Optimal blockade of RAA in Heart Failure

Optimal blockade of RAA in Heart Failure

Contents RAA system in heart failure RAA block trials in heart failure Conundrum

Heart Failure Problem Better survival of of patients with with coronary disease and and hypertension Aging of of population Heart Failure population becoming larger, older, and and frailer Classic paradox improvement in in one area of of medicine leads to to increases in in diseases in in another

Evolving Models of CHF Cardiorenal Digitalis and diuretic to perfuse kidneys Hemodynamic Vasodilators or positive inotropes to relieve ventricular wall stress Neurohormonal ACE inhibitors, beta blockers, and other agents to block neurohormonal activation 1940s 1960s 1970s 1990s 2000

Neurohormonal System - Center CV Risk Sudden death Atherosclerosis Diabetes HTN Stroke Neurohormonal System LVH MI ESRD HF ESRD = End-stage renal disease, HF = Heart failure, HTN = Hypertension LVH = Left ventricular hypertrophy, MI = Myocardial infarction

Neurohormonal System in CHF BNP Angiotensin II Norepinephrine Aldosterone Endothelin Vasopressin

The renin-angiotensin system LIVER KIDNEY Increased Blood pressure Renin Sodium retention Negative feedback Angiotensinogen Angiotensin I ACE Angiotensin II Bradykinin Inactive fragments Alternative Pathways (t-pa, Cathepsin G) Aldosterone AT 1 RECEPTORS IN ADRENAL GLAND AT 1 RECEPTORS IN BLOOD VESSELS VASOCONSTRICTION

AT receptors

Aldosterone

Heart failure

RAA block trials in heart failure

CHF treatment through the ages 1920 - Organomercurial diuretics 1958 - Thiazide diuretics introduced 1967 - Heart transplantation (C Barnard) 1975 - β blockers first used in heart failure (F Waagstein et al) 1987 - CONSENSUS shows survival benefits from ACE inhibitors (K Swedberg et al)

Medical Therapy for CHF Mortality 40% 30% 20% ACEI Beta-blockers ARB? VPI? BNP? Spironolactone 10%??? 1970 1980 1990 2000

Treat risk factors Avoid toxics A ACE-i in selected p. ACE-i β blockers B In selected patients AHA / ACC HF guidelines 2001 Stages in the Evolution of Heart Failure Treatment C ACE-i β blockers Diuretics / Digitalis D Palliative therapy Mech. Assist device Heart Transplant

ACEI MECHANISM OF ACTION VASOCONSTRICTION ALDOSTERONE VASOPRESSIN SYMPATHETIC Angiotensinogen Angiotensin I RENIN Kininogen VASODILATATION PROSTAGLANDINS tpa Kallikrein BRADYKININ A.C.E. ANGIOTENSIN II Inhibitor Kininase II Inactive Fragments

ACEI HEMODYNAMIC EFFECTS Arteriovenous Vasodilatation - PAD, PCWP and LVEDP - SVR and BP - CO and exercise tolerance No change in HR / contractility MVO 2 Renal, coronary and cerebral flow Diuresis and natriuresis

No Additional Treatment Necessary (%) ACEI FUNCTIONAL CAPACITY 100 95 90 85 80 75 Quinapril Heart Failure Trial JACC 1993;22:1557 Class II-III Weeks Quinapril continued n=114 Quinapril stopped Placebo n=110 p<0.001 2 4 6 8 10 12 14 16 18 20

ACEI ADVANTAGES Inhibit LV remodeling post-mi Modify the progression of chronic CHF - Survival - Hospitalizations - Improve the quality of life In contrast to others vasodilators, do not produce neurohormonal activation or reflex tachycardia Tolerance to its effects does not develop

ACEI Survival PROBABILITY OF DEATH CONSENSUS N Engl J Med 1987;316:1429 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 5 p< 0.002 6 7 MONTHS 8 Placebo Enalapril 9 10 p< 0.001 11 12 % MORTALITY n = 4228 No CHF symptoms EF < 35 50 40 30 20 10 0 SOLVD (Prevention) N Engl J Med 1992;327:685 p = 0.30 0 6 12 Placebo n=2117 Enalapril n=2111 18 24 30 36 42 48 Months % MORTALITY n = 2589 CHF - NYHA II-III -EF < 35 SOLVD (Treatment) N Engl J M 1991;325:293 50 40 30 20 10 0 p = 0.0036 0 6 12 Placebo n=1284 Enalapril n=1285 18 24 30 36 42 48 Months SAVE Mortality, % n = 2231 3-16 days post AMI EF < 40 12.5 --- 150 mg / day N Engl J Med 1992;327:669 30 20 10 0 0 Asymptomatic ventricular dysfunction post MI 1 2 3 Years Placebo n=1116 Captopril n=1115 ² -19% p=0.019 4

ACEI UNDESIRABLE EFFECTS Inherent in their mechanism of action - Hypotension - Dry cough - Hyperkalemia - Renal Insuff. - Angioneurotic edema Due to their chemical structure - Cutaneous eruptions - Neutropenia, - Dysgeusia thrombocytopenia - Proteinuria - Digestive upset

ACEI CONTRAINDICATIONS Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects)

ALDOSTERONE INHIBITORS INDICATIONS FOR DIURETIC EFFECT Pulmonary congestion (dyspnea) Systemic congestion (edema) FOR ELECTROLYTE EFFECTS Hypo K +, Hypo Mg + Arrhythmias Better than K + supplements FOR NEUROHORMONAL EFFECTS Please see RALES results, N Engl J Med 1999:341:709-717

Benefits of Aldosterone Receptor Blockade Are not primarily due to a diuretic effect, but are most likely the result of other antialdosterone effects Include: Decreased myocardial and vascular fibrosis Increased myocardial NE reuptake Improved arterial compliance Improved endothelial dysfunction Improved baroreceptor function Improved potassium and magnesium homeostasis

Probability of Survival 1.00 0.90 0.80 0.70 0.60 0.50 RALES Standard Therapy (ACEi + Loop diuretics + Digoxin) Spironolactone + Standard therapy 0 6 12 18 24 30 36 Months

ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION RENIN Angiotensinogen Other paths AT1 RECEPTOR BLOCKERS AT1 Angiotensin I ANGIOTENSIN II RECEPTORS ACE AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

ELITE II: Endpoint Results All-Cause Mortality or Hospital Admission 1.0 All-cause mortality 1.0 All-cause mortality or hospital admission Probability of survival 0.8 0.6 0.4 0.2 0 Losartan Captopril p=0.16 Event-free probability Losartan Captopril p=0.18 0 100 200 300 400 500 600 700 0 100 200 300 400 500 600 700 0.8 0.6 0.4 0.2 0 Follow-up (days) Follow-up (days) Pitt B, et al. Lancet 2000;355;1582-87

Val-HeFT Results Primary Endpoint: All Cause Mortality 1.0 Survival Probability 0.9 0.8 p=0.8 0.7 Valsartan Placebo 0 3 6 9 12 15 18 21 24 27 Time Since Randomization (Months)

Val-HeFT Results Primary Endpoint: Combined All Cause Mortality and Morbidity 1.0 Event Free Probability 0.9 0.8 0.7 13.3 % Risk Reduction p=0.009 0.6 Valsartan Placebo 0 3 6 9 12 15 18 21 24 27 Time Since Randomization (Months)

Val-HeFT Results Secondary Endpoint: HF Hospitalization 1.0 Event Free Probability 0.9 0.8 27.5 % Risk Reduction p=0.00001 0.7 Valsartan Placebo 0 3 6 9 12 15 18 21 24 27 Time Since Randomization (Months)

Val-HeFT Results Combined Morbidity/Mortality in Subgroups % Patients Favours Valsartan Favours Placebo All Patients <65 >65 Male Female EF < 27 EF > 27 ACEI(Yes) ACEI(No) BB(Yes) BB(No) IHD(Yes) IHD(No) 100 47 53 80 20 50 50 93 7 35 65 57 43 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4

CHARM Programme 3 component trials comparing candesartan to placebo in patients with symptomatic heart failure CHARM Alternative n=2028 LVEF 40% ACE inhibitor intolerant CHARM Added n=2548 LVEF 40% ACE inhibitor treated CHARM Preserved n=3025 LVEF >40% ACE inhibitor treated/not treated Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death Pfeffer et al, Lancet 2003

CHARM results CHARM-Alternative Primary outcome, CV death or CHF hospitalisation CHARM-Added % 50 Primary outcome, 406 (40%) CV death or CHF hospitalisation Placebo 40 % 334 (33%) CHARM-Preserved 50 30 Candesartan Placebo 538 (42.3%) 40 483 (37.9%) 20 % 10 30 30 HR 0.77 (95% CI 0.67-0.89), p=0.0004 Candesartan Placebo 366 (24.3%) Adjusted HR 0.70, p<0.0001 25 20 333 (22.0%) 0 20 Number at risk 0 1 2 10 3 3.5 years HR 0.85 (95% CI 0.75-0.96), 15 p=0.011 Candesartan Candesartan 1013 929 831 434 122 Adjusted HR 0.85, p=0.010 10 Placebo 1015 887 798 0 427 126 Number at risk 0 Granger 1 et al, Lancet 22003 53 3.5 years HR 0.89 (95% CI 0.77-1.03), p=0.118 Adjusted HR 0.86, p=0.051 Candesartan 1276 1176 1063 948 0 457 Placebo 1272 1136 1013 906 0 422 1 2 3 3.5 years Number at risk McMurray et al, Lancet 2003 Candesartan 1514 1458 1377 833 182 Placebo 1509 1441 1359 824 195 Primary outcome, CV death or CHF hospitalisation Yusuf et al, Lancet 2003

Post-MI heart failure OPTIMAAL VALIANT

Renin inhibitors New drugs?

Conundrum To combine or not to combine? Which first?; ACEi vs BB, ARB vs Aldo antag Hit the bottom? Optimal dosage

ACE Post-MI: Enalapril 20 mg BID

ACE escape Plasma Ang II pg/ml 24 20 16 12 8 4 0 Placebo 4h 24h 1 2 3 4 5 6 Months

Aldosterone escape

Combine ARB, ACEI & - blocker : Val-HeFT

Combine ARB, ACEI & - blockers: CHARM-Added Added % 50 40 30 20 Placebo Candesartan 538 (42.3%) 483 (37.9%) Number at risk 10 0 HR 0.85 (95% CI 0.75-0.96), p=0.011 Adjusted HR 0.85, p=0.010 0 1 2 3 3.5 years Candesartan 1276 1176 1063 948 457 Placebo 1272 1136 1013 906 422

CHARM-Added Added Prespecified subgroups, CV death or CHF hospitalisation Candesartan event/n Placebo event/n p-value for treatment interaction Beta- Yes 223/702 274/711 blocker No 260/574 264/561 Recom. Yes 232/643 275/648 dose of No 251/633 263/624 ACE inhib All patients 483/1276 538/1272 0.14 0.26 0.6 0.8 Candesartan 1.0 Hazard 1.2 1.4 Placebo better ratio better McMurray et al, Lancet 2003

Which first? : -blocker vs ACEI 78 idiopathic DCM NYHA FC II to III Digoxin & diuretics for 7 days ACEI-first group (40) Perindopril for 6 Mo Carvedilol add for 6 Mo BB-first group (38) Carvedilol for 6 Mo Perindopril add for 6 Mo

?Hit the bottom Placebo ACE inhibitors Event rate Beta-blockers Bucindolol Omapatrilat ELITE-II II Etanercept Endothelin Antagonists Val-HeFT CHARM 1975 2002 Time (years)

? Optimal Dosage

(Dose-dependency) (Luzier AB, et al:am J Cardiol 1998;82:465 469

Proven ACE inhibitors

Potential target beyond neurohormonal model Optimal blockade of RAA system