Luis Ruilope, Unidad de Hipertension Madrid, Spain Cardio-renal - PowerPoint PPT Presentation

Asian Chapter Asian Chapter Achieving Blood Pressure targets: Current & future options in blocking the Renin Angiotensin System Luis Ruilope, Unidad de Hipertension Madrid, Spain

Cardio-renal continuum REGRESS Target organ damage Asymptomatic CKD New risk factors Target organ Atherosclerosis damage Symptomatic Risk factors ESRD Death CKD=chronic kidney disease; ESRD=end-stage renal disease

USE OF RAAS SUPPRESSION -ARTERIAL HYPERTENSION -HEART FAILURE -POST-MI -DIABETIC NEPHROPATHY WITH PROTEINURIA -HIGH CV RISK (HOPE, EUROPA & PEACE) -PATIENTS WITH 3 OR MORE ASSOCIATED CVRF -PATIENTS WITH METABOLIC SYNDROME -PATIENTS WITH TOD -PATIENTS WITH DIABETES -Actually 30-50% of hypertensives in Europe receive either an ACEi or an ARB since stage 1

Meta-Analysis based on US New Drug Application Evaluation Reports Reduction in diastolic BP (mmHg) -0 -2 -4 Losartan Valsartan -6 Irbesartan Candesartan -8 -10 0 25 50 100 mg Losartan 0 80 160 320 mg Valsartan 0 75 150 300 mg Irbesartan 0 4 8 16 mg Candesartan Elmfeldt et al 2002

ESH 2010 Oral Presentation Schematic of Study Design Placebo (N=154)* AZL- M 20 → 40 mg (N =280)* Run-in Period AZL- M 40 → 80 mg (N =285)* Screening VAL 160 → 320 mg (N =282)* (Day -28 to -21) OLM- M 20 → 40 mg ( N=290)* Week 6 Baseline Week 2 Week 4 Final ABPM & Forced ABPM Randomization Titration *Number of patients randomized.

ESH 2010 Oral Presentation 24-Hour Mean Systolic BP by ABPM Change from Baseline to Week 6 (LS mean ± SE, mm Hg) Placebo -2 -0.3 AZL-M 40 mg AZL-M 80 mg VAL 320 mg -6 OLM-M 40 mg -10 -10.2 a -12.0 a -14 -13.4 a,b* -14.5 a,b,c -18 P ≤ 0.001 vs VAL. c a P<0.001 vs placebo. b P=0.009 vs OLM-M. *Superiority of AZL-M 40 mg vs VAL 320 mg was not examined because the stepwise analysis was halted at a previous step.

ESH 2010 Oral Presentation 24-Hour Mean Diastolic BP by ABPM Change from Baseline to Week 6 (LS mean ± SE, mm Hg) Placebo -0.1 AZL-M 40 mg -2 AZL-M 80 mg VAL 320 mg OLM-M 40 mg -6 -7.1 a -7.7 a -8.7 a,b -10 -9.4 a,c,d a P<0.001 vs placebo. b P=0.02 vs VAL. P < 0.001 vs VAL. d c P=0.011 vs OLM-M.

ESH 2010 Oral Presentation 24-Hour Systolic BP Profile by ABPM Placebo VAL 320 mg AZL-M 40 mg 155 OLM-M 40 mg AZL-M 80 mg 150 145 140 SBP (mm Hg) 135 130 125 120 0 6 12 18 24 Hour After Dosing

ESH 2010 Oral Presentation Safety & Tolerability AZL-M AZL-M VAL OLM-M Placebo 40 mg 80 mg 320 mg 40 mg N=155 N=280 N=284 N=277 N=290 Adverse event 74 (47.7) 134 (47.9) 145 (51.1) 131 (47.3) 151 (52.1) 3 (1.9) 7 (2.5) 8 (2.8) 7 (2.5) 6 (2.1) Leading to DC 2 (1.3) 2 (0.7) 3 (1.1) 3 (1.1) 4 (1.4) Serious 0 0 0 0 0 Death In ≥3% of all subjects Headache 14 (9.0) 18 (6.4) 12 (4.2) 21 (7.6) 23 (7.9) Dizziness 4 (2.6) 10 (3.6) 10 (3.5) 5 (1.8) 9 (3.1) Data are n (%) of subjects. DC = discontinuation.

ASH 2010 Late-Breaking Clinical Trials Study udy Desi sign Phase 3, multicenter, double-blind AZL-M – CLD randomized study 40 mg + 25 mg AZL-M – CLD 40 mg + 12.5 mg AZL-M 40 mg AZL-M + HCTZ Follow-up 2-Week 40 mg + 25 mg Week 12 Placebo Run-In AZL-M + HCTZ 40 mg + 12.5 mg AZL-M 40 mg Monotherapy Forced addition Target BP of CLD or HCTZ titration Day 1 Week 2 Week 6 Week 10 Randomization, ABPM Final ABPM baseline ABPM

ASH 2010 Late-Breaking Clinical Trials Primary ary Ef Efficacy y En Endp dpoi oint nt Change in Trough Sitting Clinic SBP (mm Hg) Week 6 Week 10 0 Baseline Baseline Baseline Baseline AZL-M – CLD 164.7 ± 164.4 ± 164.7 ± 164.4 ± AZL-M + HCTZ 0.55 0.56 0.55 0.56 -10 a P<0.001 -20 -30 -29.5 -32.8 -35.1 a -40 -37.8 a Data are least-squares mean ± SE.

ASH 2010 Late-Breaking Clinical Trials Change nge by y Stud udy y Week Change in Trough Sitting Clinic SBP (mm Hg) 0 AZL-M – CLD -10 AZL-M + HCTZ -20 -30 -40 0 2 4 6 8 10 Study Week Monotherapy Forced addition Target BP of CLD or HCTZ titration

ASH 2010 Late-Breaking Clinical Trials Change nge in SBP by AB y ABPM Change in Mean 24-Hour SBP (mm Hg) by ABPM Week 6 Week 10 0 Baseline Baseline Baseline Baseline AZL-M – CLD 146.5 ± 145.4 ± 146.5 ± 145.4 ± 0.89 0.88 0.89 0.88 AZL-M + HCTZ -10 a P<0.001 -20 -19.9 -22.4 -25.7 a -30 -26.6 a Data are least-squares mean ± SE.

Safety Results CLD vs. HCTZ on background of AZL-M AZL-M – CLD AZL-M + HCTZ N=303 N=302 Any adverse event 144 (47.5) 158 (52.3) Event leading to 22 (7.3) 28 (9.3) Discontinuation Serious adverse event 6 (2.0) 5 (1.7) Death a 1 (0.3) 1 (0.3) Data are n (%) of subjects. a Two sudden deaths were considered not related (n=1, AZL-M – CLD group) or possibly related (n=1, AZL-M + HCTZ group) to the study drug by the investigators. Creatinine elevations were more frequent with AZL-M_CLD than with AZL-M+HCTZ; most were transient Bakris et al. Results of a double-blind randomized study comparing CLD and HCTZ combined with the new ARB Azilsartan Medoxomil in primary HTN. Late breaking Clinical Trial session presented at:: American Society of Hypertension Annual Scientific Meeting and Exposition; 2010 May 1-4; NYC,NY

Study Design Azilsartan Medoxomil in Combination with Amlodipine Day -21 ABPM ABPM Week 7 (or -28) Day -14 Day -7 Week 4 Follow-up Day 1 Week 2 Week 6 Placebo + AML 5 mg QD N=189* Screening and Single-Blind AZL-M 40 mg QD Placebo Run-in AML 5 mg QD N=190* AZL-M 80 mg QD AML 5 mg QD N=188* ABPM = ambulatory blood pressure monitoring; QD = once daily *number of patients randomized; includes 1 subject given AZL-M 40 mg + AML 5 mg who was treated but not randomized Weber et al. Antihypertensive Efficacy of the New Angiotensin Receptor Blocker Azilsartan Medoxomil in Combination with Amlodipine . Poster session presented at: American Society of Hypertension Annual Scientific Meeting and Exposition; 2010 May 1-4; NYC,NY

Primary Endpoint: Change from Baseline to Week 6 in 24-Hour Mean SBP by ABPM Azilsartan Medoxomil in Combination with Amlodipine 0 Placebo + AML 5 mg -4 AZL-M 40 mg + AML 5 mg AZL-M 80 mg + AML 5 mg -8 a P<0.001 vs placebo + -12 AML 5 mg -16 -13.6 -20 -24 -24.5 a -24.8 a -28 Weber et al. Antihypertensive Efficacy of the New Angiotensin Receptor Blocker Azilsartan Medoxomil in Combination with Amlodipine . Poster session presented at: American Society of Hypertension Annual Scientific Meeting and Exposition; 2010 May 1-4; NYC,NY

Change from Baseline to Week 6 in 24-Hour Mean DBP by ABPM Azilsartan Medoxomil in Combination with Amlodipine -2 Placebo + AML 5 mg AZL-M 40 mg + AML 5 mg AZL-M 80 mg + AML 5 mg -6 a P<0.001 vs placebo + AML 5 mg -7.8 -10 -14 -15.3 a -15.4 a -18 Weber et al. Antihypertensive Efficacy of the New Angiotensin Receptor Blocker Azilsartan Medoxomil in Combination with Amlodipine . Poster session presented at: American Society of Hypertension Annual Scientific Meeting and Exposition; 2010 May 1-4; NYC,NY

PHARMACOLOGICAL NEEDINGS IN HYPERTENSION  - One drug 20%  - Two drugs 50%  - Three or more 30% *  * Includes resistant hypertension (12%)  CAN AZILSARTAN CONTRIBUTE TO DIMINISH THE PHARMACOLOGICAL NEDINGS AND IMPROVE BP CONTROL IN THE HYPERTENSIVE POPULATION?