Approach to Heart Failure in

2018: What Do the Recent

Guidelines Tell Us?
Biykem Bozkurt, MD, FACC
The Mary and Gordon Cain Chair &
Professor of Medicine
Medical Care Line Executive,
DeBakey VA Medical Center,
Director, Winters Center for HF Research,
Associate Director, CV Research Institute
Baylor College of Medicine, Houston, TX
Outline
▪ Guidelines for HFrEF
▪ New Therapies: ARNI,Ivabradine
▪ HTN
▪ Anemia
▪ Sleep Apnea
▪ HFpEF
▪ HFmEF
▪ Diabetes
▪ Biomarkers

2
HF Guidelines: AHA/ACC/HFSA and ESC
Heart Failure
Neprilysin Inhibition and ARNI

4
 Natriuretic
peptides
(ANP,BNP,CNP)

Bradykinin

Substance P

Adrenomedullin
NEPRILYSIN

NEP is a zinc dependent cleaves peptides containing

membrane endopeptidase up to 40–50 amino acids
 Natriuretic
peptides
(ANP,BNP,CNP) Angiotensin I

Angiotensin II
Bradykinin

Endothelin I
Substance P

Neurotensin
Adrenomedullin
NEPRILYSIN

NEP is a zinc dependent cleaves peptides containing

membrane endopeptidase up to 40–50 amino acids
Amyloid β Enkephalins, Gastrin, Cholecystokinin-8,
Corticotropin Neuropeptide Y Somatostatin, Glucagon, Oxytocin
Peptide Endomorphins
VIP

Natriuretic
peptides
(ANP,BNP,CNP) Angiotensin I

Angiotensin II
Bradykinin

Endothelin I
Substance P

Neurotensin
Adrenomedullin
NEPRILYSIN

NEP is a zinc dependent cleaves peptides containing

membrane endopeptidase up to 40–50 amino acids
Amyloid β Enkephalins, Gastrin, Cholecystokinin-8,
Corticotropin Neuropeptide Y Somatostatin, Glucagon, Oxytocin
Peptide Endomorphins
VIP

Natriuretic
peptides
(ANP,BNP,CNP) Angiotensin I

Angiotensin II
Bradykinin

Endothelin I
Substance P

Neurotensin
Adrenomedullin
NEPRILYSIN

✓ NEP is a zinc dependent

membrane endopeptidase
cleaves peptides containing
up to 40–50 amino acids x
 Balance of NEP Inhibition

Reduced breakdown of ANP, BNP, CNP,

Vasodilation ,  Fibrosis, Hypertrophy

Reduced breakdown of angiotensin II,

(endothelin I) Vasoconstriction,  Fibrosis, 
Hypertrophy

The antihypertensive effects may be offset by an increased activity of the RAAS and
sympathetic nervous system and/or by downregulation of ANP receptors.

Corti R, et al. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation. 2001;104:1856–1862.
Neprilysin • Mixed results due
inhibition to potentiation of
alone angiotensin

NEP + ACE • Potentiation of

inhibition angioedema

Nep Inh +
•?
ARB
 Mechanisms of Action of ARNI

Natriuretic Peptides Renin Angiotensin System

Angiotensinogen
LCZ696
Angiotensin I

Angiotensin II
Sacubitril Valsartan

Neprilysin AT1 Receptor

PRA, plasma renin

 BP, Vasodilation
 Fibrosis
*NT-proBNP not a neprilysin substrate  Hypertrophy
Vardeny O. et al. Clin. Pharmacol Ther 2013; 94:445-448
▪ NYHA class II-IV (<1 % NYHA IV)
▪ LVEF ≤ 40% then ≤35%: 8442 Patients
▪ BNP ≥ 150 (or NT-proBNP ≥ 600)
▪ β-blockers , MRA,
▪ ACEi of ARB enalapril 10 mg/d ≥4 wks
▪ SBP ≥ 95 mm Hg, eGFR ≥ 30, K ≤ 5.4 mEq/L
LCZ696 (200 mg enalapril (10 mg
twice daily) or twice daily)
 Run-In Before Randomization
10,513 patients screened
• 10 % (n=1102)
a single-blind run-in dropped out
enalapril (10 mg bid x 2 (hypotension, cough,
weeks ) , if tolerated; hyperkalemia, renal
dysfunction)

single-blind run-in • another 10 %

period LCZ696 x 4-6 dropped out (n=977)
weeks (100 mg bid then (hypotension, cough,
hyperkalemia, renal
escalated to 200mg bid) dysfunction)

if tolerated, then • 17.8% of LCZ696

randomized • 19.8% of enalapril
(n=8442) discontinued
 PARADIGM-HF: CV Death or HF Hospitalization
(Primary Endpoint)
40

Enalapril 1117
Kaplan-Meier Estimate of

32 (n=4212)
Cumulative Rates (%)

914
24
LCZ696
(n=4187)
16

HR = 0.80 (0.73-0.87)
8 P = 0.0000002
Number needed to treat = 21
0
0 180 360 540 720 900 1080 1260
Patients at Risk Days After Randomization
LCZ696 4187 3922 3663 3018 2257 1544 896 249
Enalapril 4212 3883 3579 2922 2123 1488 853 236
McMurray J. et al. New Engl J Med. 2014; 371 (11): 993-1004
PARADIGM-HF: Other Key Endpoints

1. McMurray JJ et al. N Engl J Med. 2014;371:993-1004. 2. Desai AS et al. Eur Heart J. 2015;36:1990-1997.
 PARADIGM-HF: Adverse Events
LCZ696 Enalapril P
(n=4187) (n=4212) Value
Prospectively identified adverse events
Symptomatic hypotension 588 (14%) 388 (9.2%) < 0.001
Serum potassium > 6.0 mmol/l 181 (4.3%) 236 (5.6%) 0.007
Serum creatinine ≥ 2.5 mg/dl 139 (3.3%) 188 (4.5%) 0.007
Cough 474 (11.3%) 601 (14.3%) < 0.001
Discontinuation for adverse event 449 516 0.02
Discontinuation for hypotension 36 29 NS
Discontinuation for hyperkalemia 11 15 NS
Discontinuation for renal impairment 29 59 0.001
Angioedema (adjudicated)
Medications, no hospitalization 16 (0.3%) 9 (0.2%) NS
Hospitalized; no airway compromise 3 (0.1%) 1 (<0.1%) NS
Airway compromise 0 0 ----
Angioedema in OVERTURE 0.5 %, OCTAVE 0.68 %
 New Studies with ARNI
NAME TITLE Primary End Point
PARAGON- Efficacy and Safety of LCZ696 Compared to Valsartan, on CV death and HF
HF Morbidity and Mortality in HFpEF hospitalizations

TITRATION Safety and Tolerability of Initiating LCZ696 in Heart Failure Hypotension, Renal
Patients 200 mg twice daily (bid) over 3 weeks vs 6 weeks) Dysfunction,
Hyperkalemia and
Angioedema

PARABLE ARNI in Asymptomatic Patients With Elevated Natriuretic impact on LV diastolic

Peptide and Elevated Left Atrial Volume function

PIONEER comParIson Of Sacubitril/valsartaN Versus Enalapril on Change from baseline in

Effect on ntpRo-bnp in Patients Stabilized From an Acute NT-proBNP
Heart Failure Episode (hypotension, hyperkalemia,
angioedema)

PARASAIL Description of Tolerability of LCZ696 (Sacubitril / Valsartan) % Pts tolerated LCZ696

in Heart Failure With Reduced Ejection Fraction (HFrEF) at the dose of 97.2 mg
Treated in Real Life Setting (PARASAIL) in CANADA sacubitril / 102.8 mg
valsartan bid at month 6

Source: ClinicalTrials.gov
2017 ACC/AHA/HFSA Update:
Recommendations for Stage C HFrEF

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
ARB: A with ACE inhibitors (LOE:A), OR ARBs (LOE: A), OR ARNI (Level of
Evidence: B-R) in conjunction with evidence based beta blockers,
ARNI: B-R and aldosterone antagonists in selected patients, is
recommended for patients with chronic HFr EF to reduce
morbidity and mortality

Yancy C. et al. J Am Coll Cardiol. 2017 Aug 8;70(6):776-803, Circulation. 2017;136:e137-e161, J Card Fail. 2017 Aug;23(8):628-651.
2017 ACC/AHA/HFSA Update:
Recommendations for Stage C HFrEF
Recommendations for Renin-Angiotensin System Inhibition With ACE-I or ARB or ARNI
COR LOE Recommendations
I ACE: A The use of ACE inhibitors is beneficial for patients with prior or
current symptoms of chronic HFr EF to reduce morbidity and
mortality
I ARB: A The use of ARBs to reduce morbidity and mortality is recommended
in patients with prior or current symptoms of chronic HFr E F who
are intolerant to ACE inhibitors because of cough or angioedema
I ARNI: B-R In patients with chronic symptomatic HFr E F NYHA class II or III who
tolerate an ACE inhibitor or ARB, replacement by an ARNI is
recommended to further reduce morbidity and mortality
III: B-R ARNI should not be administered concomitantly with ACE inhibitors
Harm or within 36 hours of the last dose of an ACE inhibitor
III: C-EO ARNI should not be administered to patients with a history of
Harm angioedema

Yancy C. et al. J Am Coll Cardiol. 2017 Aug 8;70(6):776-803, Circulation. 2017;136:e137-e161, J Card Fail. 2017 Aug;23(8):628-651.
 Treatment of HFrEF Stage C and D

ACC, AHA, HFSA HF Guidelines ESC Guidelines

† The combination of ISDN/HYD with ARNI has not been robustly tested. BP response should be
carefully monitored.

AHA/ACC/HFSA HF Guidelines. Yancy C. et al. Circulation/ JACC/JCF 2017

ESC HF Guidelines.Ponikowsky et al EHJ 2016
Heart Failure
Ivabradine

21
Ivabradine : Specific and Selective Inhibitor of the If Ion
Channel

If ion channel (the funny current) is highly expressed in spontaneously active cardiac regions, such as the
sinoatrial node, the AV node and the Purkinje fibers. The funny current is a mixed Na/ K current that activates
upon hyperpolarization at voltages in the diastolic range

Di Francesco D, Camm JA. Drugs 2004; 64: 1757-1765

 SHIFT Study Design

Ivabradine
• Patients >18 years old 5 mg bid
• NSR and HR ≥70 bpm x 2 weeks,
then 7.5 mg bid
• NYHA FC II-IV and stable on meds
for ≥4 weeks N=3268
• LVEF ≤35%
• On target or maximally tolerated Placebo bid
doses of BBs
• Hospitalization for HF in ≤12 mo N=3290

N=6558 Median follow-up duration 22.9 months

14-day run-in
BB, beta-blocker; bpm, beats per minute; HF, heart failure; HR, heart rate; LVEF, left ventricular ejection fraction; meds, medications;
mo, months; NSR, normal sinus rhythm; NYHA FC, New York Heart Association functional classification.
Swedberg K, et al. Lancet. 2010;376(9744):875-885.
Heart Rate Modulation with Ivabradine-
The Systolic HF treatment with the If inhibitor Ivabradine Trial SHIFT Trial

CV Mortality & HF HF Hospitalization

Hospitalization

NYHA II–IV, EF < 35%, SR rate of ≥70 b.p.m.

background therapy β-blocker (90%), and an MRA (60%)
Only 26% of patients were on full-dose β-locker
Swedberg et al. Lancet 2010. 376:875-85
Heart Rate Modulation with Ivabradine-
The Systolic HF treatment with the If inhibitor ivabradine Trial SHIFT Trial
No significant reduction in all cause or CV mortality
CV Mortality All cause mortality

Swedberg et al. Lancet 2010. 376:875-85

Effect of ivabradine in prespecified subgroups

Test for interaction

Age
<65 years
≥65 years
Sex
Male
Female
Beta-blockers
No
Yes
Aetiology of heart failure
Non-ischaemic
Ischaemic
NYHA class
NYHA class II
NYHA class III or IV
Diabetes
No
Yes P = 0.029
Hypertension
No
Yes
Baseline heart rate
<77 bpm
≥77 bpm
0.5 1.0 1.5
Hazard ratio
Favours ivabradine Favours placebo
Swedberg K, et al. Lancet. 2010;376(9744):875-885
Incidence of selected adverse events
Patients with an event

Ivabradine Placebo
p value
N=3232, n (%) N=3260, n (%)
All serious adverse events 1450 (45%) 1553 (48%) 0.025

All adverse events 2439 (75%) 2423 (74%) 0.303

Symptomatic bradycardia 150 (5%) 32 (1%) <0.0001

Asymptomatic bradycardia 184 (6%) 48 (1%) <0.0001

Atrial fibrillation 306 (9%) 251 (8%) 0.012
Phosphenes 89 (3%) 17 (1%) <0.0001
Blurred vision 17 (1%) 7 (<1%) 0.042

Swedberg K, et al. Lancet. 2010;376(9744):875-885

 Indications for Use: Ivabradine (FDA)

• To reduce hospitalization risk for worsening HF in patients with stable, symptomatic

chronic HF with LVEF ≤35% in sinus rhythm with resting HR of ≥70 bpm or higher 1,2
– AND on maximally tolerated doses of beta-blockers
– OR have a contraindication to beta-blocker use
 Contraindications:
– Acute decompensated HF ▪ Resting HR <60 bpm prior to treatment
– BP <90/50 mm Hg ▪ Severe hepatic impairment
– Sick sinus syndrome
▪ Pacemaker dependence
– Sinoatrial or third-degree AV block*
 Most common (≥1%) adverse events:
– Bradycardia, HTN, AF, and temporary vision disturbances

*Unless a functioning demand pacemaker is present.

AF, atrial fibrillation; AV, atrioventricular; BP, blood pressure; HTN, hypertension.
1. Swedberg K, et al. Lancet. 2010;376(9744):875-885.
2. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products [drug label].
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206143Orig1s000lbl.pdf. Revised April 2015. Accessed August 31, 2016.
2017 ACC/AHA/HFSA Update:
Recommendations for Stage C HFrEF
Recommendations for Ivabradine

COR LOE Recommendations

IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for
patients with symptomatic (NYHA class II-III) stable chronic
HFr EF (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.

2016 ESC HF Guidelines

Yancy C. et al. Circulation. 2017;136:e137-e161

Yancy et al. J Am Coll Cardiol. 2018 Jan 16;71(2):201-230.
 Treat HF APP

▪ 2017 ACC Expert Consensus Decision Pathway for Optimization of HF Treatment,

▪ 2017 ACC/ AHA/HFSA Focused Update of HF Guidelines
▪ 2013 ACCF/AHA Guideline for the Management of Heart Failure.
http://tools.acc.org/TreatHF/#!/content/evaluate
Heart Failure
HF-pEF

32
 Pharmacological Treatment for Stage C HF With Preserved EF

COR LOE Recommendations

Diuretics should be used for relief of symptoms due to volume

I C
overload
Systolic and diastolic BP should be controlled in patients with
I B HFpEF in accordance with published clinical practice guidelines
to prevent morbidity
Coronary revascularization is reasonable in patients with CAD in
IIa C whom symptoms (angina) or demonstrable myocardial ischemia
having an adverse effect on symptomatic HFpEF despite GDMT.
Management of AF according to published clinical practice
IIa C guidelines in patients with HFpEF is reasonable to improve
symptomatic HF.
The use of beta-blocking agents, ACE inhibitors, and ARBs in
IIa C patients with hypertension is reasonable to control BP in patients
with HFpEF.

Clyde W. Yancy et al. Circulation. 2017;136:e137-e161

 combined endpoint of death,
CVD, Cardiac HFH,
cardiac death
aborted Arrest,

TOPCAT

JACC; Volume 66, Issue 24, December 2015

16 % RR
 Pharmacological Treatment for Stage C HF With Preserved EF

COR LOE Recommendations

In appropriately selected patients with HFpEF (with EF ≥45%,

elevated BNP or Hfadm/year, eGFR >30 mL/min, creatinine
IIb B-R
<2.5 mg/dL, K <5.0 mEq/L), aldosterone receptor antagonists
might be considered to decrease hospitalizations.

Clyde W. Yancy et al. Circulation. 2017;136:e137-e161

 NEAT-HF RELAX-HF

▪ 110 patients with HFEF ≥50% randomized to either ▪ PDE-5 inh augments the NO by upregulating cGMP
isosorbide mononitrate or placebo ▪ Randomized 216 patients with HFEF ≥50% on and
▪ no beneficial effects on activity levels, QoL, exercise pVo2 <60% to sildenafil or placebo.
tolerance, or NT-proBNP levels. ▪ No improvement in O2 consumption or exercise
tolerance
 Pharmacological Treatment for Stage C HF With Preserved EF

COR LOE Recommendations

The use of ARBs might be considered to decrease

IIb B
hospitalizations for patients with HFpEF.

III: No Routine use of nitrates or PDE-5 inhibitors to increase activity

B-R
Benefit or QoL in patients with HFpEF is ineffective.

Clyde W. Yancy et al. Circulation. 2017;136:e137-e161

Heart Failure
Mid-Range LVEF

40
 GWTG-HF data linked to Medicare data, ~ 40 k pts,

Mortality Hospitalization

All 3 groups had similar 5-year mortality (HFrEF 75.3% vs. HFpEF 75.7%; HFbEF 75.7%)
CVH and HFH higher in HFrEF and HFbEF compared with those with HFpEF
▪ The Beta-blockers in Heart Failure Collaborative Group (BBmeta-HF) pool individual patient data from 11
major HF RCTs : :Australia/New Zealand Heart Failure Study (ANZ), BEST, CAPRICORN, CHRISTMAS, CIBIC
I , CIBIS II, COPERNICUS, MDC, MERIT-HF, SENIORS, U.S.Carvedilol HF Program (US-HF)
▪ to determine efficacy of beta blockers in mid range and preserved EF and also atrial fibrillation patients
▪ Though guidelines suggest to treat mid-range EF as HF-PEF, in practice most of these patients are treated
as HFrEF
▪ 14262 patients in sinus rhythm, 3050 patients in atrial fibrillation
▪ Pts with baseline LVEF and ECG that showing either sinus rhythm or AF/atrial flutter included
 Treat HFmEF like HFrEF

β-blockers improve outcomes for all pts with HF any reduced EF and in SR.
Most robust for LVEF<40%, but similar benefit in LVEF 40–49 %
Heart Failure
Hypertension

44
Hypertension Management in HF
ACC, AHA, HFSA HF Guidelines

COR LOE Recommendations

In patients at increased risk, stage A HF, the optimal BP in those with HTN should be <130/80 mm Hg.
I B-R

Patients with HFrEF and HTN should be prescribed GDMT titrated to attain SBP < 130 mm Hg.
I C-EO

Patients with HFpEF & persistent HTN after management of volume overload should be prescribed
I C-LD
GDMT to attain SBP<130 mm Hg

Yancy C. et al. J Am Coll Cardiol. 2017 Aug 8;70(6):776-803, Circulation. 2017;136:e137-e161, J Card Fail. 2017 Aug;23(8):628-651.
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/
APhA/ASH/ASPC/NMA/PCNA
Guideline for the Prevention, Detection, Evaluation, and
Management of High Blood Pressure in Adults
Recommendations for BP Goal for Patients With
COR LOE
Hypertension
For adults with confirmed hypertension and known CVD or
SBP:
10-year ASCVD event risk of 10% or higher a BP target of less
I B-RSR
than 130/80 mm Hg is recommended.
DBP: C-
EO
SBP: For adults with confirmed hypertension, without additional
B-NR markers of increased CVD risk, a BP target of less than
IIb 130/80 mm Hg may be reasonable.
DBP: C-
EO
BP Thresholds for and Goals of Pharmacological Therapy in Patients With Hypertension
According to Clinical Conditions

BP
BP Goal,
Clinical Condition(s) Threshold,
mm Hg
mm Hg
General
Clinical CVD or 10-year ASCVD risk ≥10% ≥130/80 <130/80
No clinical CVD and 10-year ASCVD risk <10% ≥140/90 <130/80
Older persons (≥65 years of age; noninstitutionalized, ≥130 (SBP) <130 (SBP)
ambulatory, community-living adults)
Specific comorbidities
Diabetes mellitus ≥130/80 <130/80
Chronic kidney disease ≥130/80 <130/80
Chronic kidney disease after renal transplantation ≥130/80 <130/80
Heart failure ≥130/80 <130/80
Stable ischemic heart disease ≥130/80 <130/80
Secondary stroke prevention ≥140/90 <130/80
Secondary stroke prevention (lacunar) ≥130/80 <130/80
Peripheral arterial disease ≥130/80 <130/80

ASCVD indicates atherosclerotic cardiovascular

disease; BP, blood pressure; CVD, cardiovascular
disease; and SBP, systolic blood pressure.
Heart Failure
Anemia

48
 Stages of Iron Deficiency

Stage I Stage II Stage III

Prelatent Latent Anemia
BM Iron Absent Absent

Ferritin <12 ug/L <12 ug/L

Hb Normal Normal

MCV Normal Normal

Symptoms +/- +/- +

treat
 FAIR-HF

▪ 459 patients NYHA II –III, LVEF < 40 % ,

▪ iron deficiency (ferritin level <100 μg / L or 100 - 300 μg /L, if the transferrin
saturation was <20%), and a Hb 9.5 to 13.5 g /dL.

▪ 200 mg of IV ferric carboxy maltose or saline (placebo) for 24 weeks

▪ 50% reported being much or moderately improved vs 28% of placebo

▪ Improvements in 6 MWT and QOL with FCM
▪ Death, adverse events, and SAEs similar
N Engl J Med 2009;361:2436-48.
 CONFIRM-HF

▪ 304 patients NYHA II –III, LVEF < 45 % , elevated natriuretic peptides

▪ iron deficiency (ferritin level <100 μg / L or or 100 - 300 μg /L, if the transf saturation <20%).

▪ 200 mg of IV ferric carboxy maltose or

▪ saline (placebo) for 52 weeks

Primary End-Point

FCM prolonged 6MWT distance at 6 mo (difference FCM vs. placebo: 33 ± 11 m,

P = 0.002)
Ponikowski P. et al . Eur Heart J. 2015 Mar 14;36(11):657-68.
 META-ANALYSIS-Anker 2018

Individual patient data from 4 RCTs of FCM vs

placebo in patients with systolic HF & iron def

4 Studies 839 pts: FER-CARS-01 FAIR-HF

EFFICACY-HF, CONFIRM-HF
CV Hospitalizations
CV Mortality and

IV iron associated with

▪  CV mortality & CV hosp (RR: 0.59; p=0.009)
▪  CV mortality & HFH (RR 0.53, p = 0.011)
▪ All cause mortality and recurrent CV Hosp (RR 0.6, p = 0.009)
Anker S. BA, at al. Eur J Heart Fail.2018;20:125-133
▪ No increase in adverse events
 No efficacy with oral iron in HF in clinical trials
ORAL IRON
• Convenient, vailable and inexpensive, but oral iron is not absorbed well
• Elevated hepcidin prevents iron absorption
• Tolerability and compliance with of oral iron is low due to GI side effects

IRON-OUT HF
▪ largest phase 2 , double blind RCT
▪ 225 patients with NYHA class II-IV HF with HFrEF
▪ Hb 9-15 g/dL (men) or 9-13.5 g/dL women) and ID (ferritin 15-100 ug/L or
100-299 ug/L with TSAT <20%)
▪ oral iron polysaccharide 150 mg twice daily or placebo
At 16 weeks, there was no significant difference in
▪ primary end point : change in peak VO2 from baseline,
▪ Or secondary endpoints : 6MWD, NT-proBNP levels or KCCQ score
▪ oral iron increased TSAT, ferritin and hepcidin, and reduced soluble
transferrin receptor levels
Lewis GD, et al. IRONOUT HF Randomized Clinical Trial. JAMA. 2017;317:1958-1966
 Possible Explanations for Failure of Oral Iron in HF

▪ Inadequate repletion of iron stores with oral iron despite large

doses

STUDY Total Iron Dose TSAT increase Ferritin Increase

ORAL IRON-OUT 33.6 gm 3% 11 ug/L
IV FAIR-HF 2 gm 11.3 % 259.5 ug/L

▪ Higher hepcidin levels associated with less improvement in TSAT

and ferritin
▪ Higher hepcidin levels inhibit duodenal iron absorption
RED-HF TRIAL

(death or HF hospitalization)

N Engl J Med 2013; 368:1210-1219

 Anemia
COR LOE Recommendations

In patients with NYHA class II and III HF and iron deficiency

(ferritin <100 ng/mL or 100 to 300 ng/mL if transferrin
IIb B-R
saturation is <20%), IV iron replacement might be reasonable
to improve functional status and QoL.

III: No In patients with HF and anemia, erythropoietin-stimulating

B-R
Benefit agents should not be used to improve morbidity and mortality.

Clyde W. Yancy et al. Circulation. 2017;136:e137-e161

Heart Failure
Sleep Anemia

59
 Sleep Disorders
COR LOE Recommendations

In patients with NYHA class II–IV HF and suspicion of sleep

IIa C-LD disordered breathing or excessive daytime sleepiness, a formal
sleep assessment is reasonable.

In patients with cardiovascular disease and obstructive sleep

apnea, CPAP may be reasonable to improve sleep quality and
IIb B-R
daytime sleepiness.

In patients with NYHA class II–IV HFrEF and central sleep

III: Harm B-R
apnea, adaptive servo-ventilation causes harm.

Clyde W. Yancy et al. Circulation. 2017;136:e137-e161

Heart Failure
Diabetes / Metabolic Syndrome

61
AHA / ACCF 2013 HF Guidelines Stage A

I IIa IIb III Other conditions that may lead to or contribute to HF, such
as obesity, diabetes mellitus, tobacco use, and known
cardiotoxic agents, should be controlled or avoided.

Yancy CW, Jessup M et al. 2013 ACCF/AHA Guideline for the Management of
Heart Failure, Circulation; 2013 Oct 15;128
 Glucose Lowering Agents in DM and HF
Glucose Lowering Incident HF Risk in High CV risk Outcomes in Established HF
Agents Patients Patients
Sulfanylurea Not increased No large scale RCT
Insulin Possibly increased (residual No large scale RCT
confounding)
Metformin Not increased Reduced HFH / all cause
mortality in population based
retrospective cohorts,
No large scale RCT
DPP4 inh (increase Increased HF with saxagliptin Not studied
GLP-1) (SAVOR-TIMI 53), no signal with
others (TECOS, EXAMINE Trials)
GLP-1 Agonists No effect HF, Reduced CVD Post ADHF discharge increased
(LEADER, SUSTAIN trials) trend for HFH+ Mortality with
liraglutide (FIGHT- NIH Trial)
SGLT2i Reduced HFH, CVD, MACE Ongoing
(EMPA-REG, CANVAS Trials)
 Potential Mechanisms of Empagliflozin for Benefit in HF Outcomes

3-4 mmHg drop

in SBP

outcome curves diverged early –

hemodynamic effects rather than
glucose control effects?

myocardial fuel/energetics hypothesis:?, increase blood β-

hydroxybutyrate a ‘‘superfuel’’ oxidized by the heart in preference
to fatty acids and glucose, ? increase mechanical efficiency, From Pham D. et al. Trends in Cardiovascular
prevent pro-hypertrophic transcription pathways. Medicine Aug 4, 2016, Ferrannini et al., 2016; Mudaliar
et al., 2016, Tahara et al.,2014, Aubert et al., 2016
Primary and Secondary Prevention of HF with
SGLT2i

Stage B :
Stage C: Stage D:
Stage A: At Structural
Prevalent Advanced
Risk HF Heart
HF HF
Disease

✓ ✓
Heart Failure
Biomarkers

72
2017 ACC/AHA/HFSA Update:
Biomarkers Indications for Use

Yancy C. et al. J Am Coll Cardiol. 2017 Aug 8;70(6):776-803, Circulation. 2017;136:e137-e161, J Card Fail. 2017 Aug;23(8):628-651.
 Biomarkers
Biomarkers for Prevention of HF (Stage A/B)
COR LOE Recommendation
For patients at risk of developing HF, natriuretic
peptide biomarker–based screening followed by
team-based care, including a cardiovascular
specialist optimizing GDMT, can be useful to prevent
IIa B-R the development of left ventricular dysfunction
(systolic or diastolic) or new-onset HF.

▪ Yancy C. et al. Circulation. 2017;136:e137-e161

▪ Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA.
2013;310:66-74.
▪ Huelsmann M, Neuhold S, Resl M, et al. PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac
disease): a prospective randomized controlled trial. J Am Coll Cardiol. 2013;62:1365-72.
 Biomarkers
Biomarkers for Diagnosis, Prognosis
COR LOE Recommendation
In patients presenting with dyspnea, measurement of natriuretic peptide
I A biomarkers is useful to support a diagnosis or exclusion of HF.

Measurement of BNP or NT-proBNP is useful for establishing prognosis or

I A
disease severity in chronic HF.
Measurement of baseline levels of natriuretic peptide biomarkers and/or cardiac
I A troponin on admission to the hospital is useful to establish a prognosis in acutely
decompensated HF.

During a hospitalization for HF, a predischarge natriuretic peptide level can be

IIa B-NR useful to establish a postdischarge prognosis.

In patients with chronic HF, measurement of other clinically available tests, such
IIb B-NR as biomarkers of myocardial injury or fibrosis, may be considered for additive
risk stratification.

Clyde W. Yancy et al. Circulation. 2017;136:e137-e161

 GUIDE-IT

HFH or CVD Mortality

▪ 894 of 1100 enrolled

▪ HFrEF prior HFH, NT-proBNP >2000 or
BNP>400
▪ Target NT-proBNP < 1000 pg/mL
 Change in NT-proBNP

NP Guided Usual p
Achieved target NT-proBNP < 1000 pg/mL 46 % 40 % 0.21

 Similar NP levels can be achieved with empirical adjustment in HFrEF medications

ADHF patients with NT-proBNP levels of >
1700
After achieving clinical stability, 405 pts
randomized

Treatment to achieve Conventional

30% reduction in Treatment
NT-proBNP

https://doi.org/10.1161/CIRCULATIONAHA.117.029882
December 14, 2017
 Biomarkers

NP Guided therapy in Guidelines

“Because of the absence of clear and consistent evidence for improvement in
mortality and CV outcomes, there are insufficient data to inform specific guideline
recommendations related to NP-guided therapy or serial measurements of BNP or NT-
proBNP levels for the purpose of reducing hospitalization or deaths”

Clyde W. Yancy et al. Circulation. 2017;136:e137-e161

Individualization

▪ It is not ONE magical marker

(example: rise in creatinine with successful
decongestion not associated bad outcomes)

80
It is the ART of what we do with many
markers

Unidirectional Heat Map Analysis of Potential Markers

/Biomarkers: Phenomapping
stretch, fibrosis, injury, cytokines/ proinflammatory
neurohormones, cGMP, genetics, metabolomics, miRNA ?
 Georges Seurat, “A Sunday Afternoon on the Island of La
Grande Jatte”

▪ It is the ART of what we do with many markers representing

multiple pathway targets, in relation to each other and journey of
each organism
▪ Role of AI Technology ?
Heart Failure Stage C Treatment
According to Pheno-groups
Stage II Stage III Stage III Stage II-III Tachycardia
frequent Stage III
HFrEF with LV+RV HFrEF and / Injury
hosp HFrEF HTN
stable /congestion failure DM Pattern

ACEI/AR
Maximiz
B, BB, ACEI/AR
e GDMT ACEi, ACEI,
switch B, BB,
ACEi, BB, BB,
to ARNI, switch BB, ACEI
BB, then MRA, MRA,
HYD+ISD to ARNI,
switch diuretics diuretics
N for SGLT2i
to ARNI
MRA

83
 Anticipatory Management in Journey of
the Patient-Stage CStage D
HF
admission HF
admission HF
HF Hospitalizations
admission HF
admission

▪ Decongestion, maintaining QOL

▪ Treatment and prevention of precipitating factors
▪ Guideline driven medical treatment –
▪ Disease modifying approaches such as CRT
▪ Consideration for advanced care such as transplant /VAD
▪ Palliative Care, Decision making strategies, End of Life
Heart Failure
Stage C/D Treatment Strategies Need to be
Individualized for
Patient’s severity of illness and trajectory

Responsiveness to therapy

Goals of care

Comorbidities and side effect profile

Tolerability

Phenogroups

85
 Individualized / Precision Medicine in HF
Treat According to Etiology and Patient Preference
Patient management
should be • scaffold/foundation alone
individualized may not be adequate
• each patient will likely need
Other organ a different approach
involvement/comorbiditi
es help further refine
targeted therapies
Specific diagnoses usually warrant
specific treatment strategies
different than/in addition to GDMT

Patient Preference, Toxicity and Tolerance

Differ

Further diagnostic strategies should be carried out

to define specific etiology

Guideline directed medical therapy is the foundation /

scaffold of HF therapy, but needs to be built on