Optimal Management of Heart Failure

Transcription

1 Curriculum Vitae Name : Prof. DR. Dr. Idrus Alwi SpPD, K-KV, FACC, FESC, FAPSIC, FINASIM, FACP. Current Position : Professor of Internal Medicine Faculty of Medicine UI Medical Student : Faculty of Medicine University of Indonesia 1986 Internist : Faculty of Medicine University of Indonesia 1996 Cardiovascular Consultant : The Indonesian Society of Internal Medicine, 2001 PhD : Faculty of Medicine University of Indonesia, 2006 FACC : American College of Cardiology, 2006 FESC : European Society of Cardiology, 2008 FAPSIC : Asia Pacific Society of Interventional Cardiology, 2009 FINASIM : Indonesian Society of Internal Medicine, 2009 FACP : American Colleague of Physician, 2013 Advanced Course in Cardiology, Melbourne 1997 Advanced Course on Echocardiography and Others Non Invasive Cardiology, Melbourne Stem cell NOGA course, Cincinnatti, Ohio, 2009 ASAN Interventional Cardiology Course, Seoul, 2011

2 Optimal Management of Heart Failure Prof. Idrus Alwi MD, PhD, FINASIM, FACP, FACC, FESC, FAPSIC Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia

3 Outline Epidemiology, Diagnosis and Classification of Heart Failure Therapeutic Approach of Chronic HF Management ARNI as the New Therapy in Chronic HF Conclusion

4 Heart Failure Definition ESC 2016 HF is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/ or elevated intracardiac pressures at rest or during stress. ACCF/AHA 2013 HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood 2 ESC: European Society of Cardiology; AHA: American Heart Association; ACCF: American College of Cardiology Foundation 1. Ponikowski et al. Eur Heart J 2016; 37(27): ; 2. Yancy et al. JACC 2013;62:e

5 Heart failure Unmet needs Poor survival Poor quality of life if symptoms not controlled High risk of (re)hospitalisation

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7 However, mortality rates in heart failure are high Heart failure mortality statistics even for patients compliant with the best available treatments 1 ~50 % DIE WITHIN 5 YEARS OF DIAGNOSIS 2 When heart failure symptoms are stabilised by current treatments, it may seem that patients are doing well, but the neurohormonal imbalance underlying heart failure is still silently occurring, resulting in disease progression Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; Gerber et al. JAMA Intern Med 2015;175: and Zarrinkoub et al. European Journal of Heart Failure 2013;15:

8 Cumulative Adverse Consequences of Acute Episodes (Hospitalization) Clinical manifestations Cardiac function quality of life (QoL) Acute episodes Mortality Disease progression With each acute event, myocardial and renal injury may contribute to progressive LV (left ventricle) dysfunction High frequency of acute events + disease progression = increasing risk of hospitalization and mortality Gheorghiade et al. Am J Cardiol 2005;96:11G 17G; Gheorghiade & Pang. J Am Coll Cardiol 2009;53:

9 Definition of Heart failure ACC-AHA

10 Classification of Heart Failure ACC/AHA HF Stage A At high risk for heart failure but without structural heart disease or symptoms of heart failure (eg, patients with hypertension or coronary artery disease) NYHA Functional Class None B Structural heart disease but without symptoms of heart failure I Asymptomatic C Structural heart disease with prior or current symptoms of heart failure II Symptomatic with moderate exertion III Symptomatic with minimal exertion D Refractoric heart failure requiring specialized interventions IV Symptomatic at rest 10

11 Outline Epidemiology, Diagnosis and Classification of Heart Failure Therapeutic Approach of Chronic HF Management ARNI as the New Therapy in Chronic HF Conclusion

12 Guidelines for the Diagnosis and Management of Heart Failure ESC Guideline 2016 ACC-AHA Guideline 2017

13 Established Therapy of Chronic Heart Failure 1. Diuretics 2. ACE-inhibitors or/and AT 1 -receptor antagonists 3. -blockers (Bisoprolol, Carvedilol, Metoprolol, Nebivolol) 4. Aldosterone antagonists (spironolactone, eplerenone) 5. ARNI (Angiotensin Receptor Nephrilysin inhibitor) 5. Ivabradine, Digitalis, Hidralazine-ISDN 6. Devices (CRT, ICD)

14 ACE Inhibitors Reduced Mortality in Heart Failure and/or LV dysfunction Mortality reduction by about 20-30% in NYHA class II-III patients and nearly 40% in class IV patients R E E C R E L

15 -Blockers Reduce the Risk of All-cause Mortality in HFrEF Risk reduction (versus placebo) 34% 35% 34% CIBIS II (1999) COPERNICUS (2001 MERIT-HF (1999) p< p<0.001 p=0.0062

16 Reduction in relative risk of all-cause mortality The Key Disease-Modifying Drugs Targeting Renin-angiotensin and Sympathetic Signalling Reduce Mortality Risks in Chronic HF ACEIs* vs Placebo ARBs* vs Placebo -Blockers* + ACEI/ARB vs. ACEI/ARB alone MRAs* + ACEI/ARB + -blockers vs. ACEI/ARB + -blockers 16% 17% (4.5% ARR; (3.0% ARR; mean follow median follow up of 41.4 up of % months) months) SOLVD 4,5 CHARM- Alternative 6 Drugs that inhibit RAS have modest effects on survival rate (3.8% ARR; mean follow up of 1.3 years) MERIT-HF 7 24% (7.6% ARR; mean follow up of 24 months) EMPHASIS- HF 1,8 *On top of standard therapy at the time of study, except in CHARM-Alternative where patients were intolerant to ACEI. Patient populations varied between trials and as such relative risk reductions cannot be directly compared ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor blocker; HF=heart failure; ARR=absolute risk reduction; HFrEF=heart failure with reduced ejection fraction; LVEF=left ventricular ejection fraction; MRA=mineralocorticoid receptor antagonist 1. Go et al. Circulation 2014;129:e28-e292; 2. Yancy et al. Circulation 2013;128:e ; 3. Levy et al. N Engl J Med 2002;347: ; 4. McMurray et al. Eur Heart J 2012;33: ; 5. SOLVD Investigators. N Engl J Med 1991;325: ; 6. Granger et al. Lancet 2003;362:772 66; 7. MERIT-HF study group. Lancet 1999;353: ; 8. Pitt et al. N Engl J Med 1999;341:709-17

17 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure Developed in Collaboration With the American Academy of Family Physicians, American College of Chest Physicians, and International Society for Heart and Lung Transplantation

18 Treatment of HFrEF (ACC-AHA Stage C 2017) and D (ACC-AHA 2017)

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22 Outline Epidemiology, Diagnosis and Classification of Heart Failure Therapeutic Approach of Chronic HF Management ARNI as the New Therapy in Chronic HF Conclusion

23 Secretion of natriuretic peptides could counter RAAS and SNS over-activation and slow HF progression NP system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy Inactive fragments HF SYMPTOMS & PROGRESSION Epinephrine Norepinephrine SNS α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility RAAS! However, the benefits of NPs in cardiac injuries are diminished, due to rapid degradation by Neprilysin enzyme ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012; ; Schrier et al. Kidney Int 2000;57: ; Schrier & Abraham N Engl J Med 2009;341:577 85; Boerrigter, Burnett. 23 Expert Opin Invest Drugs 2004;13:643 52; Ferro et al. Circulation 1998;97: ; Brewster et al. Am J Med Sci 2003;326:15 24 Ang II AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis Sodium and water retention

24 ARNI: Angiotensin-Receptor blockade and Neprilysin Inhibition SNS β-blockers Epinephrine Norepinephrine α 1, β 1, β 2 receptors NP system Neprilysin inhibitors HF SYMPTOMS & PROGRESSION Vasoconstriction RAAS activity Vasopressin Heart rate Contractility NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy INACTIVE FRAGMENTS ARNI RAAS Ang II AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis RAAS inhibitors (ACEI, ARB, MRA) ARNI simultaneously enhances the beneficial effects of NP system, while suppress negative effects of RAAS 24 ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker; AT 1 R=angiotensin II type 1 receptor; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system 1. McMurray et al. Eur J Heart Fail 2013;15: 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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26 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Enalapril (n=4212) Patients at Risk LCZ696 Enalapril Days After Randomization

27 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Enalapril (n=4212) LCZ696 Sacubitril/Valsartan (n=4187) 8 Patients at Risk LCZ696 Enalapril Days After Randomization

28 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Enalapril (n=4212) Patients at Risk LCZ696 Enalapril Days After Randomization LCZ696 Sacubitril/Valsartan (n=4187) HR = 0.80 ( ) P = Number needed to treat =

29 % Decrease in Mortality Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction 0% Angiotensin receptor blocker ACE inhibitor Beta blocker Mineralocorticoid receptor antagonist 10% 20% 30% 40% Drugs that inhibit the renin-angiotensin system have modest effects on survival Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

30 Angiotensin Neprilysin Inhibition With LCZ696 (Sacubitril/Valsartan) 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

31 Recommendations for Renin-Angiotensin System Inhibition Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI COR LOE Recommendations I ACE: A The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (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. ACC-AHA Guideline 2016

32 Patient-1 62 years old man NYHA class III Prior hospitalization five times in 5 years for reasons of AF and HF Non-ischemic cardiomyopathy AF=atrial fibrillation; HF=heart failure; LVEF=left ventricular ejection fraction; NT-proBNP=N-terminal pro B-type natriuretic peptide; NYHA=New York Heart Association

33 Clinical features BP=110/66 mmhg AF average HR of 112 bpm SaO2=96% room air egfr 72.2 ml/min/1.73 NT-proBNP 2,488 pg/ml Echo LVEF=35%, markedly dilated LA and left ventricle BP=blood pressure; bpm=beats per minute; echo=echocardiogram; egfr=estimated glomerular filtration rate; HR=heart rate; LA=left atrium SaO2=saturated oxygen

34 ECG

35 ESC Guidelines: Management of Suspected HF Ponikowski P, et al. Eur Heart J. 2016;18:

36 Medications Furosemide 40 mg twice a day Aldactone 50 mg/day Bisoprolol 2.5 mg/day Digoxin mg/day ACE inhibitor off and on due to BP drops Apixaban 5 mg twice a day ACE=angiotensin-converting enzyme

37 QUESTION 1 is this medication adequate to control HF symptoms?

38 Admitted for stabilization

39 Course in hospital Furosemide dose was titrated Digoxin was omitted Question of rhythm control was addressed Dose of bisoprolol was increased to 5 mg/day BP now 105/60 mmhg

40 ESC Guidelines for HF: Patient with Symptomatic HFrEF *up-titrate to maximum tolerated evidende-based doses; + No further action required, Consider reduction diuretic dose. Ponikowski P, et al. Eur Heart J. 2016;18:

41 QUESTION 2 should we add ACEI, ARB or ARNI? ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor-neprilysin inhibitor

42 Discharge medications Furosemide 20 mg/day Aldactone 50 mg/day Bisoprolol 5 mg/day ARNI (sacubitril/valsartan) 50 mg twice a day Apixaban 5 mg twice a day Serum K at discharge 4.8 meq/dl

43 Further course in next 3 months Feeling much, much better In NSR with 100 mg amiodarone 200 mg twice a day of sacubitril/valsartan But still scared No emergency room visits or hospitalizations since last visit NSR=normal sinus rhythm

44 Things that made the difference Reducing diuretics and adding ARNI Restoration of SR Cautious monitoring and gradual dose increase

45 ESC Guidelines: Therapy for Symptomatic HFrEF (cont) Consult published guidelines for additional treatment recomendations Ponikowski P, et al. Eur Heart J. 2016;18:

46 Pharmacological treatment Recommended in Selected Patients with Symptomatic (NYHA Class II-IV) HFrEF Ponikowski P, et al. Eur Heart J. 2016;18:

47 QUESTION 3 what is the prognosis of this individual at 1 year?

48 Step-wise, incremental, reduction in 1-year mortality with combination neurohumoral blockade in patients with systolic heart failure Aldo=aldosterone; CIBIS=Cardiac Insufficiency Bisoprolol Study; COPERNICUS=Carvedilol Prospective Randomized Cumulative Survival; CR=continuous release; EMPHASIS-HF=Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; MERIT-HF=Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; MRA=mineralocorticoid receptor antagonist; RALES=Randomized Aldactone Evaluation Study; SOLVD-T=Studies of Left Ventricular Dysfunction trial; XL=extended release McMurray. Eur J Heart Fail 2011;13:929 36

49 Biomarkers Indications for Use (ACC-AHA Guideline 2017)

50 ACC-AHA 2017

51 Patient-2

52 Patient Background 52yr old man, married, 6 children Under care of district hospital Hypertension Dyslipidemia Chronic smoker Atrial fibrillation

53 1st Hospitalisation for HF (Oct 2015) Pneumonia & de novo HF Severe congestive HF Required ventilation Cardiohepatic & cardiorenal syndrome Total length of stay 20 days Echocardiography LVEF 30%, global hypokinesia Severe functional mitral regurgitation Pulmonary hypertension, RHF Upon discharge, refer to HF clinic HF, heart failure; LVEF, left ventricular ejection fraction; RHF, right heart failure

54 Subsequent Investigations Coronary angiography confirmed 3 VD Cardiac MRI: minimal scarring of RCA territory Indecisive regarding coronary artery bypass graft MRI, magnetic resonance imaging; RCA, right coronary artery; TVD, tricuspid valve disease

55 Clinical Progress ( ) Readmission HF 4x (last admission: August 2016) Poor compliance to fluid/salt restriction Worsening HF Stop working NYHA III-IV Fatigue, orthopnoea, oedema Loss of appetite Weight loss (~13 kg over 1 year) NYHA, New York Heart Association

56 Clinical progress.. Intensify patient & carer education regarding fluid and salt restriction Improve medication compliance 2 4 weekly follow-up to up-titrate medications.

57 November NYHA I-II 6MWT: 350 metres Warm and dry HR 89 bpm, AF BP 140/78 mmhg Weight gain (10 kg over 5 months) BNP 1150 pg/ml Na 139 mmol/l, K 3.9 mmol/l, urea 5.4 mmol/l, creatinine 107 umol/l AF, atrial fibrillation; BP, blood pressure; bpm, beats per minute; HR, heart rate; 6MWT, 6-minute walking test

58 Good enough? NYHA I Shortness of breath severity? How far can you walk? Can you climb stairs? Can you cross the road? Effort intolerance, fatigability Are you getting better? What s the hardest thing you can do? Are you back to normal? Are you able to return to work? Are there things you wish you are able to do?

59 Medication prior to sacubitril/valsartan Frusemide 40 mg OD Bisoprolol 10 mg OD Perindopril 2 mg ON (cough) Spironolactone 12.5 mg OD Slow K 600 mg OD Isosorbide mononitrate 30 mg OD Warfarin (good TTR, INR 2 3) Pantoprazole 40 mg ON INR, international normalized ratio for blood clotting time; OD, once daily; ON, once nightly; TTR, transthyretin

60 Sacubitril/valsartan: initiation & follow-up Withheld perindopril for 2 days Initiate 50 mg BD (~6 weeks) Well tolerated Uptitrate 100 mg home Well tolerated, occasional dizziness Able & willing to continue After 4 weeks, clinic visit (January 2017) HR 84, BP 128/74 mmhg Further titrate 200 mg BD Complained of more dizziness BD, twice daily

61 Early February Cheerful. Dry and warm HR 75 bpm, BP 118/70 mmhg Complaint of dizziness Tends to be postural Decision to reduce to 100 mg BD Maintain previous medication

62 Learning points HF is chronic, progressive and inherently unstable Subjective & objective assessment Sacubitril/valsartan: Start low, go slow Especially in frail patients Anticipate potential side-effects Close monitoring Optimise HF education

63 Conclusion Heart failure is common and has high mortality Drug therapy improves survival Betablockers, ACE-I, ARB, aldosterone antagonists Newer drug therapy ARNI (sacubitril/valsartan) are showing promise for symptom relief and improved survival Angiotensin Neprilysin Inhibition doubles effect on cardiovascular death of current inhibitors of the renin-angiotensin system

64 Thank You