2/15/2017. Disclosures. Heart Failure = Big Problem. Heart Failure Update Reducing Hospitalizations and Improving Patient Outcomes 02/18/2017

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1 Heart Failure Update Reducing Hospitalizations and Improving Patient Outcomes 02/18/2017 Julio A. Barcena, M.D. South Miami Heart Specialists Disclosures I have no relevant commercial relationships to disclose. Heart Failure = Big Problem 1

2 CHF - Prevalence Prevalence by Sex and Age HF Hospital Discharges Readmission rate 30% at 6 months! 2

3 Etiology - Coronary artery disease - Hypertension - Valvular heart disease - Other - Toxin (Alcohol, Chemotherapy, Methamphetamines) - Myocarditis - Infiltrative diseases sarcoid, amyloid, iron - Familial - ARVD - Hypertrophic cardiomyopathy Diabetes and Onset of Heart Failure: Impact of Glycemic Control on Risk CHF Rate/Year Per N=48,858 P< < >10 Hemoglobin A 1c (%) Iribarren C et al. Circulation. 2001;103: Pathophysiology Cycle of Progression Myocardial Injury Growth Factors Decreased Cardiac Output Cytokines Increased Preload and Afterload Neurohormonal Activation Renin AT-II AVP ANP NE Increased Contractility Vasoconstriction Na and H 20 Retention Front. Physiol., 01 October 2015 Compensated Function 3

4 Prognosis Levy et al. Circulation. 2006;113:1430 4

5 Medical Therapy Natriuretic peptides are cleared by NPR-C and neprilysin NP signaling and effects NP degradation and clearance RAAS over-activation in HF ANP BNP CNP ANP/CNP/BNP Inactive NP fragments ANP/CNP Ang II NPR-A NPR-B NPR-C Neprilysin AT 1 receptor GTP GTP cgmp Internalization Receptor recycling Signaling cascades Inactive peptides Vasodilation Cardiac fibrosis/hypertrophy Natriuresis/diuresis Vasoconstriction Cardiac fibrosis/hypertrophy Sodium/water retention ANP: atrial natriuretic peptide; Ang:angiotensin; AT 1: angiotensin II type 1; BNP: B-type natriuretic peptide; cgmp: cyclic guanosine monophosphate; CNP: C-type natriuretic peptide; GTP: guanosine triphosphate; HF: heart failure; 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 & Griendling. Am J Physiol Cell Physiol 2007;292:C82 97 Mechanisms of Progression in Heart Failure Myocardial or vascular stress or injury Decreased activity or response to adaptive mechanisms Angiotensin receptor blocker Inhibition of neprilysin Evolution and progression of heart failure 5

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) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Neprilysin Neprilysin inhibition Inactive metabolites LCZ696: Angiotensin Receptor Neprilysin Inhibition LCZ696 Angiotensin receptor blocker Inhibition of neprilysin (all comparisons are versus enalapril 20 mg daily, not versus placebo) 6

7 PARADIGM-HF LCZ696 = Valsartan + neprilysin inhibitor sacubitril (AHU377) Neprilysin is an enzyme that degrades natriuretic peptides, bradykinin, and adrenomedullin so inhibition increases endogenous levels 8442 patients with NYHA II-IV HF and EF <40% Primary outcome was composite of CV death or HF hospitalization McMurray JJV et al, NEJM 2014;371:11: PARADIGM-HF: Cardiovascular Death Kaplan-Meier Estimate of Cumulative Rates (%) HR = 0.80 ( ) P = Number need to treat = 32 Enalapril (n=4212) LCZ696 (n=4187) Days After Randomization Patients at Risk LCZ696 Enalapril 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 Days After Randomization LCZ Enalapril

8 PARADIGM-HF: SUMMARY OF FINDINGS In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril: LCZ696 was more effective than enalapril in... Reducing the risk of CV death and HF hospitalization Reducing the risk of CV death by incremental 20% Reducing the risk of HF hospitalization by incremental 21% Reducing all-cause mortality by incremental 16% Incrementally improving symptoms and physical limitations LCZ696 was better tolerated than enalapril... Less likely to cause cough, hyperkalemia or renal impairment Less likely to be discontinued due to an adverse event More hypotension, but no increase in discontinuations Not more likely to cause serious angioedema 2016 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 Class I B r The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A) (9 14), OR ARBs (Level of Evidence: A) (15 18), OR ARNI (Level of Evidence: B-R) (19) in conjunction with evidence-based beta blockers (20 22), and aldosterone antagonists in selected patients (23,24), is recommended for patients with chronic ARNI: B-R HFrEF to reduce morbidity and mortality In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality 8

9 Ivabradine Inhibits I f current in sinoatrial node lowers HR Used for chronic angina SHIFT study (n=6558) Inclusion: HF with LV dysfunction, HR >70 98% were NYHA II/III Reduced mean HR by 10.9 bpm Side effects: Bradycardia, 1% increase Afib, phosphenes and blurred vision Swedberg K et al, Lancet 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 Class II a Br Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF 35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest Yancy et al JACC VOL. 68, NO. 13,

10 To STICH or Not To STICH Surgical Treatment for Ischemic Heart Failure Trial (STICH) Surgical Revascularization Hypothesis In patients with HF, LVD and CAD amenable to surgical revascularization, CABG added to intensive medical therapy (MED) will decrease all-cause mortality compared to MED alone. 10

11 Important Inclusion Criteria LVEF 0.35 within 3 months of trial entry CAD suitable for CABG MED eligible Absence of left main CAD as defined by an intraluminal stenosis of 50% Absence of CCS III angina or greater (angina markedly limiting ordinary activity) STICH: CABG Does Not Extend Survival Over Medical Therapy in Heart Failure Patients April

12 CABG 16% lower death rate from any cause over 10 years Diastolic Heart Failure A.K.A. HFPEF, HFNEF Echocardiographic/clinical diagnosis Common (~50%) Evidence-based treatment is very limited Ventricular rate control in atrial fibrillation Blood pressure control Management of congestion Consider revascularization if CAD 12

13 Data on Diuretics No long-term studies of diuretic therapy Meta-analysis showed reduced risk of death & worsening HF Other retrospective studies suggest increased mortality after chronic use of non-potassium sparing diuretics Mannekin Pis, Brussels Domanski M in JACC 2003 Domanski M in J Card Fail2006 Ahmed A in EurHeart J 2006 Eshaghian S in Am J Cardiol 2006 Treatment Of Preserved Cardiac Function Heart Failure with an Aldosterone antagonist (TOPCAT) Objective To determine if treatment with spironolactone can produce a clinically meaningful reduction in the composite endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for the management of heart failure, compared with placebo, in adults with HF-Preserved EF. Inclusions: Symptomatic Heart Failure, Age 50, LVEF 45%, stratified according to: Hospitalization within the past year for management of heart failure, or Elevated natriuretic peptides (BNP 100 pg/ml or NT-proBNP 360 pg/ml) Major Exclusions: egfr<30 ml/min/1.7m 2, serum potassium 5 mmol/l, uncontrolled hypertension, AF with rate > 90/min, recent ACS, restrictive, infiltrative, or hypertrophic cardiomyopathy Rationale and design: (A. Desai, Am Heart J 2011) Summary Primary Outcome Hospitalization for Heart Failure Spironolactone (N = 1722) 320 (18.6%) 5.9/100pt-yr 206 (12.0%) 3.8/100pt-yr Placebo (N = 1723) 351 (20.4%) 6.6/100pt-yr 245 (14.2%) 4.6/100pt-yr Conclusions: TOPCAT population with HFpEF: Rx with spironolactone did not alter the 1 composite Reductions in heart failure were observed Use of spironolactone in these patients requires careful monitoring of K + and creatinine HR (95% CI) 0.89 ( ) P= ( ) P=0.042 Multiple HF Hosp P<

14 IAS for HFpEF REDUCE LAP-HF trial 68 patients in phase 1 study, 21 centers Transcatheter interatrial shunt device (Corvia) EF >40%, Age >40, HFpEF symptoms despite therapy PCWP >15 at rest or >25 with exercise 52% had reduction of PCWP at rest, 58% reduction with exertion, and 39% met both Pivotal trial pending (Samara/Sorajja) HasenfussG et al, Lancet2016;387: CHAMPION - CardioMems 64 centers, 550 patients, NYHA III Wireless implantable hemodynamic monitor versus usual care 83 vs 120 admits for HR 0.7 ( , p<0.0001) with device Abraham WT et al for CHAMPION, Lancet CardioMEMS Abraham WT et al for CHAMPION, Lancet

15 Who is eligible? NYHA III heart failure 1 heart failure hospitalization Typically egfr >25 Able to comply with daily monitoring Heart failure with preserved ejection fraction Conclusions In Heart failure with reduced EF the use of ARB plus Neprilysin inhibition improves survival and reduces rehospitalizations. Ivrabadine can reduce hospitalization in patients with reduced ef and heart rate above 70bpm. CABG reduces mortality inpatient with heart failure and CAD. 15