Practical considerations for the use of ARNI in CHF: clinical cases. J. Parissis, Heart Failure Clinic, University of Athens, Athens, Greece

Transcription

1 Practical considerations for the use of ARNI in CHF: clinical cases J. Parissis, Heart Failure Clinic, University of Athens, Athens, Greece

2 Disclosures: Research grants and honoraria for lectures from Pfizer, Servier and Novartis International

3 Benefit from guideline-recommended therapies in CHF: IMPROVE-HF a plateau at 4 to 5 therapies Fonarow et al, J Am Heart Assoc 2012

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5 Natriuretic peptides have potential beneficial actions in HF Release of ANP and BNP from heart and CNP in vasculature 1 Sympathetic outflow 2 Vasopressin 2 Salt appetite and water intake 2 CNP (endothelium) 3 ANP/BNP 2 Relaxation; arterial stiffness 4 Hypertrophy 2,5 7 Fibroblast proliferation 4,8,9 Na + /H 2 O loss 2 Aldosterone 2 Renin 2 Vasodilation 2,3,4 Systemic vascular resistance 4 Pulmonary artery pressure 4 Pulmonary capillary wedge pressure 4 Right atrial pressure 4 1. Forssmann et al. Arch Histol Cytol 1989;52 Suppl: ; 2. Levin et al. N Engl J Med 1998;339;321 8; 3. Lumsden et al. Curr Pharm Des 2010;16:4080 8; 4. Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131 9; 5. Gardner et al. Hypertension 2007;49:419 26; 6. Tokudome et al. Circulation 2008;117; ; 7. Horio et al. Endocrinology 2003;144: ; 8. D'Souza et al. Pharmacol Ther 2004 ;101:113 29; 9. Cao & Gardner. Hypertension 1995;25:227 34;

6 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

7 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril HR = 0.80 ( ) P = Number needed to treat = Days After Randomization JJV McMurray et al NEJM 2014 online

8 2016 ESC HF Guidelines and ACC/AHA/HFSA Focused Updates 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 Yancy CW et al., ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, JACC. 21 May 2016

9 2016 ESC Guideline - Sacubitril/valsartan ESC-HF guidelines provide strong Class I recommendation for sacubitril/valsartan Endorsement showing in section 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 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 with an ACEi, a beta-blocker and I B 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 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 doi: /eurheartj/ehw128 Yancy et al. J Am Coll Cardiol. Published 21 May doi: /j.jacc ;

10 ACC/AHA/HFSA Focused Update Sacubitril/valsartan level of evidence ACC/AHA/HFSA guidelines provide strong Class I recommendation for sacubitril/valsartan Pharmacological treatments for Stage C* HFrEF Recommendations Class Level The clinical strategy of inhibition of the renin-angiotensin system with ACEi (Level of Evidence: A), OR ARBs (Level of Evidence: A), OR ARNI (Level of Evidence: B-R) in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic HFrEF to reduce morbidity and mortality. The use of ACEi is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACEi because of cough or angioedema In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACEi or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality * Stage C: structural heart disease with prior or current symptoms of HF I I I I ACEi: A ARB: A ARNI: B-R A A B-R 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; MRA, mineralocorticoid receptor antagonists; NYHA, New York Heart Association.Yancy et al. JACC. Published 21 May doi: /j.jacc

11 2016 ESC 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

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13 TITRATION Evidence-based doses of disease-modifying drugs in key randomized trials in HF with reduced ejection fraction (or after myocardial infarction) Ponikowski P et al. Eur Heart J. 21 May doi: /eurheartj/ehw128

14 Beneficial effect of Sacubitril/Valsartan (vs. enalapril) in reducing the primary outcome was maintained even at lower than target doses Dose (Sacubitril/Valsartan vs enalapril) Events (N) Hazard ratio (95% CI) 200 mg bid vs 10 mg bid ( ); P< mg bid vs 5 10 mg bid ( ); P=0.008 <100 mg bid vs <5 mg bid ( ); P=0.043 Favors Sacubitril/Valsartan Hazard ratio Favors enalapril CI=confidence interval Vardeny O, et al. J Card Fail. 2015; 21(8):S9 S10

15 RISK OF HYPERKALEMIA WITH LCZ696+MRA vs ENALAPRIL+MRA Desai AS et al. JAMA Cardiol 2016

16 Sacubitril/valsartan in management of ventricular arrhythmias Recommendations for the management of ventricular tachyarrhythmias in heart failure Recommendations Class Level Treatment with beta-blocker, MRA and sacubitril/valsartan reduces the risk of sudden death and is recommended for patients with HFrEF and ventricular arrhythmias (as for other patients) (Section 10.2). I A 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 doi: /eurheartj/ehw128

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18 LCZ696 Attenuates Cardiac Remodeling and Dysfunction After Myocardial Infarction by Reducing Cardiac Fibrosis and Hypertrophy

19 Open issues - NYHA IV - Asymptomatic LV dysfunction - Hospitalized, Acute - Naive to ACEi - With borderline SBP - With renal function worsening (on ARNI) - Natriuretic peptide values as a routine practice Filippatos, Farmakis, Parissis BMC Medical 2015

20 LCZ696 MPP (I) ATTIKO UNIVERSITY HOSPITAL 1 st patient enrolled: 11/12/2015 Total no of patients who have received Sacubitril/valsartan: 40 (66% NYHA II/ 34% NYHA III, 60% Ischemic CM/40% Dilated CM) mean LVEF: 27±6%, mean NT-proBNP: 1378±453 pg/ml Total no of patients who actively receive Sacubitril/valsartan w/o drug interruption: 37 Total no of patients who discontinued Sacubitril/valsartan permanently: 3 (1 due to hypotension, 1 due to cough, 1 due to colitis)

21 LCZ696 MPP (II) ATTIKO UNIVERSITY HOSPITAL Total no of patients in whom dose of Sacubitril/valsartan was down-titrated: 2 (1 due to hypotension---led to permanent discontinuation, 1 due to worsening renal function: downtitrated from 200mg to 100mg---improved w/o further dose adjustment) Total no of patients who have been titrated to Sacubitril/valsartan 200mg: 20 Total no of patients who have been titrated to Sacubitril/valsartan 100mg: 8 Total no of patients who are currently on titration of Sacubitril/valsartan : 7 Total no of pts awaiting approval for enrollment: 6

22 Clinical Case: Chronic ischemic heart failure with reduced LVEF

23 History and clinical presentation Male, 63 years old 1990 ASD closure (surgical) 1992 Permanent pacemaker due to AV block 2005 NSTEMI, PCI LCX, RCA, HF 2010 ICD, permanent AF 2015 unsuccessful attempt to upgrade ICD to CRT-D Diabetes mellitus, sleep apnea syndrome (CPAP use) NYHA III, BP 105/65mmHg, HR 73bpm HF hospitalization 3 months ago Hb 12.4g/dl, BUN 54mg/dl, creatinine 1.6mg/dl, egfr 44ml/min/1.73m 2, Sodium 138mmol/l, potassium 4.4mmol/l, NT-proBNP 2920pg/ml

24 Medications Lisinopril 10mg 1 X 1 Carvedilol 12.5mg 1 X 2 Eplerenone 50mg 1 X 1 Furosemide 40mg 2 X 2 Simvastatin 20mg 1 X 1 Amiodarone 200mg 1 X 1 Acenocoumarol

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26 LVEF 20% LVEDD 68mm RV mod-sev reduced systolic function TAPSE 11mm Mod-sev MR

27 Which would be the first therapeutic choice? 1. Replace ACEI with sacunitril/valsartan 2. Add digoxin 3. Evaluate for LVAD/HT 4. Correction of mitral regurgitation (percutaneous, surgical)

28 FOLLOW UP CLINIC VISIT After 3 months, NYHA II, BP 120/70mmHg, HR 67bpm No episodes of hypotension Creatinine 1.5mg/dl, egfr 49ml/min/1.73m 2, potassium 4.8mmol/l, NT-proBNP 1200pg/ml Sacubitril/valsartan 49mg/51mg BID (started at 24mg/26mg BID) Furosemide 40mg 1 ½ X 2 Other meds unchanged

29 Baseline LVEF 15-20% LVEDD 68mm S/V 100mg BID LVEF 25% LVEDD 64mm

30 FOLLOW UP CLINIC VISIT After 5 months, ΝΥΗΑ ΙΙ, no HF hospitalizations/er visits BP 110/70mmHg, HR 65bpm, Creatinine 1.4mg/dl, egfr 51ml/min/1.73m2, potassium 4.7mmol/l Sacubitril/valsartan 93mg/107mg BID Furosemide 40mg BID Other medications unchanged Percutaneous mitral valve repair postponed due to reduction of MR

31 Key points NYHA III on optimal conventional treatment No hypotension, improvement of exercise capacity and less congestion with S/V Less use of diuretics, reduction of NT-proBNP and protection of renal function with S/V Optimization of medical treatment in sympomatic HF using S/V instead of RASi is crucial and reasonable approach before to consider other major interventions (LVAD,transplantation, etc).

32 Clinical Case: Dilated cardiomyopathy of recent onset

33 Initial presentation Female, 55 years old Smoker, dyslipidemia, familial history of CAD Medical therapies: Rosuvastatin 10mg OD 8/2015: New onset of dyspnea on exertion, progressively worsening 10/2015: Acute decompensated heart failure- hospitalized TTE: severely dilated LV, LVEF 20% Coronary angiography: normal coronary arteries Cardiac MRI: LVEF 14%; RVEF 19%; LGE (-) Holter ECG: PAF, NSVT

34 First Clinic Visit NYHA II, BP110/80, HR 100/min, 6-MWD 320m BUN 41mg/dl, Creatinine 1.3mg/dL, egfr 45ml/min/1.73m 2, potassium 4.7mmol/L, Hb 13.3g/dl, NT-proBNP 2881pg/ml Carvedilol 6.25mg 1/2 X 2 Ramipril 2.5mg 1 X 1 Eplerenone 25mg 1 X 1 Furosemide 40mg 1 X 2 Amiodarone 200mg 1 X 1 Acenocoumarol, Pravastatin 40mg OD

35 ECG & TTE LVEF 20% LVEDD 64mm RV moderately reduced systolic fynction Moderate MR

36 Which is the next therapeutic step? 1. Continue treatment as is. 2. Increase triple life saving therapy 3. Start ivabradine. 4. Replace ACEi with sacubitril/valsartan 5. Implant CRT-P/-D

37 Clinic Visit After 4 months, ΝΥΗΑ ΙΙ, BP 108/80mmHg, HR 68bpm BUN 49mg/dl, creatinine 1.0mg/dL, egfr 58ml/min/1.73m 2, potassium 4.3mmol/L, NT-proBNP 680pg/ml Ramipril 5mg 1 ½ X 1 Carvedilol 12.5 mg 1 X 2 Eplerenone 50mg 1 X 1 Furosemide 40mg 1 X 2 ICD implanted

38 What would you do next? 1. Continue treatment as is. 2. Increase furosemide 3. Replace ACEI with ARNI 4. Start ivabradine

39 Clinic visit After 2 months, ΝΥΗΑ Ι, BP 105/75mmHg, HR 70bpm No hypotension BUN 40mg/dl, creatinine 0.9mg/dL, egfr 65ml/min/1.73m 2, Potassium 5.6mmol/L, NT-proBNP 59pg/ml Sacubitril/valsartan 97mg/103mg 1 X 2 Furosemide 40mg 1 X 1 Other medications unchanged

40 What would you do now? 1. No changes in treatment 2. Reduce sacubitril/valsartan 3. Reduce eplerenone 4. Reduce furosemide 5. Discontinue eplerenone

41 Follow-up Clinic visit After 2 weeks, NYHA I, BP 110/75mmHg, HR 67/min, 6MWD 510m No episodes of hypotension Creatinine 0.9mg/dl, egfr 65ml/min/1.73m 2, Potassium 5.0mmol/l Unchanged other meds

42 Initial exam Maximal tolerated standard therapies Sacubitril/valsartan 200mg BID

43 NT-proBNP response to therapies 3500 NT-proBNP st O/P visit (11/2015) pre-s/v (3/2016) S/V 200mg (5/2016) 59

44 Key points NYHA II, recent onset DCM, no significant comorbidities S/V was initiated at dose level 2, up-titrated to dose level 3 after 1 month, well tolerated Care should be exercised with adjustment of concomitant medications (MRA, diuretic) Improvement of exercise capacity, additional reduction of NT-proBNP with S/V Reverse remodeling could have been enhanced with S/V (?) Is The earlier the better the case with S/V?

45 TAKE HOME MESSAGES In real-life HFREF patients: 1.ARNi improves symptoms, exercise capacity and allows less use of diuretics in HFREF 2.ARNi preserved renal function even in moderate-severe chronic renal dysfunction, and was associated with less hyperkalemia 3.Long-term effectiveness of ARNi on LV remodeling, secondary mitral regurgitation need to be addressed 4.Initiation dose and up-titration scheme of sacubitril/valsartan: CONSIDER previous ACE/ARB dose, SBP, and renal function. Low starting dose with slow up-titration in patients with: borderline SBP, chronic renal dysfunction, advanced NYHA, multiple comorbidities 5.In case of hypotension: adjustment of diuretic dose (to correct hypovolemia), check for other hypotensive drugs (i.e. nitrates, Calcium channel blockers, a-blockers for prostate hyperplasia) 6.In case of increased potassium levels: Adjust MRA dose