Systolic Dysfunction Clinical/Hemodynamic Guide for Management; New Medical and Interventional Therapeutic Challenges

Systolic Dysfunction Clinical/Hemodynamic Guide for Management; New Medical and Interventional Therapeutic Challenges Clyde W. Yancy, MD, MSc, FACC, FAHA, MACP Magerstadt Professor of Medicine Professor, Department of Medical Social Sciences Chief of Cardiology Northwestern University, Feinberg School of Medicine & Associate Medical Director Bluhm Cardiovascular Institute Chicago, IL cyancy@nmff.org

Heart Failure Clinic, Northwestern, 12/11/14; 2 patients #1 59 year old man with known dilated CM and class IIIB HF; LVEF 0.11. BNP ~ 450 pg/ml; MEDS- Carvedilol (LA) 10 mg qd; lisinopril 2.5 mg QD; spironolactone 25 mg QD. BP 90/74; JVP 12 cm H20; soft S3; no edema #2 48 year old woman with dilated CM; + family history (but negative genetic screen); NYHA class I/II HF symptoms; LVEF 0.30. BNP 125 pg/ml. MEDS Carvedilol 25 mg BID, Lisinopril 10 mg QD, ICD in place; BP 128/78; o/w compensated exam Which patient is appropriate for LCZ 696 #1 #2 Both Neither

Heart Failure; a new era emerges- the proof: Outcomes have improved We can prevent heart failure Biomarkers are potent aids in the management of HF Guideline Directed Medical Therapy (GDMT) for HF works A new PARADIGM has emerged

Improving HF Outcomes

Stages, Phenotypes and Treatment of HF At Risk for Heart Failure Heart Failure STAGE A At high risk for HF but without structural heart disease or symptoms of HF STAGE B Structural heart disease but without signs or symptoms of HF STAGE C Structural heart disease with prior or current symptoms of HF STAGE D Refractory HF e.g., Patients with: HTN Atherosclerotic disease DM Obesity Metabolic syndrome or Patients Using cardiotoxins With family history of cardiomyopathy Structural heart disease e.g., Patients with: Previous MI LV remodeling including LVH and low EF Asymptomatic valvular disease Development of symptoms of HF e.g., Patients with: Known structural heart disease and HF signs and symptoms Refractory symptoms of HF at rest, despite GDMT e.g., Patients with: Marked HF symptoms at rest Recurrent hospitalizations despite GDMT HFpEF HFrEF THERAPY Goals Heart healthy lifestyle Prevent vascular, coronary disease Prevent LV structural abnormalities Drugs ACEI or ARB in appropriate patients for vascular disease or DM Statins as appropriate THERAPY Goals Prevent HF symptoms Prevent further cardiac remodeling Drugs ACEI or ARB as appropriate Beta blockers as appropriate In selected patients ICD Revascularization or valvular surgery as appropriate THERAPY Goals Control symptoms Improve HRQOL Prevent hospitalization Prevent mortality Strategies Identification of comorbidities Treatment Diuresis to relieve symptoms of congestion Follow guideline driven indications for comorbidities, e.g., HTN, AF, CAD, DM Revascularization or valvular surgery as appropriate THERAPY Goals Control symptoms Patient education Prevent hospitalization Prevent mortality Drugs for routine use Diuretics for fluid retention ACEI or ARB Beta blockers Aldosterone antagonists Drugs for use in selected patients Hydralazine/isosorbide dinitrate ACEI and ARB Digoxin In selected patients CRT ICD Revascularization or valvular surgery as appropriate THERAPY Goals Control symptoms Improve HRQOL Reduce hospital readmissions Establish patient s endof-life goals Options Advanced care measures Heart transplant Chronic inotropes Temporary or permanent MCS Experimental surgery or drugs Palliative care and hospice ICD deactivation

Prevalence and prognostic significance of HF Stages Survival (years) Ammar et al. Circulation 2007; 115:1563

From: Natriuretic Peptide Based Screening and Collaborative Care for Heart Failure: The STOP-HF Randomized Trial JAMA. 2013;310(1):66-74. doi:10.1001/jama.2013.7588 Figure Legend: Kaplan-Meier Analysis of Major Adverse Cardiovascular Events in the Full Study Sample and in Participants With BNP 50 pg/mlbnp indicates brain-type natriuretic peptide. Major adverse cardiovascular events included arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure. In the full sample, 51 (7.3%) of 697 patients were admitted for major adverse cardiovascular events in the intervention group and 71 (10.5%) of 677 were admitted in the control group. In participants with BNP 50 pg/ml, 35 (13.3%) of 263 were admitted for major adverse cardiovascular events in the intervention group and 45 (19.1%) of 235 were admitted in the control group. Copyright 2014 American Medical Association. All rights reserved.

BNP Reflects Ventricular Wall Stress Iwananga, JACC 2006

Death or Readmission, % Predischarge BNP Is Strong Predictor of Post- Discharge Events 100 BNP >700 ng/l* (n = 41, events = 38) p<.0001 15.2 75 BNP 350-700 ng/l* (n = 50, events = 30) 50 p<.0001 25 BNP <350 ng/l* (n = 111, events = 18) 5.1 0 0 30 60 90 120 150 180 Follow-up, Days 1 Hazard Ratios Logeart D, et al. J Am Coll Cardiol. 2004;43:635-641.

new biomarkers?

Growth Differentiation Factor [GDF]-15 is a member of the transforming growth factor-beta cytokine superfamily and is Soluble strongly ST2 induced represents in response a to metabolic cellular response stress and to is stress involved in cell and differentiation is indicative and tissue repair of LV remodeling and fibrosis Figure 2 CV Events, by Categories of Biomarker Time in Response (A) sst2; (B) GDF-1; and (C) hstnt. There was a direct relationship between percentage of time spent below prognostic thresholds ( time in response ) and cardiovascular (CV) event rates... Hanna K. Gaggin, Jackie Szymonifka, Anju Bhardwaj, Arianna Belcher, Benedetta De Berardinis, Shweta Motiwala... Head-to-Head Comparison of Serial Soluble ST2, Growth Differentiation Factor-15, and Highly-Sensitive Troponin T Measurements in Patients With Chronic Heart Failure JACC: Heart Failure, Volume 2, Issue 1, 2014, 65-72 http://dx.doi.org/10.1016/j.jchf.2013.10.005

Pharmacological Treatment for Stage C HFrEF I IIa IIb III See recommendations for stages A, B, and C LOE for LOE Measures listed as Class I recommendations for patients in stages A and B are recommended where appropriate for patients in stage C. (Levels of Evidence: A, B, and C as appropriate) I IIa IIb III GDMT as depicted in Figure 1 should be the mainstay of pharmacological therapy for HFrEF. Yancy, C. et al. JACC, 2013

Pharmacologic Treatment for Stage C HFrEF HFrEF Stage C NYHA Class I IV Treatment: Class I, LOE A ACEI or ARB AND Beta Blocker For all volume overload, NYHA class II-IV patients For persistently symptomatic African Americans, NYHA class III-IV For NYHA class II-IV patients. Provided estimated creatinine >30 ml/min and K+ <5.0 meq/dl Add Add Add Class I, LOE C Loop Diuretics Class I, LOE A Hydral-Nitrates Class I, LOE A Aldosterone Antagonist Yancy, C. et al. JACC, 2013

Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in RCTs GDMT RR Reduction in Mortality NNT for Mortality Reduction (Standardized to 36 mo) RR Reduction in HF Hospitalizations ACE inhibitor or ARB 17% 26 31% Beta blocker 34% 9 41% Aldosterone antagonist 30% 6 35% Hydralazine/nitrate 43% 7 33% Yancy, C. et al. JACC, 2013

The newest Paradigm in HF

Cardiac antiremodeling effects of angiotensin receptor neprilysin inhibitors (ARNi) in vitro and in vivo. von Lueder T G et al. Circ Heart Fail. 2013;6:594-605 Copyright American Heart Association, Inc. All rights reserved.

Cardiac antiremodeling effects of angiotensin receptor neprilysin inhibitors (ARNi) in vitro and in vivo. von Lueder T G et al. Circ Heart Fail. 2013;6:594-605

Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure by Milton Packer, Robert M. Califf, Marvin A. Konstam, Henry Krum, John J. McMurray, Jean-Lucien Rouleau, and Karl Swedberg Circulation Volume 106(8):920-926 August 20, 2002 Copyright American Heart Association, Inc. All rights reserved.

Figure 1. Kaplan-Meier analysis of time to death or hospitalization for heart failure requiring intravenous treatment in the omapatrilat and enalapril groups. Packer M et al. Circulation. 2002;106:920-926 Copyright American Heart Association, Inc. All rights reserved.

Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696 LCZ696 sacubitril valsartan Natriuretic peptides BK, ADM Subs-P, VIP, CGRP Angiotensin II Vasodilation Natriuresis Diuresis Inhibition of pathologic growth/fibrosis Neprilysin Degradation products AT 1 Receptor Vasoconstriction Sodium/water retention Fibrosis/hypertrophy

PARADIGM HF

Kaplan Meier Curves for Key Study Outcomes, According to Study Group. McMurray JJ et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1409077

Adverse Events during Randomized Treatment. McMurray JJ et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1409077

Mean Baseline Characteristics of Patients with Heart Failure and a Reduced Ejection Fraction in Five Trials. Jessup M. N Engl J Med 2014. DOI: 10.1056/NEJMe1409898

New data: Pre-specified exploratory outcomes Selected outcomes reflecting disease progression

Summary and conclusions Compared with enalapril, patients on LCZ696: Are less likely to show symptomatic deterioration Are less likely to need intensification of oral therapy/addition of iv therapy Are less likely to visit the emergency department Are less likely to be admitted to hospital When admitted, are less likely to go to the ICU and less likely to need iv inotropic therapy Are less likely to require devices/surgery for worsening/ end-stage heart failure (not statistically significant) Are less likely to die prematurely (either suddenly or from worsening HF) Less likely to show biomarker evidence of cardiac wall-stress and myocyte injury (data not shown see Circulation) Compared with enalapril, LCZ696 slows progression of heart failure, delaying/preventing non-fatal and fatal worsening.

The Critical Question

Pharmacologic Treatment for Stage C HFrEF HFrEF Stage C NYHA Class I IV Treatment: Class I, LOE A ACEI or ARB AND Beta Blocker ARNI For all volume overload, NYHA class II-IV patients For persistently symptomatic African Americans, NYHA class III-IV For NYHA class II-IV patients. Provided estimated creatinine >30 ml/min and K+ <5.0 meq/dl Add Add Add Class I, LOE C Loop Diuretics Class I, LOE A Hydral-Nitrates Class I, LOE A Aldosterone Antagonist

Next Steps?

Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF) The primary objective compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF patients (New York Heart Association [NYHA] Class II-IV) with preserved ejection fraction (left ventricular ejection fraction [LVEF] 45%). Inclusion Criteria: Left ventricular ejection fraction (LVEF) 45% prior to study entry. Symptom(s) of heart failure (HF) and requiring treatment with diuretic(s) for HF 30 days prior to study entry Current symptom(s) of HF Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram At least one of the following: a HF hospitalization within 9 months prior to study entry and/or an elevated NT-proBNP.