Angiotensin II antagonism and its effects on Hypertension and - - PowerPoint PPT Presentation

Angiotensin II antagonism and its effects on Hypertension and cardio-renal protection

Haralambos Gavras MD Professor of Medicine

Experimental Evidence

Clinical Evidence

IRMA 2 IRMA 2 Mean Change in Urinary Albumin Excretion Mean Change in Urinary Albumin Excretion

Parving H-H, et al. NEJM 345:870, 2001

• 50
• 40
• 30
• 20
• 10

10 20 Months Change in UAE (%) Placebo irbesartan 150 mg irbesartan 300 mg

3 6 12 18 3 6 12 18 24 24

MARVAL

Microalbuminuria Reduction With Valsartan

• 14
• 12
• 10
• 8
• 6
• 4
• 2

mm Hg SBP DBP Valsartan Amlodipine

Blood Pressure Changes in Hypertensive Cohort

MARVAL Study Group, Presented at ASH, May 2001

MARVAL

Microalbuminuria Reduction With Valsartan

• 29.6

17.2

• 30
• 20
• 10

10 20 % Change in UAER All Patients Valsartan Amlodipine

Changes in Urinary Albumin Excretion Rate From Baseline*

* P<0.001

MARVAL Study Group, Presented at ASH, May 2001

6 12 18 24 30 36 42 48 54 Study Month 40 60 80 100 120 140 160 180

Systolic Diastolic

Blood Pressure (mmHg) Atenolol Losartan

Atenolol 145.4 mmHg Losartan 144.1 mmHg

P<0.001 vs. atenolol

Atenolol 80.9 mmHg Losartan 81.3 mmHg

Blood Pressure Reduction

LIFE

Dahlöf et al. Lancet. 2002;359:995–1003.

Significant Reduction in Fatal/Nonfatal Stroke with Losartan

LIFE

% Patients With Fatal/Nonfatal Stroke Adjusted Risk Reduction: 25%, P=0.001 Study Month

6 12 18 24 30 36 42 48 54 60 66 1 2 3 4 5 6 7 8 Atenolol Losartan Dahlöf et al. Lancet. 2002;359:995–1003.

LIFE Study Diabetes Subgroup Total Mortality

Adjusted risk reduction 3 8 ·7 % , P= 0 ·0 0 2 Unadjusted risk reduction 4 0 ·1 % , P= 0 ·0 0 1

Lindholm LH, et al. Lancet. 2 0 0 2 ;3 5 9 :1 0 0 4 - 1 0 1 0 . Reprinted w ith perm ission from Elsevier Science. w w w .hypertensiononline.

• rg

Study Month

Proportion of patients w ith first event( % ) 2 4 2 0 1 6 1 2 8 4

Losartan Atenolol

6 1 2 1 8 2 4 3 6 4 2 4 8 5 4 6 0 6 6 3 0

LI FE Study Change in Cornell Voltage Duration Product and Sokolow -Lyon

• 1 8
• 1 6
• 1 4
• 1 2
• 1 0
• 8
• 6
• 4
• 2

Cornell Product Sokolow -Lyon

Change from baseline ( % )

Losartan Atenolol P< 0 .0 0 0 1 P< 0 .0 0 0 1

Dahlof B, et al. Lancet. 2 0 0 2 ;3 5 9 :9 9 5 - 1 0 0 3 . Reprinted w ith perm ission from Elsevier Science. w w w .hypertensiononline.

• rg

LIFE: Pre-Existing Atrial Fibrillation

Medical History ECG Either n (%) 185 (4.0) 75 (1.6) 196 (4.3) Atenolol n (%) 157 (3.4) 60 (1.3) 166 (3.6) Losartan

LIFE: New Onset Atrial Fibrillation

Post-Hoc Analysis

Atrial Fibrillation Atrial Fibrillation by ECG Atrial Fibrillation by Inv./ECG Endpoints

• No. of Events

by Investigator

Los925 ACM Atrial Febr B Jan. 2, 2003

Los 304 165 346 Atl 360 240 416 416 416 416 416 416 416 416 416 416 416 416 416 0.5 1 1.5 2 Favors Favors Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) ← Losartan Atenolol →

LIFE: Baseline Subgroups - Atrial Fibrillation

Stroke

Los 213 19

• No. of Events
• No. of Events
• No. of Events
• No. of Events

Atl 269 40

Los925 ACM AF-Stroke Dec. 26, 2002

Favors Favors Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) ←Losartan Atenolol → 0.3 1 2

←

N Atrial Fibrillation Yes No 8831 362 Interaction p-value 0.120

Postulated role of A-II on Structure and Function

A-II Growth / Apoptosis Migration Thrombosis Leukocyte Adhesion Oxidative Stress

Adapted from Gibbons, GH: Curr Opin Neph & HTN 1995, 4:189-196: Gibbons, GH et al: NEJM. 330 : 20; 1431-1438.

Wood JM, et al. 2003

Aliskiren: the first orally available direct renin inhibitor

• Molecular weight = 609.8
• High solubility in water and biological fluids
• Non-peptide drug suitable for oral administration

O N H CONH2 OH H2N CH3O O CH3O

Aliskiren monotherapy provides dose-dependent reductions in DBP and SBP

Mean ∆ BP (mmHg) −15 −5 −20 −10

n=133 n=129 n=130 n=127 n=130

** * *** ***

p=0.005 p=0.01

Placebo 150 300 600 150

*p<0.02 vs placebo; **p<0.005; ***p<0.001 vs placebo Gradman AH, et al. 2005 (Study 2201) n=133 n=129 n=130 n=127 n=130

*** *** *** ***

Aliskiren (mg)

DBP SBP

Irbesartan

(mg)

Aliskiren (mg) Irbesartan

(mg)

Placebo 150 300 600 150

−6.34 −9.28 −11.77 −11.50 −8.88 −5.29 −11.36 −15.76 −15.73 −12.50

Aliskiren neutralizes the rise in PRA induced by HCTZ

Calhoun D, et al. 2006 (Study 2204)

−60 −40 −20 40 80

Aliskiren HCTZ 75 Combination 40 42 42 42 40 43 36 42 36 40 39 150 300 75 150 300 300 75 150 75 150 6.25 12.5 25 6.25 12.5 25 6.25 12.5 25 12.5 25 Aliskiren (mg) HCTZ (mg)

−80

n=

Mean change from baseline in PRA (%)

20 60 80

45 45 38 41 1 −54 −66 −58 4 45 72 −55 −51 −49 −64 −50 −46 −49 −62

40 −20 −80 −100 −60 −40 20

Suppression of PRA is maintained following discontinuation of aliskiren treatment

Herron J, et al. 2006 (Study 2308)

Change from baseline in PRA (%) Week 10 8

Placebo (n=66) Aliskiren 150 mg (n=66) Aliskiren 300 mg (n=66) Aliskiren 600 mg (n=66)

Double-blind treatment Treatment-free withdrawal

Study Design: Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

Primary Endpoint: Difference in UACR at 24 weeks

Mean Blood Pressure at Baseline and End of Study