Herzinsuffizienz BNP-gesteuerte Therapie -

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3 der Universität Regensburg Herzinsuffizienz BNP-gesteuerte Therapie - Akademisches Lehrkrankenhaus Prof. Dr. med. Robert H.G. Schwinger Medizinische Klinik II Kardiologie Pneumologie Nephrologie Internistische Intensivmedizin

4 Biomarker BNP Diagnostik: Akute Dyspnoe vs. Akute Herzinsuffizienz Prognose Rehospitalisierung, Mortalität Therapiesteuerung Chronische Herzinsuffizienz Cost effectiveness +? Herzinsuffizienz-Diagnostik-BNP_ _1

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7 Synthese und Sekretion von BNP Herzinsuffizienz-Diagnostik-BNP_ _1

8 Normale Bedingung

9 BNP-Abhängigkeit von Geschlecht und Alter Luchner et al., Hypertension 2002; 39: Herzinsuffizienz-Diagnostik-BNP_ _1

10 BNP-Abhängigkeit von der Nierenfunktion GFR > 50 ml/h GFR < 50 ml/h Luchner et al., Hypertension 2002; 39: Herzinsuffizienz-Diagnostik-BNP_ _1

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12 Stress / AHF

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14 Natriuretische Peptide (NP): Druck- und Volumengesteuerte Freisetzung Semiquantitativer Marker für Cardiac stress, HF und korreliert zu Kardialer Dysfunktion Weder spezifisch für HI noch für Herzerkrankung Dysfunktion der NP bei HI mit deutlich erhöhtem inaktivem pro BNP BNP entsteht aus pro BNP und wird in das aktive BNP und NT-pro BNP gespalten BNP und NT probnp werden renal eliminiert und sind erhöht bei NI NT pro BNP wegen der längeren HWZ höher als BNP

16 Dyspnoe: Definitionen Dyspnoe (griechisch: pnoe = Atmung) Subjektiv empfundenes Gefühl der unangenehmen Atmungswahrnehmung American Thoracic Society (ATS): Subjektiv empfundene Atmungsbehinderung, die aus qualitativ unterschiedlichen Sensationen besteht und in ihrer Intensität variiert Patient empfindet subjektiv die Notwendigkeit einer gesteigerten Atemtätigkeit Ausprägung der Symptomatik Schwere der Erkrankung

17 Differenzialdiagnose Dyspnoe Dyspnoe Pulmonale Ursachen Kardiale Ursachen Hämatologisch/ metabolisch Andere Ursachen COPD Asthma Lungenfibrose Lungenödem Lungenembolie Pneumonie ARDS Atelektase Alveolitis Pneumokoniose Pleuritis Pleuraerguß Pneumothorax Neoplasien Sarkoidose Pulmonale Hypertonie Fremdkörperaspiration Glottisödem Trachealstenose Herzinsuffizienz KHK Klappenvitien Diastolische Dysfunktion Perikarderkrankungen Endokarditis Myokarditis Cor pulmonale Arrhythmien Angeborene Herzfehler Anämie CO-Vergiftung Hyperthyreose Urämie Coma diabeticum Psychogen / Hyperventilation Adipositas Schwangerschaft Thoraxdeformität Neurogen / neuromuskulär Rosenkranz S, Differentialdiagnose der Dyspnoe, 2008

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35 pg/ml LCZ696 significantly reduced levels of NT-proBNP, a marker of cardiac wall stress 2,500 NT-proBNP Consistently lower levels of NTproBNP were observed in LCZ696- treated patients, compared with enalapril-treated patients, as early as 4 weeks and sustained at 8 months 2,000 1,500 p<0.0001* p<0.0001* Unlike BNP, NT-proBNP is not a substrate for neprilysin 1,000 Levels of NT-proBNP reflect drug effects on cardiac wall stress Entry ENL LCZ 4 weeks 8 months Run-in Double-blind *p-values denote significant difference between the two treatment groups All patients received enalapril, followed by LCZ696, during the single-blind run-in period. Groups represented here show division by final randomization group = median Bars represent 25%/75% interquartile ranges for: LCZ696 Enalapril 35 Packer et al. Circulation 2015;131(1):54-61

36 Proportion of patients (%) Fewer HFrEF patients on LCZ696 were treated in the emergency department for worsening of heart failure and discharged without hospitalization HR 0.66 (95% CI: ) p=0.001 p=0.003 LCZ696 (N=4,187) Enalapril (N=4,212) p=0.003 p=0.003 n=102 n=150 n=78 n=111 n=15 n=27 n=9 n=12 n=12 Total number of patients visiting the emergency department once and multiple times n=15 n=27 n=9 n= Number of emergency department visits 36 Packer et al. Circulation 2015;131(1):54-61

37 Proportion of patients (%) Treatment with LCZ696 resulted in a lower likelihood of multiple hospitalizations for heart failure HR 0.79 (95% CI: ) p<0.001 LCZ696 (N=4,187) Enalapril (N=4,212) p< % fewer HFrEF patients were hospitalized more than once for heart failure with LCZ696 than with enalapril (n=170 and n=240, respectively; p=0.001) p<0.001 p<0.001 p<0.001 n=537 n=658 Total number of patients hospitalized for heart failure once and multiple times n=367 n=418 n=110 n=143 n=33 n=53 n=27 n= Number of admissions for heart failure 37 Packer et al. Circulation 2015;131(1):54-61

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54 Overactivation of the RAAS and SNS is detrimental in HFrEF and underpins the basis of therapy SNS β-blockers Natriuretic peptide system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy HFrEF SYMPTOMS & PROGRESSION Epinephrine Norepinephrine RAAS Ang II α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis RAAS inhibitors (ACEI, ARB, MRA) The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs 1 Benefits of β-blockers indicate that the SNS also plays a key role McMurray et al. Eur Heart J 2012;33: Figure references: Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012; ; Schrier & Abraham. N Engl J Med 2009;341:577 85;

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57 pg/ml LCZ696 significantly reduced levels of NT-proBNP, a marker of cardiac wall stress 2,500 NT-proBNP Consistently lower levels of NT-proBNP were observed in LCZ696-treated patients, compared with enalapril-treated patients, as early as 4 weeks and sustained at 8 months 2,000 1,500 p<0.0001* p<0.0001* Unlike BNP, NT-proBNP is not a substrate for neprilysin 1,000 Levels of NT-proBNP reflect drug effects on cardiac wall stress Entry ENL LCZ 4 weeks 8 months Run-in Double-blind *p-values denote significant difference between the two treatment groups All patients received enalapril, followed by LCZ696, during the single-blind run-in period. Groups represented here show division by final randomization group = median Bars represent 25%/75% interquartile ranges for: LCZ696 Enalapril 57 Packer et al. Circulation 2015;131(1):54-61

58 ng/l Levels of troponin T, a marker of myocardial injury, were lower in LCZ696 patients LCZ696 treatment was associated with an early and sustained reduction in troponin T (a biomarker of myocardial wall-injury), compared with enalapril treatment 1 Small increases in the levels of troponin reflect a higher risk of disease progression in heart failure 2, Troponin T p<0.0001* p<0.0001* 5 *p-values denote significant difference between the two treatment groups Troponin T was not measured at the end of the enalapril phase of the run-in period. All patients received enalapril, followed by LCZ696, during the single-blind run-in period to ensure an acceptable side effect profile. Groups represented here show division by final randomization group 0 Entry = median ENL LCZ 4 weeks 8 months Run-in Double-blind Bars represent 25%/75% interquartile ranges for: LCZ696 Enalapril Packer et al. Circulation 2014; epub ahead of print: DOI: /CIRCULATIONAHA Jungbauer et al. Clin Chem Lab Med 2011;49: ; 3. Masson et al. Circulation 2012;125:280 8

59 pg/ml Increased level of BNP reflects neprilysin inhibition with LCZ BNP In heart failure, levels of BNP and NTproBNP characteristically parallel each other 400 p<0.0001* p<0.0001* However, in the presence of a neprilysin inhibitor, this is no longer the case since BNP is a substrate for neprilysin BNP levels are reflective of the action of LCZ696, whereas NT-proBNP levels reflect the effects of LCZ696 on the heart Entry ENL LCZ 4 weeks 8 months Run-in Double-blind *p-values denote significant difference between the two treatment groups All patients received enalapril, followed by LCZ696, during the single-blind run-in period to ensure an acceptable side effect profile. Groups represented here show division by final randomization group = median Bars represent 25%/75% interquartile ranges for: LCZ696 Enalapril 59 Packer et al. Circulation 2014; epub ahead of print: DOI: /CIRCULATIONAHA

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61 BNP- und NT pro BNP - Unterschied! NPV (99%) zum Ausschluß einer AHI sehr hoch! Sinnvoll zur Prognose-Abschätzung(AHI; CHI) NT probnp-geführte Therapie sinnvoll bei CHI zur Optimierung der Medikation/Dosis bei Pat. + <75J (cave Hypotension, NW) markergesteuerte Therapie signif. Überlegen (Metaanalyse: Trougthon RW Eur heart J 2013) und reduziert Kosten aber inkonstante Daten zwischen Studien, gilt nicht für alte Patienten Herzinsuffizienz-Diagnostik-BNP_ _1

62 Danke für die Aufmerksamkeit

63 ng/l Increased levels of cgmp reflect neprilysin inhibition by LCZ696 cgmp is a secondary messenger of the natriuretic peptide system that is generated when natriuretic peptides bind to the natriuretic peptide receptors A (NPR-A) and B (NPR-B) 1 2,000 1,600 Urinary cgmp p<0.0001* p<0.0001* Urinary cgmp levels were higher early in the study (4 weeks) with LCZ696 compared with enalapril; higher levels were maintained to 8 months 2 1, The early and sustained increase in cgmp indicates the enhancement of natriuretic and vasoactive peptides activity via neprilysin inhibition 2 *p-values denote significant difference between the two treatment groups Urinary cgmp was not measured at the end of the enalapril phase of the run-in period. All patients received enalapril, followed by LCZ696, during the single-blind run-in period to ensure an acceptable side effect profile. Groups represented here show division by final randomization group Entry = median ENL LCZ 4 weeks 8 months Run-in Double-blind Bars represent 25%/75% interquartile ranges for: LCZ696 Enalapril Potter et al. Handb Exp Pharmacol 2009;191:341 66; 2. Packer et al. Circulation 2014; epub ahead of print: DOI: /CIRCULATIONAHA

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65 Biomaker treiben den Behandler zu Therapie und Therapieeskalation (fast alle Patienten mit HF sind unterversorgt) biomarkergetriebene Therapie führt zu mehr Nebenwirkungen (Hypotension und Übelkeit) markergesteuerte Therapie signif. überlegen ( Metaanalyse: Trougthon RW Eur heart J 2013) und reduziert Kosten aber inkonstante Daten zwischen Studien, gilt nicht für alte Patienten Therapiesteuerung Cave LCZ 696 Cost effectiveness +? Herzinsuffizienz-Diagnostik-BNP_ _1

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