Optimal blockade of the Renin- Angiotensin-Aldosterone. in chronic heart failure

Transcription

1 Optimal blockade of the Renin- Angiotensin-Aldosterone Aldosterone- (RAA)-System in chronic heart failure Jan Östergren Department of Medicine Karolinska University Hospital Stockholm, Sweden

2 Key Issues in Heart Failure Chronic heart failure is: Common 2% of the population Dangerous high mortality Disabling high morbidity Costly 2% of health care budget Treatable very succesful pharmacological therapy developed

3 Stewart et al EHJ 2001 More malignant than cancer? Survival (%) Women Month of follow-up Breast MI Bowel Ovarian Heart Failure Lung Survival (%) Men Month of follow-up MI Bladder Prostate Bowel Heart Failure Lung

4 The Vicious Circle of Heart Failure Cardiac lesion Impedance Cardiac output Salt and water retention Salt and water retention Vasoconstriction Compensatory mechanism Renin-Angiotensin-Aldosteron Sympathetic activity Arginine vasopressin

5 Angiotensin II Plays a Central Role in Organ Damage Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction A II AT1 receptor LV hypertrophy Fibrosis Remodeling Apoptosis GFR Proteinuria Aldosterone release Glomerular sclerosis Stroke Hypertension MI Heart failure Renal failure * Preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate DEATH

6 Neuroendocrine Activation and Mortality in Severe Heart Failure Six month mortality (%) by plasma levels of hormones From CONSENSUS I Placebo Group n= Noradrenaline Angiotensin II Aldosterone P< Quartile (Modified from Swedberg et al 1990)

7 Inhibition of angiotensin II in chronic heart failure ACE-inhibition

8 CONSENSUS Original Study Result 253 patients in NYHA class IV. High doses of diuretics, nitrates, spiro. Mean age 70. Study stopped by DSMB Mortality Placebo Enalapril p= Year NEJM 1987

9 SOLVD Treatment Trial All Cause Mortality Mortality % Placebo Enalapril p= Months Placebo n = Enalapril n =

10 Meta-analysis analysis of Studies With ACE-Inhibitors in Heart Failure Study Mortality Mortality or hospitalisation (OR; 95% CI) for CHF (OR; 95% CI) SOLVD 0.82 ( ) 0.97) 0.68 ( ) 0.80) CONSENSUS 0.56 ( ) 0.91) 0.89 ( ) 1.57) Total (32 trials) 0.77 ( ) 0.88) 0.65 ( ) 0.74) (Garg & Yusuf JAMA 1995,273:1450)

11 ACE-inhibitors in heart failure Prescription in relation to speciality Practitioners Internal med Cardiologists 90 % Mild - moderate Severe 95 (Edep et al. JACC 1997;30:518)

12 ACE-inhibitors in heart failure Dose levels in relation to speciality % Practitioners Intern med Cardiologists Low Medium High (Edep et al. JACC 1997;30:518)

13 Mortality Benefit of Beta-blockers and ACE-inhibitors in CHF trials % death at 1 year SOLVD (1991) CIBIS II MERIT-HF (1999) diuretic digoxin diuretic digoxin ACE-I diuretic digoxin ACE-I diuretic digoxin ACE-I beta-blocker

14 Further pharmacological manipulation of the Renin-Angiotensin Angiotensin-AldosteroneAldosterone System in CHF Angiotensin II and Aldosterone is not optimally suppressed by ACE-inhibitors Blocking these molecules will add benefit

15 Rales All-cause mortality Risk Reduktion 30% (-18-40) p <0.001 Probability of Survival Spironolactone Placebo Months 39 (Pitt et al NEJM 1999)

16 Inhibition of angiotensin II AT 1 -receptor blockade May treatment of patients with heart failure improve even further?

17 Randomized trial of losartan vs captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE) Probability of survival Losartan Captopril Relative risk reduction (95% CI) = 0.46 ( ) p= Follow-up (days) Pitt et al. Lancet 1997

18 ELITE II Losartan Heart Failure Survival Study 3152 pts HF (EF<40%) + >60 yrs Losartan target dose 50 mg vs captopril target dose 150 mg Endpoint: Total mortality Lancet 2000

19 Losartan Heart Failure Survival Study ELITE II Probability of Survival All cause mortality Captopril Losartan (N=1574) (N=1578) 250 Events 280 Events Captopril/Losartan Hazard Ratio (95% CI) 0.88 (0.75, 1.05) P= Days of Follow-up (Pitt et al Lancet 2000, 355)

20 ELITE II: Summary of Major Findings 3152 elderly CHF patients randomised to losartan (50 mg od) or captopril (50 mg tid) All cause Mortality 15.9% v 17.7%: p=0.16 Sudden death/resuscitated arrest 7.3% v 9.0%: p=0.08 All cause Mortality/hospitalisations 44.9% v 47.7%: p=0.21 Withdrawal rate 14.5% vs 9.4% p<0.001 Favours captopril Favours losartan Odds ratio 1.25

21 Combination of ACE Inhibitor and AT 1 Receptor Blocker Is it superior to ACE inhibitor monotherapy?

22 Renin-Angiotensin Aldosterone System Angiotensinogen renin Non-ACE Pathways (e.g., chymase) Angiotensin I ACE Angiotensin II Vasoconstriction Cell growth Na/H 2 O retention Sympathetic activation AT 1 Aldosterone AT 2 Cough, Angioedema Benefits? Bradykinin Inactive Fragments Vasodilation Antiproliferation (kinins)

23 ACE inhibitor escape Angiotensin II back to high pathologic pretreatment levels after some time despite complete inhibition of circulating ACE Biollaz et al. J Cardiovasc pharmacol 1982;4: Rousseau et al. Am J Cardiol 1994;73: % of ACE inhibitor treated CHF patients have escape and those patients have a worse prognosis Roig et al. Eur Heart J 2000;21:53-7 Probably due to non-ace conversion of Ang I to Ang II Insufficient blockade of tissue ACE?

24 Combination of ACE Inhibitor and AT 1 Receptor Blocker More complete inhibition of influence of Ang II Bradykinin accumulation benefits Combination therapy may therefore be superior to ACE inhibitor monotherapy

25 Val-HeFT Valsartan Heart Failure Trial 5,010 pts HF (EF<40%) + LVED >2.9 cm/m 2 Valsartan target dose 320 mg vs placebo Patients on stable standard treatment (93%ACE-i, 1/3 beta-blockers) Endpoint: Total mortality Death or resuscitated sudden death, HF hospitalization, IV inotropics or vasodilators Cohn et al. NEJM 2001;345:1667

26 Survival probability Val-HeFT All-Cause Mortality 0.85 p= Valsartan Placebo Time since randomization (months) Cohn et al. NEJM 2001;345:1667

27 Val-HeFT Combined All-Cause Mortality and Morbidity Event free probability Valsartan Placebo 27.5 % reduction of CHF hospitalisation Benefit on signs and symptoms of CHF Benefit on QoL 13.3% Risk Reduction p= Months Cohn et al. NEJM 2001;345:1667

28 Val-HeFT Reduction in Mortality (No ACEi) Proportion Survived (%) Placebo (N = 181) Risk reduction= 33.1% P = Valsartan (N = 185) Time Since Randomisation (months) Maggioni et al. J Am Coll Cardiol 2002; 40:1414

29 Val-HeFT Subgroup Combined Mortality/Morbidity All Patients 100 < Male 8 Female 20 EF <27 50 EF IHD (Yes) 57 IHD (No) 43 ACEI (Yes) 93 ACEI (No) 7 BB (Yes) 35 BB (No) 65 % patients Favours valsartan Favours placebo Hazard ratio Cohn et al. NEJM 2001;345:1667

30 Questions remaining after ELITE II and Val-HeFT ARB in patients who don t tolerate an ACE-i? Is there a mortality benefit of combining ACE-i and ARB? Is triple therapy safe? May an ARB reduce morbidity and mortality in preserved left ventricular function CHF?

31 Euroheart Failure Distribution of left ventricular ejection fraction patients from 115 hospitals in 24 countries Percentage of Patients < Figure Women Men Left Ventricular Ejection Fraction (%) Cleland et al EHJ 2003

32 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

33 CHARM Programme: % CHARM-Alternative Placebo 406 (40%) 334 (33%) Candesartan % CHARM-Added Placebo 538 (42.3%) 483 (37.9%) Candesartan 10 HR 0.77 (95% CI ), p= Adjusted HR 0.70, p< years 10 HR 0.85 (95% CI ), p= Adjusted HR 0.85, p= years % 50 CHARM-Preserved % 50 CHARM-Overall Placebo Candesartan 366 (24.3%) 333 (22.0%) HR 0.89 (95% CI ), p= Adjusted HR 0.86, p= years Placebo Candesartan 1310 (34.5%) 1150 (30.2%) HR 0.84 (95% CI ), p< Adjusted HR 0.82, p< years

34 CHARM-Added Added Prespecified subgroups, CV death or CHF hosp. Candesartan Placebo Beta- Yes 223/ /711 blocker No 260/ /561 p-value for treatment interaction 0.14 Recom. Yes 232/ /648 dose of No 251/ /624 ACE inhib All patients 483/ / candesartan better 1.0 Hazard ratio placebo better

35 CHARM-Overall: All-cause death % HR 0.70 p<0.001 HR 0.82 p<0.001 Placebo 945 (24.9%) 886 (23.3%) Candesartan Number at risk HR 0.91 (95% CI ), p=0.055 Adjusted HR 0.90, p= years Candesartan Placebo

36 Number at risk CHARM Overall: CV deaths and non-cv deaths % Placebo Candesartan Candesartan Placebo CV death HR 0.88 (95%CI ), p=0.012 Adjusted HR 0.87, p= Candesartan Non-CV death Placebo p= years

37 CHARM - Low EF (Alternative and Added) All-cause death % HR 0.71 p<0.001 HR 0.78 p<0.001 Placebo 708 (31.0%) 642 (28.0%) 20 Candesartan Number at risk Candesartan Placebo HR 0.88 (95% CI ) p=0.018 years

38 CHARM - Low EF trials CV death or CHF hospitalisation Candesartan Placebo Test for interaction ACEi+Bb+ No 778/ /2159 Spiro Yes 39/ / 128 ACE No 333/ /1015 inhibitors Yes 484/ /1272 Beta- No 432/ /1023 blocker Yes 385/ /1264 Spirono- No 602/ /1839 lactone Yes 215/ / 448 Overall 817/ /2287 Young et al, Circulation Candesartan better Hazard ratio Placebo better p=0.93 p=0.26 p=0.75 p=0.26

39 All cause mortality and relative risk reduction (RRR) at 12 months Proportion of patients with events, % RRR Investigational drug Baseline therapy Placebo Investigational drug SOLVD MERIT-HF CHARM low EF 23% ACE-I diuretic, digoxin 34% beta-blocker diuretic, digoxin ACE-I 33% Candesartan diuretic, digoxin ACE-I, spironolactone, beta-blocker Young et al, Circulation 2004

40 Optimal blockade of the RAA-System in chronic heart failure ACE-i should be used at maximal tolerated dose if not tolerated an ARB should be given The combination of ACE-i/ARB more effective than ACE-i alone in symptomatic patients with CHF with LVEF<0.40 Spironolactone should be added if patient has severe symptoms (class (III-)IV)

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