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The Heart Outcomes Prevention Evaluation (HOPE) – 3 Trial

The Heart Outcomes Prevention Evaluation (HOPE) – 3 Trial. Eva Lonn, Jackie Bosch, Salim Yusuf For the HOPE-3 Investigators Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada. Disclosures. Eva Lonn

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The Heart Outcomes Prevention Evaluation (HOPE) – 3 Trial

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  1. The Heart Outcomes Prevention Evaluation (HOPE) – 3 Trial Eva Lonn, Jackie Bosch, Salim Yusuf For the HOPE-3 Investigators Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada

  2. Disclosures • Eva Lonn • Institutional Research Grants/ Contracts: Astra Zeneca, CIHR, Amgen, Bayer, GSK, Merck Shering, Eli Lilly, Sanofi • Consulting/ Lectures fees: Amgen, Cadila Pharmaceuticals, Novartis, Sanofi, Servier • Jackie Bosch • Institutional Research Grants/ Contracts: Astra Zeneca, CIHR, Cadila Pharmaceuticals, Bayer, Boehringer-Ingelheim, Novartis • Consulting Fees: Bristol-Myers Squibb • Salim Yusuf • Institutional Research Grants/ Contarcts: Astra Zeneca, CIHR, Cadila Pharmaceuticals, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Novartis • Consulting/Lecture fees and Travel Expenses: Bayer

  3. Study Rationale • Graded increase in CVD risk for SBP >115 mmHg & for LDL throughout documented ranges in populations • BP lowering trials indicate reductions in CVD in high risk people and those with SBP>150 -160 mmHg • Statins lower CVD in secondary prevention and in primary prevention mainly in Whites with increased LDL-C or CRP, diabetes, or hypertension

  4. Study Objectives To evaluate in an intermediate risk population without CVD the effects on CV events of: • BP lowering with combined Candesartan 16 mg + HCTZ 12.5 mg daily • Cholesterol lowering with Rosuvastatin 10 mg daily • Combined BP and cholesterol lowering

  5. Intermediate-Risk Population • No strict BP or LDL-C criteria for entry • Uncertainty principle

  6. The HOPE-3 Trial Global Trial: 228 centers in 21 countries Argentina, Australia, Brazil, Canada, China, Colombia, Czech Republic, Ecuador, Hungary, India, Israel, Korea, Malaysia, Netherlands, Philippines, Russia, Slovakia, South Africa, Sweden, United Kingdom, Ukraine

  7. HOPE-3: 2 by 2 Factorial Design 14,682 Entered Single-blind 4 week Active Run-in 12,705 (87%) Randomized Candesartan 16 mg + HCTZ 12.5 mg n= 6,356 Placebo n = 6,349 Rosuvastatin 10 mg n=6,361 Rosuvastatin Cand+HCTZ n = 3,180 Rosuvastatin n = 3,181 Placebo n = 6,344 Cand+HCTZ n = 3,176 Double Placebo n = 3,168 Simple follow-up and few blood tests

  8. Adherence and Follow-up • Median Follow up: 5.6 years • Participant Follow-up: 99.1% • High adherence

  9. Outcomes • Co-Primary 1 • Composite of CV death, MI, stroke (p<0.04) • Co-Primary 2 • Composite 1 + resuscitated cardiac arrest, heart failure, revascularizations (p<0.02) • Secondary Outcomes • Composite of Co-Primary 2 + angina with objective ischemia • Stroke

  10. Pre-Specified Hypothesis Based Subgroup Analyses • According to thirds of baseline: • Systolic BP • LDL-C • INTERHEART Risk Score

  11. Baseline Characteristics

  12. BP Lowering vs. Placebo: SBP Changes 140 Placebo 135 130 Systolic Blood Pressure (mmHg) Candesartan/HCTZ 125 Δ BP=6.0/3.0 mmHg 120 0 1 2 3 4 5 6 7 Years Cand/HCTZ 6356 5907 5667 5446 5213 3862 1437 350 Placebo 6347 5879 5623 5442 5186 3822 1424 334

  13. BP Lowering vs. Placebo

  14. CV Death, MI, Stroke, Cardiac Arrest, Revascularization, Heart Failure 0.10 HR (95% CI) = 0.95 (0.81-1.11) 0.08 P-value = 0.51 0.06 Placebo Cumulative Hazard Rates 0.04 Candesartan+HCTZ 0.02 0.0 0 1 2 3 4 5 6 7 Years No. at Risk Cand + HCTZ 6356 6272 6200 6103 5968 4969 2076 522 Placebo 6349 6270 6198 6096 5967 4970 2075 488

  15. Coronary Heart Disease HR (95% CI) = 0.83 (0.64-1.06) 0.04 Stroke P-value = 0.14 0.020 HR (95% CI) = 0.80 (0.59-1.08) 0.03 P-value = 0.14 0.015 Placebo Cumulative Hazard Rates Placebo 0.010 0.02 0.005 Candesartan+HCTZ Candesartan+HCTZ 0.01 0.0 0 1 2 3 4 5 6 7 Years 0.0 0 1 2 3 4 5 6 7 Years BP Lowering vs. Placebo Coronary Heart Disease: Fatal/non-fatal MI, Coronary Revascularization

  16. Prespecified Subgroups: By Thirds of SBP CV Death, MI, Stroke SBP Mean Placebo Event Rate% Cutoffs Diff P Trend HR (95% CI) 2.9 122 ≤131.5 6.1 1.16 (0.82-1.63) 0.021 131.6-143.5 138 5.6 3.8 1.08 (0.80-1.46) 154 >143.5 6.5 5.8 0.73 (0.56-0.94) 0.5 1.0 2.0 Cand + HCTZ Better Placebo Better

  17. Prespecified Subgroups: By Thirds of SBP CV Death, MI, Stroke, Cardiac Arrest, Revasc, HF SBP Mean P Trend HR (95% CI) Placebo Event Rate% 3.5 1.25 (0.92-1.70) 0.009 Cutoffs Diff 4.6 1.02 (0.77-1.34) 122 ≤131.5 6.1 7.5 0.76 (0.60-0.96) 131.6-143.5 138 5.6 154 >143.5 5.8 0.5 1.0 2.0 Candesartan + HCTZ Better Placebo Better

  18. BP Lowering Arm: Safety

  19. 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

  20. Cholesterol Lowering Arm Results J. Bosch

  21. LDL-C(mg/dL) APO B-100 (g/L) 0.8 Placebo 130 1.1 0.7 120 1.0 0.6 110 0.9 0.5 100 0.4 0.8 90 Rosuvastatin 0.3 0.7 80 0 Year 1 Year 3 Study End 0 Year 1 Year 3 Study End 0 Year 1 Year 3 Study End CRP (log)(mg/L) Cholesterol Lowering Arm:Change in LDL, Apo-B, and CRP Placebo Placebo mean Δ 34.6 mg/dl* mean Δ 0.23 g/l* log mean Δ 0.19* Rosuvastatin Rosuvastatin * P< 0.001

  22. Cholesterol Lowering: Outcomes

  23. CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure 0.10 HR (95% CI) = 0.75 (0.64-0.88) P-value = 0.0004 0.08 Placebo 0.06 Cumulative Hazard Rates 0.04 Rosuvastatin 0.02 0.0 0 1 2 3 4 5 6 7 Years Rosuva 6361 6241 6039 2122 Placebo 6344 6192 5970 2073

  24. 0.020 0.04 Stroke Coronary Heart Disease HR (95% CI) = 0.74 (0.58-0.96) HR (95% CI) = 0.70 (0.52-0.95) P-value = 0.0227 P-value = 0.0214 0.015 0.03 Placebo Placebo 0.010 0.02 Rosuvastatin Rosuvastatin Cumulative Hazard Rates 0.005 0.01 0.0 0.0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years Years Coronary Heart Disease: MI, Coronary revascularization

  25. Cholesterol Lowering:Subgroups Co-Primary 2 % Events Placebo Hazard Ratio (95% CI) P Interaction* Overall 5.7 0.75 ( 0.64 - 0.88 ) LDL <=112 6.0 0.69 ( 0.52 - 0.92 ) LDL 112-141 6.0 % 0.75 ( 0.57 - 1.00 ) LDL >141 5.5 % 0.93 ( 0.71 - 1.22 ) 0.145 INTERHEART Risk Score Tertile 1 <=12 4.6 % 0.66 ( 0.49 - 0.89 ) Tertile 2 13-16 5.6 % 0.81 ( 0.61 - 1.07 ) Tertile 3 >16 7.2 % 0.77 ( 0.60 - 0.98 ) 0.486 CRP <=2.0 5.6 % 0.79 ( 0.62 - 0.99 ) CRP >2.0 6.1 % 0.78 ( 0.63 - 0.98 ) 0.992 SBP <=131.5 4.7 % 0.65 ( 0.47 - 0.88 ) SBP 131.6-143.5 5.2 % 0.79 ( 0.60 - 1.05 ) SBP >143.5 7.3 % 0.80 ( 0.63 - 1.01 ) 0.335 Ethnicity European descent 6.0 % 0.62 ( 0.43 - 0.89 ) Chinese 4.5 % 0.73 ( 0.52 - 1.02 ) Other Asian 6.3 % 0.82 ( 0.59 - 1.13 ) Latin American 5.9 % 0.82 ( 0.61 - 1.09 ) Other 10.3 % 0.76 ( 0.40 - 1.42 ) 0.790 *P for trend for LDL, Risk Score, and SBP 0.5 1.0 2.0 Rosuvastatin Better Placebo Better

  26. Cholesterol Lowering: Safety

  27. Cholesterol Lowering: Conclusions • Rosuvastatin 10mg/day reduced: • LDL-C by 34.6 mg/dl (0.9 mmol/l; i.e. 26% in LDL-C) • CVD by 25% • Consistent benefits regardless of: • LDL-C • SBP • Risk • CRP • Ethnicity • No excess in rhabdomyolysis, myopathy or diabetes; excess in muscle pain/weakness (reversible) and cataracts surgery (requires confirmation)

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

  29. HOPE-3: 2 by 2 Factorial Design N = 12,705 Cand 16 mg+ HCTZ 12.5 mg n= 6,356 Placebo n = 6,349 Rosuva 10 mg n=6,361 Rosuva + Cand+HCTZ n = 3,180 Rosuvan = 3,181 Placebo n = 6,344 Cand+HCTZ n = 3,176 Double Placebo n = 3,168

  30. 140 Combination vs Double Placebo:Change in SBP and LDL-C Double placebo 135 Rosuva SBP Cand + HTCZ 130 Mean Δ 6.2 mmHg Combination 125 120 Week 6 0 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Month 6 Double Placebo Rosuva. 140 Cand+HCTZ Cand + HCTZ Combination 120 Double placebo LDL-C 100 Rosuva Mean Δ 33.7 mg/dl 90 Combination 80 0 Year 1 Year 3 Study End 232 232 232 232 Rosuvastatin 247 247 247 247 Candesartan/HCTZ 248 248 248 248 Double placebo

  31. Combination vs Double Placebo

  32. CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure 0.10 Double Placebo Cand + HCTZ 0.08 Rosuvastatin Combination 0.06 Cumulative Hazard Rates 0.04 0.02 HR (95% CI) = 0.72 (0.57-0.89) P-value = 0.0030 0.0 0 1 2 3 4 5 6 7 Years Combination 3180 4 3063 1057 Rosuvastatin 3181 3061 1045 Candesartan/HCTZ 3176 3040 1019 Double Placebo 3168 3035 1030

  33. Coronary Heart Disease Stroke 0.025 0.05 HR (95% CI) = 0.56 (0.36-0.87) HR (95% CI) = 0.62 (0.43-0.88) 0.020 P-value = 0.0094 0.04 P-value = 0.0085 0.015 0.03 0.010 0.02 Cumulative Hazard Rates 0.005 0.01 0.0 0.0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years Years Candesartan/HCTZ only Double Placebo Rosuvastatin only Combination Coronary Heart Disease: Fatal/non-fatal MI, Coronary Revascularization

  34. Lower Two SBP Thirds 50% 50% Overall 40% 40% 31% 28% 26% 30% 30% RRR 20% 20% 20% 6% 10% 10% Candesartan/HCTZ Only 0% 0% Combination Combination Rosuvastatin Only Rosuvastatin Only Cand + HCTZ Only -7% Benefits of Combination and Each Intervention vs. Double Placebo Highest SBP Third 50% 39% 40% 30% 21% RRR 18% 20% 10% 0% Rosuvastatin Only Combination Candesartan/HCTZ Only

  35. Combination vs Double Placebo: Safety

  36. Combination vs Double Placebo: Conclusions • About a 30% reduction in major vascular events • Benefits of combination therapy: • Largely seen in those in the upper third of SBP (40% RRR in CVD) • In lower two thirds the benefit is from Rosuvastatin only (30% RRR in CVD)

  37. Clinical Implications • Statins beneficial in all participants • BP lowering benefits only those with elevated BP • Combination therapy: • In hypertensives, leads to a 40% risk reduction (benefits from both BP lowering and statin) • In others, 30% RRR from statin alone • Pragmatic strategy without: • Lipid or BP criteria • Dose titration • Frequent monitoring HOPE-3 strategy is simple, effective, safe and low cost, and is globally applicable

  38. HOPE-3 Results Published today in the NEJM: • 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. • Yusuf, S., Bosch, J., Dagenais, G., et al. for the HOPE-3 Investigators. Rosuvastatin in intermediate-risk people without cardiovascular disease. NEJM 2016. • 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.

  39. Acknowledgements • We would like to thank: • The Steering Committee • The Data and Safety Monitoring Committee • The Investigators and Study Coordinators for all their efforts We are very appreciative of the efforts made by all participants!!

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