Effects of blood pressure and lipid lowering on cognition: Results from the HOPE-3 study

Jackie Bosch; Martin O'Donnell; Balakumar Swaminathan; Eva Marie Lonn; Mikul Sharma; Gilles Dagenais; Rafael Diaz; Kamlesh Khunti; Basil S Lewis; Alvaro Avezum; Claes Held; Matyas Keltai; Christopher Reid; William D Toff; Antonio Dans; Lawrence A Leiter; Karen Sliwa; Shun Fu Lee; Janice M Pogue; Robert Hart; Salim Yusuf; HOPE-3 Investigators

doi:10.1212/WNL.0000000000007174

Effects of blood pressure and lipid lowering on cognition: Results from the HOPE-3 study

Neurology. 2019 Mar 26;92(13):e1435-e1446. doi: 10.1212/WNL.0000000000007174. Epub 2019 Feb 27.

Authors

Jackie Bosch¹, Martin O'Donnell², Balakumar Swaminathan², Eva Marie Lonn², Mikul Sharma², Gilles Dagenais², Rafael Diaz², Kamlesh Khunti², Basil S Lewis², Alvaro Avezum², Claes Held², Matyas Keltai², Christopher Reid², William D Toff², Antonio Dans², Lawrence A Leiter², Karen Sliwa², Shun Fu Lee², Janice M Pogue², Robert Hart², Salim Yusuf²; HOPE-3 Investigators

Collaborators

HOPE-3 Investigators:
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, C Cuneo, S Cusimano, C Damonte, M De Landaluc, E De Martino, R Diez, A Fernandez, A Ferrari, L Forti, M Galello, C Garcia, R Garcia Duran, M Garrido, F Giachello, O Gomez Vilamajo, M Gonzalez, F Guerlloy, R Guerrero, M Hominal, A Hrabar, H Imposti, P Lanchiotti, C Laugle, G Liniado, M R Litvak, A Longhi, H Luciardi, I Mackinnon, R Manzano, J Marino, B Merlo, R Milesi, C Mulazzi, S Nemi, S Orio, M Pelagagge, S Raimondi, L Rodino, C 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, A Villamil, D Vogel, C Zaidman, W Abhayaratna, J Canalese, H Krum, A Patel, C K O L Brasil, C B Alves, A R Alves Jr, J C A Ayoub, L C C Bergoli, M G Blacher, L C Bodanese, J C F Braga, O M C Costa, M K M Costa, D G de Faria, M I Del Monaco, L Fabian Restelatto, F Filho, R J S Franco, M V Furtado, P E Leaes, Paulo Leaes, L N Maia, J A MarinNeto, E T B Mattar, C M Melo, F S Mothe, G B F 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, 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 Hung Ly, M Juneau, P Keegan, A Kelly, D Kilby, M Lavoi, 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, X J Bai, L G Dong, Y W Duan, J Z Feng, P Fu, M M Gao, P Gao, H Ge, Yuan Ge, Q Hua, D J Li, X L Liu, X L Liu, Z D Liu, Y J Liu, F Y Liu, L H Liu, F H Lu, T Lv, S P Ma, H Ma, R H Man, Hui Qiong Tan, Y Shen, J F Shi, X D Sun, S Y Wang, B Wang, Y Q Wang, Y J Wei, X C Yang, H S Yang, K Yu, L T Yu, J H Yu, Wei Zhang, W Zhang, F Zhang, H Y Zhang, B Zhang, J G Zhao, Y Zhao, J Accini, E Arcos, G Aroca, M Casanova, C Celemin, B J Coronel, C Cotes, C Cure, M Diego-Olite, A Duarte, D Escobar, M Figueredo, L Garcia, H Garcia, M Grisales, K Martinez, D I Molina de Salazar, B Nino Castellanos, I Posada, A Quintero, F Quiros, G Sanchez, A Sotomayor, M Suarez, M Urina, 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, Y Duarte Vera, M Espinel, M Lopez-Jaramillo, J McDermont, E Penaherrera, F Plascencia, F Pow-Chon-Long, D Tettamanti, 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, D K Aggarwal, K G Alexander, S D Aman, V Ayyar, Y Balaji, G Bantwal, B Bosco, N Chidambaram, A Dabra, S Daniel, N Deshpande, H R Devendra, D Ghoshroy, S Gnanasekaran, R Gupta, M Z Gutti, G S Joshi, S Joshi, S P Kalantri, A Kapoor, A Khan, R S Khedar, A R Manjunath, K Mehta, V Mohan, S Murthy, A Nambiar, J Narendra, S K Paul, M A Qureshi, S Rajasekaran, M Ramu, K Rangadham, R L Ranka, S Roy, M R Sathyanarayan, K Selvam, J P Sethuraman, M Shunmugvavelu, G Sidhu, B Singh, R Singh, N Sinha, J Srinivas, A Srinivas, B Srinivasulu, N Thomas, R Umarani, K Varghese, S Varma, S Yelvatkar, A Biton, A Goldhaber, S Ivri, I Shapiro, N Shveydel, E Shveydel, D Tsalihin, S Vinker, C Yosefy, K H Choe, S Kil Kim, D Ambigga, M A Aris, K A Ghapar, C Krishnan, P Mahadasa, M Maizatullifah, Y Mazapuspavina, L Ramanathan, A Shah Mohd Shah, K Yusoff, 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, 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, S Boytsov, I Chukaeva, Y Karpov, O Kisliak, Z Kobalava, A Ledyacva, Y Lopatin, S Nedogoda, M Solovieva, V Tsoma, T Tyurina, M Hranai, A Badat, K Sliwa, T Gerntholtz, F Al-Khalili, B Carlberg, A Dotevall, P Nilsson, A Olsson, A Rosengren, S Soderberg, D Artomov, T Babanina, A Bagriy, 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, N Miroshnchenko, O Onyschenko, A Parkhomenko, N Petryk, S Pivovarova, I Rakytskay, L Sapozhnychenko, I Smymova, O Soya, V Tashchuk, N Turubarova-Leunova, L Vasilyeva, N Velichko, A Yagensky, S ZhurbaK Khunti, I Loke, W D Toff

Affiliations

¹ From the Population Health Research Institute (J.B., M. O., B.S., E.M.L., M.S., S.F.L., J.M.P., R.H., S.Y.) and Hamilton Health Sciences (J.B.), School of Rehabilitation Science, McMaster University, Ontario; Institut Universitaire de Cardiologie et Pneumologie de Québec (G.D.), Université Laval, Québec; Li Ka Shing Knowledge Institute (L.A.L.), St. Michael's Hospital, University of Toronto, Ontario, Canada; Research Board Clinical Research Facility (M.O.), Department of Medicine, NUI Galway, Ireland; Instituto Cardiovascular de Rosario (R.D.), Argentina; Diabetes Research Centre (K.K.), University of Leicester; Department of Cardiovascular Sciences and the National Institute for Health Research (W.D.T.), Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, UK; College of Medicine (A.D.), University of the Philippines, Manila, Philippines; Lady Davis Carmel Medical Center (B.S.L.), Ruth and Bruce Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa; Dante Pazzanese Institute of Cardiology (A.A.), São Paulo, Brazil; Department of Medical Sciences (C.H.), Cardiology, Uppsala Clinical Research Center, Uppsala University, Sweden; Semmelweis University (M.K.), Budapest, Hungary; Monash University (C.R.), Melbourne, Victoria; School of Public Health (C.M.R.), Curtin University, Perth, Australia; and Hatter Institute for Cardiovascular Research in Africa (K.S.), Department of Medicine, University of Cape Town, Soweto Cardiovascular Research Group, South Africa. [email protected].
² From the Population Health Research Institute (J.B., M. O., B.S., E.M.L., M.S., S.F.L., J.M.P., R.H., S.Y.) and Hamilton Health Sciences (J.B.), School of Rehabilitation Science, McMaster University, Ontario; Institut Universitaire de Cardiologie et Pneumologie de Québec (G.D.), Université Laval, Québec; Li Ka Shing Knowledge Institute (L.A.L.), St. Michael's Hospital, University of Toronto, Ontario, Canada; Research Board Clinical Research Facility (M.O.), Department of Medicine, NUI Galway, Ireland; Instituto Cardiovascular de Rosario (R.D.), Argentina; Diabetes Research Centre (K.K.), University of Leicester; Department of Cardiovascular Sciences and the National Institute for Health Research (W.D.T.), Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, UK; College of Medicine (A.D.), University of the Philippines, Manila, Philippines; Lady Davis Carmel Medical Center (B.S.L.), Ruth and Bruce Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa; Dante Pazzanese Institute of Cardiology (A.A.), São Paulo, Brazil; Department of Medical Sciences (C.H.), Cardiology, Uppsala Clinical Research Center, Uppsala University, Sweden; Semmelweis University (M.K.), Budapest, Hungary; Monash University (C.R.), Melbourne, Victoria; School of Public Health (C.M.R.), Curtin University, Perth, Australia; and Hatter Institute for Cardiovascular Research in Africa (K.S.), Department of Medicine, University of Cape Town, Soweto Cardiovascular Research Group, South Africa.

Abstract

Objective: To assess whether long-term treatment with candesartan/hydrochlorothiazide, rosuvastatin, or their combination can slow cognitive decline in older people at intermediate cardiovascular risk.

Methods: The Heart Outcomes Prevention Evaluation-3 (HOPE-3) study was a double-blind, randomized, placebo-controlled clinical trial using a 2 × 2 factorial design. Participants without known cardiovascular disease or need for treatment were randomized to candesartan (16 mg) plus hydrochlorothiazide (12.5 mg) or placebo and to rosuvastatin (10 mg) or placebo. Participants who were ≥70 years of age completed the Digit Symbol Substitution Test (DSST), the modified Montreal Cognitive Assessment, and the Trail Making Test Part B at baseline and study end.

Results: Cognitive assessments were completed by 2,361 participants from 228 centers in 21 countries. Compared with placebo, candesartan/hydrochlorothiazide reduced systolic blood pressure by 6.0 mm Hg, and rosuvastatin reduced low-density lipoprotein cholesterol by 24.8 mg/dL. Participants were followed up for 5.7 years (median), and 1,626 completed both baseline and study-end assessments. Mean participant age was 74 years (SD ±3.5 years); 59% were women; 45% had hypertension; and 24% had ≥12 years of education. The mean difference in change in DSST scores was -0.91 (95% confidence interval [CI] -2.25 to 0.42) for candesartan/hydrochlorothiazide compared with placebo, -0.54 (95% CI -1.88 to 0.80) for rosuvastatin compared with placebo, and -1.43 (95% CI -3.37 to 0.50) for combination therapy vs double placebo. No significant differences were found for other measures.

Conclusions: Long-term blood pressure lowering with candesartan plus hydrochlorothiazide, rosuvastatin, or their combination did not significantly affect cognitive decline in older people.

Clinicaltrialsgov identifier: NCT00468923.

Classification of evidence: This study provides Class II evidence that for older people, candesartan plus hydrochlorothiazide, rosuvastatin, or their combination does not significantly affect cognitive decline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Antihypertensive Agents / therapeutic use*
Benzimidazoles / therapeutic use*
Biphenyl Compounds
Cognition
Cognitive Dysfunction / epidemiology*
Drug Combinations
Female
Humans
Hydrochlorothiazide / therapeutic use*
Hypolipidemic Agents / therapeutic use*
Male
Rosuvastatin Calcium / therapeutic use*
Tetrazoles / therapeutic use*

Substances

Antihypertensive Agents
Benzimidazoles
Biphenyl Compounds
Drug Combinations
Hypolipidemic Agents
Tetrazoles
Hydrochlorothiazide
Rosuvastatin Calcium
candesartan

Associated data

ClinicalTrials.gov/NCT00468923

Grants and funding

CIHR/Canada