ESC Guidelines for diagnosis and management of HF 2012: What s new? John Parissis, MD Athens, GR

ESC Guidelines for diagnosis and management of HF 2012: What s new? John Parissis, MD Athens, GR

Disclosures ALARM INVESTIGATOR RESEARCH GRANTS BY ABBOTT USA AND ORION PHARMA

The principal changes from the 2008 guidelines 1. An expansion of the indica2on for mineralocor2coid receptor antagonists (MRAs) 2. A new indica2on for the sinus node inhibitor ivabradine 3. An expanded indica2on for cardiac resynchroniza2on therapy (CRT) 4. New informa2on on the role of coronary revasculariza2on in HF 5. Addi2on of MR- proanp to biomarkers for HF diagnosis ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

Diagnostic algorithm for AHF: ESC guidelines 2012

The NYHA classification Class I No limitations on activity. No fatigue, breathlessness or palpitation on ordinary physical activity Annual mortality 3-5% Class II Patients are comfortable at rest but ordinary physical activity such as climbing stairs or doing housework results in symptoms Mild heart failure Annual mortality 10% Class III Patients have a marked limitation of physical activity. Although patients are comfortable at rest, less than ordinary physical activity will lead to symptoms Moderate heart failure Annual mortality 12-16% Class IV Patients have symptoms even at rest and are unable to undertake any physical activity without discomfort Severe heart failure Annual mortality 15-20% Adapted from ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure; Eur Heart J, 2008

Effect of β-blockade on Outcome in Patients With HF and Post-MI LVD Target HF Dosage Study Drug Severity (mg) Outcome US Carvedilol 1 carvedilol mild/ 6.25-25 48% disease progression moderate BID (P=.007) CIBIS-II 2 bisoprolol moderate/ 10 QD 34% mortality severe (P<.0001) MERIT-HF 3 metoprolol mild/ 200 QD 34% mortality succinate moderate (P=.0062) COPERNICUS 4 carvedilol severe 25 BID 35% mortality (P=.0014) CAPRICORN 5 carvedilol Post-MI LVD 25 BID 23% mortality (P=.031) SENIORS nebivolol mild/ moderate HF (plus preserved) reduces CV hosp 1 Colucci WS, et al. Circulation. 1996;94:2800-2806. 2 CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 3 MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 4 Packer M, et al. N Engl J Med. 2001;344:1651-1658. 5 The CAPRICORN Investigators. Lancet. 2001;357:1385-1390.

CHARM and Val-HeFT Trials Addition of candesartan 1 or valsartan 2 to ACEI and β-blocker in NYHA functional Class II-III 0%-10% lower risk of death (P>.05) 13%-15% lower risk of death or hospitalization for HF in both trials (both P<.01) Higher risk for hypotension, renal insufficiency, and hyperkalemia with ARB treatment 1 Pfeffer MA, et al. Lancet. 2003;362:759-766. 2 Cohn JN, et al. N Engl J Med. 2001;345:1667-1675.

ARBs: Stage C Heart Failure Class I Indication: ARBs approved for HF are recommended in patients with current or prior symptoms of HF and reduced LVEF who are ACEI intolerant Level of Evidence: A Class IIa Indication: ARBs are reasonable to use as alternatives to ACEIs as first-line therapy for patients with mild to moderate HF and reduced LVEF, especially for patients already taking ARBs for other indications Level of Evidence: A Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005

ARBs: Stage C Heart Failure (cont d) Class IIb Indication: The addition of an ARB may be considered in persistently symptomatic patients with reduced LVEF who are already being treated with conventional therapy (ie, ACEI and β-blocker) Level of Evidence: B Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005

Aldosterone s Role in Cardiovascular Disease Prothrombotic effects Vascular inflammation and injury Potassium and magnesium loss Myocardial fibrosis Catecholamine potentiation Deleterious Effects of Aldosterone Sodium retention Ventricular arrhythmias Cardiovascular Disease Central hypertensive effects Endothelial dysfunction McMahon EG. Current Opinion Pharmacol. 2001;1:190-196.

Mineralocorticoid Receptor Antagonists (MRAs) in Heart Failure Survival 30% RR, P < 0.001 Total Mortality 15% RR, P=0.008 1.00 0.90 0.80 Spironolactone 20 Placebo 0.70 0.60 0.50 Placebo 10 Eplerenone 0.40 0 6 12 18 24 30 36 Months 0 0 6 12 18 Months 24 30 36 RALES (LVSD, CHF severe symptoms) PiV B, Zannad F, Remme WJ, et al. N Engl J Med. 1999 EPHESUS (LVSD + HF ater MI) PiV B, Remme W, Zannad F, et al. N Engl J Med. 2003

EMPHASIS TRIAL EMPHASIS-HF Investigators (29 countries, 278 sites) 2737 Randomized 1364 Randomized to eplerenone 25-50 mg/d 1373 Randomized to placebo 4 did not start study drug 17 lost to follow up 4 did not start study drug 15 lost to follow up Median follow-up time 21 months, 4783 patient-years of follow-up

Primary Endpoint Cardiovascular Death or Hospitalization for HF 50 40 HR [95% CI] = 0.63 [0.54, 0.74] P < 0.0001 Placebo 356 (25.9%) Primary Endpoint: Cumulative K- M Rate (%) 30 20 10 Eplerenone 249 (18.3%) 0 0 1 2 3 No. at Risk Years from Randomization Placebo 1373 848 512 199 Eplerenone 1364 925 562 232 *Unadjusted HR 0.66; 0.56, 0.78; p<0.0001

Mortality From Any Cause 40 HR [95% CI] = 0.76 [0.62, 0.93] P = 0.0081 All-Cause Mortality: Cumulative K-M Rate (%) 30 20 10 Placebo 213 (15.5) Eplerenone 171 (12.5) 0 0 1 2 3 No. at Risk Years from Randomization Placebo 1373 947 587 242 Eplerenone 1364 972 625 269 *Unadjusted HR, 0.78; 0.64, 0.95; p=0.01

New ESC guidelines: expanded indications for MRA ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

Heart rate as a risk factor in patients with heart failure SHIFT placebo arm (3264 pa2ents with heart failure and LVSD) 50 40 Patients with first hospital admission for HF (%) P<0.001 87 bpm 30 20 10 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm 0 0 6 12 18 24 30 Months Böhm M et al. Lancet 2010;376:886-94

SHIFT: Baseline characteristics Ivabradine N=2052 Placebo N=2098 Mean age, years 60 60 Male, % 77 77 BMI, kg/m 2 28 28 Mean HF duration, years 3.4 3.4 HF ischemic cause, % 66 65 NYHA class II, % 48 47 NYHA class III, % 50 51 Mean LVEF, % 28.7 28.5 Mean HR, bpm 84.3 84.6 Böhm M, et al. Clin Res Cardiol. 2012 ;102:1-12.

SHIFT:Effect of ivabradine on primary outcome (CV death or HF hospitalization) Hazard ratio=0.76 Patients with primary composite end point (%) 40 30 20 10 P<0.0001 Placebo Ivabradine 0 0 6 12 18 24 30 Time (months) Böhm M, et al. Clin Res Cardiol. 2012 ;102:1-12.

How to define an optimal HR for CHF patients? Outcomes in the ivabradine group according to HR achieved at 28 days 35 30 25 20 15 10 CV death & HF hospitalization HF hospitalization 5 <60 60-64 65-69 70-74 75 HR at day 28, bpm Böhm M et al. Lancet 2010;376:886-94

New ESC guidelines: new indications for ivabradine New EMA indica2on Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfuncton, in patents in sinus rhythm and whose heart rate is 75 bpm, in combinaton with standard therapy including beta- blocker therapy or when beta- blocker therapy is contraindicated or not tolerated ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

Ivabradine in the management of systolic CHF: new ESC Guideline ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

Heart Failure Guidelines and Clinical Practice (Please mind the gap)

Dangers by not minding the gap

Overall, only 25% of patients are discharged from hospital receiving ACE/ARB + BB combination therapy, suggesting poor compliance with guidelines (ALARM REGISTRY) Oral heart failure medications on discharge All patients receiving BB + ACE or ARB + Aldo Inhibitor Mexico 5% 16% 16% 20% 20% 25% 19% 31% 38% 60% Brazil Australia Turkey Greece UK Spain Italy Germany 0% 10% 20% 30% 40% 50% 60% 70% Sample =All discharged/surviving AHF patients, 4491 France Mebazaa A, Parissis J, Porcher R, et al. Intensive Care Med 2011 Feb;37(2):290-301

Women with HF are under-treated in real world β-blockers 25 p=0.026 11.1% in females vs 10.5% in males, p=0.475 20 Percentage (%) 15 10 5 0 WOMEN MEN Parissis et al. Int J Cardiol 2012 December 2012

Maggioni A P et al. Eur J Heart Fail 2010;12:1076-1084

EURObservational Research Programme: The Heart Failure Pilot Survey (ESC-HF Pilot) Maggioni A P et al. Eur J Heart Fail 2010;12:1076-1084

ESC Guidelines 2012

ESC guidelines 2012

Heart Failure with preserved EF-HFpEF 3032 pts Candersartan in Heart Failure 850 pts Perindopril for Elderly with Chronic Heart Failure 4128 pts Irbersartan in Chronic Heart Failure

Sleep-disordered breathing Angina

Acute Heart Failure: The Cinderella of HF Decompensated Chronic HF Pulnonary Edema Hypertensive HF Cardiogenic Shock Isolated Right HF ACS and HF ESC Classification, EHJ 2008.

ACUTE PULMONARY OEDEMA: PROGNOSTIC VALUE OF SBP Parissis J, Nikolaou M, Mebazaa A, et al. Eur J Heart Fail. 2010 Nov;12(11):1193-202

Treatment goals in AHF ESC Guidelines 2012.

Short-term Survival by Treatment Among Patients Hospitalized with Acute Heart Failure: The Global ALARM-HF Registry Using Propensity Scoring Methods 0.4 In-hospital mortality 0.3 0.2 0.1 Inotropes Whole cohort Diuretics Vasodilators 0.0 0 5 10 15 20 25 30 Days Mebazaa A, Parissis J, Porcher R, et al. Intensive Care Med 2011;137:290-301

Recommendations for the treatment of patients with acute heart failure

Recommendations for the treatment of patients with acute heart failure ESC Guidelines 2012.

The challenge of cardiac myocin activation - Target the force generating enzyme cardiac myosin ATPase, accelerating its activity. - Increase fractional shortening of cardiac myocytes without altering intracellular calcium levels in experimental models. Malic et al. AHA Scientific Sessions 2005 Dallas TX

Circ Heart Fail 2010;3:522-527

Effect of serelaxin on AHF symptoms (RELAX-AHF) Teerlink et al. Lancet 2013;381:29-39

Serelaxin for the treatment of AHF (RELAX-AHF) Teerlink et al. Lancet 2013;381:29-39