Heart failure randomized clinical trials: how we changed standard of - PowerPoint PPT Presentation

Heart failure randomized clinical trials: how we changed standard of care. Karl Swedberg Senior professor of Medicine University of Gothenburg Professor of Cardiology Imperial College, London Disclosures: Honoraria/Consultancy: Amgen, Astrazeneca, Novartis, Pfizer, Servier, Vifor Research grants: Amgen, Servier

Treatment of heart failure From two textbooks 1929 and 1974 ”…and for all this there is only digitalis and rest…” Paul Dudley White: Textbook in Cardiology, 1929 Moderately severe heart failure Decrease physical activity Institute digitalis Give thiazide every day plus potassium If not enough use furosemide and if insufficient, combine them J Willis Hurst 1920-2011 J W Hurst: The Heart 3rd edition, 1974

ESC HF Guidelines 2012

Beta-blockade in heart failure Beta-blockade in heart failure Slow introduction of efficient therapy Slow introduction of efficient therapy •1975 •First report (Waagstein et al) •1979 •Indication improved survival (Swedberg et al) •? ? • •1993 •! ! • •Confirmed in large clinical trials •to •carvedilol, bisoprolol and metoprolol •1999 •

ACC/AHA Guidelines for the management of CHF 1995

ACC/AHA Guidelines 1995 • ” use of beta-blockers for the treatment of chronic heart failure remains investigational, but the official status of beta- blockers may change as recent data are reviewed. Hence, physicians might consider the use of a beta-blocker in selected patients with chronic heart failure.”

US Carvedilol Programme COPERNICUS: COPERNICUS: Survival Survival Carvedilol 100 100 1.0 (n=696) 90 90 Carvedilol Carvedilol 0.9 Placebo 80 80 0.8 (n=398) Placebo Placebo 70 70 Risk reduction = 65% 0.7 Risk reduction = 35% p <0.001 60 60 p = 0.00013 0.6 p = 0.00013 0 0 0.5 0 0 3 3 6 6 9 9 12 12 15 15 18 18 21 21 0 50 100 150 200 250 300 350 400 Months Months Days Packer et al (1996) Packer et al (1996) Packer et al (2001) Survival Mortality 1.0 CIBIS-II (%) 20 MERIT-HF Placebo Bisoprolol 15 0.8 Metoprolol CR/XL 10 Placebo Risk reduction = 34% Risk reduction = 34% 5 0.6 p =0.0062 p <0.0001 0 0 0 200 400 600 800 0 3 6 9 12 15 18 21 Time after inclusion (days) Months of follow-up CIBIS-II Investigators (1999) The MERIT-HF Study Group (1999) CIBIS-II Investigators (1999) The MERIT-HF Study Group (1999)

Meta-analysis of 22 beta-blocker studies in CHF Brophy et al Ann Int Med 2001

ESC HF Guidelines 2012

Renin-angiotensin in aldosterone system · Vasoconstriction · Cell growth · Na/H 2 O retention · Sympathetic activation Angiotensinogen AT 1 Angiotensin I renin Angiotensin II X ACE AT 2 Aldosterone · Vasodilation Cough, Inactive · Antiproliferation Bradykinin Angioedema Fragments (kinins) Benefits? McMurray et al, , Circ 2004 Circ 2004 McMurray et al

Classes of RAAS-inhibitors Natriuretic peptides Givertz, M Circ. 2001

CONSENSUS •253 patients in NYHA class IV 253 patients in NYHA class IV • •Randomized to placebo/enalapril Randomized to placebo/enalapril • Mortality Mortality •From first patient to end of study 20 month From first patient to end of study 20 month • 1.0 •118 deaths 118 deaths • 0.9 0.8 0.7 0.6 0.5 p=0.002 0.4 0.3 Placebo 0.2 Enalapril 0.1 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Year Year Swedberg et al NEJM 1987 1987 Swedberg et al NEJM

Neuroendocrine Activation and Mortality Six Month Mortality (%) by Plasma Levels of Hormones From CONSENSUS I Placebo Group N=120 % % P<0.01 P<0.01 Modified from Swedberg et al 1990 Modified from Swedberg et al 1990

Worsening HF Mean dose enalapril 16.6 mg RR 0.84; (CI 0.74-0.95) p=0.007 Months

ACE-inhibitor Trials in Heart Failure/LV-dysfunction Mortality •Randomized large (>1000 patients), long-term (1 year) trials Randomized large (>1000 patients), long-term (1 year) trials • •ACEI vs. placebo ACEI vs. placebo • •12763 patients in 4 trials 12763 patients in 4 trials • 0.74 0.74 SAVE, AIRE, SAVE, AIRE, TRACE TRACE 0.87 0.87 SOLVD 0.80 Total Total 0.75 0.75 1.0 1.0 0.5 0.5 ACE-inhibitor ACE-inhibitor Better Better Worse Worse Flather et al Lancet 2000 Flather et al Lancet 2000

CONSENSUS 10-Year Follow-Up All Randomized Patients, Original and Follow-Up Mortality Mortality 1.0 0.9 0.8 p=0.008 0.7 0.6 0.5 0.4 0.3 Placebo 0.2 Enalapril 0.1 0.0 1 2 3 4 5 6 7 8 9 10 11 Year Year Swedberg et al EHJ 1999 Swedberg et al EHJ 1999

Classes of RAAS-inhibitors Natriuretic peptides Givertz, M Circ. 2001

VAL-Heft 5010 pts in NYHA class II (61.7%), III (36.2%) or IV (3.1%). 5010 pts in NYHA class II (61.7%), III (36.2%) or IV (3.1%). Mean EF 27% and mean age 62 years Mean EF 27% and mean age 62 years Background: ACEI 92.3%, Beta-blocker 35.5% Background: ACEI 92.3%, Beta-blocker 35.5% Placebo Valsartan RR (C.I.) P P Placebo Valsartan RR (C.I.) Primary endpoints N=2511 N=2499 Primary endpoints N=2511 N=2499 All cause mortality 484 (19.4%) (495(19.7%) 1.02 0.8 All cause mortality 484 (19.4%) (495(19.7%) 1.02 0.8 (0.9-1.15) (0.9-1.15) Mortality Mortality and all cause hosp. 801 (32.1%) 723(28.8%) 0.87 0.009 and all cause hosp. 801 (32.1%) 723(28.8%) 0.87 0.009 (0.79-0.96) (0.79-0.96) Cohn et al NEJM 2002 Cohn et al NEJM 2002

•All Cause Mortality in the Val-HeFT Trial 1.0 •Probability of Survival 0.9 P = 0.8 0.8 •n=5010 0.7 Valsartan Placebo 0 3 6 9 12 15 18 21 24 27 Time after randomization (months)

CHARM Programme 3 component trials (N=7601) comparing candesartan to placebo in patients with symptomatic heart failure CHARM CHARM CHARM Alternative Added Preserved n=2548 n=3025 n=2028 LVEF  40% LVEF >40% LVEF  40% ACE inhibitor ACE inhibitor ACE inhibitor treated treated/not treated intolerant Primary outcome for each trial: CV death or CHF hospitalization Primary outcome for Overall Programme: All-cause death 20

CHARM: Primary endpoint • % •50 •35 • % •Added •Overall •538 (42.3%) •30 •Placebo •40 •483 (37.9%) •945 (24.9%) •25 •886 (23.3%) •Placebo •30 •20 •Candesartan •15 •20 •Candesartan •10 •10 HR 0.85 (95% CI 0.75-0.96), p=0.011 •HR 0.91 (CI 95 % 0.83-1.00), p=0.055 •5 adjusted HR 0·85 (CI 95 % 0.75–0.96), p=0.010 • adjusted HR 0.90 (CI 95 % 0.82–0.99), p=0•032 •0 •0 •0 •1 •2 •3 •3.5 •anni •0 •1 •2 •3 •3.5 •anni •50 •30 • % • % •Alternative •Preserved •406 (40.0%) •366 (24.3%) •Placebo •25 •40 •Placebo •333 (22.0%) •334 (33.0%) •20 •30 •Candesartan •15 •Candesartan •20 •10 •10 HR 0.89 (CI 95 % 0.77-1.03), p=0.118 •HR 0.77 (CI 95 % 0.67-0.89), p=0.0004 •5 adjusted HR 0·86 (CI 95 % 0.74–1.0) p=0·051 adjustedHR 0.70 (CI 95 % 0·60–0·81), p<0.0001 •0 •0 21 •0 •1 •2 •3 •3.5 •anni •0 •1 •2 •3 •3.5 •anni

CHARM-Overall: All-cause death % 35 Placebo 30 945 (24.9%) HR 0.82 25 886 (23.3%) P<0.001 HR 0.70 20 Candesartan P<0.001 15 10 HR 0.91 (95% CI 0.83-1.00), p=0.055 5 Adjusted HR 0.90, p=0.032 0 0 1 2 3 3.5 years Number at risk Candesartan 3803 3563 3271 2215 761 Placebo 3796 3464 3170 2157 743 Pfeffer et al Lancet 2003 Pfeffer et al Lancet 2003 22

CHARM - Low EF trials All-cause death All cause death (%) 40 35 Placebo 708 (31.0%) 30 25 Candesartan 20 642 (28.0%) 15 10 Hazard ratio 0.88 (95% CI 0.79 – 0.98), 5 p=0.018 0 0 1 2 3 3.5 yrs Number at risk Candesartan 2289 2105 1894 1382 580 Placebo 2287 2023 1811 1333 548 Young et al Circ 2004 Young et al Circ 2004 23 CHARM Result meeting Hennekens 030827

Improving survival in CHF 1 year mortality SOLVD-T (1991) CIBIS-2 (1999) CHARM-Added (2003) (  blocker subgroup) RRR 21% RRR 33% RRR 30% diuretic diuretic diuretic diuretic diuretic diuretic digoxin digoxin digoxin digoxin digoxin digoxin ACE-I ACE-I ACE-I ACE-I ACE-I  blocker  blocker  blocker ARB

ESC HF Guidelines 2012

ACC/AHA Guidelines 1995 • ” trials support the use of ACE inhibitors in all patients with symptomatic heart failure, unless the inhibitors are contraindicated or not tolerated.”

Classes of RAAS-inhibitors Givertz, M Circ. 2001

RALES Randomized ALdactone Evaluation Study • 1663 pts HF (NYHA III or 30% risk reduction IV, EF <35%) • spironolactone vs. placebo • Endpoint: – Total mortality NEJM 1999 N Engl J Med., 341(10):709-17, 1999 Pitt et al NEJM 1999

Inclusion Criteria • Inclusion – > 55 years of age – NYHA functional class II – Ejection fraction < 30% (or, if between 30% and 35%, QRS >130 msec) – Treated with the recommended or maximally tolerated dose of ACE inhibitor (or an ARB or both) and a beta-blocker (unless contraindicated). – within 6 months of hospitalization for a cardiovascular reason [ or, if no such hospitalization, BNP > 250 pg/ml or Nt-pro-BNP >500 pg/ml (males) or 750 pg/ml (females).] • Exclusion – Serum potassium > 5.0 mmol/L – eGFR < 30 ml/min/1.73 m 2 – Need for a potassium-sparing diuretic – Any other significant comorbid condition.