Optimal blockade of RAA in Heart Failure

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Martti Mäkinen
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1 Optimal blockade of RAA in Heart Failure

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

3 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

4 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

5 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

6 Neurohormonal System in CHF BNP Angiotensin II Norepinephrine Aldosterone Endothelin Vasopressin

7 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

8 AT receptors

9 Aldosterone

10 Heart failure

11 RAA block trials in heart failure

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

13 Medical Therapy for CHF Mortality 40% 30% 20% ACEI Beta-blockers ARB? VPI? BNP? Spironolactone 10%???

14 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

15 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

16 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

17 No Additional Treatment Necessary (%) ACEI FUNCTIONAL CAPACITY Quinapril Heart Failure Trial JACC 1993;22:1557 Class II-III Weeks Quinapril continued n=114 Quinapril stopped Placebo n=110 p<

18 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

19 ACEI Survival PROBABILITY OF DEATH CONSENSUS N Engl J Med 1987;316: p< MONTHS 8 Placebo Enalapril 9 10 p< % MORTALITY n = 4228 No CHF symptoms EF < SOLVD (Prevention) N Engl J Med 1992;327:685 p = Placebo n=2117 Enalapril n= Months % MORTALITY n = 2589 CHF - NYHA II-III -EF < 35 SOLVD (Treatment) N Engl J M 1991;325: p = Placebo n=1284 Enalapril n= Months SAVE Mortality, % n = days post AMI EF < mg / day N Engl J Med 1992;327: Asymptomatic ventricular dysfunction post MI Years Placebo n=1116 Captopril n=1115 ² -19% p=

20 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

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

22 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:

23 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

24 Probability of Survival RALES Standard Therapy (ACEi + Loop diuretics + Digoxin) Spironolactone + Standard therapy Months

30 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

31 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 Losartan Captopril p=0.16 Event-free probability Losartan Captopril p= Follow-up (days) Follow-up (days) Pitt B, et al. Lancet 2000;355;

32 Val-HeFT Results Primary Endpoint: All Cause Mortality 1.0 Survival Probability p= Valsartan Placebo Time Since Randomization (Months)

33 Val-HeFT Results Primary Endpoint: Combined All Cause Mortality and Morbidity 1.0 Event Free Probability % Risk Reduction p= Valsartan Placebo Time Since Randomization (Months)

34 Val-HeFT Results Secondary Endpoint: HF Hospitalization 1.0 Event Free Probability % Risk Reduction p= Valsartan Placebo Time Since Randomization (Months)

35 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)

36 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

37 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 Candesartan Placebo 538 (42.3%) (37.9%) 20 % HR 0.77 (95% CI ), p= Candesartan Placebo 366 (24.3%) Adjusted HR 0.70, p< (22.0%) 0 20 Number at risk years HR 0.85 (95% CI ), 15 p=0.011 Candesartan Candesartan Adjusted HR 0.85, p= Placebo Number at risk 0 Granger 1 et al, Lancet years HR 0.89 (95% CI ), p=0.118 Adjusted HR 0.86, p=0.051 Candesartan Placebo years Number at risk McMurray et al, Lancet 2003 Candesartan Placebo Primary outcome, CV death or CHF hospitalisation Yusuf et al, Lancet 2003

38 Post-MI heart failure OPTIMAAL VALIANT

39 Renin inhibitors New drugs?

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

41 ACE Post-MI: Enalapril 20 mg BID

42 ACE escape Plasma Ang II pg/ml Placebo 4h 24h Months

43 Aldosterone escape

44 Combine ARB, ACEI & - blocker : Val-HeFT

45 Combine ARB, ACEI & - blockers: CHARM-Added Added % Placebo Candesartan 538 (42.3%) 483 (37.9%) Number at risk 10 0 HR 0.85 (95% CI ), p=0.011 Adjusted HR 0.85, p= years Candesartan Placebo

46 CHARM-Added Added Prespecified subgroups, CV death or CHF hospitalisation Candesartan event/n Placebo event/n p-value for treatment interaction Beta- Yes 223/ /711 blocker No 260/ /561 Recom. Yes 232/ /648 dose of No 251/ /624 ACE inhib All patients 483/ / Candesartan 1.0 Hazard Placebo better ratio better McMurray et al, Lancet 2003

47 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

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

49 ? Optimal Dosage

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

51 Proven ACE inhibitors

52 Potential target beyond neurohormonal model Optimal blockade of RAA system

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