6)
51 (1.7)
39 (1.6)
45 (1.5)
53 (1.7)
49 (1.6)
58 (1.9)
59 (1.9)
69 (2.8)
87 (2.9)
8 (0.3)
10 (0.3)
23 (0.7)
25 (0.8)
30 (1.2)
42 (1.4)
11 (0.3)
21 (0.7)
22 (0.7)
31 (1.0)
38 (1.6)
47 (1.6)
1 (0)
2 (0.1)
9 (0.3)
14 (0.5)
14 (0.6)
23 (0.8)
489 (15.9)
518 (17.6)
16 (0.5)
31 (1.0)
50 (1.6)
61 (2.0)
62 (2.5)
77 (2.6)
B. Double Placebo
On Open Label
N (%)
On Study Drug
N (%)
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
3143
3120
3079
3027
2386
2979
Both
Candesartan/HCTZ
and Rosuvastatin
Placebo
2700 (85.9)
2598 (83.3)
2489 (80.8)
2367 (78.2)
1666 (69.8)
2140 (71.8)
Only
Candesartan/HCTZ
Placbeo
Only
Rosuvastatin
Placebo
ARB
ACE-I
Thiazide
Other BP*
Statin
53 (1.7)
60 (1.9)
72 (2.3)
102 (3.4)
99 (4.1)
103 (3.5)
47 (1.5)
36 (1.2)
44 (1.4)
40 (1.3)
52 (2.2)
48 (1.6)
20 (0.6)
38 (1.2)
42 (1.4)
62 (2.0)
58 (2.4)
78 (2.6)
24 (0.8)
38 (1.2)
38 (1.2)
48 (1.6)
62 (2.6)
79 (2.7)
4 (0.1)
13 (0.4)
21 (0.7)
32 (1.1)
33 (1.4)
42 (1.4)
744 (24.4)
836 (28.7)
38 (1.2)
87 (2.8)
105 (3.4)
147 (4.9)
150 (6.3)
196 (6.6)
*measured only at baseline two years and end of study; beta blockers or calcium channel blockers were used by 448 (14.6) at 2
years and 478 (16.2) at study end
measured only at baseline two years and end of study; beta blockers or calcium channel blockers were used by 705 (23.1) at
2 years and 794 (27.2) at study end
48
Table S6: Predefined Safety Outcomes in Candesartan/HCTZ and Placebo Groups
Cancer
Myopathy
Rhabdomyolysis
Hospitalizations Cardiovascular
Hospitalizations Non-cardiovascular
Total Hospitalizations
Candesartan/HCTZ
N=6,356
N (%)
277 (4.4)
1 (0)
0
319 (5.0)
899 (14.1)
1112 (17.5)
Placebo
N=6,349
N (%)
276 (4.3)
1 (0)
1 (0)
331 (5.2)
861 (13.6)
1079 (17.0)
P value
1.0
1.0
0.50
0.63
0.34
0.47
49
Table S7: Reasons for Hospitalization in the Candesartan/HCTZ and Placebo Groups
Cardiovascular Hospitalizations
Myocardial infarction
Stroke
Transient ischemic attack
Congestive heart failure
Unstable/new/worsening angina
Cardiac arrest
Supraventricular arrhythmia
Sustained ventricular tachycardia/arrhythmia
Pulmonary embolism
Coronary angiography
CABG
Percutaneous Coronary Intervention
Peripheral angioplasty/stent/abdominal aortic
aneurysm/other vascular surgery
Carotid angioplasty/stent/surgery
Limb amputation due to vascular insufficiency
Valve surgery
Other cardiovascular
Non-cardiovascular hospitalizations
Eye complications
Laser treatment/vitrectomy
Limb/foot infections
Other diabetic issues
Cancer
Injury
Fractures
Renal transplant
Renal dialysis
Hematologic
Sepsis
Candesartan/HCTZ
N=6,356
N (%)
1112 (17.5)
319 (5.0)
47 (0.7)
78 (1.2)
13 (0.2)
24 (0.4)
41 (0.6)
6 (0.1)
37 (0.6)
6 (0.1)
9 (0.1)
53 (0.8)
18 (0.3)
40 (0.6)
Placebo
N=6,349
N (%)
1079 (17.0)
331 (5.2)
63 (1.0)
90 (1.4)
13 (0.2)
22 (0.3)
44 (0.7)
13 (0.2)
37 (0.6)
8 (0.1)
10 (0.2)
67 (1.1)
19 (0.3)
52 (0.8)
6 (0.1)
4 (0.1)
0.75
3 (0)
2 (0)
9 (0.1)
76 (1.2)
899 (14.1)
1 (0)
1 (0)
4 (0.1)
10 (0.2)
160 (2.5)
28 (0.4)
73 (1.1)
0
2 (0)
7 (0.1)
27 (0.4)
1 (0)
0
9 (0.1)
67 (1.1)
861 (13.6)
4 (0.1)
2 (0)
3 (0)
5 (0.1)
172 (2.7)
32 (0.5)
75 (1.2)
0
4 (0.1)
12 (0.2)
18 (0.3)
0.62
0.5
1.0
0.50
0.34
0.22
0.62
1.0
0.30
0.51
0.61
0.87
P value
0.47
0.63
0.13
0.35
1.0
0.88
0.75
0.11
1.0
0.61
0.82
0.20
0.87
0.21
0.45
0.26
0.23
50
Psychiatric
Genito-urinary
Gastrointestinal
Other non-cardiovascular
Candesartan/HCTZ
N=6,356
N (%)
3 (0)
80 (1.3)
116 (1.8)
579 (9.1)
Placebo
N=6,349
N (%)
5 (0.1)
88 (1.4)
113 (1.8)
545 (8.6)
P value
0.51
0.54
0.89
0.30
51
Table S8: Causes of Death in the Candesartan/HCTZ and Placebo Groups*
Total death
Cardiovascular death
Non cardiovascular death
Cancer
Pulmonary
Gastrointestinal
Hepatobiliary
Sepsis
Infection
Accidental/Trauma
Suicide
Drug overdose
Renal
Other
Candesartan/HCTZ
N=6,356
N (%)
342 (5.4)
155 (2.4)
187 (2.9)
110 (1.7)
20 (0.3)
12 (0.2)
1 (0)
4 (0.1)
11 (0.2)
16 (0.3)
1 (0)
0
3 (0)
9 (0.1)
Placebo
N=6,349
N (%)
349 (5.5)
170 (2.7)
179 (2.8)
112 (1.8)
17 (0.3)
4 (0.1)
0
6 (0.1)
18 (0.3)
12 (0.2)
2 (0)
0
1 (0)
7 (0.1)
* Note this is not a prespecified safety outcome; total mortality is a predefined adjudicated efficacy outcome. We provide a
listing of causes of death with details on the causes of non-cardiovascular death to further describe the safety in out trial.
52
Permanent Study Drug Discontinuations

Social circumstances
Dizziness/lightheadedness/ hypotension
Syncope
Renal dysfunction/potassium
Acute kidney injury
Gastrointestinal disorders
Gout
Angioedema
Muscle related (all)
Anemia
Rhabdomyolysis or Myopathy
Liver function abnormality
Neuropsychological abnormalities
New diabetes/glycemia
Lipid abnormality
Cancer
Cataract
Candesartan/HCTZ
N=6,356
N (%)
1552 (24.4)
1072 (16.9)
217 (3.4)
7 (0.1)
32 (0.5)
0
28 (0.4)
2 (0)
1 (0)
39 (0.6)
1 (0)
0
3 (0)
25 (0.4)
13 (0.2)
23 (0.4)
56 (0.9)
1 (0)
Placebo
N=6,349
N (%)
1598 (25.2)
1128 (17.8)
130 (2.0)
4 (0.1)
20 (0.3)
0
33 (0.5)
2 (0)
1 (0)
30 (0.5)
1 (0)
0
7 (0.1)
26 (0.4)
8 (0.1)
28 (0.4)
53 (0.8)
3 (0)
P value
0.33
0.18
<0.0001
0.55
0.13
0.52
1.00
1.00
0.33
1.00
0.23
0.89
0.38
0.49
0.85
0.37
53
Temporary Study Drug Discontinuations

Syncope
Acute kidney injury
Gout
Angioedema
Anemia
Lipid abnormality
Cancer
Cataract
Candesartan/HCTZ
N=6,356
N (%)
1654 (26.0)
494 (7.8)
171 (2.7)
5 (0.1)
10 (0.2)
0
54 (0.8)
0
0
23 (0.4)
2 (0)
0
1 (0)
8 (0.1)
1 (0)
2 (0)
6 (0.1)
7 (0.1)
Placebo
N=6,349
N (%)
1551 (24.4)
483 (7.6)
82 (1.3)
1 (0)
6 (0.1)
0
63 (1.0)
1 (0)
1 (0)
22 (0.3)
2 (0)
0
2 (0)
8 (0.1)
0
5 (0.1)
11 (0.2)
5 (0.1)
P value
0.04
0.74
<0.0001
0.22
0.45
0.41
0.50
0.50
1.0
1.0
0.63
1.0
1.0
0.29
0.24
0.77
54
Candesartan/HCTZ and Placebo Groups*
Total Patients with Reported SUSAR

Blood pressure abnormalities
Diabetes/glycemia
Dizziness/syncope/presyncope
Blood and lymphatic system disorders
Cardiac disorders
Congenital, familial and genetic disorders
Ear and labyrinth disorders
Endocrine disorders
Eye disorders
General disorders & administration site conditions
Hepatobiliary disorders
Immune system disorders
Infections and infestations
Injury, poisoning and procedural complications
Investigations
Metabolism and nutrition disorders
Musculoskeletal and connective tissue disorders
Neoplasms benign, malignant and unspecified
Nervous system disorders
Psychiatric disorders
Renal and urinary disorders
Reproductive system and breast disorders
Respiratory, thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
Surgical and medical procedures
Vascular disorders
Candesartan/HCTZ
N=6,356
N (%)
93 (1.5)
3 (0)
1 (0)
5 (0.1)
2 (0)
9 (0.1)
1 (0)
0
1 (0)
2 (0)
11 (0.2)
11 (0.2)
1 (0)
0
8 (0.1)
9 (0.1)
3 (0)
5 (0.1)
5 (0.1)
14 (0.2)
4 (0.1)
3 (0)
6 (0.1)
2 (0)
5 (0.1)
4 (0.1)
4 (0.1)
1 (0)
Placebo
N=6,349
N (%)
90 (1.4)
3 (0)
2 (0)
3 (0)
0
13 (0.2)
0
1 (0)
0
1 (0)
0
15 (0.2)
7 (0.1)
1 (0)
14 (0.2)
7 (0.1)
1 (0)
3 (0)
4 (0.1)
7 (0.1)
8 (0.1)
3 (0)
4 (0.1)
1 (0)
2 (0)
1 (0)
5 (0.1)
2 (0)
P value
0.88
1.0
0.62
0.73
0.5
0.40
1.0
0.50
1.0
1.0
0
0.44
0.04
0.50
0.21
0.80
0.62
0.73
1.0
0.19
0.27
1.0
0.75
1.0
0.45
0.37
0.75
0.62
* none were confirmed on central adjudication as meeting the criteria for SUSARs
55
Table S12: Causes of Death in the Rosuvastatin and Placebo Groups*
Total death
Cancer
Pulmonary
Gastrointestinal
Hepatobiliary
Sepsis
Infection
Accidental/Trauma
Suicide
Drug overdose
Renal
Other
Rosuvastatin
N=6,361
N (%)
334 (5.3)
154 (2.4)
180 (2.8)
108 (1.7)
20 (0.3)
8 (0.1)
1 (0)
5 (0.1)
17 (0.3)
12 (0.2)
2 (0)
0
0
7 (0.1)
Placebo
N=6,344
N (%)
357 (5.6)
171 (2.7)
186 (2.9)
114 (1.8)
17 (0.3)
8 (0.1)
0
5 (0.1)
12 (0.2)
16 (0.3)
1 (0)
0
4 (0.1)
9 (0.1)
* Note this is not a safety outcome; total mortality is a predefined adjudicated efficacy outcome. We provide a listing of
causes of death with details on the causes of non-cardiovascular death to further describe the safety in out trial.
56
Table S13: Predefined Safety Outcomes in the Rosuvastatin and Placebo Groups
Cancer
Myopathy
Rhabdomyolysis
Rosuvastatin
N=6,361
N (%)
267 (4.2)
1 (0)
1 (0)
281 (4.4)
881 (13.9)
1066 (16.8)
Placebo
N=6,344
N (%)
286 (4.5)
1 (0)
0
369 (5.8)
879 (13.9)
1125 (17.7)
P value
0.41
1.0
1.0
0.0004
1.0
0.15
57
Table S14: Reasons for Hospitalization in the Rosuvastatin and Placebo Groups
Stroke
Cardiac arrest
Sustained ventricular tachycardia/arrhythmia
Pulmonary embolism
CABG
Percutaneous Coronary Intervention
Peripheral angioplasty/stent/abdominal aortic
aneurysm/other vascular surgery
Limb amputation due to vascular insufficiency
Valve surgery
Eye complications
Cancer
Injury
Fractures
Renal transplant
Renal dialysis
Hematologic
Sepsis
Rosuvastatin
N=6,361
N (%)
1066 (16.8)
281 (4.4)
46 (0.7)
68 (1.1)
14 (0.2)
19 (0.3)
38 (0.6)
7 (0.1)
32 (0.5)
6 (0.1)
8 (0.1)
54 (0.8)
13 (0.2)
34 (0.5)
Placebo
N=6,344
N (%)
1125 (17.7)
369 (5.8)
64 (1.0)
100 (1.6)
12 (0.2)
27 (0.4)
47 (0.7)
12 (0.2)
42 (0.7)
8 (0.1)
11 (0.2)
66 (1.0)
24 (0.4)
58 (0.9)
6 (0.1)
4 (0.1)
0.75
2 (0)
1 (0)
9 (0.1)
65 (1.0)
881 (13.9)
5 (0.1)
3 (0)
6 (0.1)
8 (0.1)
165 (2.6)
30 (0.5)
69 (1.1)
0
2 (0)
13 (0.2)
24 (0.4)
2 (0)
1 (0)
9 (0.1)
78 (1.2)
879 (13.9)
0 (0)
0 (0)
1 (0)
7 (0.1)
167 (2.6)
30 (0.5)
79 (1.2)
0 (0)
4 (0.1)
6 (0.1)
21 (0.3)
1.0
1.0
1.0
0.28
1.0
0.06
0.25
0.12
1.0
0.91
1.0
0.41
P value
0.15
0.0004
0.09
0.01
0.84
0.24
0.33
0.26
0.25
0.61
0.50
0.27
0.07
0.01
0.45
0.17
0.77
58
Psychiatric
Genito-urinary
Gastrointestinal
Rosuvastatin
N=6,361
N (%)
2 (0)
81 (1.3)
116 (1.8)
567 (8.9)
Placebo
N=6,344
N (%)
6 (0.1)
87 (1.4)
113 (1.8)
557 (8.8)
P value
0.18
0.64
0.89
0.80
59
Table S15: Adverse Events Leading to Permanent Study Drug Discontinuations in the Rosuvastatin
and Placebo Groups

Syncope
Acute kidney injury
Gout
Angioedema
Anemia
Lipid abnormality
Cancer
Cataract
Rosuvastatin
N=6,361
N (%)
1510 (23.7)
1104 (17.4)
80 (1.3)
2 (0)
16 (0.3)
0
44 (0.7)
2 (0)
1 (0)
83 (1.3)
2 (0)
2 (0.1)
16 (0.3)
25 (0.4)
10 (0.2)
123 (1.9)
50 (0.8)
3 (0)
Placebo
N=6,344
N (%)
1664 (26.2)
1088 (17.2)
90 (1.4)
5 (0.1)
11 (0.2)
0
41 (0.6)
0
1 (0)
76 (1.2)
0
1 (0)
9 (0.1)
29 (0.5)
19 (0.3)
284 (4.5)
57 (0.9)
1 (0)
P value
0.001
0.76
0.44
0.29
0.44
0.83
0.50
1.0
0.63
0.50
1.0
0.23
0.59
0.10
<0.0001
0.50
0.62
60
Table S16: Adverse Events Leading to Temporary Study Drug Discontinuations in the Rosuvastatin
and Placebo Groups

Syncope
Acute kidney injury
Gout
Angioedema
Anemia
Lipid abnormality
Cancer
Cataract
Rosuvastatin
N=6,361
N (%)
1643 (25.8)
517 (8.1)
88 (1.4)
1 (0)
8 (0.1)
0
79 (1.2)
0
1 (0)
84 (1.3)
4 (0.1)
0
9 (0.1)
17 (0.3)
3 (0)
26 (0.4)
5 (0.1)
8 (0.1)
Placebo
N=6,344
N (%)
1633 (25.7)
480 (7.6)
77 (1.2)
3 (0)
3 (0)
0
51 (0.8)
0
1 (0)
41 (0.6)
1 (0)
0
5 (0.1)
18 (0.3)
2 (0)
70 (1.1)
8 (0.1)
8 (0.1)
P value
0.92
0.25
0.43
0.37
0.23
0.02
1.0
0.0001
0.37
0.42
0.87
1.0
<0.0001
0.42
1.0
61
Table S17: Reported Serious Unexpected Suspected Adverse Reactions (SUSARS) in the Rosuvastatin
and Placebo Groups*
Total Patients with Reported SUSAR

Diabetes/glycemia
Cardiac disorders
Endocrine disorders
Eye disorders
Investigations
Vascular disorders
* none confirmed
Rosuvastatin
N=6,361
N (%)
91 (1.4)
3 (0)
1 (0)
5 (0.1)
2 (0)
9 (0.1)
0
0
0
3 (0)
6 (0.1)
14 (0.2)
4 (0.1)
1 (0)
12 (0.2)
8 (0.1)
2 (0)
4 (0.1)
6 (0.1)
12 (0.2)
5 (0.1)
1 (0)
4 (0.1)
2 (0)
3 (0)
4 (0.1)
5 (0.1)
0
Placebo
N=6,344
N (%)
92 (1.5)
3 (0)
2 (0)
3 (0)
0
13 (0.2)
1 (0)
1 (0)
1 (0)
0
5 (0.1)
12 (0.2)
4 (0.1)
0
10 (0.2)
8 (0.1)
2 (0)
4 (0.1)
3 (0)
9 (0.1)
7 (0.1)
5 (0.1)
6 (0.1)
1 (0)
4 (0.1)
1 (0)
4 (0.1)
3 (0)
P value
0.94
1.0
0.62
0.73
0.50
0.40
0.50
0.50
0.50
0.25
1.0
0.84
1.0
1.0
0.83
1.0
1.0
1.0
0.51
0.66
0.58
0.12
0.55
1.0
0.73
0.37
1.0
0.12
62
Table S18: Causes of Death in the Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone,

Candesartan/HCTZ Alone and Double Placebo Broups*
Total death
Cancer
Pulmonary
Gastrointestinal
Hepatobiliary
Sepsis
Infection
Accidental/Trauma
Suicide
Drug overdose
Renal
Other
Candesartan/HCTZ+
Rosuvastatin
N=3,180
N (%)
163 (5.1)
75 (2.4)
88 (2.8)
55 (1.7)
10 (0.3)
6 (0.2)
1 (0)
2 (0.1)
5 (0.2)
7 (0.2)
1 (0)
0
0
1 (0)
Rosuvastatin
Alone
N=3,181
N (%)
171 (5.4)
79 (2.5)
92 (2.9)
53 (1.7)
10 (0.3)
2 (0.1)
0
3 (0.1)
12 (0.4)
5 (0.2)
1 (0)
0
0
6 (0.2)
Candesartan/HCTZ
Alone
N=3,176
N (%)
179 (5.6)
80 (2.5)
99 (3.1)
55 (1.7)
10 (0.3)
6 (0.2)
0
2 (0.1)
6 (0.2)
9 (0.3)
0
0
3 (0.1)
8 (0.3)
Double
Placebo
N=3,168
N (%)
178 (5.6)
91 (2.9)
87 (2.7)
59 (1.9)
7 (0.2)
2 (0.1)
0
3 (0.1)
6 (0.2)
7 (0.2)
1 (0)
0
1 (0)
1 (0)
* Note this is not a safety outcome; total mortality is a predefined adjudicated efficacy outcome. We provide a listing of
causes of death with details on the causes of non-cardiovascular death to further describe the safety in out trial.
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
63
Table S19: Predefined Safety Outcomes in the Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone,

Candesartan/HCTZ Alone and Double Placebo Groups
Cancer
Myopathy
Rhabdomyolysis
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
135 (4.2)
1 (0)
0
141 (4.4)
463 (14.6)
560 (17.6)
Rosuvastatin
Alone
N=3,181
N (%)
132 (4.1)
0
1 (0)
140 (4.4)
418 (13.1)
506 (15.9)
Candesartan/
HCTZ Alone
N=3,176
N (%)
142 (4.5)
0
0
178 (5.6)
436 (13.7)
552 (17.4)
Double
Placebo
N=3,168
N (%)
144 (4.5)
1 (0)
0
191 (6.0)
443 (14.0)
573 (18.1)
P
value*
0.58
1.0
0.005
0.52
0.62
* P values refer to the comparison of the double active to the double placebo
64
Table S20: Reasons for Hospitalization in the Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone,

Stroke
Cardiac arrest
Sustained ventricular
tachycardia/arrhythmia
Pulmonary embolism
CABG
Percutaneous Coronary
Intervention
Peripheral
angioplasty/stent/abdominal
aortic aneurysm/other vascular
surgery
Limb amputation due to vascular
insufficiency
Valve surgery
Eye complications
Candesartan/HCTZ+
Rosuvastatin
N=3,180
N (%)
560 (17.6)
141 (4.4)
20 (0.6)
31 (1.0)
5 (0.2)
11 (0.3)
20 (0.6)
2 (0.1)
20 (0.6)
Rosuvastatin
Alone
N=3,181
N (%)
506 (15.9)
140 (4.4)
26 (0.8)
37 (1.2)
9 (0.3)
8 (0.3)
18 (0.6)
5 (0.2)
12 (0.4)
Candesartan/HCTZ
Alone
N=3,176
N (%)
552 (17.4)
178 (5.6)
27 (0.9)
47 (1.5)
8 (0.3)
13 (0.4)
21 (0.7)
4 (0.1)
17 (0.5)
Double
Placebo
N=3,168
N (%)
573 (18.1)
191 (6.0)
37 (1.2)
53 (1.7)
4 (0.1)
14 (0.4)
26 (0.8)
8 (0.3)
25 (0.8)
3 (0.1)
3 (0.1)
3 (0.1)
5 (0.2)
0.51
5 (0.2)
28 (0.9)
8 (0.3)
3 (0.1)
26 (0.8)
5 (0.2)
4 (0.1)
25 (0.8)
10 (0.3)
7 (0.2)
41 (1.3)
14 (0.4)
0.58
0.12
0.21
14 (0.4)
20 (0.6)
26 (0.8)
32 (1.0)
0.01
4 (0.1)
2 (0.1)
2 (0.1)
2 (0.1)
0.69
2 (0.1)
1 (0)
1 (0)
1.0
1 (0)
1 (0)
1.0
2 (0.1)
36 (1.1)
463 (14.6)
1 (0)
1 (0)
4 (0.1)
7 (0.2)
29 (0.9)
418 (13.1)
4 (0.1)
2 (0.1)
2 (0.1)
7 (0.2)
40 (1.3)
436 (13.7)
0
0
0
2 (0.1)
38 (1.2)
443 (14.0)
0
0
1 (0)
1.0
0.82
0.52
1.0
1.0
0.37
P value
0.62
0.005
0.02
0.02
1.0
0.56
0.38
0.06
0.46
65

Cancer
Injury
Fractures
Renal transplant
Renal dialysis
Hematologic
Sepsis
Psychiatric
Genito-urinary
Gastrointestinal
Candesartan/HCTZ+
Rosuvastatin
N=3,180
N (%)
5 (0.2)
84 (2.6)
18 (0.6)
41 (1.3)
0
0
5 (0.2)
11 (0.3)
2 (0.1)
37 (1.2)
59 (1.9)
296 (9.3)
Rosuvastatin
Alone
N=3,181
N (%)
3 (0.1)
81 (2.5)
12 (0.4)
28 (0.9)
0
2 (0.1)
8 (0.3)
13 (0.4)
0
44 (1.4)
57 (1.8)
271 (8.5)
Candesartan/HCTZ
Alone
N=3,176
N (%)
5 (0.2)
76 (2.4)
10 (0.3)
32 (1.0)
0
2 (0.1)
2 (0.1)
16 (0.5)
1 (0)
43 (1.4)
57 (1.8)
282 (8.9)
Double
Placebo
N=3,168
N (%)
2 (0.1)
91 (2.9)
20 (0.6)
47 (1.5)
0
2 (0.1)
4 (0.1)
5 (0.2)
5 (0.2)
44 (1.4)
56 (1.8)
274 (8.6)
P value
0.45
0.59
0.75
0.52
0.25
1.0
0.21
0.29
0.44
0.85
0.38
* P values refer to the comparison of the double active to the double placebo
66
Table S21A: Adverse Events Leading to Permanent Study Drug Discontinuation of

Candesartan/HCTZ or Candesartan/HCTZ Placebo ONLY in the Candesartan/HCTZ+Rosuvastatin,
Rosuvastatin Alone, Candesartan/HCTZ Alone and Double Placebo Groups

Syncope
Acute kidney injury
Gout
Angioedema
Anemia
Lipid abnormality
Cancer
Cataract
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
90 (2.8)
31 (1.0)
67 (2.1)
2 (0.1)
7 (0.2)
0
1 (0)
0
0
0
0
0
0
1 (0)
3 (0.1)
2 (0.1)
1 (0)
0
Rosuvastatin
Alone
N=3,181
N (%)
73 (2.3)
27 (0.8)
40 (1.3)
1 (0)
4 (0.1)
0
3 (0.1)
0
0
3 (0.1)
0
0
0
1 (0)
0
1 (0)
1 (0)
1 (0)
Candesartan/
HCTZ Alone
N=3,176
N (%)
68 (2.1)
26 (0.8)
60 (1.9)
2 (0.1)
12 (0.4)
0
2 (0.1)
2 (0.1)
0
4 (0.1)
0
0
0
1 (0)
0
0
2 (0.1)
0
Double
Placebo
N=3,168
N (%)
50 (1.6)
27 (0.9)
22 (0.7)
1 (0)
5 (0.2)
0
0
0
0
2 (0.1)
0
0
0
0
0
0
2 (0.1)
0
67
Table S21B: Adverse Events Leading to Permanent Study Drug Discontinuation of Rosuvastatin or
Rosuvastatin Placebo ONLY in the Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone,

Syncope
Acute kidney injury
Gout
Angioedema
Anemia
Lipid abnormality
Cancer
Cataract
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
49 (1.5)
21 (0.7)
3 (0.1)
1 (0)
1 (0)
0
10 (0.3)
0
0
27 (0.8)
0
1 (0)
3 (0.1)
1 (0)
0
50 (1.6)
1 (0)
0
Rosuvastatin
Alone
N=3,181
N (%)
46 (1.4)
23 (0.7)
1 (0)
0
1 (0)
0
8 (0.3)
0
0
26 (0.8)
0
1 (0)
4 (0.1)
2 (0.1)
2 (0.1)
59 (1.9)
2 (0.1)
1 (0)
Candesartan/
HCTZ Alone
N=3,176
N (%)
104 (3.3)
26 (0.8)
5 (0.2)
0
0
0
6 (0.2)
0
0
25 (0.8)
0
0
4 (0.1)
2 (0.1)
6 (0.2)
123 (3.9)
1 (0)
0
Double
Placebo
N=3,168
N (%)
106 (3.3)
33 (1.0)
3 (0.1)
1 (0)
1 (0)
0
6 (0.2)
0
0
21 (0.7)
0
1 (0)
4 (0.1)
1 (0)
3 (0.1)
127 (4.0)
0
0
68
Table S21C: Adverse Events Leading to Permanent Study Drug Discontinuation of Both
Candesartan/HCTZ and Rosuvastatin or Their Placebos in the Candesartan/HCTZ+Rosuvastatin,

Syncope
Acute kidney injury
Gout
Angioedema
Anemia
Lipid abnormality
Cancer
Cataract
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
697 (21.9)
518 (16.3)
48 (1.5)
1 (0.1)
6 (0.2)
0
10 (0.3)
0
0
18 (0.6)
1 (0)
0
3 (0.1)
10 (0.3)
5 (0.2)
9 (0.3)
28 (0.9)
0
Rosuvastatin
Alone
N=3,181
N (%)
718 (22.6)
542 (17.0)
28 (0.9)
0
8 (0.3)
0
16 (0.5)
2 (0.1)
1 (0)
12 (0.4)
1 (0)
0
6 (0.2)
12 (0.4)
3 (0.1)
5 (0.2)
19 (0.6)
2 (0.1)
Candesartan/
HCTZ Alone
N=3,176
N (%)
697 (21.9)
497 (15.6)
42 (1.3)
2 (0.1)
7 (0.2)
0
15 (0.5)
0
1 (0)
17 (0.5)
0
0
0
13 (0.4)
5 (0.2)
12 (0.4)
25 (0.8)
1 (0)
Double
Placebo
N=3,168
N (%)
757 (23.9)
532 (16.8)
40 (1.3)
2 (0.1)
3 (0.1)
0
14 (0.4)
0
0
13 (0.4)
0
0
1 (0)
13 (0.4)
5 (0.2)
22 (0.7)
31 (1.0)
0
69
Table S22A: Adverse Events Leading to Temporary Study Drug Discontinuation of

Candesartan/HCTZ or Candesartan/HCTZ Placebo ONLY in the Candesartan/HCTZ+Rosuvastatin,

Syncope
Acute kidney injury
Gout
Angioedema
Anemia
New diabetes/dysglycemia
Lipid abnormality
Cancer
Cataract
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
84 (2.6)
23 (0.7)
56 (1.8)
2 (0.1)
5 (0.2)
0
0
0
0
2 (0.1)
0
0
0
0
0
0
0
0
Rosuvastatin
Alone
N=3,181
N (%)
61 (1.9)
18 (0.6)
18 (0.6)
0
1 (0)
0
2 (0.1)
1 (0)
0
0
0
0
0
3 (0.1)
0
1 (0)
1 (0)
1 (0)
Candesartan/
HCTZ Alone
N=3,176
N (%)
73 (2.3)
26 (0.8)
25 (0.8)
1 (0)
1 (0)
0
1 (0)
0
0
1 (0)
0
0
0
0
0
1 (0)
1 (0)
0
Double
Placebo
N=3,168
N (%)
66 (2.1)
23 (0.7)
16 (0.5)
0
2 (0.1)
0
5 (0.2)
0
0
4 (0.1)
0
0
1 (0)
2 (0.1)
0
0
2 (0.1)
0
70
Table S22B: Adverse Events Leading to Temporary Study Drug Discontinuation of Rosuvastatin or
Rosuvastatin Placebo ONLY in the Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone,

Syncope
Acute kidney injury
Gout
Angioedema
Anemia
New diabetes/dysglycemia
Lipid abnormality
Cancer
Cataract
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
89 (2.8)
39 (1.2)
9 (0.3)
0
2 (0.1)
0
4 (0.1)
0
0
35 (1.1)
1 (0)
0
3 (0.1)
1 (0)
1 (0)
14 (0.4)
0
2 (0.1)
Rosuvastatin
Alone
N=3,181
N (%)
93 (2.9)
17 (0.5)
4 (0.1)
0
1(0)
0
10 (0.3)
0
0
26 (0.8)
0
0
4 (0.1)
0
1 (0)
11 (0.3)
0
1 (0)
Candesartan/
HCTZ Alone
N=3,176
N (%)
94 (3.0)
28 (0.9)
8 (0.3)
0
0
0
3 (0.1)
0
1 (0)
16 (0.5)
0
0
4 (0.1)
0
1 (0)
33 (1.0)
0
1 (0)
Double
Placebo
N=3,168
N (%)
79 (2.5)
26 (0.8)
5 (0.2)
1 (0)
1 (0)
0
4 (0.1)
0
0
10 (0.3)
0
0
1 (0)
0
1 (0)
33 (1.0)
0
1 (0)
71
Table S22C: Adverse Events Leading to Temporary Study Drug Discontinuation of Both
Candesartan/HCTZ and Rosuvastatin or Their Placebos in the Candesartan/HCTZ+Rosuvastatin,

Syncope
Acute kidney injury
Gout
Angioedema
Anemia
Lipid abnormality
Cancer
Cataract
CandesartanHCTZ/Rosuvastatin
N=3,180
N (%)
768 (24.2)
239 (7.5)
47 (1.5)
1 (0)
3 (0.1)
0
32 (1.0)
0
0
11 (0.3)
1 (0)
0
1 (0)
10 (0.3)
1 (0)
1 (0)
3 (0.1)
3 (0.1)
Rosuvastatin
Alone
N=3,181
N (%)
693 (21.8)
222 (7.0)
28 (0.9)
0
2 (0.1)
0
33 (1.0)
0
1 (0)
12 (0.4)
2 (0.1)
0
1 (0)
6 (0.2)
0
0
2 (0.1)
2 (0.1)
CandesartanHCTZ Alone
N=3,176
N (%)
729 (33.0)
205 (6.5)
43 (1.4)
1 (0)
1 (0)
0
21 (0.7)
0
0
9 (0.3)
1 (0)
0
0
9 (0.3)
0
0
2 (0.1)
4 (0.1)
Double
Placebo
N=3,168
N (%)
731 (23.1)
220 (6.9)
20 (0.6)
1 (0)
1 (0)
0
23 (0.7)
0
0
6 (0.2)
0
0
0
9 (0.3)
0
4 (0.1)
6 (0.2)
2 (0.1)
72
Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, Candesartan-HCTZ Alone and Double
Placebo Groups*
CandesartanRosuvastatin CandesartanHCTZ/Rosuvastatin
Alone
HCTZ Alone
N=3,180
N=3,181
N=3,176
N (%)
N (%)
N (%)
2 (0.1)
1 (0)
1 (0)
Diabetes/glycemia
0
1 (0)
1 (0)
5 (0.2)
0
0
2 (0.1)
0
0
Cardiac disorders
2 (0.1)
7 (0.2)
7 (0.2)
0
0
1 (0)
0
0
0
Endocrine disorders
0
0
1 (0)
Eye disorders
2 (0.1)
1 (0)
0
6 (0.2)
0
5 (0.2)
5 (0.2)
9 (0.3)
6 (0.2)
1 (0)
3 (0.1)
0
0
1 (0)
0
5 (0.2)
7 (0.2)
3 (0.1)
5 (0.2)
3 (0.1)
4 (0.1)
Investigations
2 (0.1)
0
1 (0)
2 (0.1)
2 (0.1)
3 (0.1)
3 (0.1)
3 (0.1)
2 (0.1)
9 (0.3)
3 (0.1)
5 (0.2)
2 (0.1)
3 (0.1)
2 (0.1)
1 (0)
0
2 (0.1)
2 (0.1)
2 (0.1)
4 (0.1)
2 (0.1)
0
0
2 (0.1)
1 (0)
3 (0.1)
3 (0.1)
1 (0)
1 (0)
2 (0.1)
3 (0.1)
2 (0.1)
Vascular disorders
0
0
1 (0)
Double
Placebo
N=3,168
N (%)
2 (0.1)
1 (0)
3 (0.1)
0
6 (0.2)
0
1 (0)
0
0
0
6 (0.2)
4 (0.1)
0
7 (0.2)
4 (0.1)
1 (0)
1 (0)
1 (0)
4 (0.1)
5 (0.2)
3 (0.1)
2 (0.1)
1 (0)
1 (0)
0
2 (0.1)
2 (0.1)
73

Supplementary Appendix of HOPE 3 Trial

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Supplementary Appendix of HOPE 3 Trial

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Supplementary Appendix

THE HEART OUTCOMES PREVENTION EVALUATION (HOPE)-3 TRIAL

Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, Candesartan/HCTZ Alone and

HOPE-3 Investigators and Committees

Site Principal and Co-Investigators:

Hungary (263**): L. Bajnok, E. Baranyi, E. Bartfai, E. Bod, B. Bodis, I. Czuriga, E.

Vinueza Hungary: L. Matics, J. Roll India: R. N. Ahmed, S. Babu, S. Chavhan, A.C.

Blood Pressure Measurement Protocol

Manual Blood Pressure Measurement

Collection and Measurement of Lipids and High Sensitivity C-Reactive

Definitions of Outcome Events

New significant ST-segment- T-wave changes in two or more contiguous leads: ST

Hospitalization for Heart Failure

Other non-cardiovascular deaths

Safety Monitoring and Reporting

Adjustment For Multiple Testing In HOPE-3

Figure S1: CONSORT Diagram for the Candesartan/HCTZ versus

1,977 (13.5%) Excluded

12,705 Randomized (86.5 %)

6,356 assigned to Candesartan/HCTZ

6,349 assigned to Placebo

6,291 primary outcome status ascertained

6,301 primary outcome status ascertained

6,356 were included in analysis

6,349 were included in analysis

Figure S2: CONSORT Diagram for the Rosuvastatin versus Placebo

1,977 (13.5%) Excluded

12,705 Randomized (86.5 %)

6,361 assigned to Rosuvastatin

6,344 assigned to Placebo

6,308 primary outcome status ascertained

6,284 primary outcome status ascertained

6,361 were included in analysis

6,344 were included in analysis

1,977 (13.5%) Excluded

12,705 were randomized (86.5%)

3,149 primary outcome status ascertained

3,142 primary outcome status ascertained

3,159 primary outcome status ascertained

3,142 primary outcome status ascertained

Diastolic Blood Pressure (mmHg)

Figure S5: Cumulative Incidence of Co-Primary Outcome 1 for the

Cumulative Hazard Rates

Figure S6: Cumulative Incidence of the Secondary Outcome 1 for the

Cumulative Hazard Rates

CV death, MI, Stroke, Revascularization, Heart Failure, Resuscitated

HR (95% CI) = 0.92 (0.79-1.06)

Figure S7: Cumulative Incidence of Co-Primary Outcome 1 for the

Cumulative Hazard Rates

HR (95% CI) = 0.76 (0.64-0.91)

Figure S8: Cumulative Incidence of the Secondary Outcome for the

CV Death,MI,Stroke,Resuscitated Cardiac Arrest,Revascularization,HF,Angina

Cumulative Hazard Rates

HR (95% CI) = 0.77 (0.66-0.89)

Figure S9: Cumulative Incidence of Co-Primary Outcome 1 in the

Cumulative Hazard Rates

HR (95% CI) = 0.71 (0.56-0.90)

Figure S10: Cumulative Incidence of the Secondary Outcome for the

CV Death,MI,Stroke,Resuscitated Cardiac Arrest,Revascularization,HF,Angina

Cumulative Hazard Rates

HR (95% CI) = 0.71(0.57-0.87)

CV Death, MI, Stroke, Cardiac Arrest, Revascularization, Heart Failure, Angina

Hazard Ratio (95% CI)