This document summarizes several studies on the use of ACE inhibitors and angiotensin receptor blockers (ARBs) in treating heart failure and reducing cardiovascular risk. The HOPE trial showed that the ACE inhibitor ramipril reduced cardiovascular events in high-risk patients. The CHARM trial found that the ARB candesartan reduced cardiovascular outcomes in heart failure patients, both alone and in combination with ACE inhibitors. The ONTARGET trial aimed to compare the ARB telmisartan to ramipril, and their combination, to determine if telmisartan was non-inferior to ramipril and if their combination provided additional benefit.

1. Vascular Protection in HF Studies & Learnings

2. Heart Outcomes Prevention Evaluation Study A large, simple, randomized trial of Ramipril and vitamin E in patients at high risk for cardiovascular events

4. Study rationale and design

6. Design Placebo 0 12 24 -1/2 -1 Run-in period Randomisation Follow-up Months 36 48 Perindopril Perindopril 8 mg once daily 60 4 mg 8 mg

7. Heart Failure Perindopril Placebo 5 0 1 2 3 4 Years p = 0.002 RRR: 39% 0.0 0.5 1.0 1.5 2.0 (%)

8. Conclusion

13. Comparison of Patients in the HOPE, EUROPA, and PEACE Trials 58 NA NA Mean LV EF 133/78 137/82 139/79 Mean SBP/DBP 91 92 76 Aspirin/antiplatelet 70 58 29 Lipid lowering 60 62 40 Beta blocker 55 12 65 60 EUROPA n=12218 72 17 55 64 PEACE n=8290 66 Mean age 40 Prior CABG or PCI 38 Diabetes mellitus 53 Prior MI HOPE n=9297 Characteristic % (unless otherwise specified)

14. CHF as a primary cause of hospitalization or death 1 The PEACE trial investigators. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease (the PEACE trial). N Engl J Med 2004;351:2-58-68 Risk Reduction 25% p=0.02 Placebo (absolute incidence 1529/4132) Trandolapril (absolute incidence 115/4158) 3.7% 2.8% Patients (%) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

18. ACEI and Angiotensin II Antagonism in CHF 69 1.10 >3.0 CHARM 70 1.2 >2.5 SAVE 70 1.2 >2.0 SOLVD 45 1.4 >3.4 CONSENSUS GFR (ml/min) Mean/Median (mg/dL) Mean Creatinine Exclusion

20. The role of angiotensin II in the progression of heart failure Coronary artery disease Cardiac overload Cardiomyopathy Left ventricular dysfunction  Arterial blood pressure  Angiotensin II  Peripheral organ blood flow  Skeletal muscle blood flow Exercise intolerance  Renal blood flow Oedema Cardiac remodelling Renin release Aldosterone release Vasoconstriction Na+ and water retention Inotropy and hypertrophy of vascular and cardiac cells Left ventricular dilation & hypertrophy Pump failure

21. ACEs & ARBs in patient with heart failure: implications from recent trials

27. ACE-Inhibitors (ACE-I)

30. Guidelines to ACE inhibitor therapy -HF ACE Inhibitor therapy in heart failure patients (Ejection Fraction < 0.40)

31. ARBS Can Angiotensin II receptor blockers (ARBs) be used as alternative to ACE inhibitors in ARBs?

33. Candesartan in Heart Failure CHARM Trial

35. CHARM Overall Program All-cause mortality HR 0.91 95% CI 0.83-1.00 p=0.055 European Society of Cardiology 2003 CV Mortality or CHF Hospitalization HR 0.84 p<0.0001

36. CHARM Added Trial CV Mortality or CHF hospitalization HR 0.85 p=0.011 European Society of Cardiology 2003 CV Mortality HR 0.84 p=0.02

37. CHARM Alternative Trial CV Mortality or CHF hospitalization HR 0.77 p=0.0004 European Society of Cardiology 2003 CV Mortality HR 0.85 p=0.072

38. CHARM Preserved Trial CV Mortality or CHF hospitalization HR 0.89 p=0.118 European Society of Cardiology 2003 CV Mortality HR 0.99 p=0.918

41. ON going T elmisartan A lone and in combination with R amipril G lobal E ndpoint T rial The Telmisartan trial in cardiovascular protection Presented on 31 st March, 2008 at ACC Annual Meeting, Chicago By Chief Investigator – Prof. Salim Yusuf

47. HOPE study results – primary endpoints Combined cardiovascular endpoint Cardiovascular mortality, myocardial infarction, stroke Cardiovascular mortality Myocardial infarction Stroke -22% p<0.001 -26% p<0.001 -20% p<0.001 -32% p<0.001 Ramipril n = 4645 , Placebo n=4652 The HOPE Study Investigators, 2000

48. HOPE study results – secondary endpoints All-cause mortality Need for revascularization Hospitalization for heart failure Complications relating to diabetes -16% p=0.005 -15% p=0.002 -12% p=0.25 -16% p=0.03 Ramipril n = 4645 , Placebo n=4652 The HOPE Study Investigators, 2000

50. AT 1 RECEPTOR Vasoconstriction Sodium retention Water retention SNS activation Growth-promoting effects AT 2 RECEPTOR Tissue regeneration Inhibitor of inappropriate cell proliferation SNS = Sympathetic Nervous System ANGIOTENSIN I ANGIOTENSIN II Bradykinin Inactive fragments ACE inhibitor ARB Rationale

51. ANGIOTENSIN I ANGIOTENSIN II ARB AT 1 RECEPTOR Vasoconstriction Sodium retention Water retention SNS activation Growth-promoting effects AT 2 RECEPTOR Tissue regeneration Inhibitor of inappropriate cell proliferation Angiotensin II escape Bradykinin Inactive fragments ACE inhibitor SNS = Sympathetic Nervous System Rationale

54. Europe 23 countries Australia 2 countries Asia 9 countries North America 2 countries South America 3 countries Africa 1 country A global trial

55. Argentina France Netherlands Spain Australia Germany New Zealand Sweden Austria Greece Norway Switzerland Belgium Hong Kong Philippines Taiwan Brazil Hungary Poland Thailand Canada Ireland Portugal Turkey China Italy Russia UK Czech Republic Korea Singapore Ukraine Denmark Malaysia Slovakia United Arab Emirates Finland Mexico South Africa USA Participating countries

56. Patient treatment years  ARB trial to date is the largest

58. Study Medications Run-in (Single Blind) Day 1-3 Ram 2.5 mg + Tel Placebo Day 4-10 Ram 2.5 mg + Tel 40 mg Day 11-18 Ram 5.0 mg + Tel 40 mg Randomization (Double Blind) 2 weeks Ram Placebo + Tel 80 mg Ram 5 mg + Tel Placebo Ram 5 mg + Tel 80 mg Then Full doses (Tel 80 mg daily, Ram 10 mg daily) for the 3 arms

59. Telmisartan 80 mg/day + ramipril 10 mg/day 8502 patients Ramipril 10 mg/day 8576 patients Telmisartan 80 mg/day 8542 patients 5.5 years Screening/enrolment Double-blind treatment Study Medications

60. 2001 2002 2003 2004 2005 2006 2007 2008 Randomization begins Year Timeline

62. Reasons for Not Randomizing Patients % Run-in Completed (n=29,018) 100 Not Randomized 11.71 Creatinine elevated 0.22 Potassium elevated 0.77 Persistent symptomatic hypotension 1.70 Death 0.09 Total Medical Reasons 2.78 Compliance <75% 3.87 Other reasons 3.01 Patient Decision 2.06 Total Patient Reasons 5.93

66. Key Baseline Characteristics Ramipril Telmisartan Combination N 8576 8542 8502 Age 66.4 66.4 66.5 % females 27.2 26.3 26.5 % CAD 74.4 74.5 74.7 % Stroke/TIA 21.0 20.6 20.9 % Diabetes 36.7 38.0 37.9 BP 141.8/82.1 141.7/82.1 141.9/82.1 Statins 61.0 62.0 61.8 Antiplatelet 80.5 81.1 81.1  -blocker 56.5 56.9 57.4

67. Change in BP (mmHg) Ramipril Telmisartan Combination Systolic -6.0 -6.9 -8.4 Diastolic -4.6 -5.2 -6.0

68. Time to Permanent Discontinuation of Study Medication Years of Follow-up Cumulative Hazard Rates 0.0 0.1 0.2 0.3 0.4 0 1 2 3 4 Telmisartan Ramipril # at Risk Yr 1 Yr 2 Yr 3 Yr 4 T 8542 7954 7384 6909 6478 R 8576 7796 7165 6681 6254

69. Reasons for Permanently Stopping Study Medications Ram N=8576 Tel N=8542 Tel vs. Ram RR P Hypotension 149 229 1.54 0.0001 Syncope 15 19 1.27 0.4850 Cough 360 93 0.26 <0.0001 Diarrhea 12 19 1.59 0.20 Angioedema 25 10 0.40 0.0115 Renal Impairment 60 68 1.14 0.46 Any Discontinuation 2099 1962 0.94 0.02

70. Time to Primary Outcome

71. Primary Outcome & HOPE Primary Outcome Ram Tel Tel vs Ram N (%) N (%) RR (95% CI) P (non-inf) N 8576 8542 Primary Outcome CV Death, MI, Stroke, CHF Hosp 1412 (16.46%) 1423 (16.66%) 1.01 (0.94-1.09) 0.0038 (Adjusted for SBP) 1.02 (0.95-1.10) 0.0055 HOPE Primary Outcome CV Death, MI, Stroke 1210 (14.11%) 1190 (13.93%) 0.99 (0.91-1.07) 0.0009 (Adjusted for SBP) 0.99 (0.91-1.07) 0.0012

72. ONTARGET Non-Inferiority Comparison

73. Combination vs Ramipril

74. Time to Primary Outcome

75. Telmisartan vs Ramipril:Pre-specified Subgroup Analysis No. of Patients Incidence of Primary Outcome in Ramipril Group 0.7 1.0 1.3 Relative Risk in Telmisartan Group (95% Confidence Interval) Telmisartan better Ramipril better Primary Composite Hx of CVD No Hx of CVD SBP < 134 134 - 150 > 150 Diabetes No Diabetes HOPE Risk Score Low Medium High Age < 65 65 - 75 > 75 Male Female 17118 15627 1486 5704 6042 5352 6390 10723 5709 5664 5745 7319 7310 2489 12537 4581 16.4 16.7 13.1 16.2 14.9 18.3 20.6 14.0 10.4 15.0 23.8 13.0 17.2 24.1 16.7 15.7

76. Telmisartan + Ramipril vs Ramipril : Pre-specified Subgroups Incidence of Primary Outcome 0.7 1.0 1.3 Relative Risk in Ramipril & Telmisartan Group (95% Confidence Interval) Ramipril & Telmisartan better Ramipril better Primary Composite Hx of CVD No Hx of CVD SBP <= 134 134 < SBP <= 150 SBP > 150 Diabetes No Diabetes HOPE Low Risk Score HOPE Medium Risk Score HOPE High Risk Score Age < 65 65 <= Age < 75 Age >= 75 Male Female No. of Patients 17078 15589 1484 5714 6019 5329 6364 10709 5637 5596 5845 7362 7177 2539 12497 4581 in Ramipril Group 16.4 16.7 13.1 16.2 14.9 18.3 20.6 14.0 10.4 15.0 23.8 13.0 17.2 24.1 16.7 15.7

77. Reasons for Permanently Stopping Study Medications Ram N=8576 Ram + Tel N=8502 Ram + Tel vs. Ram RR P Hypotension 149 406 2.75 <0.0001 Syncope 15 29 1.95 0.032 Cough 360 392 1.10 0.1885 Diarrhea 12 39 3.28 0.0001 Angioedema 25 18 0.73 0.30 Renal Impairment 60 94 1.58 0.0050 Any Discontinuation 2099 2495 1.20 <0.0001

82. Thank you!