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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Randomization begins Year Timeline

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

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

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

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

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

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

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

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

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

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