New Advances in the Diagnosis and Management of Acute and Chronic Heart Failure

New Advances in the Diagnosis and Management of Acute and Chronic Heart Failure Deborah Budge, MD Intermountain Healthcare Heart Failure Cardiologist Objectives: State the updates from the ACC 2013 HF Guidelines Describe guideline-directed medical therapy for HF with reduced EF Understand the mechanism of action of a new therapy for HF and the results of the initial study

Updates in Heart Failure ACC/AHA 2013 Guideline Update & PARADIGM Deborah Budge, MD

Heart Failure in the US Heart Failure Patients in US (Millions) 12 10 8 6 4 2 3.5 4.7 10 ~ 6 million symptomatic patients, estimated 10 million in 2037 Incidence: About 550,000 new cases/year More deaths from heart failure than from all forms of cancer combined Prevalence is 1% between the ages of 50 and 59, progressively increasing to >10% over age 80 Over $35 billion/year (5% to 7% of total health care cost) 0 1991 2000 2037 American Heart Association. 2012 Heart Disease and Stroke Statistical Update.

Classification I. Heart Failure with Reduced Ejection Fraction (HFrEF) II. Heart Failure with Preserved Ejection Fraction (HFpEF) a. HFpEF, Borderline Definition of Heart Failure Ejection Fraction 40% 50% 41% to 49% Description Also referred to as systolic HF. Randomized clinical trials have mainly enrolled patients with HFrEF and it is only in these patients that efficacious therapies have been demonstrated to date. Also referred to as diastolic HF. Several different criteria have been used to further define HFpEF. The diagnosis of HFpEF is challenging because it is largely one of excluding other potential noncardiac causes of symptoms suggestive of HF. To date, efficacious therapies have not been identified. These patients fall into a borderline or intermediate group. Their characteristics, treatment patterns, and outcomes appear similar to those of patient with HFpEF. b. HFpEF, Improved > 40% It has been recognized that a subset of patients with HFpEF previously had HFrEF. These patients with improvement or recovery in EF may be clinically distinct from those with persistently preserved or reduced EF. Further research is needed to better characterize these patients. Yancy CW et al. Circulation. 2013;128:e240-e327.

New Approach to the Classification of Heart Failure Stage A B C D High risk for developing heart failure (HF) Asymptomatic HF Symptomatic HF Refractory end-stage HF Patient Description Hypertension CAD Diabetes mellitus Family history of cardiomyopathy Previous MI LV systolic dysfunction Asymptomatic valvular disease Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be discharged from the hospital without specialized interventions) Modified from Jessup M. et al. Circulation.2009

Classification of Heart Failure ACC/AHA Stage and NYHA Class ACC/AHA HF Stage 1 NYHA Functional Class 2 A At high risk for heart failure but without structural heart disease or symptoms of heart failure (eg, patients with HTN or coronary artery disease) None B Structural heart disease but without symptoms of heart failure C Structural heart disease with prior or current symptoms of heart failure I Asymptomatic II Symptomatic with moderate exertion III Symptomatic with minimal exertion D Refractory heart failure requiring specialized interventions IV Symptomatic at rest Jessup M. et al. Circulation.2009 New York Heart Association/Little Brown and Company, 1964. Adapted from: Farrell MH et al.jama.2002.

590,000 Stage A Diabetes Hypertension Obesity Atherosclerosis 480,000 Stage B MI Asymptomatic systolic/diastolic dysfunction Asymptomatic valvular disease Heart Failure Prevalence by Stage, Utah * 49,000 Stage C Symptomatic HF 4,900 Stage D Advanced HF *Estimates. Go AS, et al. Heart Disease and Stroke Statistics-2013 Update. Circulation 2013;127:e6-e245. Utah Department of Health. The Impact of Heart Disease and Stroke in Utah 2012.

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 Yancy CW et al. Circulation. 2013;128:e240-e327.

Area New Changes (2013) Format Practical system Guideline-directed medical therapy (GDMT) Harmonization with other guidelines, consensus documents Content Oral pharmacologic treatment Non-pharmacological interventions Device therapy Mechanical circulatory support ADHF Role of validated risk scores Role of biomarkers Broader indications for aldosterone antagonists (mild to moderate HF) Emphasis on education and transition of care Balanced approach to Na restriction Broader indications for CRT No change for ICDs Class IIa indication for BTT, BTR, DT Loop diuretics 1 st -line therapy Class IIb low-dose dopamine Class II vasodilators

Practical System Recommendations COR LOE ICD therapy is recommended for primary prevention of SCD in selected patients with HFrEF at least 40 days post-mi with LVEF 35%, and NYHA class II or III symptoms on chronic GDMT, who are expected to live 1 year* I A CRT is indicated for patients who have LVEF 35%, sinus rhythm, LBBB with a QRS 150 ms ICD therapy is recommended for primary prevention of SCD in selected patients with HFrEF at least 40 days post-mi with LVEF 30%, and NYHA class I symptoms while receiving GDMT, who are expected to live 1 year* CRT can be useful for patients who have LVEF 35%, sinus rhythm, a non-lbbb pattern with a QRS 150 ms, and NYHA class III/ambulatory class IV symptoms on GDMT. CRT can be useful for patients who have LVEF 35%, sinus rhythm, LBBB with a QRS 120 to 149 ms, and NYHA class II, III or ambulatory IV symptoms on GDMT CRT can be useful in patients with AF and LVEF 35% on GDMT if a) the patient requires ventricular pacing or otherwise meets CRT criteria and b) AV nodal ablation or rate control allows near 100% ventricular pacing with CRT I I IIa IIa IIa A (NYHA class III/IV) B (NYHA class II) B A B B

Practical System Patient with cardiomyopathy on GDMT for >3 mo or on GDMT and >40 d after MI, or with implantation of pacing or defibrillation device for special indications LVEF <35% Evaluate general health status Acceptable noncardiac health Comorbidities and/or frailty limit survival with good functional capacity to <1 y Continue GDMT without implanted device Evaluate NYHA clinical status NYHA class I LVEF 30% QRS 150 ms LBBB pattern Ischemic cardiomyopathy QRS 150 ms Non-LBBB pattern NYHA class II LVEF 35% QRS 150 ms LBBB pattern Sinus rhythm LVEF 35% QRS 120-149 ms LBBB pattern Sinus rhythm LVEF 35% QRS 150 ms Non-LBBB pattern Sinus rhythm QRS 150 ms Non-LBBB pattern NYHA class III & Ambulatory class IV LVEF 35% QRS 150 ms LBBB pattern Sinus rhythm LVEF 35% QRS 120-149 ms LBBB pattern Sinus rhythm LVEF 35% QRS 150 ms Non-LBBB pattern Sinus rhythm LVEF 35% QRS 120-149 ms Non-LBBB pattern Sinus rhythm Special CRT Indications Anticipated to require frequent ventricular pacing (>40%) Atrial fibrillation, if ventricular pacing is required and rate control will result in near 100% ventricular pacing with CRT Colors correspond to the class of recommendations in the ACCF/AHA Table 1. Benefit for NYHA class I and II patients has only been shown in CRT-D trials, and while patients may not experience immediate symptomatic benefit, late remodeling may be avoided along with long-term HF consequences. There are no trials that support CRT-pacing (without ICD) in NYHA class I and II patients. Thus, it is anticipated these patients would receive CRT-D unless clinical reasons or personal wishes make CRT-pacing more appropriate. In patients who are NYHA class III and ambulatory class IV, CRT-D may be chosen but clinical reasons and personal wishes may make CRT-pacing appropriate to improve symptoms and quality of life when an ICD is not expected to produce meaningful benefit in survival.

Area New Changes (2013) Format Represents optimal medical therapy as defined by the Content ACCF/AHA guidelinerecommended therapies (primarily Class I) Oral pharmacologic treatment Non-pharmacological interventions Practical system Guideline-directed medical therapy (GDMT) Harmonization with other guidelines, consensus documents Role of validated risk scores Role of biomarkers Broader indications for aldosterone antagonists (mild to moderate HF) Emphasis on education and transition of care Balanced approach to Na restriction Device therapy Mechanical circulatory support ADHF Broader indications for CRT No change for ICDs Class IIa indication for BTT, BTR, DT Loop diuretics 1 st -line therapy Class IIb low-dose dopamine Class II vasodilators

Risk Scoring Potential benefits of using risk scoring in HF: - Enables patients and families to have a realistic expectation of prognosis - Promotes open communication between clinicians, patients, and families to define goals of therapy - Enables selection of therapies most likely to positively affect the quality and quantity of life - Enables appropriate allocation of resources, including transplant, MCS, and ICD Goldberg LR, Jessup M. Circulation 2007;116(4):360.

Risk Scores to Predict Outcomes in HF Risk Score Chronic HF All patients with chronic HF Seattle Heart Failure Model Reference (from full-text guideline)/link (204) / http://seattleheartfailuremodel.org Heart Failure Survival Score (200) / http://handheld.softpedia.com/get/health/calculator/hfss-calc- 37354.shtml CHARM Risk Score (207) CORONA Risk Score (208) Specific to chronic HFpEF I-PRESERVE Score (202) Acutely Decompensated HF ADHERE Classification and Regression Tree (CART) Model American Heart Association Get With the Guidelines Score EFFECT Risk Score (201) (206) / http://www.heart.org/heartorg/healthcareprofessional/getwiththeguidelines HFStroke/GetWithTheGuidelinesHeartFailureHomePage/Get-With-The-Guidelines- Heart-Failure-Home- %20Page_UCM_306087_SubHomePage.jsp (203) / http://www.ccort.ca/research/chfriskmodel.aspx ESCAPE Risk Model and Discharge Score (215) OPTIMIZE HF Risk-Prediction Nomogram (216) Yancy CW et al. Circulation. 2013;128:e240-e327.

Seattle Heart Failure Model (SHFM)

Risk Scoring I IIa IIb III Validated multivariable risk scores can be useful to estimate subsequent risk of mortality in ambulatory or hospitalized patients with HF.

Natriuretic peptides: mechanisms UpToDate

Use of Natriuretic Peptides in Chronic Heart Failure Initial diagnosis Prognosis Chronic management in the outpatient setting

Natriuretic Peptides and Prognosis in Chronic Heart Failure 32% 9% theheart.org Masson S, et al. Clin Chem 2006;52:1528-38

Use of Natriuretic Peptides in Chronic Heart Failure I IIa IIb III Measurement of BNP or NT-proBNP is useful for establishing prognosis or disease severity in chronic HF.

Use of Natriuretic Peptides in Chronic Heart Failure Initial diagnosis Prognosis Chronic management in the outpatient setting

Patient Example 76-year-old man with ischemic cardiomyopathy, LVEF 25%, seen in clinic for routine evaluation Admitted for decompensated heart failure 4 months ago, uneventful hospitalization Reports NYHA Class II symptoms, denies congestive symptoms, says he feels great Medications: carvedilol 12.5 mg BID, lisinopril 10 mg QD, furosemide 40 mg QD PE: BP 110/62, HR 66, JVP 6 cm, lungs clear, grade 2 MR murmur, trace edema Labs: creatinine 1.4 mg/dl, BNP 329

Challenges with GDMT Therapeutic inertia Differentiation responders vs non-responders Knowing if a patient is truly maximized on meds Assessing volume status Monitoring those who are ostensibly stable for impending complications

Therapies which alter BNP levels Therapy BNP Level Diuresis ACE-I ARB Beta-Blockers Aldosterone Antagonists CRT Exercise Rate control of AF

Serial NP Measurements for Prognostication in Chronic HF theheart.org Masson S, et al. J Am Coll Cardiol 2008;52:997-1003

Understanding Heterogeneous Results in Guided Therapy Trials theheart.org Motiwala SR, et al. Clin Pharm Ther 2013;93:57-67.

Objective: To compare a strategy of medical therapy titration aimed at achieving and maintaining an NT-proBNP target of < 1000 pg/ml (biomarker-guided therapy) to usual care in high risk patients with HFrEF

Use of Natriuretic Peptides in Chronic Heart Failure I IIa IIb III I IIa IIb III BNP- or NT-proBNP guided HF therapy can be useful to achieve optimal dosing of GDMT in select clinically euvolemic patients followed in a wellstructured HF disease management program. The usefulness of serial measurement of BNP or NTproBNP to reduce hospitalization or mortality in patients with HF is not well established.

Aldosterone Antagonist: Mechanism of Action

RALES Cardiosource.com NEJM 1999;341:709-17.

EPHESUS Cardiosource.com NEJM 2003;348:1309-21.

EMPHASIS-HF Cardiosource.com NEJM 2011;364:11-21.

Aldosterone Antagonists I IIa IIb III Aldosterone receptor antagonists are recommended in patients with NYHA class II-IV and who have LVEF of 35% or less, unless contraindicated, to reduce morbidity and mortality. Patients with NYHA class II should have a history of prior cardiovascular hospitalization or elevated plasma natriuretic peptide levels to be considered for aldosterone receptor antagonists. I IIa IIb III Aldosterone receptor antagonists are recommended to reduce morbidity and mortality following an acute MI in patients who have LVEF of 40% or less who develop symptoms of HF or who have a history of diabetes mellitus, unless contraindicated.

Aldosterone Antagonists I IIa IIb III Creatinine should be 2.5 mg/dl or less in men or 2.0 mg/dl or less in women (or estimated glomerular filtration rate >30 ml/min/1.73m2) and potassium should be less than 5.0 meq/l. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely followed thereafter to minimize risk of hyperkalemia and renal insufficiency. Check potassium and renal function: - 2 to 3 days after starting therapy - 1 week after starting therapy, AND - At least monthly for the first 3 months

IMPROVE-HF Fonarow G C et al. Circulation 2010;122:585-596

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

Strategies for Achieving Optimal GDMT Yancy CW et al. Circulation. 2013;128:e240-e327.

Need for Improved Care Coordination #1 reason for hospitalization for people >65 years of age National 30 day readmission rate 25% Mortality 50% at 5 years, 34% at 1 year following a hospitalization Many HF hospitalizations are driven by gaps in the process of care rather than worsening pathophysiology Collins SP, et al. J Am Coll Cardiol 2013;61:121-6.

Transitions of Care I IIa IIb III Throughout the hospitalization as appropriate, before hospital discharge, at the first postdischarge visit, and in subsequent follow-up visits, the following should be addressed: a. initiation of GDMT if not previously established and not contraindicated; b. precipitant causes of HF, barriers to optimal care transitions, and limitations in postdischarge support; Of the patients in Utah with HF, 87% c. assessment of volume status and supine/upright hypotension with have adjustment 3 or more of HF chronic therapy, conditions, as appropriate; and d. titration and optimization 54% of have chronic 5 or oral more HF therapy; chronic conditions. e. assessment of renal function and electrolytes, where appropriate; f. assessment and management of comorbid conditions; g. reinforcement of HF education, self-care, emergency plans, and need for adherence; and h. consideration for palliative care or hospice care in selected patients.

Transitions of Care I IIa IIb III I IIa IIb III I IIa IIb III Multidisciplinary HF disease-management programs are recommended for patients at high risk for hospital readmission, to facilitate the implementation of GDMT, to address different barriers to behavioral change, and to reduce the risk of subsequent rehospitalization for HF. Scheduling an early follow-up visit (within 7 to 14 days) and early telephone follow-up (within 3 days) of hospital discharge is reasonable. Use of clinical risk prediction tools and/or biomarkers to identify patients at higher risk for postdischarge clinical events is reasonable.

Sodium Restriction Mixed data evaluating sodium restriction in HF Observational data = association between sodium intake and risk for hospitalization RCTs = lower sodium intake is associated with worse outcomes in HFrEF No study has been done in optimally treated patients I IIa IIb III Sodium restriction is reasonable for patients with symptomatic HF to reduce congestive symptoms.

Indications for CRT in HF Patient with cardiomyopathy on GDMT for >3 mo or on GDMT and >40 d after MI, or with implantation of pacing or defibrillation device for special indications LVEF <35% Evaluate general health status Acceptable noncardiac health Comorbidities and/or frailty limit survival with good functional capacity to <1 y Continue GDMT without implanted device Evaluate NYHA clinical status NYHA class I LVEF 30% QRS 150 ms LBBB pattern Ischemic cardiomyopathy QRS 150 ms Non-LBBB pattern NYHA class II LVEF 35% QRS 150 ms LBBB pattern Sinus rhythm LVEF 35% QRS 120-149 ms LBBB pattern Sinus rhythm LVEF 35% QRS 150 ms Non-LBBB pattern Sinus rhythm QRS 150 ms Non-LBBB pattern NYHA class III & Ambulatory class IV LVEF 35% QRS 150 ms LBBB pattern Sinus rhythm LVEF 35% QRS 120-149 ms LBBB pattern Sinus rhythm LVEF 35% QRS 150 ms Non-LBBB pattern Sinus rhythm LVEF 35% QRS 120-149 ms Non-LBBB pattern Sinus rhythm Special CRT Indications Anticipated to require frequent ventricular pacing (>40%) Atrial fibrillation, if ventricular pacing is required and rate control will result in near 100% ventricular pacing with CRT Colors correspond to the class of recommendations in the ACCF/AHA Table 1. Benefit for NYHA class I and II patients has only been shown in CRT-D trials, and while patients may not experience immediate symptomatic benefit, late remodeling may be avoided along with long-term HF consequences. There are no trials that support CRT-pacing (without ICD) in NYHA class I and II patients. Thus, it is anticipated these patients would receive CRT-D unless clinical reasons or personal wishes make CRT-pacing more appropriate. In patients who are NYHA class III and ambulatory class IV, CRT-D may be chosen but clinical reasons and personal wishes may make CRT-pacing appropriate to improve symptoms and quality of life when an ICD is not expected to produce meaningful benefit in survival.

Clinical Events and Findings Useful for Identifying Patients With Advanced HF Repeated ( 2) hospitalizations or ED visits for HF in the past year Progressive deterioration in renal function (e.g., rise in BUN and creatinine) Weight loss without other cause (e.g., cardiac cachexia) Intolerance to ACE inhibitors due to hypotension and/or worsening renal function Intolerance to beta blockers due to worsening HF or hypotension Frequent systolic blood pressure <90 mm Hg Persistent dyspnea with dressing or bathing requiring rest Inability to walk 1 block on the level ground due to dyspnea or fatigue Recent need to escalate diuretics to maintain volume status, often reaching daily furosemide equivalent dose >160 mg/d and/or use of supplemental metolazone therapy Progressive decline in serum sodium, usually to <133 meq/l Frequent ICD shocks

Mechanical Circulatory Support Patient selection and Evaluation 1. Does the patient have a reversible cause of heart failure? 2. Is the patient on the maximum/tolerated standard medical HF therapy? 3. Is the patient candidate for CRT-D? If yes, will it make a difference? 4. What is the patient s prognosis in the next year without MCS?(High risk for mortality 50%). 5. Does the patient have any irreversible co-morbidities that will affect quality of life and survival after MCS implantation? 6. Does the patient have adequate financial and psychosocial support, and safe living environment? 7. Does the patient have high risk behavior?

HeartMate II - BTT Outcomes J Am Coll Cardiol 2009;54:312 21

HeartWare (HVAD) - BTT Outcomes Circulation. 2012; 125: 3191-3200

HeartMate II - DT Outcomes Circ Heart Fail. 2012;5:241-48

Mechanical Circulatory Support

PARADIGM-HF: Secondary Endpoints All-cause mortality Change from baseline in the clinical summary score of the Kansas City Cardiomyopathy Questionnaire at 8 months Time to new onset of atrial fibrillation Time to first occurrence of a protocol-defined decline in renal function

(all comparisons are versus enalapril 20 mg daily, not versus placebo)

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) 40 32 24 16 Patients at Risk LCZ696 Enalapril 8 0 Enalapril (n=4212) 0 180 360 540 720 900 1080 1260 4187 4212 3922 3883 Days After Randomization 3663 3579 3018 2922 2257 2123 1544 1488 LCZ696 (n=4187) HR = 0.80 (0.73-0.87) P = 0.0000002 Number needed to treat = 21 896 853 249 236 1117 914

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