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 Placebo irbesartan 150 mg irbesartan 300 mg 20 Change in UAE (%) 10 0 3 6 12 18 3 6 12 18 24 24 -10 -20 -30 -40 -50 Months Parving H-H, et al. NEJM 345:870, 2001

MARVAL M icro a lbuminuria R eduction With Val sartan Blood Pressure Changes in Hypertensive Cohort 0 -2 -4 mm Hg -6 Valsartan -8 Amlodipine -10 -12 -14 SBP DBP MARVAL Study Group, Presented at ASH, May 2001

MARVAL M icro a lbuminuria R eduction With Val sartan Changes in Urinary Albumin Excretion Rate From Baseline* 17.2 20 % Change in UAER 10 0 Valsartan Amlodipine -10 -29.6 -20 -30 All Patients * P<0.001 MARVAL Study Group, Presented at ASH, May 2001

Blood Pressure Reduction LIFE 180 Atenolol Blood Pressure (mmHg) Losartan 160 Atenolol 145.4 mmHg 140 Systolic Losartan 144.1 mmHg P <0.001 vs. atenolol 120 100 Losartan 81.3 mmHg 80 Diastolic Atenolol 80.9 mmHg 60 40 0 6 12 18 24 30 36 42 48 54 Study Month Dahlöf et al. Lancet. 2002;359:995–1003.

Significant Reduction in Fatal / Nonfatal Stroke with Losartan LIFE % Patients With Fatal/Nonfatal Stroke 8 7 Atenolol Losartan 6 5 4 3 Adjusted Risk Reduction: 25%, P =0.001 2 1 0 0 6 12 18 24 30 36 42 48 54 60 66 Study Month Dahlöf et al. Lancet. 2002;359:995–1003.

LIFE Study Diabetes Subgroup Total Mortality 2 4 Adjusted risk reduction 3 8 ·7 % , 2 0 P= 0 ·0 0 2 Proportion of patients w ith first event( % ) Unadjusted risk reduction 4 0 ·1 % , 1 6 P= 0 ·0 0 1 Atenolol 1 2 8 Losartan 4 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6 Study Month w w w .hypertensiononline. Lindholm LH, et al. Lancet. 2 0 0 2 ;3 5 9 :1 0 0 4 - 1 0 1 0 . org Reprinted w ith perm ission from Elsevier Science.

LI FE Study Change in Cornell Voltage Duration Product and Sokolow -Lyon Cornell Product Sokolow -Lyon 0 Change from baseline ( % ) -2 -4 -6 -8 -1 0 P< 0 .0 0 0 1 -1 2 -1 4 Losartan -1 6 Atenolol P< 0 .0 0 0 1 -1 8 w w w .hypertensiononline. Dahlof B, et al. Lancet. 2 0 0 2 ;3 5 9 :9 9 5 - 1 0 0 3 . org Reprinted w ith perm ission from Elsevier Science.

LIFE: Pre-Existing Atrial Fibrillation Losartan Atenolol n (%) n (%) Medical History 157 (3.4) 185 (4.0) ECG 60 (1.3) 75 (1.6) Either 166 (3.6) 196 (4.3)

LIFE: New Onset Atrial Fibrillation Post-Hoc Analysis No. of Events Los Atl 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) Endpoints Atrial Fibrillation by Investigator 304 360 165 240 Atrial Fibrillation by ECG 346 416 416 416 416 416 416 416 416 416 416 416 416 416 Atrial Fibrillation by Inv./ECG 0.5 1 1.5 2 Favors Favors Los925 ACM Atrial Febr B Jan. 2, 2003 ← Losartan Atenolol →

LIFE: Baseline Subgroups - Atrial Fibrillation Stroke Atrial Fibrillation N No. of Events No. of Events No. of Events No. of Events Los Atl Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) ← No 8831 213 269 Interaction p-value 0.120 Yes 362 19 40 0.3 1 2 Favors Favors ← Losartan Atenolol → Los925 ACM AF-Stroke Dec. 26, 2002

Postulated role of A-II on Structure and Function Growth / Apoptosis Migration A-II Thrombosis Oxidative Stress Leukocyte Adhesion Adapted from Gibbons, GH: Curr Opin Neph & HTN 1995, 4:189-196: Gibbons, GH et al: NEJM. 330 : 20; 1431-1438.

Aliskiren: the first orally available direct renin inhibitor CH 3 O OH H N H 2 N CONH 2 O O CH 3 O • Molecular weight = 609.8 • High solubility in water and biological fluids • Non-peptide drug suitable for oral administration Wood JM, et al . 2003

Aliskiren monotherapy provides dose-dependent reductions in DBP and SBP Irbesartan Irbesartan Aliskiren (mg) Aliskiren (mg) (mg) (mg) Placebo 150 300 600 150 Placebo 150 300 600 150 0 n=130 n=127 n=130 n=129 n=133 n=130 n=127 n=130 n=129 n=133 −5 − 5.29 − 6.34 −10 − 8.88 − 9.28 ** * − 11.36 − 11.77 − 11.50 − 12.50 *** *** *** −15 *** − 15.76 − 15.73 p=0.01 *** *** p=0.005 −20 Mean ∆ BP DBP SBP (mmHg) *p<0.02 vs placebo; **p<0.005; ***p<0.001 vs placebo Gradman AH, et al . 2005 (Study 2201)

Aliskiren neutralizes the rise in PRA induced by HCTZ Mean change from baseline in PRA (%) 80 72 60 45 40 20 4 1 80 n= 40 42 42 42 40 43 36 42 36 40 39 41 45 45 38 −20 −40 − 46 − 49 − 49 − 50 − 51 −60 − 54 − 55 − 58 − 62 − 64 − 66 −80 Aliskiren (mg) 75 150 300 75 75 75 150 150 150 300 300 HCTZ (mg) 6.25 12.5 25 6.25 12.5 25 6.25 12.5 25 12.5 25 Aliskiren HCTZ Combination Calhoun D, et al . 2006 (Study 2204)

Suppression of PRA is maintained following discontinuation of aliskiren treatment Change from baseline in PRA (%) Treatment-free Double-blind treatment withdrawal 40 20 0 −20 −40 −60 −80 −100 0 8 10 Week Placebo (n=66) Aliskiren 300 mg (n=66) Aliskiren 150 mg (n=66) Aliskiren 600 mg (n=66) Herron J, et al . 2006 (Study 2308)

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