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
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
Optimal medical therapy in Heart Apr. 1820 Failure Guy s hospital pill Mercury based diuretics + leaves from folium digitalis 3
Lasted 150 years Digoxin Diuretics ACEi Betablocker Angiotensin receptor blocker (ARB) Aldosterone Receptor Antagonist (MRA) 4
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)
Medical therapy in HF One size fits all 6
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%
MAGGIC SG;Eur Heart J. 2011 HF collaborative group Individual data from >45.000 with HF and LVEF available Adjusted for baseline differences
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
PEP-CHF Cleland J G et al. Eur Heart J 2006; 27:2338-2345
CHARM-Preserved Primary outcome, CV death or CHF % 30 25 20 Number at risk 0 hospitalisation Placebo similar 10 in the two treatment groups (170 vs 170, 0 99 Candesartan 1514 1458 1377 833 182 Placebo 1509 1441 1359 824 195 366 (24.3%) 333 (22.0%) The number of Candesartan 15 individuals experiencing cardiovascular deaths were [0 80 1 22], 5 p=0 92), HR as 0.89 were (95% non-cardiovascular CI 0.77-1.03), p=0.118 deaths (74 vs 67, 1 10 [0 79 1 52], Adjusted p=0 59). HR 0.86, p=0.051 0 1 2 3 3.5 years Yusuf et al, Lancet 2003; 362: 777 81
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 ;359:2456-67
HFPEF treatment: not resting on solid ground
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)
ACEi SURVIVAL MORTALITY 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Placebo p< 0.001 Enalapril CONSENSUS 0 0 N Engl J Med 1987;316:1429 1 2 3 4 5 6 7 8 MONTHS 9 10 11 12
ACEi SURVIVAL 50 40 p = 0.0036 Placebo n=1284 % MORTALITY n = 2589 CHF - NYHA II-III - EF < 35 30 20 10 SOLVD (Treatment) N Engl J M 1991;325:293 0 0 6 12 Enalapril n=1285 18 24 30 36 42 48 Months
Asymptomatic LV dysfunction Hvilken behandling? SOLVd prevention EM 1992 Pfeffer NEJM 1992;327:685-91.
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: 20-25 in order to prevent 1 death within 4 years
Probability of Event 0.4 0.35 0.3 SAVE Radionuclide EF 40% AIRE Clinical and/or radiographic signs of HF All-Cause Mortality TRACE Echocardiographic EF 35% 15 months 0.25 0.2 Placebo ACE-I 0.15 0.1 0.05 Placebo: 866/2971 (29.1%) ACE-I: 702/2995 (23.4%) OR: 0.74 (0.66 0.83) Years 0 0 1 2 3 4 ACE-I 2995 2250 1617 892 223 Placebo 2971 2184 1521 853 138 Flather MD, et al. Lancet. 2000;355:1575 1581
Prolongation of life - Trace 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Years At risk Pla At risk Tra 0 873 876 Mortality Lives saved per 1000 treated 32 55 87 66 64 64 Placebo 1 647 677 Trandolapril Difference in median lifetime 15.3 months 2 564 615 3 497 576 4 463 524 5 416 475 6 373 431 7 Lancet 1999; 354:9-12
Prolongation of median survival Trace subgroups Subgroup n Median Prolongation lifetime Months % Placebo ACEi Hypertension 400 32 m 39+4 120 No Hypertension 1349 62 m 10+4 16 Diabetes 237 22 m 23+8 104 No Diabetes 1512 64 m 11+4 17 LVEF<0.25 307 16 m 9+8 56 LVEF>0.25 1442 66 m 12+4 18
Survival 1.0 Comparison with ARB Elite II primary endpoint 0.8 0.6 0.4 0.2 Captopril - n=1574 250 events Losartan - n=1578 280 events RR= 0.88 (95%CL 0.75-1.05) p=0.16 0.0 0 100 300 300 400 500 600 700 Days - follow-up
Is losartan 50 mg OD better than placebo? Risk of ACE Elite II 0.88 (0.75-1.05) p=0.16 SOLVD treatment 0.84 (0.74-0.95) p=0.004 (ACEi vs. Placebo)
Mortality Valiant post AMI - 3 arms Reduced LVEF and/or clinical HF 0.3 0.25 0.2 Captopril Valsartan Valsartan + Captopril 0.15 0.1 Months 0.05 Valsartan vs. Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 0 0 6 12 18 24 30 36 Captopril 4909 4428 4241 4018 2635 1432 364 Valsartan 4909 4464 4272 4007 2648 1437 357 Valsartan + Cap 4885 4414 4265 3994 2648 1435 382 18 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Average dose of ACEi after admission for HF ACEi Day 0-30 Day 31-180 Day 181-360 - 5 years (mg) Trandolapril (4) 2 2 2 2 Ramipril (10) 5 5 5 5 Enalapril (20) 10 10 10 10 Captopril (150) 37.5 37.5 37.5 50 Gislason, Circ 2007;116:737-44
Interpretation Dosage of ACEi seems to be important (and we have not doing a particularly good job up-titrating)
Conclusions Are ACEi still the gold standard? Yes - In patients with reduced LVEF ACEi are still the gold standard
HF Guidelines 2012 The medical treatment flow chart 28
Heart Failure Guidelines 2012
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
ARE we on the right track searching for newer ways to block the RAAS?