Herzinsuffizienz: Die Neue Leitlinien
Carsten Tschöpe Kardiologie, Campus Virchow Klinikum
Berlin
1
Stadiengerechte Basistherapie 2012 NYHA I
NYHA II
NYHA III
NYHA IV
ACE – Hemmer (AT1 Blocker) Beta-Blocker
Aldosteronantagonismus Ivabradin Digitalis Diuretika Defi/CRT 4
Weiterhin bestehende hohe Mortalität bei der Herzinsuffizienz
Reduction in relative risk of mortality vs placebo
ACEI*
β-blocker*
MRA*
ARB*
16%
17%
(4.5% ARR; mean follow up of 41.4 months) SOLVD-T1,2
(3.0% ARR; median follow-up of 33.7 months)
30% 34% (5.5% ARR; mean follow up of 1.3 years) CIBIS-II3
(11.0% ARR; mean follow up of 24 months) RALES4
CHARMAlternative5
Iva
19% Shift
However, significant mortality remains: ~50% of patients die within 5 years of diagnosis 6–8
1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD Investigators. N Engl J Med 1991;325:293–302; 3. CIBIS-II Investigators. Lancet 1999;353:9–13; 4. Pitt et al. N Engl J Med 1999;341:709-17;–50; 5. Granger et al. Lancet 2003;362:772–6; 6. Go et al. Circulation 2014;129:e28-e292; 7. Yancy et al. Circulation 2013;128:e240–327; 8. Levy et al. N Engl J Med 2002;347:1397–402
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Ponikowski P, et al. Eur J Heart Fail 2016 & EHJ 2016 (online available) 6
Recommendations for cardiac imaging in patients with suspected or established heart failure
HFrEF HFmrEF HfpEF
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Definition of heart failure with preserved (HFpEF), midrange (HFmrEF) & reduced ejection fraction (HFrEF)
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Recommendations for treatment of patients with HF with preserved ejection fraction and heart failurewith mid-range ejection fraction
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Recommendations for diagnostic tests in patients with heart failure
Eisenkapazität
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II a - Indikation Eisendefizienz CONFIRM-HF Effekt von iv Eisengaben
Ponikowski et al EHF 201511
Gregory Lewis, presented at AHA Scientific Sessions 2016 14
Gregory Lewis, presented at AHA Scientific Sessions 2016 15
Recommendations to prevent or delay the development of overt heart failure or prevent death before the onset of symptoms
1. Metformin 2. Metformin plus Empagliflozin Ziel Hba1c bei DM und HF > 7%
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SGLT-2 Hemmer - Renale Glucose Re-Absorption wird blockiert Fast die gesamte gefilterte Glucose wird im proximalen Tubulus durch die sodium glucose co-transporter SGLT-2 und SGLT-1 re-absorbiert, In gesunden Individuen filtern die Glomeruli wobei SGLT-2 für ca. 90% in dem S1+S2 Segment, ca. 180 g Glucose pro Tag und SGLT-1 für ca. 10% in dem S3 Segment zuständig ist
Glucose
SGLT-2
~90% SGLT-1
~10%
Lee YJ, Han HJ. Kidney Int Suppl 2007
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Cardiovascular Death
3.7% vs 5.9% 38% relative risk reduction
EMPA-REG, NEJM 2015
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Hospitalization for Heart Failure
2.7% vs 4.1% 35% relative risk reduction
EMPA-REG, NEJM 2015
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Medikamentöse Therapie bei HFrEF
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Medikamentöse Therapie bei HFrEF
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Nicht-linearer Zusammenhang zwischen Ruheherzfrequenz und Auftreten von Herzinsuffizienz Metaanalyse: Ruheherzfrequenz als Risikofaktor für Auftreten von Herzinsuffizienz; n = 7.073 (1.181 x Inzidenz Herzinsuffizienz)
Kahn et al., J Am Heart Assoc. 2015;4:e001364
Therapeutic algorithm for a patient with symptomatic HF with reduced ejection fraction. (cont..)
The Do`s and Don`ts of CRT
NO
Yes
Ruschitzka HFA 2016 mod. Cleland EHJ 2013
Therapeutic algorithm for a patient with symptomatic HF with reduced ejection fraction. (cont..)
Therapeutic algorithm for a patient with symptomatic HF with reduced ejection fraction. 2016 ESC Guideline - Sacubitril/valsartan
• ESC-HF guidelines provide strong Class I recommendation for sacubitril/valsartan • Endorsement showing in section 7.3.2 of 2016 Guidelines, discussed in light of PARADIGM-HF Pharmacological treatments indicated in patients with symptomatic (NYHA Class II-IV) HFrEF Recommendations
Class
Level
An ACEi is recommended, in addition to a beta blocker, for symptomatic patients with HFrEF to reduce the risk of HF hospitalization and death
I
A
A beta blocker is recommended, in addition an ACEi, for patients with stable, symptomatic HFrEF to reduce the risk of HF hospitalization and death
I
A
An MRA is recommended for patients with HFrEF, who remain symptomatic despite treatment with an ACEi and a beta-blocker, to reduce the risk of HF hospitalization and death
I
A
Sacubitril/valsartan is recommended as a replacement for an ACEi to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACEi, a beta-blocker and an MRA*
I
B
*Patient should have elevated natriuretic peptides (plasma BNP ≥150 pg/mL or plasma NT-proBNP ≥600 pg/mL, or if HF hospitalization within the last 12 months, plasma BNP ≥100 pg/mL or plasma NT-proBNP ≥400 pg/mL) and able to tolerate enalapril 10 mg b.i.d. ACC, American College of Cardiology; AHA, American Heart Association; ACEI, angiotensin-convertingenzyme inhibitor; ARB, angiotensin II receptor blocker, ARNI, angiotensin receptor neprilysin inhibitor; CV, cardiovascular; ESC, European Society of Cardiology; HF, heart failure; HFSA, Heart Failure Society of America; HFrEF, HF with reduced ejection fraction; NYHA, New York Heart Association
Ponikowski et al. Eur Heart J. 21 May 2016. doi:10.1093/eurheartj/ehw128 Yancy et al. J Am Coll Cardiol. Published 21 May 2016. doi:10.1016/j.jacc.2016.05.011;
Therapeutic algorithm for a patient with symptomatic HF with reduced ejection fraction.
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Yancy et al JACC 2016
LCZ696 verstärkt die vorteilhaften Effekte des NP Systems und hemmt gleichzeitig nachteilige Effekte des RAAS LCZ696 Sacubitril (Prodrug) Valsartan
↑ANP ANP BNP ↑BNP
CNP ↑CNP
NPR-A
NEP-Inhibitor
ANP ANP BNP BNP CNP CNP
NPR-B
(aktiver Metabolit [LBQ657])
NPR-C Neprilysin
GTP
GTP Endozytose
↑cGMP cGMP
AT1 Rezeptor
Rezeptorrecycling
SignaSignalkaskade kaskade
Inaktivierung der NP
Vasodilation
Vasokonstriktion
Kardiale Fibrose/Hypertrophie
Kardiale Fibrose/Hypertrophie
Natriurese/Diurese
Natrium-/Wasser-Retention
Levin et al. N Engl J Med 1998; Gardner et al. Hypertension 2007; Molkentin. J Clin Invest 2003; Nishikimi et al. Cardiovasc Res 2006 8; Guo et al. Cell Res 2001; von Lueder et al. Circ Heart Fail 2013;
Primärer Endpunkt: CV-bedingter Tod oder erste Hospitalisierung wg. Herzinsuffizienz
Kumulative Wahrscheinlichkeit
1,0
Enalapril Sacubitril/Valsartan (LCZ696)
0,6 Hazard Ratio = 0,80 [95% CI: 0,73 - 0,87) p 150ms Sacubitril/Valsartan: 1b Indikation, EF < 35% und Symptomatik (NYHA II !) trotz Standardtherapie nach Absetzten von ACEI/ARB
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Case 1 NYHA II-Patient Parameter Gender Age, years
Value Female 55
Etiology
Ischemic cardiomyopathy
LVEF, %
35
Comorbidities NYHA class
DM, HTN II
Blood Pressure, mmHg
132/70
Heart Rate, bpm
66
E/E ´
15
Creatinine, mol/L
98
K, mEq/L
4.2
NT-proBNP, pg/mL Current Medication
LCZ 696?
1900 Ram 2x5mg, Meto 2x100mg, Torasemid 5mg, Eple 50mg
BNP=B-type natriuretic peptide; DM=Diabetes mellitus; HTN=hypertension; JVP=jugular venous pressure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NTproBNP=N-terminal pro-B-type natriuretic peptide
PARADIGM-HF: 70% NYHA II 70% of patients were NYHA class II – greater than in SOLVD-T (57%), possibly due to greater use of disease-modifying drugs/devices prior to enrolment in PARADIGM-HF
% of patients
NYHA class II 100 90 80 70 60 50 40 30 20 10 0
NYHA class III
100
80 73
70
69
57 49 30
50
30 24
24
20 0
SOLVD-T N=2569
CHARM-Added N=2548
HEAAL N=3834
RAFT N=1798
SHIFT EMPHASIS-HF PARADIGM-HF N=6505 N=2737 N=8442
McMurray et al. Eur J Heart Fail. 2014
Activation of the cardiac RAAS during CHF
Ang II Staining
Normal
20 Cardiac Ang II 15 Secretion 10 (pg/min/g) 79 patients 5 0 -5 -10
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DCM
ICM
*
*
* DCM ICM Normal
I II III IV --------------- NHYA ------------Serneri et al., Circ Res 88: 961-968, 2001
Heart failure is not stable ! “stabile” Phase NYHA II
“instabile” Phase
Cardiac / renal function
AHF “stabile” Phase NYHA II
Hospitalisation due to WHF Cardiac / Renalfunction
Time
1. Alla et al. Heart Fail Rev 2007;12:91–5; 2. Cleland et al. Eur Heart J 2003;24:442–636; 3. Gheorghiade et al. Am J Cardiol 2005;96:11G–17G
Beta-Blockers in patients with stable chronic Heart Failure: CIBIS-II-Study (1999)
CIBIS-II Investigators and Committes. Lancet 1999;353(9146):9-13.
Effect of treatments in „stable“ Heart Failure
Valsartan
Cohn et al. N Engl J Med 2001;345(23):1667-75.
Defi
Sport
63% NYHA II Stable HF
< Bardy et al. New Engl J Med 2005;352:225-37
O’Connor et al. JAMA 2009;301(14):1439-50
Case 1 NYHA II-Patient Parameter Gender Age, years
Value Female 55
Etiology
Ischemic cardiomyopathy
LVEF, %
35
Comorbidities NYHA class
DM, HTN II
Blood Pressure, mmHg
132/70
Heart Rate, bpm
66
E/E
`15
Creatinine, mol/L
98
K, mEq/L
4.2
NT-proBNP, pg/mL Current Medication
Would you consider prescribing LCZ 696 to this patient?
1900 Ram 2x5mg, Meto 2x100mg, Torasemid 5mg, Eple 50mg
BNP=B-type natriuretic peptide; DM=Diabetes mellitus; HTN=hypertension; JVP=jugular venous pressure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NTproBNP=N-terminal pro-B-type natriuretic peptide
NT-proBNP affects subsequent event rate NT-proBNP 1000
HR=0.41 (0.29,0.58) p 70bpm
Fortgeschrittene Therapie bei Beschwerden