This document summarizes the results of the HOPE-3 Trial, which evaluated the effects of blood pressure lowering and statin use on cognitive and functional outcomes in older adults. The trial found that while both interventions reduced cardiovascular events, they did not significantly prevent cognitive or functional decline over 5.6 years. However, there were trends toward benefit of blood pressure lowering in those with the highest baseline blood pressure and longer duration of treatment. Rosuvastatin also had no adverse effects on cognition. In conclusion, the interventions were generally not effective at preventing cognitive or functional decline, but some subgroups may benefit.

1. The Heart Outcomes
Prevention Evaluation
(HOPE) – 3 Trial:
Cognitive & Functional
Outcomes
Jackie Bosch
For the HOPE-3 Investigators
Population Health Research Institute (PHRI),
McMaster University and Hamilton Health Sciences,
Hamilton, Canada
Unrestricted grants from the Canadian Institutes of Health
Research and AstraZeneca

2. Rationale
• Cognitive impairment & dementia affect 5-7% of those
over 60 years
• Elevated BP associated with cognitive impairment
• Statins linked to short term memory loss in
observational studies, but not RCTs
• The HOPE-3 study evaluated BP lowering &
rosuvastatin use in 12,705 intermediate CV risk:
– Statin reduced CV events by 25% in all
– BP lowering reduced CV events by 24% only in
those with hypertension
• We evaluated the effect of these interventions on
cognitive & functional decline

3. 3,086 ≥ 70 years
12,705 Randomized
219 Died
1,626 Completed baseline & study end questionnaire (76%)
Cognitive Questionnaire
Completion (Primary Outcome)
2,361 Completed baseline questionnaire
Participants 70 years+ invited to complete questionnaires
2,142 Alive at study end

4. Pre-Stated Outcomes:
Cognitive & Functional
• Primary Outcome: Decline in processing speed
(Digit Symbol Substitution Test [DSST])
• Secondary Outcomes
• Decline in executive function (modified Montreal
Cognitive Assessment [mMoCA])
• Increase in psychomotor speed (Trail Making Test
Part B [TMT-B])
• Other Outcomes
– Change in function (functional questions [EQ 5D])
– Study end: Standard Assessment of Global
Activities in the Elderly [SAGE])

5. Baseline +
Study End
Baseline
Only
Age (yrs, SD) 74 (±3.5) 75 (±4.1)
Female 59% 59%
Hypertension 45% 45%
Blood Pressure (mmHg) 140/79 139/79
LDL-Cholesterol (mg/dL) 127 128
Diabetes 6% 6%
Education >12 years 24% 13%
Ethnicity
White Caucasian
Latin American
Chinese
Other Asian
24%
36%
24%
13%
18%
54%
10%
10%
Baseline Characteristics

6. SBP and LDL Changes by
Treatment Group
Years
SystolicBloodPressure(mmHg)
0 1 2 3 4 5 6 7
120125130135140
Placebo
Candesartan/HCTZ
0 Year 1 Year 3 Study End
8090100110120130
Placebo
Rosuvastatin
mean Δ BP= 6/2.9 mmHg mean Δ 24.9 mg/dl

7. Study End DSST Score
29.1 29.4 29.1 29.4 29.3 29.9
0
5
10
15
20
25
30
35
BP Pla Rosu Pla BP+Rosu Dbl Pla
DSS
Change in means: 0.1
P=0.86
Sensitivity analysis demonstrated similar results
Change in means: -0.5
P=0.38
Change in means: -0.4
P=0.63

8. Change in Cognitive Outcome
by Treatment Group
28
29
30
31
32
33
34
Basline Study End BP
DSST
BP Pla
8
9
10
11
12
Basline Study End BP
mMoCA
BP Pla
130
135
140
145
150
Basline Study End BP
TMT-B
BP Pla
28
29
30
31
32
33
34
Basline Study End BP
DSST
Rosu Pla
8
9
10
11
12
Basline Study End BP
mMoCA
Rosu Pla
130
135
140
145
150
Basline Study End BP
TMT-B
Rosu Pla
BP Lowering
Cholesterol Lowering

9. BP Lowering in Key Subgroups
-5 0 5
Cand/HCTZ
better
Placebo
better
Age-years
<=72 (Mean=71.0)
72-75 (Mean=73.3)
Overall
P Trend
>75 (Mean=78.1) 0.970
SBP-mmHg
<=133.0 (Mean=123.8)
133.0-145.0 (Mean=139.1)
>145.0 (Mean=156.3) 0.078

10. Rosuvastatin in Key Subgroups
Mean Δ DSST for Combination Treatment: High SBP and High HDL
Double Active Double Placebo p
High SBP/High LDL -4.7 (22.6) -11.8 (16.5) 0.04
-5 0 5Rosu
better
Placebo
better
Overall
Age-years
<=72 (Mean=71.0)
72-75 (Mean=73.3)
LDL-mg/dl
<=112 (Mean=88.7)
112-140 (Mean=125.7)
P Trend
>75 (Mean=78.1) 0.800
>140 (Mean=164.9) 0.110

11. Treatment Effect by Length of
Intervention
Active Placebo Difference
P (Trend)
Mean (SD) Mean (SD) Mean (95% CI)
5 yrs -5.9 (19.8) -3.2 (18.0) -2.7 (-6.4,0.98)
5-5.5 yrs -9.7 (19.0) -6.7 (17.8) -3.0 (-6.6,0.63)
5.5-6.2 yrs -3.4 (19.3) -3.6 (21.1) 0.17 (-3.8,4.1)
>6.2yrs -4.4 (14.4) -6.3 (15.7) 1.9 (-1.1,4.8) 0.036
BP Lowering
No significant difference in effects of rosuvastatin by
duration of treatment

12. Functional Outcomes
by Treatment Group
BP Pla P Ros Pla P
New functional impairment
(EQ-5D)
22% 22% 0.96 21% 23% 0.46
Overall function at study
end (SAGE)
Any functional impairment 59% 56% 0.19 57% 59% 0.89

13. Conclusions
• HOPE-3 participants experienced cognitive and
function decline over 5.6 years
• BP lowering and rosuvastatin use did not
significantly prevent cognitive or functional decline
• Rosuvastatin had no adverse effect on cognitive
function
• Subgroup analyses:
– Trend for benefit in those with highest baseline
BP and LDL
– Longer duration of blood pressure lowering
associated with less cognitive decline
– Both findings require further confirmation

14. Acknowledgements
• Steering Committee: S. Yusuf, E. Lonn, 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
• Data and Safety Monitoring Board: D. Sackett (Chair)*, D. DeMets (Chair), C. Baigent, C.
Hennekens, J. Mancini
• Event Adjudication: 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
• 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: J. Bosch, J. Wilkinson, K. Kewell, 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.
* Deceased
We thank all the investigator and study coordinators for their efforts
We thank all participants for their selfless dedication