Angiotensin II Interaction With Secondary Mediators

1
Angiotensin II Interaction With Secondary
Mediators
LDL ?
BP ?
Diabetes
Smoking
Oxidative stress
Endothelial dysfunction and smooth muscle
activation
NO ? Local mediators ? Tissue ACE ? AII
Endothelin catecholamines
PAI-1, platelet aggregation, tissue factor
VCAM/ICAMcytokines
Proteolysis inflammation
Growth factors cytokines matrix
Vasoconstriction
Thrombosis
Inflammation
Plaque rupture
Vascular lesion and remodeling
Yusuf. Am J Cardiol. 200289(suppl)18A-26A.
2
Hypertension Detection and Follow-up Program

• Renal function was followed as a secondary end
  point
• Found to be a strong outcome predictor
• Better blood pressure control was found to be
  renal protective
• Renal protection through blood pressure lowering
  was more marked among those with renal
  insufficiency at baseline

Shulman. Hypertension. 198913I80-I93
Hypertension Detection and Follow-up Program
Cooperative Group. JAMA. 19792422562-2571.
3
Patients With Renal Disease in the HOPE Study

980 had creatinine ?124 mmol/L (1.4 mg/dL) and
8307 did not
Mann. Ann Intern Med. 2001134629-636.
4
Incidence and Risk of Cardiovascular Events in
HOPE Study Participants With and Without Baseline
Microalbuminuria by Randomized Group
Total Mortality Diabetes
Plt.01
Plt.01
Percent
Gerstein. JAMA. 2001286421-426.
5
The ONTARGET Trial
The Largest ARB Trial
gt100,000
61,256
Patient Treatment Years (? 1000)
44,126
30,263
23,880
5145
IDNT
CHARM
VALIANT
LIFE
Value
ONTARGET TRANSCEND
Clinical Trial
Collaborative Study Group. N Engl J Med.
2001345851-860 Pfeffer. N Engl J Med.
20033491893-1906 Swedberg. J Card Fail.
19995276-282 Dahlöf. Lancet.
2002359995-1005 Mann. Blood Press.
19987176-183 Unger. Am J Cardiol.
200391(suppl 1)28G-34G.
6
The ONTARGET Trial
Screening
TRANSCEND
ONTARGET
Randomization (n6000)
Randomization (n23,400)

n3000
n3000
n7800
n7800
n7800
Placebo
Telmisartan 80 mg/day
Telmisartan 80 mg/day placebo
Telmisartan 80 mg/day ramipril 10 mg/day
Ramipril 10 mg/day placebo
Because of an extraordinary effort by
investigators in 40 countries, it was possible to
complete recruitment for the ONTARGET study in
May 2003, seven months ahead of the scheduled
timeline. The ONTARGET trial currently recruited
25,621 patients.
5.5 years
Follow-up at 6 weeks
Follow-up at 6 weeks
Follow-up every 6 months for 5.5 years
Follow-up every 6 months for 5.5 years
Planned. Actual25,620 Planned.
Actual5926. The ONTARGET/TRANSCEND
Investigators. Am Heart J. 200414852-61.
7
The ONTARGET Trial
Inclusion Criteria

• Age ?55 years
• At high risk of developing a CVD event, with a
  history of
• Coronary artery disease
• Peripheral arterial occlusive disease (PAOD)
• Cerebrovascular event
• Diabetes mellitus with end organ disease
• Intolerant to ACE inhibitors (TRANSCEND)

The ONTARGET/TRANSCEND Investigators. Am Heart J.
200414852-61.
8
The ONTARGET Trial
Primary End Point

• Primary composite cardiovascular end point
• Cardiovascular mortality
• Nonfatal myocardial infarction
• Nonfatal stroke
• Hospitalization for congestive heart failure

The ONTARGET/TRANSCEND Investigators. Am Heart J.
200414852-61.
9
The ONTARGET Trial
Substudies
The ONTARGET Trial Programme 31,546 patients
ONTARGET The principal trial25,620 patients
TRANSCEND The parallel trial5,926 patients
Substudies
ABPM (n1000)
Arterial Stiffness (n284)
Because of an extraordinary effort by
investigators in 40 countries, it was possible to
complete recruitment for the ONTARGET study in
May 2003, seven months ahead of the scheduled
timeline. The ONTARGET trial currently recruited
25,621 patients.
Cardiac MRI (n350)
OGTT (n4000)
Erectile Dysfunction (n1500)
Health Economics (n7000)
Blood Markers (n12,000)
Yusuf. Am J Cardiol. 200298(suppl)18A-26A
Unger. Am J Cardiol. 200391(suppl)28G-34G
Zimmerman et al. Expert Opin Pharmacother.
200451201-1208.