Cardiovascular Protection and the RAS Katalin Kauser, MD, PhD, DSc Senior Associate Director, Boehringer Ingelheim Pharmaceutical Inc. Micardis Product Pipeline Scientific Support Ridgefield, CT, USA
Cardiovascular Disease is a Major Health Concern 2009 AHA Statistics for the US: CVD (80 mil) MI (8 mil) Stroke (6.5 mil) Heart failure (5.7 mil) CVD deaths (0.86 mil) Effective treatments are needed to reduce the risk of CV events
Cardiovascular Disease Continuum Limited number of therapies available with a broad CV risk reduction indication Adapted from Dzau VJ. J Cardiovasc Pharmacol. 1993;22(suppl 5):S1-S9.
Angiotensin II is Involved in Progression of CAD from Multiple Risks to End-Stage Adapted from Dzau VJ. J Cardiovasc Pharmacol. 1993;22(suppl 5):S1-S9.
Angiotensin II a Mediator for Oxidative Stress, Inflammation and Vascular Damage Endothelial damage Endothelium Inflammation Platelet aggregation and adhesion Monocyte adherence MCP-1 PAI-1 ICAM-1 VCAM-1 NADH/ NADPH oxidase O 2 - AT 1 R NOS III NO Angiotensin II Oxidative stress ONOO Smooth muscle O 2 - NADH/ NADPH oxidase Angiotensin II Contraction Growth Migration AT 1 R NO Dilatation TGFβ 1 Fibrosis AT 1 R Angiotensin II Schiffrin L. Am J Hypertens 2004;17:1192-1200.
Cardiac/Renal Protection What To Target? Cardiac Disease Heart Failure Ischemia MI Pressure Overload Elevated Blood Pressure Inflammation Fibrosis Volume Retention Endothelial Dysfunction/ Increased Peripheral Resistance/ Vascular Remodeling Increased AngII & aldosterone Renal Disease Renal Failure
Chronic Kidney Disease It begins with - Hyperfiltration (diabetes), - Microalbuminuria, - Hypertension, and/or - Inflammation (nephritis) Once present - Underlying pathophysiological mechanisms of disease progression are similar, irrespective of cause It is "progressive - Progresses (at variable rates) to end-stage renal disease (ESRD) requiring dialysis or transplantation - However, CKD patients are more likely to die from CV disease
Role of Angiotensin II in Chronic Renal Disease Mechanical stress Mesangial changes Oxidative stress Proteinuria NF-κB activation Glomerular capillary pressure Single nephron GFR Angiotensin II Adhesion molecules Chemotactic factors Cell growth Apoptosis TGF-β, CTGF PAI-1 Macrophage infiltration Chronic Renal Disease Nephron Loss Glomerulosclerosis & Tubulo-Interstitial Fibrosis Modified from Brewster, Perazella. Am J Med 2004;116:263 272
Comorbidities: Diabetes and CKD Significantly Contribute to CVD Morbidity 60 45 5% Medicare sample, by Diabetes and CKD status, 1999-2000 60 45 %Heart Failure %Stroke/TIA 30 30 15 15 %ASHD 60 45 0 Diabetes Nondiabetes Non- CKD CKD 0 60 45 Diabetes %Amputation/PVD Nondiabetes Non- CKD CKD 30 30 15 15 0 Diabetes Nondiabetes Non- CKD CKD 0 Diabetes Nondiabetes Non- CKD CKD
Optimal Cardio-Vascular Protection There is a continuous relationship between BP, cholesterol, glucose and CV events!
Optimal Cardio-Vascular Protection Earlier and more aggressive BP, lipid and glucose control Pharmacologic blockade of the RAS
Growing Complexity of the RAS TGF-β ET-1 Pro-IL-1β Angiotensin III Angiotensin IV Angiotensinogen? Chymase Renin Ang I (1-10) Ang II (1-8) ACE (Pro)ReninR ACE2 Ang 1-9 ACE ACE2 Ang 1-7 IRAP/AT4-R AT1-R Vasoconstriction Cell growth Na/H 2 O retention Sympathetic activation AT2-R Vasodilation Antiproliferation MAS-R
The RAS Is Controlled by a Negative-Feedback Loop RENIN Angiotensin II formation decreases the production of renin ACEI s and ARBs interrupt the RAS negative-feedback loop Angiotensinogen Plasma Renin Activity (PRA) Plasma Renin Activity Ang I ACEIs ACE Feedback Loop Ang II AT 1 Receptor ARBs
Rationale for a More Complete RAS Blockade The RAS is one of the most detrimental neurohormonal pathways in the CV system Part of the target organ protection appears to be blood pressure independent highlighting the role of a local RAS The increasing appreciation of the complexity of the RAS suggests that present treatment modalities only incompletely inhibit the system Renin inhibitors are currently under development and their place in target organ protection needs to be determined in outcome studies Combination of ACEI and ARB treatment has been investigated for superior target organ protective properties
How to Achieve Optimal RAS Protection? Optimal dosing of RAS blockers - Highest doses approved by FDA for BP reduction appear to be the best doses Targeting renin - Blockade of the complex RAS at its initial point of activation without increased plasma renin activity Combining RAS (ACEI + ARB) blockers - More complete blockade of the pathway - ONTARGET trial
The ONTARGET Trial Program ONTARGET Screening TRANSCEND Run-In (n= 29,019) If ACEI intolerant Run-In (n = 6,665) Randomization (n = 25,620) Randomization (n = 5,926) n = 8542 n = 8576 n = 8502 n = 2,954 n = 2,972 Telmisartan 80 mg/day + placebo Ramipril 10 mg/day + placebo Telmisartan 80 mg/day + ramipril 10mg/day Telmisartan 80 mg/day Placebo Follow-up at 6 weeks Follow-up at 6 weeks Follow-up at 6 months for 5.5 years Follow-up at 6 months for 6 years
Design of the ONTARGET Trial Run-In (n = 29,019) Randomization (n = 25,620) Telmisartan 80 mg/day (n = 8542) Ramipril 10 mg/day (n = 8576) Telmisartan 80 mg/day + Ramipril 10mg/day (n = 8502) Test for Superiority Test for Non-inferiority
Comparison of Baseline Characteristics in HOPE and ONTARGET ONTARGET HOPE 25,620 9,297 Age (yrs) 66 66 % Women 27 27 % Coronary artery disease 75 80 % Peripheral artery disease 14 44 % Stroke/TIA 19 11 % Diabetes 38 38 % Hypertension 69 47 Blood pressure (mmhg) 142/82 139/79 % Statins 62 29 ONTARGET patients had less vascular disease and were better treated than HOPE patients % Antiplatelet 76 76 % Diuretics 28 15 % β-blocker 57 40
ONTARGET: First Primary Event (4 fold) Telmisartan, Ramipril & Combination Cumulative hazard rate 0.20 0.15 0.10 0.05 0 Telmisartan Ramipril Telmisartan plus ramipril CV death, MI, stroke and CHF hospitalization 0 1 2 3 4 5 Years of follow-up No. at risk Telmisartan 8542 8177 7778 7420 7051 1687 Ramipril 8576 8214 7832 7472 7093 1703 Telmisartan 8502 8133 7738 7375 7022 1718 plus ramipril NEJM. 2008;358;1547-1559.
Time to Permanent Discontinuation of Study Medication Cumulative Hazard Rates 0.0 0.1 0.2 0.3 0.4 # at Risk Yr 1 Yr 2 Yr 3 Yr 4 Yr 4.5 T 8542 7953 7384 6909 6481 4122 R 8576 7796 7165 6682 6255 3922 Telmisartan Ramipril Telmisartan is better tolerated: - Less cough and angio edema - More mild hypotensive symptoms 0 1 2 3 4 Years of Follow-up
ONTARGET Conclusions 1. Telmisartan is similarly effective as ramipril: Primary composite outcome (p = 0.0019) HOPE primary outcome (p = 0.0004) Most of the benefits of ramipril are preserved 2. Consistent results on a range of: Secondary outcomes Subgroups 3. Telmisartan is better tolerated: Less cough and angioedema More mild hypotensive symptoms
TRANSCEND: Effect of Telmisartan on Primary Endpoint Telmisartan Placebo Randomized 2954 2972 CV death, MI, stroke and CHF hospitalization 465 15.7% 504 17.0% CV death 140 4.7% 137 4.6% Nonfatal MI 106 3.6% 136 4.6% Non-fatal stroke 106 3.6% 127 4.3% Hospitalization for CHF 123 4.2% 112 3.8% Hazard ratio vs. placebo (95% CI) for primary endpoint 0.92 (0.81, 1.05) p = 0.22
TRANSCEND Permanent Discontinuation of Study Medication Cumulative Hazard Rates 0.0 0.1 0.2 0.3 Telmisartan Placebo Telmisartan was better tolerated than placebo control. T Pl 0 1 2 3 4 5 Years of Follow-up # at Risk Year 1 Year 2 Year 3 Year 4 Year 5 2,954 2,784 2,663 2,547 2,271 1,086 2,972 2,814 2,629 2,509 2,242 1,063
Baseline Characteristics Different in ONTARGET and TRANSCEND ONTARGET TRANSCEND N 25,620 5926 % Women 27 43 % Asians 14 21 % Hypertension 69 76 % Statins 62 55 % Diuretics 28 33 % CCBs 24 31
Renin Angiotensin System Inhibition ACE-I ARB Combination Renin-I HBP: Reduce BP ++ Heart Failure ++? Myocardial Infarction NAB? Chronic Kidney Disease NAB? Vascular Disease NAB? NAB = no added benefit
Conclusion Clinical studies indicate RAS inhibitors are very effective for reducing blood pressure The organ-protective benefits of ACEIs and ARBs are not synergistically enhanced by addressing the incomplete RAS suppression by combination treatment It remains to be shown in large outcome trials, whether renin inhibitors cause cardiovascular benefit Telmisartan appears to be as effective as Ramipril in cardiovascular protection based on the ONTARGET trial results
Signaling Pathways Include Oxidative Stress, Inflammation, Remodeling and Hypertrophy p Gp91/ Nox1/ Nox4 p22 p47 p67 p40 NAD(P)H Oxidase NAD(P)H NAD(P)+H + e - SOD 2O 2 2 O - 2 H 2 O 2 Transcription factors: NF-κB, AP-1, HIF-1 PKC, PLD c-src, PI3K Ang II AT1R MAP kinases Cell Membrane Tyrosine kinases RhoA/ Rho kinase Cytokines: IL, TNFα Chemokines: MCP-1 CAMs: selectins, ICAM, VCAM, PECAM Growth factors: ET-1, TGFβ, CTGF ECM proteins: collagen, fibronectin TIMP/MMP Inflammatory response Cell growth and fibrosis Touyz RM & Schiffrin EL. 2005