L insuffisance cardiaque chez la personne âgée

Transcription

1 L insuffisance cardiaque chez la personne âgée Congrès d automne de la SSMIG Berne, Prof. Dr. Jean-Michel Gaspoz Département de Médecine communautaire, de premier recours et des urgences

2 Conflicts of interest statment Honoraries for conferences, advisory boards or congresses: Bayer HealthCare, BMS, MSD, Menarini, Novartis, Takeda, Vifor Pharma. Educational or research grants for SMPR/HUG : AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, gsk, Lilly, Mundipharma, Novartis, Takeda, Unilabs, Vifor Pharma.

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5 Vignette Patient de 78 ans, connu pour : une HTA de longue date Il consulte pour une dyspnée en augmentation progressive depuis 6 mois chronique.

6 Quels sont les symptômes d IC chez la personne âgée

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11 Vignette Examen clinique: TA : 120 / 70 mmhg, pouls 100 / min, régulier Râles de stase pulmonaire sur 1 main; Ø turgescence jugulaire, Ø reflux HJ ou OMI.

12 Quels examens allez-vous demander?

13 2016 ESC-HF Guidelines: Diagnostic Algorithm Diagnostic algorithm for a diagnosis of heart failure of non-acute onset BNP - B-type natriuretic peptid; CAD - coronary artery disease; HF - heart failure; MI - myocardial infarction; NTproBNP - N-terminal pro-b type natriuretic peptide. a Patient reporting symptoms typical of HF (see Table 4.1). b Normal ventricular and atrial volumes and function. c Consider other causes of elevated natriuretic peptides (Table 12.3). 13 Ponikowski P et al. Eur Heart J. 21 May doi: /eurheartj/ehw128

14 Echocardio: VG dilaté; FE 30%; IM discrète.

15 A quelles étiologies pense-vous?

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21 HF diagnostics HF symptoms (dyspnea, paroxysmal nocturnal dyspnea, peripheral edema, astenia, etc). + Clinical symptoms of HF (jugular turgidity, hepatojugular reflux, edema, pulmonary stases, ascites etc). + ECHO LVEF 45% LVEF > 45% + Indirect signs of filling pressure (left atrium dilatation, hypertrohphy of left ventricle, diastolic dysfunction) Heart failure with reduced LVEF (HFrEF) Heart failure with preserved LVEF (HFpEF)

22 Quelle proportion d HFpEF chez les patients âgés?

23 Quelle proportion d HFpEF chez les patients âgés? 45 % Plus âgés Femmes HTA, FA, Insuffisance rénale

24 Quel traitement si HFrEF?

25 digoxine 0,125 mg / jour ramipril 5 mg/jour torasémide 5 mg/jour TTT:

26 Proven treatments for HFrEF TO IMPROVE SYMPTOMS Diuretics Digoxin Ivabradin AND TO REDUCE HOSPITALIZATIONS Digoxin Ivabradin AND TO IMPROVE SURVIVAL ACE inhibitors ANG II receptor blockers β blockers Oral nitrates and hydralazine Spironolactone / Eplerenone (MRA)

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28 Evolution clinique: Rapidement favorable sous diurétiques i-v. TTT de candesartan, metoprolol, spironolactone Dyspnée au moindre effort persiste. Echocardio: VG dilaté; FE 30% inchangée

29 Que penser du traitement? Que modifier? Que rajouter?

30 PARADIGM-HF 30 McMurray JJ. et al. N Engl J Med. 2014;371(11):

31 Overactivation of the RAAS and SNS is detrimental in HFrEF and underpins the basis of therapy Sympathetic nervous system (SNS) Natriuretic peptide system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy HFrEF SYMPTOMS & PROGRESSION Epinephrine Norepinephrine Renin-angiotensinaldosterone system (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 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;

32 Natriuretic peptides are cleared in target cells via NPR-C and degraded by the neutral endopeptidase, neprilysin NPR-A Cardiomyocytes 1 ANP and BNP NPR-B Endothelial cells 1 CNP NPR-C ANP BNP CNP NEP Neprilysin Inactive cleavage products GTP cgmp GTP cgmp Endocytosis Receptor recycling Vasodilation 1,2 Antihypertrophy 1,2 Antiproliferation 2 Vascular regeneration 1 Myocardial relaxation 1 Diuresis, natriuresis 1,2 Antiapoptosis 1 Anti-aldosterone 1 Renin secretion inhibition 1,3 Reduced sympathetic tone 4 Lipolysis 1 Vasodilation 1,2 Antihypertrophy 1,2 Antiproliferation 2 Vascular regeneration 1 Venodilation 1 Antifibrosis 1 Inactivation of NPs 1,2,5 Natriuretic peptide degradation and clearance Natriuretic peptide signaling and effects 32 ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; cgmp=cyclic guanosine monophosphate; CNP=C-type natriuretic peptide; GTP=guanosine triphosphate; NP=natriuretic peptide; NPR=natriuretic peptide receptor 1. Mangiafico et al. Eur Heart J 2013;34:886 93; 2. Gardner et al. Hypertension 2007;49:419 26; 3. Pandey. J Am Soc Hypertens 2008;2:210 26; 4. Levin et al. N Engl J Med 1998;339;321 8; 5. Von Lueder et al. Pharmacol Ther 2014 [Epub ahead of print]

33 Neprilysin degrades other substrates, including Ang II and vasoactive peptides relevant for cardiovascular physiology NPR-A ANP BNP CNP NPR-B ANP BNP CNP ANP BNP CNP NPR-C Neprilysin Ang II Ang I Bradykinin Inactive cleavage products Ang II AT 1 receptor GTP cgmp GTP Endocytosis Inactivation of NPs Receptor recycling Signaling cascades Vasodilation Cardiac fibrosis/hypertrophy Natriuresis/diuresis Vasoconstriction Cardiac fibrosis/hypertrophy Sodium/water retention 33 ANP=atrial natriuretic peptide; Ang=angiotensin; AT1=angiotensin II type 1; BNP=B-type natriuretic peptide; cgmp=cyclic guanosine monophosphate; CNP=C-type natriuretic peptide; ET-1=endothelin-1; GTP=guanosine triphosphate; NP=natriuretic peptide; NPR=natriuretic peptide receptor; RAAS=renin-angiotensin-aldosterone system Levin et al. N Engl J Med 1998;339;321 8; Gardner et al. Hypertension 2007;49:419 26; Molkentin. J Clin Invest 2003;111: ; Nishikimi et al. Cardiovasc Res 2006;69:318 28; Guo et al. Cell Res 2001;11:165 80; Von Lueder et al. Circ Heart Fail 2013;6: ; Yin et al. Int J Biochem Cell 2003;35:780 3; Mehta and Griendling. Am J Physiol Cell Physiol 2007;292:C82 97; Mangiafico et al. Eur Heart J 2013;34:886 93; Potter. FEBS J 2011;278: ; Erdos, Skidgel. FASEB J 1989;3:145 51; Stephenson et al. Biochem J 1987;243:183 7; Abassi et al. Metabolism 1992;41:683 5; Murphy et al. Br J Pharmacol 1994;113:137 42; Jiang et al. Hypertens Res 2004;27:109 17; Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131 9

34 Neprilysin inhibition must be accompanied by simultaneous RAAS blockade Neprilysin metabolizes Ang I and Ang II via several pathways 1,2 Inhibition of neprilysin alone is insufficient as it associated with an increase in Ang II levels, counteracting the potential benefits of neprilysin inhibition 2 Neprilysin inhibition must be accompanied by simultaneous RAAS blockade (e.g. AT 1 receptor blockade) 2 Angiotensinogen Ang I Ang II Renin ACE Neprilysin inhibitor Neprilysin Neprilysin inhibitor Neprilysin AT 1 receptor Inactive fragments Inactive fragments Free Calcium Biological actions Hypertrophy Fibrosis Vasoconstriction Hypertrophy Na + /H 2 O retention Aldosterone release Norepinephrine release Sympathetic tone 34 ACE=angiotensin-converting enzyme; AT 1 =angiotensin II type 1; Ang=angiotensin; RAAS=renin-angiotensin- aldosterone system 1. Von Lueder et al. Circ Heart Fail 2013;6: ; 2. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131 9

35 LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks the AT 1 receptor (via valsartan) LCZ696 Natriuretic and other vasoactive peptides* RAAS Sacubitril (AHU377; pro-drug) Angiotensinogen (liver secretion) Ang I Inactive fragments LBQ657 (NEP inhibitor) Valsartan Ang II Enhancing Vasorelaxation Blood pressure Sympathetic tone Aldosterone levels Fibrosis Hypertrophy Natriuresis/diuresis HN O HO O OH O O N O OH N N N NH AT 1 Receptor Inhibiting Vasoconstriction Blood pressure Sympathetic tone Aldosterone Fibrosis Hypertrophy 35 *Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNP Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Schrier & Abraham N Engl J Med 2009;341:577 85; Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131 9; Feng et al. Tetrahedron Letters 2012;53:275 6

36 PARADIGM-HF: Study design Randomization n=8442 Double-blind Treatment period Single-blind active run-in period LCZ mg BID Enalapril 10 mg BID* LCZ mg BID LCZ mg BID Enalapril 10 mg BID 2 Weeks 1 2 Weeks 2 4 Weeks Median of 27 months follow-up On top of standard HFrEF therapy (excluding ACEIs and ARBs) 36 *Enalapril 5 mg BID (10 mg TDD) for 1 2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for those patients who are treated with ARBs or with a low dose of ACEI; 200 mg TDD; 400 mg TDD; 20 mg TDD. McMurray et al. Eur J Heart Fail. 2013;15: ; McMurray et al. Eur J Heart Fail. 2014;16:817 25; McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

37 PARADIGM-HF: Key inclusion criteria Chronic HF NYHA II IV with LVEF 40%* BNP (or NT-proBNP) levels as follows: 150 (or 600 pg/ml), or 100 (or 400 pg/ml) and a hospitalization for HFrEF within the last 12 months 4 weeks stable treatment with an ACEI or an ARB #, and a β-blocker Aldosterone antagonist should be considered for all patients (with treatment with a stable dose for 4 weeks, if given) *The ejection fraction entry criteria was lowered to 35% in a protocol amendment # Dosage equivalent to enalapril 10 mg/day 37 McMurray et al. Eur J Heart Fail. 2013;15:

38 Primary endpoint: Death from CV causes or first hospitalization for HF 1.0 Cumulative probability Hazard ratio = 0.80 (95% CI: ) p<0.001 Enalapril (n=4,212) LCZ696 (n=4,187) % NNT = Days since randomization No at risk LCZ Enalapril McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

39 Primary endpoint: Death from CV causes or first hospitalization for HF 40 20% reduction in risk of CV death HR: 0.80 (95% CI 0.71, 0.89) p= % reduction in risk of hospitalization HR: 0.79 (95% CI 0.71, 0.89) p= Cumulative proportion of patients who died from CV causes (%) Enalapril (n=4,212) LCZ696 (n=4,187) Cumulative proportion of patients who were hospitalized for HF (%) Enalapril (n=4,212) LCZ696 (n=4,187) ,080 1, ,080 1,260 Days after randomization Days after randomization 39 1-sided p value McMurray et al. N Engl J Med 2014;371: ; Novartis Data on File: PARADIGM-HF Clinical Study Report

40 The reduction in HF hospitalization with LCZ696 was evident within the first 30 days after randomization 1.5 HR = 0.60 (95% CI: ) p=0.027 Kaplan-Meier estimate of cumulative rate Enalapril (n=4,212) LCZ696 (n=4,187) Days after randomization Number of patients at risk LCZ696 4,187 4,174 4,153 4,140 Enalapril 4,212 4,192 4,166 4, Shown is the Kaplan-Meier estimate of the cumulative probability of a first hospitalization for HF during the first 30 days after randomization. The analysis at 30 days was prespecified and also represented the earliest time point at which the difference between the LCZ696 and enalapril groups was statistically significant. CI=confidence interval; HF=heart failure; HR=hazard ratio Packer et al. Circulation 2015;131:54 61

41 Death from any cause Cumulative probability Enalapril LCZ696 Hazard ratio = 0.84 (95% CI: ) p< n = 4212 n = Days since randomization No at risk LCZ Enalapril McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

42 Prospectively defined safety events Event, n (%) LCZ696 (n=4187) Enalapril (n=4212) p-value Hypotension Symptomatic 588 (14.0) 388 (9.2) <0.001 Symptomatic with SBP <90 mmhg 112 (2.7) 59 (1.4) <0.001 Elevated serum creatinine 2.5 mg/dl 139 (3.3) 188 (4.5) mg/dl 63 (1.5) 83 (2.0) 0.10 Elevated serum potassium >5.5 mmol/l 674 (16.1) 727 (17.3) 0.15 >6.0 mmol/l 181 (4.3) 236 (5.6) Cough 474 (11.3) 601 (14.3) <0.001 Angioedema (adjudicated by a blinded expert committee) No treatment or use of antihistamines only 10 (0.2) 5 (0.1) 0.19 Catecholamines or glucocorticoids without hospitalization 6 (0.1) 4 (0.1) 0.52 Hospitalized without airway compromise 3 (0.1) 1 (<0.1) 0.31 Airway compromise Fewer patients in the LCZ696 group than in the enalapril group stopped their study medication because of an AE (10.7 vs 12.3%, p=0.03) McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

43 Angiotensin-receptor-neprylisin-inhibition via LCZ696 doubles reduction of CV mortality compared to standard RAAS inhibitors Placebo ARB ACEI ARNI 15 % 18 % % Reduction of CV mortality 20 % Efficacy of ARB versus Placebo - CHARM-Alternative study Efficacy of ACEI versus Placebo SOLVD-T study Efficacy of LCZ696 versus ACEI - PARADIGM-HF study 43 1 McMurray et al. Eur Heart J 2012; 33: ; 2 Investigateurs des SOLVD. N Engl J Med 1991; 325: ; 3 Granger et al. Lancet 2003; 362:772 66;

44 2016 ESC HF Guidelines and ACC/AHA/HFSA Focused Updates 2016 ESC-HF Guidelines Ponikowski P et al., ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 21 May 2016 ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker, ARNI, angiotensin receptor neprilysin inhibitor; CV, cardiovascular; ESC, European Society of Cardiology; HF, heart failure; HFrEF, HF with reduced ejection fraction; NYHA, New York Heart Association

45 2016 ESC-HF Guidelines: Treatment Algorithm a Symptomatic=NYHA Class II-IV; b HFrEF=LVEF<40%; c If ACEI not tolerated/contra-indicated, use ARB; d If MR antagonist not tolerated/contra-indicated, use ARB; e With a hospital admission for HF within the last 6 months or with elevated natriuretic peptides (BNP >250 pg/ml or NTproBNP >500 pg/ml in men and 750 pg/ml in women); f With an elevated plasma NP level (BNP 150 pg/ml or plasma NT-proBNP 600 pg/ml, or if HF hospitalization within recent 12 months plasma BNP 100 pg/ml or plasma NT-proBNP 400 pg/ml); g In doses equivalent to enalapril 10 mg b.i.d.; h With a hospital admission for HF within the previous year; i CRT is recommended if QRS 130 msec and LBBB (in sinus rhythm); j CRT should/may be considered if QRS 130 msec with non-lbbb (in a sinus rhythm) or for patients in AF provided a strategy to ensure bi-ventricular capture in place (individualized decision) Ponikowski P et al. Eur Heart J. 21 May doi: /eurheartj/ehw128

46 2016 ESC-HF Guidelines 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 A beta blocker is recommended, in addition an ACEi, for patients with stable, symptomatic HFrEF to reduce the risk of HF hospitalization and death 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 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 I B with an ACEi, a beta-blocker and an MRA * *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. I I I A A A Ponikowski et al. Eur Heart J. 21 May doi: /eurheartj/ehw128 Yancy et al. J Am Coll Cardiol. Published 21 May doi: /j.jacc ;

47 Quel pronostic si HFpEF?

48 Patients avec fraction d éjection préservée (HFpEF)

49 Quel traitement si HFpEF?

50 Proven treatments for HFpEF NO DRUG HAS YET PROVEN TO REDUCE MORTALITY AND MORBIDITY. RECOMMENDED TREATMENTS Diuretics Calcium channel blockers limiting heart rate Beta-blockers AVOID Digoxin

51 Other important aspects Look for precipitating factors and correct them: Non-compliance with diet or medications Negative inotropes (anti-arrhythmics, Ca blockers) Medications that worsen renal dysfunction (NSAIDS) Treat hypertension vigorously Life style modification and exercise

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