Management of chronic heart failure: update 2015 J. Parissis Attikon University Hospital Disclosures: received honoraria for lectures from Servier, Pfizer, Novartis
Discharges in Thousands Heart Failure Hospitalizations 1.0 Million Hospitalizations a Year and Rising 700 600 500 400 300 200 100 0 79 80 85 90 95 00 06 Years 30-Day Rehospitalization Rates in HF 24.8% (Medicare) Male Female The majority of patients hospitalized with HF were previously hospitalized with HF United States: 1979-2006 Source: NHDS/NCHS, NHLBI. Hospital Compare 2007-2010 10
Impact of ICDs on survival and recurrent hospitalization in advanced CHF Nazarian et al. Am Heart J 2005;150:955-60.
Economic burden of chronic HF Hospitalization accounts for most CHF-associated costs Stewart S et al. Eur J Heart Fail 2002;4:361 71
Κόζηος καρδιακής ανεπάρκειας: ελληνικά ζηοιτεία Μέσο κόστος ανά ασθενή: 3177,12 2504,72 551,60 J. Parissis et al. Int J Cardiol 2014 120,79 labwork medications hospitalization Cost variables absolute percent labwork 551,6 17,4% medications 120,79 3,8% hospitalization (ward) 2504,72 78,8% total 3177,12 100,0%
Πολσπαραγονηικό μονηέλο πρόβλευης κόζηοσς J. Parissis et al. Int J Cardiol 2014
Causes of Hospital Readmission for Heart Failure Over 2/3 of HF Hospitalizations Preventable Diet Noncompliance 24% Rx Noncompliance 24% 16% Inappropriate Rx Annals of Internal Medicine 122:415-21, 1995 19% Failure to Seek Care 17% Other 14
Diagnostic flowchart for patients with suspected HF ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
Established biomarkers for diagnosis: Greater value as a rule out approach BNP/NT-proBNP for diagnosis of CHF and ADHF Hs troponin for diagnosis of new ACS complicating HF Procalcitonin for diagnosis of infection MR-proANP for diagnosis of HF in grey zones of NPs N-gaL/ Cystatin-C for early diagnosis of acute kidney injury
Limitations of biomarkers for diagnosis of HF Their levels are affected by: - Age, gender, BMI, - Renal function, Hb levels - Timing of evaluation, - Type of HF (systolic vs diastolic, backward vs forward) - Severity of disease and background treatment (e.g beta blockers)
BACKGROUND HF guidelines still based on NYHA classification and LVEF 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
Evidence-Based Treatment for Heart Failure with Reduced LVEF Reduce Mortality Control Volume ACEI or ARB -Blocker ivabradine Aldosterone Antagonist Sodium Restriction* Diuretics* ICD* CRT an ICD* Hyd/ISDN* Treat Residual Symptoms Digoxin* *For select indicated patients. Enhance Adherence Education Disease Management Performance Improvement Systems Treat Comorbidities Aspirin* Warfarin* Statin* 18
Patients with primary composite end point (%) SHIFT:Effect of ivabradine on primary outcome (CV death or HF hospitalization) Hazard ratio=0.76 40 P<0.0001 Placebo 30 20 Ivabradine 10 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
ESC 2012
Prescription life saving medications at discharge (ALARM-HF) 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
Maggioni A P et al. Eur J Heart Fail 2010;12:1076-1084
ESC HF LONG TERM REGISTRY
Benefit from guideline-recommended therapies in CHF: IMPROVE-HF a plateau at 4 to 5 therapies Fonarow et al, J Am Heart Assoc 2012
New agents for the management of chronic heart failure - ARNI (Phase III) - Fenerenone (Phase II, ARTS) - Riaciquat ( Phase II, SOCRATES)
Angiotensin Receptor Neprilysin Inhibition LCZ696 Angiotensin receptor blocker Inhibition of neprilysin
Neprilysin inhibition potentiates actions of endogenous vasoactive peptides that counter maladaptive mechanisms in heart failure Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Inactive metabolites Neprilysin Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Neprilysin inhibition
Study Design Single-blind run-in period Double-blind period Enalapril LCZ696 LCZ696 200 mg BID 10 mg BID 100 mg 200 mg BID BID R 8399 patients randomized for ITT analysis Enalapril 10 mg BID 2 weeks 1-2 weeks 2-4 weeks M. Packer and JJV McMurray
PARADIGM-HF: Summary of baseline characteristics Characteristic* LCZ696 (n=4187) Enalapril (n=4212) Age, years 63.8 ± 11.5 63.8 ± 11.3 Women, n (%) 879 (21.0) 953 (22.6) Ischemic cardiomyopathy, n (%) 2506 (59.9) 2530 (60.1) LV ejection fraction, % 29.6 ± 6.1 29.4 ± 6.3 NYHA functional class, n (%) II III 2998 (71.6) 969 (23.1) 2921 (69.3) 1049 (24.9) SBP, mmhg 122 ± 15 121 ± 15 Heart rate, beats/min 72 ± 12 73 ± 12 NT pro-bnp, pg/ml (IQR) 1631 (885 3154) 1594 (886 3305) BNP, pg/ml (IQR) 255 (155 474) 251 (153 465) History of diabetes, n (%) 1451 (34.7) 1456 (34.6) Treatments at randomization, n (%) Diuretics 3363 (80.3) 3375 (80.1) Digitalis 1223 (29.2) 1316 (31.2) β-blockers 3899 (93.1) 3912 (92.9) Mineralocorticoid antagonists 2271 (54.2) 2400 (57.0) ICD 623 (14.9) 620 (14.7) CRT 292 (7.0) 282 (6.7) *mean ± standard deviation, unless stated McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: 10.1056/NEJMoa1409077.
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) 40 32 24 16 Enalapril (n=4212) LCZ696 (n=4187) 1117 914 Patients at Risk LCZ696 Enalapril 8 0 4187 4212 3922 3883 3663 3579 HR = 0.80 (0.73-0.87) P = 0.0000002 Number needed to treat = 21 0 180 360 540 720 900 1080 1260 Days After Randomization 3018 2922 2257 2123 1544 1488 896 853 249 236 JJV McMurray et al NEJM 2014 online
PARADIGM-HF: Summary of safety findings In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril the LCZ696 was: Less likely to cause cough, hyperkalemia or renal impairment Less likely to be discontinued due to an adverse event More hypotension, but no increase in discontinuations Not more likely to cause serious angioedema M. Packer and JJV McMurray
LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System % Decrease in Mortality 0% Angiotensin receptor blocker ACE inhibitor Angiotensin neprilysin inhibition 10% 15% 18% 20% 30% 20% 40% Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial Eur Heart J 2014 November
DIET Approach to the Patient With Heart Failure Diagnose Etiology Severity (LV dysfunction) Initiate Diuretic/ACE inhibitor -blocker MRAs Ivabradine Educate Diet Exercise Lifestyle CV Risk Titrate Optimize ACE inhibitor Optimize -blocker Optimize MRA Achieve optimal heart rate
Acute Heart Failure Syndrome(s) Acute heart failure (AHF) is defined as a rapid onset or change in the signs and symptoms of HF, resulting in the need for urgent therapy. Symptoms are primarily the result of severe pulmonary congestion due to elevated left ventricular (LV) filling pressures (with or without low cardiac output). AHFS can occur in patients with preserved or reduced ejection fraction (EF). Concurrent cardiovascular conditions such as coronary heart disease (CHD), hypertension, valvular heart disease, atrial arrhythmias, and/or noncardiac conditions (including renal dysfunction, diabetes, anemia) are often present and may precipitate or contribute to the pathophysiology of this syndrome
Clinical Outcomes in Patients Hospitalized with Acute Heart Failure All-cause mortality: In hospital 3-11% At 60-90 days 10-16% Readmissions: At 60-90 days 20-25% Mean length of stay 6-10 days Cuffe SM et al. JAMA. 2002; 287: 1541 Gheorghiade M et al. JAMA. 2004; 291: 1963 Gattis WA et al. J Am Coll Cardiol. 2004; 43: 1534 Cleland JGF et al. Eur Heart J. 2003; 24: 442
Classical therapies are insufficient to protect peripheral organs ESC HF pilot, ALARM-HF, ADHERE, SURVIVE demonstrated: Worsening of renal function (30-45%) Hepatic dysfunction (20-30%) Ongoing myocardial injury (Tn release) (30%) Hyponatremia, CNS abnormalities ( 12-20%)
iv Serelaxin: Rapid and sustained change in PCWP * * * * Ponikowski et al., Eur Heart J 2014;35:431 441
Changes over time for creatinine clearance Creatinine clearance significantly increased with serelaxin over 20 h of infusion 20% increase from baseline with serelaxin (1.20 [0.90, 1.60]) 24% decrease from baseline with placebo (0.77 [0.58, 1.01]) Statistically significant treatment difference of 39% in change from baseline: Ratio of LS mean ratio to baseline 1.39 [1.07, 1.81], p=0.0143 on post-hoc ANCOVA Creatinine clearance (ml/min) Ponikowski et al., Eur Heart J 2014;35:431 441 *
RELAX-AHF Effect of serelaxin on AHF symptoms Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects Inclusion criteria (1161pts) dyspnoea congestion on Rx Increased BNP/NT-proBNP GFR: 30-75ml/min Systolic BP>125 mm Hg. 48-h i.v. serelaxin or placebo (30 μg/kg per day) within 16 h from presentation Teerlink et al. Lancet 2013;381:29-39
RELAX-AHF Effect of serelaxin on 180d mortality Teerlink et al. Lancet 2013;381:29-39
Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in RELAX-AHF J Am Coll Cardiol 2013;61:196 206)
Ventricular function Natural History of Acutely Decompensated Heart Failure Discharge status and chronic optimization may prevent worsening Acute event With each event, hemodynamic alterations contribute to progressive ventricular dysfunction Time Gheorghiade M, De Luca L, Fonarow G, et al. Am J Cardiol 2005.