Beyond neuro-hormonal blockade

Transcription

1 Beyond neuro-hormonal blockade Giuseppe M.C. Rosano, MD, PhD, MSc, FESC, FHFA St George s Hospitals NHS Trust University of London KCS Congress: Impact through collaboration CONTACT: Tel kcardiacs@gmail.com Web:

2 Disclosures I have no conflicts of interest for this talk Travel and accommodation provided by Les Laboratories Servier

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4 Last decades in chronic heart failure - outstanding reduction in mortality Landscape at the beginning of the 21 st century Mortality of patients with chronic HF (Italy ) IN CHF Courtesy A. Maggioni

5 History of the landmark trials in HF captopril propranolol spironolactone Potential benefit: vasodilatation CONSENSUS SOLVD V-HeFT II SAVE, ISIS-4 Hy-C USCP losartan OPTIMAAL Beta-blockers contra-indicated: 1973; (-) Sweden inotropic Waagstein effects et al. CIBIS MDC ; Swedberg et al. Lancet; Br Heart J Recognition of neurohormonal activation AIRE, TRACE MERIT-HF CIBIS II CIBIS III SENIORS COMET COPERNICUS CHARM Val-HeFT ELITE II VALIANT RALES SHIFT EMPHASIS - HF EPHESUS PARADIGM HF

6 IN-HF Outcome registry 1-year mortality Worsening HF: 27.7% De Novo HF: 19.2% Chronic HF: 5.9% Maggioni A, Ital Cardiol 2012;13:23S-30S

7 Is neuro-hormonal blockade enough?

8 IN-HF Outcome registry 1-year mortality Worsening HF: 27.7% De Novo HF: 19.2% Chronic HF: 5.9% Maggioni A, Ital Cardiol 2012;13:23S-30S

9 Elevated HR at discharge is an predictor of one-year mortality in HF patients (OFICA) N=1658 (170 hospitals); HR at discharge 71 bpm; 1 year mortality: 33% 41% Logeart D, et al. Eur Heart J 2012;33 - Abstract Supplement 485

10 Patients (%) HF registries: more than 50% of patients have heart rate 70 bpm IMPACT RECO III 1407 patients HF OUTCOME* 3480 patients ESC PILOT HF** 2450 patients HR 70 bpm HR >75 bpm HR >80 bpm

11 Failure to reach target dose of β-blockers in clinical practice IMPACT RECO III, 1407 patients 1 Patients, % Patients achieving target doses of BB in OPTIMIZE-HF, 5791 patients with HF 2 Patients, % % % % 7.9% 0 Target dose At least 50% of the target dose 0 Carvedilol Metoprolol XL 1-P. de Groote et al. Eur J Heart Fail 2007;9, ; 2-Fonarow GC et al Am J Cardiol 2008;102:

12 Failure to achieve target dose of BB - CIBIS-ELD: RCT aimed to reach guidelines-recommended target doses HF patients: NYHA class II, 65 years old; without contraindications or intolerance to BB) Dose level achieved after 12 weeks Bisoprolol Carvedilol 25% >50% % Dungen HD et al. Eur J Heart Fail 2011;13,

13 Reasons for non reaching target dose - CIBIS-ELD: RCT aimed to reach guidelines-recommended target doses HF patients: NYHA class II, 65 years old; without contraindications or intolerance to BB) Selected adverse effects Bisoprolol, % Carvedilol, % Worsening heart failure Bradycardia New AV block Hypotension Fatigue/ drowsiness Vertigo Pulmonary Renal dysfunction Dungen HD, et al. Eur J Heart Fail 2011;13,

14 Dose vs Outcome MERIT-HF Cause-specific Mortality Total mortality Both dose groups Low-dose meto CR/XL High-dose meto CR/XL Sudden death Both dose groups Low-dose meto CR/XL High-dose meto CR/XL Death from worsening CHF Both dose groups Low-dose meto CR/XL High-dose meto CR/XL 0.0 Favors Meto CR/XL 1.0 Risk reduction 38% 44% 48% 14 Wikstrand J et al, JACC 2002;40:491-8 Relative risk and 95% confidence interval

15 Relation between magnitude of heart rate reduction with beta-blockers and outcomes in heart failure Death (log risk ratio) Heart rate reduction (bpm) McAlister FA, et al. Ann Intern Med. 2009:150:

16 Primary composite endpoint Cumulative frequency (%) Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY) Ivabradine Placebo HR = 0.82 p< % Months Swedberg et al. Lancet 2010; 376:

17 Primary composite endpoint according to heart rate* in the ivabradine group Patients with primary composite endpoint (%) 50 After Adjustment for Change in Heart Rate at 28 Days: HR 0.95, , p = bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm <60 bpm Day Months HR 0.82, , p =

18 Drugs that reduce mortality in heart failure with reduced ejection fraction 0 ACEi Beta-blockers* MRAs** Ivabradine*** LCZ696**** *in stable patients receiving ACEi ** in patients receiving ACEi and beta-blockers *** in patients with HR >75 bpm receiving ACEi, beta-blockers and MRAs **** in patients with elevated natriuretic peptides receiving ACEi, beta-blockers and MRAs

19 Pharmacological treatments recommended in selected patients with symptomatic (NYHA Class II-IV) HFrEF Available online on Eur J Heart Fail

20 Cumulative incidence of all-cause hospitalisations following first hospitalisation for heart failure Effect of ivabradine on all-cause hospitalizations in the 3 months after a first hospital admission for HF IRR=0.75 P=0.03 IRR=0.79 P=0.04 Placebo Ivabradine 0.2 IRR=0.70 p< Time (days) after hospital admission for heart failure Vulnerable phase Komajda M et al. Eur J Heart Fail. 2016; doi: /ejhf.582

21 Effect of ivabradine on repeated hospitalisations Ivabradine was associated with 13% more days alive out of hospital

22 NNT for Ivabradine in Heart Failure patients Primary endpoint First HF hospitalization Reccurent HF hospitalization First all cause hospitalization Reccurent all cause hospitalization Rogers JK et al Curr Med Res Opin Sep 11:1-7.

23 Effect of early combination therapy ivabradine/beta-blockers versus beta-blockers alone in patients hospitalised with HFrEF (ETHIC-AHF) Percentage of patients with heart rate values <70 bpm. International Journal of Cardiology, Volume 217, 2016, 7 11

24 % change compared to baseline Primary endpoint Change in exercise capacity CARVIVA -HF * * * * 0 MVO2 Exercise cap 6 MWT *P<0.01 vs baseline. P<0.01, P<0.02 vs carvediolol Ivabradine Carvedilol Combination Volterrani M et al. Int J Cardiol 2011

25 Ivabradine in patients unable to tolerate BB Available online on Eur J Heart Fail

26 Pharmacological treatments recommended in patients with symptomatic (NYHA Class II-IV) HFrEF and IHD/CAD Available online on Eur J Heart Fail

27 Normal LV Myocardium Failing LV Myocardium Sabbah et al., J Mol Cell Cardiol 24: , 1992

28 (µmol glucoseunits x min -1 ) (µmol x min -1 ) Carbohydrate and FFA metabolism in Heart Failure Carbohydrate Oxidation * Fatty Acid Oxidation * Normal Heart Failure Patients 0 * p < 0.05 vs. control Normal Heart Failure Patients Paolisso et al, Metabolism 43:174, 1994

29 Agents acting on cardiac metabolism Metformin GLP1 Glucose Pyruvate Pyruvate Trimetazidine Carnitine palmitoyl transferase 1 inhibitor Free fatty acids Niacin Acyl CoA Metformin PDH Parexhelline Etomoxir - ß - OX AA Dichloroacetate Acetyl CoA ATP/O 2 = 6.3 ATP/O 2 = 5.6 Krebs cycle Bendavia

30 Effect of trimetazidine in elderly patients with heart failure EF WMSI LVEDD LVESD Min-Max Median 25%-75% Vitale C et al. Eur Heart J 2004; 25:

31 Meta-analysis of the effect of trimetazidine on LVEF in patients with HFrEF Gao D et al. Heart 2011;97: by BMJ Publishing Group Ltd and British Cardiovascular Society

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34 How optimise treatment beyond neurohormonal control 1. ACEi beta-blockers (slow increase) MRAs 2. Ivabradine in all patients in SR 3. LCZ696 in all patients who remain symptomatic 4. Trimetazidine in all patients with ischaemic origin or underlying CAD/diabetes 5. IV Iron in all iron-deficient patients

35 Available on Eur J Heart Fail

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37 4 days of scientific exchange healthcare professionals abstracts and cases submitted 120+ scientific sessions 300+ expert faculty members 100+ countries represented 45+ industry sessions /workshops Call for abstracts: 3 November - 13 January