Updates on Heart Failure 2018 from Abbott, Amgen, AstraZeneca, - - PowerPoint PPT Presentation

6/18/2018 1

Updates on Heart Failure 2018

John R. Teerlink, M.D.

FACC, FAHA, FESC, FHFA, FHFSA, FRCP(UK) Professor of Clinical Medicine, University of California San Francisco Director of Heart Failure, San Francisco Veterans Affairs Medical Center San Francisco, CA, USA

• Financial Disclosure

– J.R. Teerlink has received research grants and/or consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Cytokinetics, Janssen, Medtronic, Novartis, Relypsa.

• Unlabeled/unapproved uses disclosure

– I will be discussing investigational therapies that are not approved by the FDA.

Presenter Disclosure Information: UCSF Advances in Internal Medicine 2018 Welcome to UCSF… Home of Evidence-based Medicine!

• 2013 ACC/AHA Heart Failure Guideline

(Yancy CW, et al. J Am Coll Cardiol 2013;62:e147–239. 924 references)

• 2016 ACC/AHA Focused Update on New

Pharmacological Therapy for Heart Failure

(Yancy CW, et al. J Am Coll Cardiol 2016;68:1476-88. 40 references)

• 2017 ACC/AHA/HFSA Focused Update of the 2013

ACCF/AHA Guideline for the Management of Heart Failure

(Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803. 205 references)

Heart Failure Evidence-base

6/18/2018 2

Updates on Heart Failure 2018

Goal to:

• Remind you of what you know you should be doing
• Discuss what you may not know that you should be

doing

• Share what you may be doing in the future

Updates on Heart Failure 2018

• Definition, Nomenclature, Epidemiology
• Evaluation and Diagnosis
• Treatment of Stages of Heart Failure
• Co-morbidities
• Future directions

Updates on Heart Failure 2018

• Definition, Nomenclature, Epidemiology
• HF is a complex clinical syndrome that results from any structural or

functional impairment of ventricular filling or ejection of blood.

• May result from disorders of the pericardium, myocardium,

endocardium, heart valves, or great vessels or from certain metabolic abnormalities, but most patients with HF have symptoms due to impaired left ventricular (LV) myocardial function.

• No single diagnostic test for HF; a clinical diagnosis based on careful

history and physical examination, supplemented by diagnostic studies.

• Heart failure (not Congestive Heart Failure)

Heart Failure

6/18/2018 3

• Lifetime risk of developing HF is 20% for Americans 40 years of age
• >1,000,000 new HF cases diagnosed annually
• Approximately 6.5 million persons in the US have clinically manifest HF
• Blacks have the highest risk for HF and a greater 5-year mortality rate

than whites

• Absolute mortality rates for HF remain approximately 40-50% within 5

years of diagnosis

• Cost of heart failure in 2012: $71-$127 billion

(Voigt J, et al. Clin Cardiol 2014 37, 5, 312–321.)

Heart Failure: Here Comes Everybody

Benjamin EJ, et al. Circulation 2018;137:e67–e492.

Heart Failure with Reduced/Preserved Ejection Fraction (HFrEF and HFpEF)

Yancy CW, et al. J Am Coll Cardiol 2013;62:e147–239.

Stages of Heart Failure

Yancy CW, et al. J Am Coll Cardiol 2013;62:e147–239.

ACCF/AHA Stages Compared to NYHA Functional Class

Yancy CW, et al. J Am Coll Cardiol 2013;62:e147–239.

6/18/2018 4

Updates on Heart Failure 2018

• Definition, Nomenclature, Epidemiology
• Evaluation and Diagnosis

Physical Exam in Heart Failure

“First, strike for the jugular and let the rest go”

• Oliver Wendell Holmes, Jr.

Diagnosis of Heart Failure

• Symptoms

– Dyspnea (Exertional, PND, Orthopnea) – Cough – Fatigue – Abd discomfort (bloating, anorexia) – Sleep disturbances

• Physical Exam

– Edema (Legs, Abd, Sacral) – Rales, Effusion – JVP, HJR/AJR – Weight – Cool extremities – MR murmur – S3 (S4) – Blood/ pulse pressure – Pulsus alternans

Natriuretic peptide Biomarker-based Screening

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

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St Vincent’s Screening to Prevent Heart Failure (STOP-HF) Study

• 1374 participants with CV risk

factors, ≥40 years and had a history of ≥1 of the following: Hypertension; Obesity; Hypercholesterolemia; Vascular disease; Diabetes mellitus; Arrhythmia requiring therapy; Moderate to severe Valvular disease.

• Randomized to:

Usual care BNP Screening. If BNP≥50, Echo and Collaborative Care Ledwidge M, et al. JAMA 2013;310:66-74.

Indications for Use of Biomarkers in Heart Failure

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT)

• 894 (1100 planned) pts with HFrEF:

 LVEF ≤40%  h/o HF event within the prior 12 months,  NT-proBNP >2000 pg/mL or BNP >400 pg/mL within prior 30 days.

• Randomized to:

 NT-proBNP–guided strategy (n=446): HF therapy titrated with target NT- proBNP <1000 pg/mL.  Usual care (n=448): Intensive guideline-based care Primary endpoint: time-to-first HF hospitalization or cardiovascular mortality (stopped early for futility) Felker GM, et al. JAMA 2017;318:713-720.

Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT)

Felker GM, et al. JAMA 2017;318:713-720. Secondary Outcomes

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Selected Potential Causes of Elevated Natriuretic Peptide Levels

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III HF Patients (CHAMPION)

• 550 pts with heart failure:

 ≥18 years old  NYHA III for at least 3 months  Any LVEF  HF hospitalization within past 12 months,  On optimal GDMT

• All patients implanted and take daily
• readings. Randomized to:

 Physician access (n=270)  Usual care (n=280) Primary endpoint: rate of heart failure- related hospitalizations at 6 months Abraham WT, et al. Lancet 2011;377:658-66.

CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III HF Patients (CHAMPION)

Abraham WT, et al. Lancet 2011;377:658-66.

All-cause Death or HF-related Hospitalization Cumulative HF-related Hospitalizations

Ambulatory Hemodynamic Monitoring Reduces Heart Failure Hospitalizations in “Real-World” Clinical Practice

• Retrospective cohort study, U.S. Medicare

claims data from patients undergoing pulmonary artery pressure sensor implant (June 1, 2014-December 31, 2015)

• 1114 pts with full 6-month pre-implant data

480 pts with full 12-month pre-implant data Desai AS, et al. J Am Coll Cardiol 2017;69:2357-65.

Post-Implant Pre-Implant

6/18/2018 7

Updates on Heart Failure 2018

• Definition, Nomenclature, Epidemiology
• Evaluation and Diagnosis
• Treatment of Stages of Heart Failure

Stage A Heart Failure: “When you’re a Hammer, Everything looks like a Nail!”

Stages of Heart Failure Risk Factor Modification in HF

• Weight loss
• Smoking cessation
• Hypertension therapies
• Diabetes management
• Lipid control
• Sleep apnea
• Exercise

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Dickstein K, et al. Eur Heart J 2008;29:2388-442.

Essential Topics in Patient Education Stages of Heart Failure Stages of Heart Failure

Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

6/18/2018 9

Use of Diuretics in Heart Failure Patients

• Self-titration: need “dry” weight on patient’s scale

– Daily weights (routine; daily log with symptoms, etc.) – If weight increased by >3-5 lbs, take double diuretic – If patient requires supplemental potassium, also double – If worsening at any time or no improvement after 2-3 days, call

• Some patients can be maintained on thiazides (i.e. HCTZ)
• Many patients will require loop diuretics; furosemide has short duration
• f action, should be dosed b.i.d. (AM and mid-afternoon/ early evening)
• Many patients may not require diuretics when ACE inhibitor, beta

blocker, mineralocorticoid receptor antagonist, etc. are optimized; reassess diuretic requirements after time on stable regimen

Use of Diuretics in Heart Failure Patients-Redux

• Often increasing creatinine can be evidence of worsening heart failure,

elevated CVP and need for more diuretics

• Furosemide’s poor bioavailability is worse in the setting of abdominal

edema/ congestion.

• Diuretic resistance may be treated with switch to bumetanide/ torsemide,

metolazone, (or adding spironolactone).

• Sequential nephron blockade with loop diuretic and metolazone very

effective for diuresis, but should be done VERY cautiously or by specialist

• Frequent monitoring of electrolytes is imperative; HYPOkalemia is as

dangerous as HYPERkalemia (maintain K+ ≥4.0).

Importance of Afterload Reduction

Use of ACE Inhibitors in Heart Failure Patients

• Indicated in potentially ALL pts with HF and EF≤40%
• Some ACE Inhibitor is better than none
• Start low dose, up-titrate q2 wks or so; check labs within 1-2 weeks of dose

adjustment, then about q4 months

• Asymptomatic low blood pressure: usually no change
• Symptomatic Hypotension: Re-evaluate other meds (nitrates, diuretics, etc.);

may improve with time (reassure);

• Cough: Other causes, rechallenge, consider ARB
• Worsening renal function: Increase in creatinine up to 50% above baseline is

acceptable; K<5.5

• ARBs may be INFERIOR to ACEi in CHF/
• Sacubitril/Valsartan BETTER than ACEi

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ACE inhibitors/ ARBs for Heart Failure

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

Use of Beta blockers in Heart Failure Patients

• Indicated in potentially ALL pts with HF and EF≤40%
• Some beta blocker is better than none
• Some beta blocker probably better than more ACE inhibitor
• Start low dose, up-titrate q2 wks or so.
• Severe asthma is a contraindication (NOT COPD)
• Asymptomatic low blood pressure: usually no change
• Symptomatic Hypotension: Re-evaluate other meds (nitrates, diuretics, etc.);
• ften improves with time (reassure);
• Worsening HF: Congestion, Increase diuretic; Fatigue, usually reassurance
• Low heart rate: if <55 bpm, halve dose
• Other beta blocker side effects minimal in HF patients

Magnitude of Benefit of Therapies for Heart Failure

Yancy CW, et al. J Am Coll Cardiol 2013;62:e147–239.

Use of Mineralocorticoid Receptor Antagonists (MRAs) in HF Patients

• Indicated in potentially ALL NYHA II-IV pts with HF and EF≤35%
• Start low dose, up-titrate after q4-8 wks or so; check labs within 1

and 4, 8 and 12 weeks of dose adjustment, at 6,9,12 months, and then q4 months

• Avoid potassium repletion and K-containing salt substitutes
• Hyperkalemia: If K>5.5 or Cr ≥2.5 mg/dL, halve dose and f/u; if

K>6.0 or Cr >3.5 mg/dL, d/c dose and f/u. Consider rechallenge if reversible cause identified.

• Gynecomastia in males: change to eplerenone

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MRAs, Beta-blockers and ISDN/Hydralazine for Heart Failure (HFrEF)

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

An Approach to Management of Patient with Stage C Symptomatic HF-REF

• Control volume overload with diuretics
• Initiate ACE inhibitor therapy (2.5-5 mg lisinopril);

substitute with ARB only if absolutely necessary

• Initiate Beta blocker therapy (prefer Carvedilol 3.125 or

6.25 mg po bid) and up-titrate to max tolerated

• Initiate spironolactone (switch to eplerenone if needed)
• Maximize ACE inhibitor/ Switch to ARNI (discussed later)
• If after stable therapy and meets criteria, ICD/CRT
• If still symptomatic, consider ISDN/ Hydral

Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

Sacubitril/ Valsartan – A First-in-Class Angiotensin Receptor Neprilysin Inhibitor (ARNI)

AT1 receptor

Vasoconstriction  blood pressure  sympathetic tone  aldosterone  fibrosis  hypertrophy Angiotensinogen (liver secretion) Angiotensin I Angiotensin II

Renin Angiotensin System

Vasodilation  blood pressure  sympathetic tone aldosterone levels  fibrosis  hypertrophy Natriuresis/Diuresis Inactive fragments BNP pro-BNP NT-pro BNP Neprilysin

Natriuretic Peptide System Heart Failure

X X

Valsartan Sacubitril (AHU377)

↓

LBQ657 LCZ696

6/18/2018 12 PARADIGM-HF: Study design

2 weeks ~ 17 to 52 months (event-driven) N = 8458 pts randomized

Enalapril 10 mg bid LCZ696 200 mg bid

LCZ696 200 mg bid On top of standard heart failure therapy (excluding ACEIs and ARBs) Primary outcome: CV death or HF hospitalization (event driven: 2,410 pts with primary events) Testing tolerability to target doses of Enalapril and LCZ696 LCZ696 100 mg bid Enalapril 10 mg bid‡

1-2 weeks 2-4 weeks Single-blind run-in period Double-blind treatment period 36-hour washout period McMurray JJV, et al. Eur J Heart Fail 2013;15:1062–1073. CHF NYHA Class II-IV, LVEF < 35%, Elevated BNP/ NT-proBNP; on stable standard therapy

PARADIGM-HF: Main Results

McMurray JJV, et al. N Engl J Med 2014;371:993-1004.

PARADIGM-HF: Adverse Events

McMurray JJV, et al. N Engl J Med 2014;371:993-1004.

PARADIGM-HF: Adverse Events

McMurray JJV, et al. N Engl J Med 2014;371:993-1004.

6/18/2018 13

Physicians love ACE inhibitors/ ARBs

From Medical School on…

• Decades of familiarity
• Improves clinical outcomes

in multiple disease states

• Guidelines
• Quality metrics

PARADIGM-HF: Putative Placebo Analysis

CV Death + HF Hosp CV Death HF Hosp All-Cause Death

McMurray JJV, et al. Eur Heart J 2015;36:434-9.

Sacubitril/Valsartan better than Enalapril in…

• Preventing worsening HF: HF hosp, ED, observation ward, and

clinic visits with intensification of therapy for HF

(Okumura N, et al. Circulation 2016;133:2254-2262.)

• Decreasing recurrent HF hospitalizations

(Packer M, et al. Circulation 2015;131:54-61.)

• Reducing 30-day Rehospitalizations

(Desai A, et al. J Am Coll Cardiol 2016;68:241–8.)

• Improving Health-related quality of life

(Lewis EF, et al. Circ Heart Fail 2017 Aug;10(8). pii: e003430.)

• Increasing Physical and Social Activity

(Chandra A, et al. JAMA Cardiol 2018 Apr 4. doi: 10.1001/jamacardio.2018.0398.)

Secondary Studies from PARADIGM-HF

Sacubitril/Valsartan better than Enalapril…

• In all risk levels- MAGGIC, EMPHASIS

(Simpson J, et al. J Am Coll Cardiol 2015; 66:2059-71.)

• With/without baseline diuretic, digoxin, MRA, ICD, Coronary

revascularization, optimal beta blocker dose, etc.

(Okumura N, et al. Circ Heart Fail 2016;9:e003212.)

• In all EF ranges <40%

(Solomon SD, et al. Circ Heart Fail 2016;9:e002744.)

• Regardless of percentage of target dose achieved

(Vardeny O, et al. Eur J Heart Fail 2016;18: 1228-34.)

Secondary Studies from PARADIGM-HF

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2016 ACC/AHA/HFSA Guideline Update: Sacubitril/ Valsartan

Yancy CW, et al. J Am Coll Cardiol 2016;68:1476–88.

Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

Ivabradine: Mechanism of Action

Psotka M, Teerlink JR. Circulation 2016;133:2066-2075. Hyperpolarization-activated cyclic nucleotide- gated (HCN) channels in sino-atrial node

Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT)

Swedberg K, et al. Lancet 2010; 376: 875-85.

• Event-driven, multinational,

randomized, double-blind, placebo- controlled, parallel-group trial

• NYHA II-III, LVEF ≤35%, NSR>70 bpm,

HF Hospitalization within 12 months

• 6558 total

3268 Ivabradine (2.5-7.5 mg bid) 3290 Placebo

• Median f/u 22±9 (IQR 18–28)

months

CV Death or HF Hospitalization

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Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT)

Swedberg K, et al. Lancet 2010; 376: 875–85. CV Death HF Hospitalization

Adverse Events in SHIFT

Swedberg K, et al. Lancet 2010; 376: 875–85.

Adverse Events in SHIFT

Swedberg K, et al. Lancet 2010; 376: 875–85.

Compared to placebo, Ivabradine…

• Prevented recurrent Heart Failure hospitalizations

(Borer JS, et al. Eur Heart J 2012;33, 2813–2820.)

• Improved health-related quality of life

(Ekman I, et al. Eur Heart J 2011;32:2395-404.)

• Effective and safe in patients with Diabetes mellitus

(Komajda M, et al. Eur J Heart Fail 2015;17:1294-301.)

Secondary Studies from SHIFT

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Ivabradine Approvals

Approved in the US in April 15, 2015.

• Indicated to reduce the risk of hospitalization for

worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are

• n maximally tolerated doses of beta-blockers or have a

contraindication to beta-blocker use.

Teerlink JR. Lancet 2010; 376: 847-9.

Relative Contraindications to Beta-blockers in Heart Failure

• Heart rate <60 bpm
• Symptomatic hypotension
• Signs of peripheral hypoperfusion
• PR interval >0.24 sec
• Second- or third-degree atrioventricular block (without

electronic pacemaker)

• History of asthma or reactive airways (NOT COPD)
• Peripheral artery disease with resting limb ischemia

2016 ACC/AHA/HFSA Guideline Update: Ivabradine

Yancy CW, et al. J Am Coll Cardiol 2016;68:1476–88.

6/18/2018 17

Vamos M, et al. Eur Heart J 2015; doi:10.1093/eurheartj/ehv143.

Digoxin-Associated Mortality in Patients with Atrial Fibrillation or Heart Failure: A Meta-Analysis

Atrial fibrillation

• 9 studies of only AF
• 3 studies of AF + HF
• Total 235,047

AFib pts Heart Failure

• 7 studies of only HF
• 3 studies of AF + HF
• Total 91,379 HF pts

Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

Recommendations for Stage C Heart Failure with preserved Ejection Fraction (HFpEF)

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

Recommendations for Stage C Heart Failure with preserved Ejection Fraction (HFpEF)

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

6/18/2018 18

Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT)

Pitt B, et al. N Engl J Med 2014;370:1383-1392.

• Randomized, double-blind, placebo-controlled,

multicenter trial

• Target 3515 pts with ≥1 sign and ≥1 symptom of HF,

LVEF ≥45%, SBP <140 mm Hg (or ≤160 mm Hg if ≥3 BP meds), serum K <5.0 mmol/L; either HF hosp ≤12 months or BNP ≥100 pg/mL or NTproBNP ≥360 pg/mL

• 3445 pts randomized to Placebo or

Spironolactone 15-45 mg qd

• Potassium monitored baseline, wks 1 & 4, then q4 mo
• Hyperkalemia: Spiro 18.7% vs. 9.1% Placebo
• Hypokalemia: Spirono 16.2% vs. 22.9% Placebo
• Worsening renal function: Spiro 10.2% vs. 7.0%

Placebo; p <0.001.

TOPCAT: Regional Outcomes

Pfeffer MA, et al. Circulation 2015;131:34-42.

• ≈4-fold greater composite event rate in 1767 enrolled from the United States, Canada, Brazil,

Argentina (Americas) compared to the 1678 patients randomized from Russia/Georgia

• Significant differences in patient characteristics and outcomes

Recommendations for Stage C Heart Failure with preserved Ejection Fraction (HFpEF)

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803. PDE5i in HFpEF: RELAX (Redfield MM, et al. JAMA 2013;309:1268-1277.) Nitrates in HFpEF: NEAT-HFpEF (Redfield MM, et al. N Engl J Med 2015;373:2314-24.)

Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE-HFpEF )

Reddy YNV, et al. Circ Heart Fail 2017;10:e003862.

• Multicenter, randomized, double-blind,

placebo-controlled, crossover study

• 105 Ambulatory patients with HF, ≥40 yo;

LVEF ≥50%; NYHA II-IV (dyspnea); Evidence of heart failure, with one or more of following criteria within 12 months:

 Prior HF hosp with CXR demonstrating pulmonary congestion  LVEDP at rest ≥18 mmHg or PCWP at rest ≥15 mmHg or with exercise ≥25 mmHg  NT-proBNP>400 pg/mL or BNP >200 pg/mL  Doppler echo evidence of diastolic dysfunction.  Peak VO2 ≤75% predicted with peak respiratory exchange ratio ≥1.0 on CPET

1° endpoint: peak VO2 on CPET after 4 weeks treatment

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Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE-HFpEF )

Borlaug BA, et al. ACC.18 Late-breaking Clinical Trial. Primary Endpoint

Placebo Nitrite

Secondary Endpoints

Treatment Effect

Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D

Yancy CW, et al. J Am Coll Cardiol 2017;776-803.

Advanced Therapies: Mechanical Cardiac Support

Heartmate 3

Kirlin JK, et al. INTERMACS Quarterly Report; accessed 23.April, 2018.

Palliative Care in Heart Failure (PAL-HF Study)

Rogers JG, et al. J Am Coll Cardiol 2017;70:331-41.

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Updates on Heart Failure 2018

• Definition, Nomenclature, Epidemiology
• Evaluation and Diagnosis
• Treatment of Stages of Heart Failure
• Co-morbidities

Management of Co-morbidities in Patients with Stage C HFrEF

Yancy CW, et al. J Am Coll Cardiol 2013;62:e147-239.

Co-Morbidities: Hypertension

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

Surgical/ Percutaneous/ Transcatheter Interventions in Heart Failure

Yancy CW, et al. J Am Coll Cardiol 2013;62:e147–239.

6/18/2018 21

Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES)

Velazquez EJ, et al. N Engl J Med 2016;374:1511-20.

• Multicenter, randomized, open-label,

blinded-endpoint assessment trial

• 1212 patients (July 2002-May 2007):

and an ejection fraction of 35% or lower. Coronary artery disease amenable to CABG LVEF ≤35% Randomized 1:1 to: CABG (n=610) Medical Therapy (n=602) *Also Surgical Ventricular Reconstruction Arm All-cause Mortality

Co-Morbidities: Anemia

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803. RED-HF: Darbepoetin alfa, 2278 pts (Swedberg K, et al. N Engl J Med 2013;368:1210-9.)

All cause death or HF Hosp

Co-Morbidities: Iron Deficiency

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803. FAIR-HF (459 pts): Anker SD, et al. N Engl J Med 2009;361:2436-48. CONFIRM-HF (304 pts): Ponikowski P, et al. Eur Heart J 2015;361:2436-48.

1° endpoint

Co-Mobidities: Diabetes Mellitus EMPA-REG Outcome Trial

Zinman B, et al. N Engl J Med 2015;373:2117-28.

CV Death, nonfatal MI, or nonfatal stroke 7020 patients Randomized to Placebo vs. Empagliflozin (10 or 25 mg) Patients were:

• Type 2 Diabetics
• Adults (≥18 years of age)
• BMI ≤ 45
• eGFR ≥ 30 ml per minute per 1.73 m2

(MDRD)

• Established cardiovascular disease
• Received no glucose-lowering agents

for at least 12 weeks before randomization

• HgbA1c 7.0-9.0% or had received stable

glucose-lowering therapy for at least 12 weeks before randomization and HgbA1c 7.0-10.0%.

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EMPA-REG Outcome Trial: Heart Failure-related Outcomes

Fitchett D, et al. Eur Heart J 2016;37:1526-34.

Co-Morbidities: Hyperkalemia Hyperkalemia (K> 5.0 mmol/L):

• 1-10% in hospitalized patients
• Patients with CKD, HF, DM 2-3 times higher risk
• ACEi, ARB, ARNI, MRA can all cause/ exacerbate
• Sodium polystyrene sulfonate (Kayexalate):

– Binds Na+, K+, Ca2+, Mg2+ (esp. Ca2+) – Works mostly in colon – Potential severe GI side effects (colonic necrosis)

Sarwar CMS, et al. J Am Coll Cardiol 2016;68:1575–89. Sarwar CMS, et al. J Am Coll Cardiol 2016;68:1575-89.

Co-morbidity: Hyperkalemia

Patiromer ZS9

Co-Morbidities: Sleep-Disordered Breathing

Yancy CW, et al. J Am Coll Cardiol 2017;70:776-803.

6/18/2018 23

Marrouche NF, et al. N Engl J Med 2018;378:417-27.

Catheter Ablation versus Standard Conventional Therapy in Patients with LV Dysfunction and Atrial Fibrillation (CASTLE-AF)

398 patients:

• Paroxysmal/ persistent A Fib
• Absence of response to, unacceptable

side effects from, or unwillingness to take antiarrhythmic drugs

• NYHA II-IV chronic heart failure
• LVEF ≤35%

Randomized to:

• Catheter ablation
• Medical therapy

Updates on Heart Failure 2018

• Definition, Nomenclature, Epidemiology
• Evaluation and Diagnosis
• Treatment of Stages of Heart Failure
• Co-morbidities
• Future directions

Antithrombotic Therapy in Heart Failure with Normal Sinus Rhythm

Hopper I, et al. Eur J Heart Fail 2013;15:69-78. All Cause Mortality All Stroke

Cardiovascular Outcome Modification, Measurement AND Evaluation of Rivaroxaban in patients with HF

Zannad F, et al. Eur J Heart Fail 2015;17:735-742.

6/18/2018 24

Vericiguat: Soluble Guanylate Cyclase (sGC) Stimulator

Armstrong PW, et al. J Am Coll Cardiol HF 2018;6:96-104.

Target enrollment 4872 Vericiguat 2.5 mg uptitrated to 10 mg qd vs. Placebo Primary Outcome Measure: Time to Cardiovascular (CV) Death or Heart Failure Hospitalization Inclusion Criteria:

• History of chronic HF (NYHA Class II-IV) on standard therapy before qualifying HF

decompensation

• Previous HF hospitalization within 6 months prior to randomization or intravenous (IV) diuretic

treatment for HF (without hospitalization) within 3 months.

• BNP levels: NSR-≥ 300 pg/mL; A Fib-≥ 500 pg/mL and NT-proBNP levels: NSR- ≥ 1000 pg/mL;

A Fib- ≥ 1600 pg/mL within 30 days prior to randomization

• LVEF<45% assessed within 12 months prior to randomization by any method

VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA)

Armstrong PW, et al. J Am Coll Cardiol HF 2018;6:96-104.

Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator

Increases duration of systole Increases stroke volume No increase in myocyte calcium No change in dP/dtmax No increase in MVO2 OM increases the entry rate of myosin into the tightly-bound, force-producing state with actin “More hands pulling on the rope”

Malik FI, et al. Science 2011; 331:1439-43. Shen YT, et al. Circ Heart Fail 2010;3:522-7. Planelles-Herrero VJ, et al. Nat Commun 2017;8:190.

Mechanochemical Cycle of Myosin

Force production

LS, Least square; LVEDD, LVESD: Left ventricular end-diastolic (systolic) dimension; LVFS, left ventricular fractional shortening; SE, standard error; SET, systolic ejection time

Overall Effects of Omecamtiv Mecarbil

Teerlink JR, et al. Lancet 2016; 388: 2895-903.

Placebo, n= 149; All PK-Titration, n= 146

6/18/2018 25

• Chronic HF pts on standard of care therapy, LVEF

≤35%, NYHA II-IV, HF hospitalization within 12 months, elevated natriuretic peptides

• 1° endpoint: CV death & HF Hospitalization
• ~8,000 patient, event-driven trial,

powered for CV death

GALACTIC-HF

NCT02929329 clinicaltrials.gov; accessed 10.March, 2018.

Potential Mechanisms of Improvement in Heart Failure by SGLT2 Inhibition

Butler J, et al. Eur J Heart Fail 2017; doi:10.1002/ejhf.933.

On-going SGLT2 Inhibitor Trials in Heart Failure

Butler J, et al. Eur J Heart Fail 2017; doi:10.1002/ejhf.933.

PARAGON: Study design

≥55 yo LVEF ≥ 45% LAE or LVH Symptomatic HF (NYHA II-IV) Diuretics for HF ≥30d AND either: 1) Elevated BNP/ NT-proBNP; or 2) HF Hosp within 9 mo Solomon SD, et al. JACC Heart Fail 2017;5:471-482.

6/18/2018 26

Updates on Heart Failure 2018

• Definition, Nomenclature, Epidemiology
• Evaluation and Diagnosis
• Treatment of Stages of Heart Failure
• Co-morbidities
• Future directions

Improving Adherence: Focus On The Patient

Medication and Disease Education Care Coordination/Integration Shared Decision Making Consider Cost and Access

Domain Management Approach to Heart Failure in the Geriatric Patient

Gorodeski EZ, et al. J Am Coll Cardiol 2018;71:1921–36

• More than 50% of HF

hospitalizations occur in adults ≥75 years

• New proposed model
• f care for the

geriatric HF patient

San Francisco Veterans Affairs Medical Center

Thank you!

6/18/2018 27

Heart Failure Society of America

www.hfsa.org

• Ms. “HCE” (Here Comes Everybody):

Question #1

• Intake sheet reports: 68 yo woman with h/o diabetes

mellitus (oral agents), hypertension, COPD, and

• besity

According to the ACC/AHA 2013/2017 Heart Failure Guidelines, does Ms. HCE have heart failure?

• A. Yes
• B. No
• C. Maybe; Need more information
• Ms. “HCE” (Here Comes Everybody)

Question #1: Discussion

• 68 yo woman with h/o diabetes mellitus (oral

agents), hypertension, COPD, and obesity

• Does Ms. HCE have heart failure?

A. Yes B. No C. Maybe; Need more information

• Ms. “HCE” (Here Comes Everybody)
• Intake sheet reports: 68 yo woman with h/o diabetes

mellitus, hypertension, COPD, and obesity

• ECG: NSR @88bpm, LAE, LVH, possible inferior MI

6/18/2018 28

• Ms. “HCE” (Here Comes Everybody)
• 68 yo woman with h/o DM, HTM, COPD, and obesity
• ECG: NSR @88bpm, LAE, LVH, possible inferior MI
• Reports early satiety, abdominal discomfort, mildly increasing

abdominal girth, 5 kg weight gain

• HR 90 bpm, BP 134/76, RR 14, O2 sat 98%

Lungs: clear to A&P CV: JVP~10 cm, -A(H)JR; S1,S2 +S4, no S3, Abd: mild RUQ tenderness, abd distension; ?ascites Extrem: No peripheral edema

• Ms. “HCE” (Here Comes Everybody)
• 68 yo woman with h/o diabetes mellitus, hypertension, COPD, and obesity
• ECG: NSR @88bpm, LAE, LVH, possible inferior MI
• Reports early satiety, abdominal discomfort, mildly increasing abdominal girth, 5 kg

weight gain

• HR 90 bpm, BP 134/76, RR 14, O2 sat 98%

Lungs: clear to A&P CV: JVP~10 cm, -A(H)JR; S1,S2 +S4, no S3, Abd: mild RUQ tenderness, abd distension; ?ascites Extrem: No peripheral edema

• Labs: Na 135, K 3.9, BUN 30, Cr 1.6; BNP 825 pg/mL
• Echo: moderate LAE, mild LVH, mild LVE,

EF 30%, global hypokinesis

• Ms. “HCE”: Question #2
• 68 yo woman with h/o diabetes mellitus, hypertension, COPD, obesity
• ECG: NSR @88bpm, LAE, LVH, possible inferior MI
• Reports early satiety, abd discomfort, mildly increasing abd girth, 5 kg weight gain
• HR 90 bpm, BP 134/76, RR 14, O2 sat 98%; Lungs: clear to A&P

CV: JVP~10 cm, -A(H)JR; S1,S2 +S4, no S3, Murmur; Abd: mild RUQ tenderness, abd distension, ?ascites; Extrem: No peripheral edema

• Labs: Na 135, K 3.9, BUN 30, Cr 1.6; BNP 825 pg/mL
• Echo: moderate LAE, mild LVH, mild LVE, EF 30%, global hypokinesis

The optimal initial therapy for this patient is:

• A. Furosemide 20 mg po qd
• B. Lisinopril 10 mg po qd
• C. Furosemide 20 mg po bid and

Lisinopril 2.5 mg po qd

• D. Metoprolol tartrate 25 mg po bid
• Ms. “HCE”: Question #2
• 68 yo woman with h/o diabetes mellitus, hypertension, COPD, obesity
• ECG: NSR @88bpm, LAE, LVH, possible inferior MI
• Reports early satiety, abd discomfort, mildly increasing abd girth, 5 kg weight gain
• HR 90 bpm, BP 134/76, RR 14, O2 sat 98%; Lungs: clear to A&P

CV: JVP~10 cm, -A(H)JR; S1,S2 +S4, no S3, Murmur; Abd: mild RUQ tenderness, abd distension, ?ascites; Extrem: No peripheral edema

• Labs: Na 135, K 3.9, BUN 30, Cr 1.6; BNP 825 pg/mL
• Echo: moderate LAE, mild LVH, mild LVE, EF 30%, global hypokinesis

The optimal initial therapy for this patient is:

• A. Furosemide 20 mg po qd
• B. Lisinopril 10 mg po qd
• C. Furosemide 20 mg po bid and

Lisinopril 2.5 mg po qd

• D. Metoprolol tartrate 25 mg po bid

6/18/2018 29

• Ms. “HCE”: Question #3

One week later, Ms. HCE presents to clinic with:

• Improvement in early satiety and abdominal bloating;

5 kg weight loss

• BP 128/76, HR 84, RR 14;

JVP ~6 cm; abdomen soft, non-tender

• Labs: Na 136, K 3.8, BUN 24, Cr 1.8

An optimal next step would be to: A. Add Carvedilol 3.125 mg po bid B. Repeat echocardiogram to re-assess EF C. Serially uptitrate Lisinopril to goal of 40 mg po qd with symptom, blood pressure, and lab monitoring D. Add Spironolactone 25 mg po qd

• Ms. “HCE”: Question #3 Discussion

One week later, Ms. HCE presents to clinic with:

• Improvement in early satiety and abdominal bloating;

5 kg weight loss

• BP 128/76, HR 84, RR 14;

JVP ~6 cm; abdomen soft, non-tender

• Labs: Na 136, K 3.8, BUN 24, Cr 1.8

An optimal next step would be to: A. Add Carvedilol 3.125 mg po bid B. Repeat echocardiogram to re-assess EF C. Serially uptitrate Lisinopril to goal of 40 mg po qd with symptom, blood pressure, and lab monitoring D. Add Spironolactone 25 mg po qd

• Ms. “HCE”: Question #4

One year later, Ms. HCE presents to clinic with:

• Bendopnea; Early satiety and abdominal bloating; 5 kg wt gain; no cough, fever
• Current meds: Furosemide 40 –>80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg

qd; Spironolactone 25 mg qd

• BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w

no change

• Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5)

An optimal diagnostic step would be to: A. Order BNP (or NT-proBNP) B. Repeat echocardiogram C. Obtain Chest X-ray D. None of the above

Question #4: Discussion

An optimal diagnostic step would be to: A. Order BNP (or NT-proBNP) B. Repeat echocardiogram C. Obtain Chest X-ray D. None of the above

6/18/2018 30

• Ms. “HCE”: Question #5

One year later, Ms. HCE presents to clinic with:

• Bendopnea; Early satiety and abdominal bloating; 8 kg wt gain; no cough, fever
• Current meds: Furosemide 40 –>80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg

qd; Spironolactone 25 mg qd

• BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w

no change

• Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5)

An optimal therapeutic diuretic step would be to: A. Increase Furosemide to 160 mg bid B. Increase Spironolactone to 50 mg qd C. Hold all diuretics D. Discontinue Furosemide and start Bumetanide/ Torsemide E. Add Metolazone 5 mg qd

Question #5: Discussion

One year later, Ms. HCE presents to clinic with:

• Bendopnea; Early satiety and abdominal bloating; 8 kg wt gain
• Current meds: Furosemide 40 –>80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg

qd; Spironolactone 25 mg qd

• BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w

no change

• Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5)

An optimal therapeutic diuretic step would be to: A. Increase Furosemide to 160 mg bid B. Increase Spironolactone to 50 mg qd C. Hold all diuretics D. Discontinue Furosemide and start Bumetanide/ Torsemide E. Add Metolazone 5 mg qd

• Ms. “HCE”: Question #6

One year later, Ms. HCE presents to clinic with:

• Bendopnea; Early satiety and abdominal bloating; 8 kg wt gain
• Current meds: Furosemide 40 –>80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg

qd; Spironolactone 25 mg qd

• BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w

no change

• Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5)

Optimal management of concomitant medications includes: A. Discontinue Carvedilol B. Discontinue Lisinopril C. Discontinue Spironolactone D. Discontinue Carvedilol and Lisinopril E. None of the above

Question #6: Discussion

One year later, Ms. HCE presents to clinic with:

• Bendopnea; Early satiety and abdominal bloating; 8 kg wt gain
• Current meds: Furosemide 40 –>80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg

qd; Spironolactone 25 mg qd

• BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w

no change

• Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5)

Optimal management of concomitant medications includes: A. Discontinue Carvedilol B. Discontinue Lisinopril C. Discontinue Spironolactone D. Discontinue Carvedilol and Lisinopril E. None of the above