1. The Heart Outcomes Prevention Evaluation (HOPE) – 3 Trial
Eva Lonn, Jackie Bosch, Salim Yusuf
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. Unique Aspects of HOPE-3
BP lowering trial with wide range of BP entry criteria
Cholesterol lowering treatment based on risk opposed to baseline LDL or HDL measurement
Diverse population 4

3. CV Death, MI, Stroke, Cardiac Arrest, Revascularization, Heart Failure
Years
Cumulative Hazard Rates
0.0
0.02
0.04
0.06
0.08
0.10 1 2 3 4 5 6 7
6356
6272
6200
6103
5968
4969
2076
522
6349
6270
6198
6096
5967
4970
2075
488
No. at Risk
Cand + HCTZ
Placebo
Candesartan + HCTZ
HR (95% CI) = 0.95 ( )
P-value = 0.51
CV Death, MI, Stroke, Cardiac Arrest,
Revascularization, Heart Failure 14

4. Prespecified Subgroups: By Thirds of SBP
CV Death, MI, Stroke, Cardiac Arrest, Revasc, HF
0.5
1.0
2.0
Candesartan + HCTZ Better
Placebo Better
3.5
4.6
7.5
1.25 ( )
1.02 ( )
0.76 ( )
0.009
SBP
Mean
Placebo
Event Rate%
HR (95% CI)
P Trend
Cutoffs
Diff
≤131.5
122
6.1
138
5.6
>143.5
154
5.8 17

5. Meta analysis of BP Lowering Trials in DM
Results by Baseline Levels
Brunström & Carlberg, BMJ 2016

6. BP Lowering Arm: Conclusions
Fixed dose combination of Candesartan 16 mg + HCTZ 12.5 mg/day reduced BP by 6.0/3.0 mmHg, but did not reduce CV events
CV events were significantly reduced in the highest third of SBP
SBP >143.5 mmHg, mean 154 mmHg
Results were neutral in the middle third, and trended towards harm in the lowest third of SBP
Treatment increased lightheadedness, but not syncope or renal dysfunction 19

7. Cholesterol Lowering Arm Results
Jackie Bosch 20

8. Unique Aspects of Cholesterol Lowering Arm
No entry criteria based on lipid level
No routine  monitoring
No dose titration
Low dose of rosuvastatin 

9. Cholesterol Lowering: Outcomes
Rosuvastatin N (%)
Placebo
N (%) HR
(95% CI) p
Co-Primary 1
235 (3.7)
304 (4.8)
0.76 ( )
0.002
Co-Primary 2
277 (4.4)
363 (5.7)
0.75 ( )
0.0004
Secondary 1
306(4.8)
393 (6.2)
0.77 ( )
0.0006
CV Death
154 (2.4)
171 (2.7)
0.89 ( )
0.31 MI
45 (0.7)
69 (1.1)
0.65 ( )
0.02
Stroke
70 (1.1)
99 (1.6)
0.70 ( )
CV Hosp.
281 (4.4)
369 (5.8)
0.0003 22

10. CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure
Years
Cumulative Hazard Rates
0.0
0.02
0.04
0.06
0.08
0.10 1 2 3 4 5 6 7
Placebo
Rosuvastatin
HR (95% CI) = 0.75 ( )
P-value =
Rosuva
6361
6241
6039
2122
Placebo
6344
6192
5970
2073 23

11. HOPE-3 & Other Studies of LDL Lowering and CVD

12. Cholesterol Lowering: Conclusions
Rosuvastatin 10mg/day reduced:
LDL-C by 34.6 mg/dl (0.9 mmol/l; i.e. 27% in LDL-C)
CVD by 25%
Consistent benefits regardless of:
LDL-C
SBP
Risk
CRP
Ethnicity
Excess in muscle pain/weakness (reversible) and perhaps cataract surgery
No excess in rhabdomyolysis, myopathy or new diabetes 27

13. Combined BP & Cholesterol Lowering vs Double Placebo
Salim Yusuf 28

14. Unique Aspects of BP & Chol Lowering
First formal testing of polypill concept on clinical events
Demonstrates that the concept is valid in people with elevated BP; in others there is no benefit

15. CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure
0.10
0.08
Combination
Double Placebo
0.06
Cumulative Hazard Rates
0.04
0.02
HR (95% CI) = 0.72 ( )
P-value =
0.0 1 2 3 4 5 6 7
Years
Combination
3180 4
3063
1057
Rosuvastatin
3181
3061
1045
Candesartan/HCTZ
3176
3040
1019 32
Double Placebo
3168
3035
1030

16. RRR of Combination and Each Intervention vs Double Placebo
Overall
RRR 0%
10%
20%
30%
40%
50%
28%
26% 6%
Combo
Rosuva
Only
Cand + HCTZ
Co-Primary 2
RRR 0%
10%
20%
30%
40%
50%
24%
Combo
Rosuva Only
Cand+HCTZ Only
Highest Third of SBP 0%
10%
20%
30%
40%
50%
19%
31%
-8%
Combo
Rosuva Only
Cand + HCTZ Only
Lower Two Thirds of SBP 34

17. Clinical Implications
Statins beneficial in intermediate-risk individuals without CVD
BP lowering benefits only those with elevated BP
Combined BP & cholesterol lowering:
Leads to a 40% risk reduction in hypertensives (benefits from both BP lowering and statin)
In others, 30% RRR from statin alone
Pragmatic strategy:
No Lipid or BP entry criteria or targets
No Dose titration
Infrequent safety monitoring
Strategy used in HOPE-3 is simple, safe and effective and widely applicable 37

18. Back up

19. BP Lowering by CV Risk 5 yr Risk <11% (6.5%) 11-15% 15-21% >21%
Active Control BP Diff HR (95%CI)
5 yr Risk
<11%
(6.5%)
11-15%
15-21%
>21%
Overall
SBP
155
159
162
165
158
BPLTC Lancet 2014

20. 1st & Recurrent CV Events
Total Events
HR: 0.65
P Value: 53 96 57 48
First Event
HR: 0.72
P Value:
Dbl Active Rosuva Only Cand + HCTZ Dbl Plac
Only

21. NNT Combination vs Double Placebo: Recurrent CV Events (Secondary)
Overall 30
Upper 1/3rd 16
Lower 2/3rd 41