1. ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial The telmisartan trial in cardiovascular protection Sponsored by Boehringer Ingelheim

2. ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial The Micardis trial in cardiovascular protection Sponsored by Boehringer Ingelheim

3. Trial Programme ONTARGET The principal trial 23,400 patients TRANSCEND The parallel trial 5000 patients ONTARGET Trial Programme 28,400 patients

4. Background Telmisartan is: an angiotensin II AT 1 receptor blocker (ARB) approved for hypertension, alone or in combination with another antihypertensive agent

5. Background Ramipril is: an angiotensin converting enzyme (ACE) inhibitor approved for –hypertension –congestive heart failure post myocardial infarction –reduction of cardiovascular risk in high-risk patients aged  55 years

6. ONTARGET will be the largest ARB clinical trial ever conducted It will build on the positive results from the landmark Heart Outcomes Prevention Evaluation (HOPE) trial, which investigated the effect of ramipril on cardiovascular risk From HOPE to

7. The HOPE study Double-blind, randomized, placebo-controlled trial Over 9500 patients at high risk of cardiovascular disease 4.5-year treatment period Compared the risk of cardiovascular events with the ACE inhibitor, ramipril (10 mg/day), vs placebo, both given as add-on to existing antihypertensive therapy

8. 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

9. 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

10. 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

11. 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

12. Telmisartan and ramipril combination therapy should: avert the negative consequences of angiotensin II escape associated with ramipril treatment prevent any excess angiotensin II acting at AT 1 receptors retain potential tissue-protective benefits associated with increased bradykinin levels Rationale

13. To compare the efficacy of telmisartan with the ACE inhibitor, ramipril, in preventing cardiovascular morbidity and mortality To determine any additional benefit of combining telmisartan with an ACE inhibitor, compared with the ACE inhibitor alone Objectives

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

15. ArgentinaFrance Netherlands Spain AustraliaGermany New Zealand Sweden AustriaGreece Norway Switzerland BelgiumHong KongPhilippines Taiwan BrazilHungary Poland Thailand Canada Ireland Portugal Turkey ChinaItaly Russia UK Czech RepublicKorea Singapore Ukraine Denmark Malaysia Slovakia United Arab Emirates FinlandMexico South Africa USA Participating countries

16. Patient treatment years  ARB trial to date will be the largest

17.  55 years of age At high risk of cardiovascular disease No patients with congestive heart failure Patient profile

18. Double-blind, double dummy, parallel-group study with three treatment arms: –telmisartan 80 mg once daily –ramipril 10 mg once daily –telmisartan 80 mg + ramipril 10 mg once daily Study design

19. Micardis ® 80 mg/day + ramipril 10 mg/day 7800 patients Ramipril 10 mg/day 7800 patients Micardis ® 80 mg/day 7800 patients 5.5 years Screening/enrolment Double-blind treatment Study design

20. 20012002200320042005200620072008 Randomization begins Year Timeline

21. Composite primary endpoint of: cardiovascular mortality stroke acute myocardial infarction hospitalization for congestive heart failure Primary endpoint

22. Newly diagnosed congestive heart failure Revascularization procedures Newly diagnosed diabetes Dementia New-onset atrial fibrillation Microvascular complications of diabetes Secondary endpoints

23. Telmisartan Randomized AssessmeNt Study in ACE-I INtolerant Subjects with Cardiovascular Disease Sponsored by Boehringer Ingelheim

24. In HOPE, ramipril reduced the risk of cardiovascular events (cardiovascular mortality, myocardial infarction and stroke) by 22% But, many patients cannot tolerate ACE inhibitor treatment due to side-effects, such as cough TRANSCEND is the parallel study of ONTARGET to assess the protective effects of telmisartan in ACE inhibitor intolerant patients Background

25. To evaluate the efficacy of telmisartan 80 mg monotherapy vs placebo in reducing cardiovascular morbidity and mortality in high-risk patients who are intolerant to ACE inhibitors Objectives

26.  55 years of age At high risk of cardiovascular disease No patients with congestive heart failure Intolerant to ACE inhibitors Patient profile

27. Double-blind, parallel-group study Two treatment arms: –telmisartan 80 mg once daily –placebo Study design

28. Placebo 2500 patients Micardis ® 80 mg/day 2500 patients 5.5 years Screening/enrolment Double-blind treatment Study design

29. Composite primary endpoint of: cardiovascular mortality stroke acute myocardial infarction hospitalization for congestive heart failure Primary endpoint

30. Newly diagnosed congestive heart failure Revascularization procedures Newly diagnosed diabetes Dementia New-onset atrial fibrillation Microvascular complications of diabetes Secondary endpoints