ACE inhibitors: still the gold standard?

Transcription

1 ACE inhibitors: still the gold standard? Session: Twenty-five years after CONSENSUS What have we learnt about the RAAS in heart failure? Lars Køber, MD, D.Sci Department of Cardiology Rigshospitalet University of Copenhagen Denmark Heart Failure congress 2012 Belgrade 1

2 Presenter Disclosure Information Lars V Køber ACE inhibitors: still the gold standard? FINANCIAL DISCLOSURE: Speaker for Sanofi-Aventis, Novartis, Astra-Zenca, Servier UNLABELED/UNAPPROVED USES DISCLOSURE: None 2

3 Optimal medical therapy in Heart Apr Failure Guy s hospital pill Mercury based diuretics + leaves from folium digitalis 3

4 Lasted 150 years Digoxin Diuretics ACEi Betablocker Angiotensin receptor blocker (ARB) Aldosterone Receptor Antagonist (MRA) 4

5 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)

6 Medical therapy in HF One size fits all 6

7 Heart Failure with reduced ejection fraction vs. preserved ejection fraction HFREF vs. HFPEF No agreement on where to put the cut-off value in LVEF between HFPEF and HFREF Most often: >40-50%

8 MAGGIC SG;Eur Heart J HF collaborative group Individual data from > with HF and LVEF available Adjusted for baseline differences

9 Guidelines ESC guidelines: No proven therapy for patients with HFPEF RAAS is involved in many aspects of HFPEF (hypertension, LV hypertrophy, myocardial fibrosis), thus blockers of the RAAS would be logical

10 PEP-CHF Cleland J G et al. Eur Heart J 2006; 27:

11 CHARM-Preserved Primary outcome, CV death or CHF % Number at risk 0 hospitalisation Placebo similar 10 in the two treatment groups (170 vs 170, 0 99 Candesartan Placebo (24.3%) 333 (22.0%) The number of Candesartan 15 individuals experiencing cardiovascular deaths were [ ], 5 p=0 92), HR as 0.89 were (95% non-cardiovascular CI ), p=0.118 deaths (74 vs 67, 1 10 [ ], Adjusted p=0 59). HR 0.86, p= years Yusuf et al, Lancet 2003; 362:

12 I-PRESERVE primary endpoint Death or hospitalization for prespecified CV cause (worsening HF, MI, stroke, UAP, ventricular or atrial arrhythmias) HR: 0.95 (0.86 to 1.05) P = 0.35) Death as part of PE: 221 (Irb) vs. 226 Total death: 445 (Irb) vs. 436 Massie et al NEJM 2008 ;359:

13 HFPEF treatment: not resting on solid ground

14 Heart Failure with reduced ejection fraction A series of well conducted randomized trials showing clinical meaningful reduction in mortality with ACEi/ARB Beta-blockers Mineralocorticoid receptor antagonist (MRA)

15 ACEi SURVIVAL MORTALITY Placebo p< Enalapril CONSENSUS 0 0 N Engl J Med 1987;316: MONTHS

16 ACEi SURVIVAL p = Placebo n=1284 % MORTALITY n = 2589 CHF - NYHA II-III - EF < SOLVD (Treatment) N Engl J M 1991;325: Enalapril n= Months

17 Asymptomatic LV dysfunction Hvilken behandling? SOLVd prevention EM 1992 Pfeffer NEJM 1992;327:

18 Implementation and interpretation Guidelines: Enalapril 10 mg BID CONSENSUS: 20 mg BID NYHA III-IV; NNT: 6-7 in order to prevent 1 death within 1 year SOLVD prevention: 10 mg BID NYHA II-III; NNT: in order to prevent 1 death within 4 years

19 Probability of Event SAVE Radionuclide EF 40% AIRE Clinical and/or radiographic signs of HF All-Cause Mortality TRACE Echocardiographic EF 35% 15 months Placebo ACE-I Placebo: 866/2971 (29.1%) ACE-I: 702/2995 (23.4%) OR: 0.74 ( ) Years ACE-I Placebo Flather MD, et al. Lancet. 2000;355:

20 Prolongation of life - Trace Years At risk Pla At risk Tra Mortality Lives saved per 1000 treated Placebo Trandolapril Difference in median lifetime 15.3 months Lancet 1999; 354:9-12

21 Prolongation of median survival Trace subgroups Subgroup n Median Prolongation lifetime Months % Placebo ACEi Hypertension m No Hypertension m Diabetes m No Diabetes m LVEF< m LVEF> m

22 Survival 1.0 Comparison with ARB Elite II primary endpoint Captopril - n= events Losartan - n= events RR= 0.88 (95%CL ) p= Days - follow-up

23 Is losartan 50 mg OD better than placebo? Risk of ACE Elite II 0.88 ( ) p=0.16 SOLVD treatment 0.84 ( ) p=0.004 (ACEi vs. Placebo)

24 Mortality Valiant post AMI - 3 arms Reduced LVEF and/or clinical HF Captopril Valsartan Valsartan + Captopril Months 0.05 Valsartan vs. Captopril: HR = 1.00; P = Valsartan + Captopril vs. Captopril: HR = 0.98; P = Captopril Valsartan Valsartan + Cap Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

25 Average dose of ACEi after admission for HF ACEi Day 0-30 Day Day years (mg) Trandolapril (4) Ramipril (10) Enalapril (20) Captopril (150) Gislason, Circ 2007;116:737-44

26 Interpretation Dosage of ACEi seems to be important (and we have not doing a particularly good job up-titrating)

27 Conclusions Are ACEi still the gold standard? Yes - In patients with reduced LVEF ACEi are still the gold standard

28 HF Guidelines 2012 The medical treatment flow chart 28

29 Heart Failure Guidelines 2012

30 Conclusions Are ACEi still the gold standard? Yes - In patients with reduced LVEF ACEi are still the gold standard Prolongation of life is substantial The dose may be important In patients with preserved LVEF HF treatment with ACEi has not been proven to be of any value

31 ARE we on the right track searching for newer ways to block the RAAS?