heart failure with reduced ejection fractionheart failure with reduced ejection fraction state of...

79
HEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018

Upload: others

Post on 05-Jun-2020

10 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

HEART FAILURE WITH

REDUCED EJECTION FRACTION

STATE OF THE ART

Felix J. Rogers, DO, FACOI

February 28, 2018

Page 2: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Heart Failure Management

If your only tool is a hammer…• Models of pharmacologic management

• Volume overload

Page 3: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

A Traditional Model for

Chronic Heart Failure

Page 4: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

A Clinical ModelFrom Mann, DL Circulation 1999; 100: 999-1008

Page 5: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

A Comprehensive ModelFrom Mann, DL Circulation 1999; 100: 999-1008

Page 6: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

The New Paradigm, 2008

Electromechanical therapy

• AICD

Restoration of myocardial function

• Cardiac resynchronization therapy

• Restoration of myocardial twist

• Surgical approaches to remodeling

• Prevention of sudden death

Page 7: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Bardy GH et al. N Engl J Med 2005;352:225-237.

Kaplan–Meier Estimates of Death from Any Cause for the Prespecified Subgroups of Ischemic CHF (Panel A) and Nonischemic CHF (Panel B).Amiodarone vs AICD in HFrEF

Page 8: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

CRT for HFrEF,

CARE HF Study.

Page 9: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Cleland JG et al. N Engl J Med 2005;352:1539-1549.

Kaplan–Meier Estimates of the Time to the Primary End Point (Panel A) and the Principal Secondary Outcome (Panel B).

CARE – HF Trial of CRT vs medical therapy in HFrEF

Page 10: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

New models for management of HF

• Pharmacologic

• Electromechanical

• Mechanical

• Systemic

Page 11: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

New models for management of HF

• Pharmacologic• Sacubritil/Valsartan

• Beta blocker

• Diuretic

• Electromechanical• AICD

• CRT + AICD

• Mechanical• LVAD

• Transplant

• Systemic• Sleep apnea

• Exercise

Page 12: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

New models for management of HF

• Pharmacologic• Sacubritil/Valsartan

• Beta blocker

• Diuretic

• Anticoagulation

• Electromechanical• AICD

• CRT + AICD

• Pulmonary vein isolation for atrial fibrillation

• Mechanical• LVAD

• Systemic interventions: • Detection of CAD, Anemia, Sleep apnea

Page 13: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Not covered today

• Ivradabine

• Valvular interventions

• TAVR

• TAMR

• TATR

• Coronary artery revascularization

• Heart failure with mid-range ejection fraction (HFmrEF)

Page 14: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Not covered today

• Ivradabine

• Valvular interventions

• TAVR

• TAMR

• TATR

• Coronary artery revascularization

• Heart failure with mid-range ejection fraction (HFmrEF)

• Now, on to

Pharmacologic therapy

Page 15: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

15

Suppress deleterious

effects of RAAS

Enhance the beneficial

effects of endogenous

compensatory peptides

Sacubitril/Valsartan

1. Kemp CD, Conte JV. Cardiovasc Pathol. 2012;21(5):365-371. 2. Mangiafico S et al. Eur Heart J. 2013;34:886-893. 3. Nathisuwan S, Talbert RL. Pharmacotherapy. 2002;22:27-42. 4. Hasenfuss G, Mann DL. Pathophysiology of heart failure. In: Mann DL et al, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Elsevier; 2015. 5. Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.

SNS1,4

HF SYMPTOMS &

PROGRESSION

Epinephrine

Norepinephrineα1, β1, β2

receptors

VasoconstrictionRAAS activity

Heart rateContractility

Endogenous Compensatory

Peptides2-4

VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy

NPs, Bradykinin, ADM

Sacubitril/

valsartan5

RAAS1,2

VasoconstrictionBlood pressure

Sympathetic toneVasopressinAldosteroneHypertrophy

Fibrosis

Ang II AT1R

Neprilysin

Inhibitor

VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy

NPs, Bradykinin, ADM

Endogenous Compensatory

Peptides2-4

+

ARB

RAAS1,2,4

VasoconstrictionBlood pressure

Sympathetic toneVasopressinAldosteroneHypertrophy

Fibrosis

Ang II AT1R

Effects of Sacubitril/valsartan in HFrEF

Slide has animation

NPR-A, NPR-B, B2, calcitonin

receptor-like receptor

Page 16: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

16

Sacubitril/ValsartanEffect on BNP and NT-proBNP

BNPs, brain natriuretic peptides; NT-proBNP, N-terminal of the prohormone brain natriuretic peptide.aVasoactive peptides include the NPs (atrial NPs, BNPs, C-type NPs), adrenomedullin, and bradykinin.Modified from Vardeny O et al. Clin Pharmacol Ther. 2013;94:445-448.

Inactive

fragments

⬆ Myocardial

wall tension

in HF

Inactive

(inert) marker

of HF

Vasoactive

peptidea with

cardioprotective

effects

BNP NT-proBNP

⬆ proBNP secretion

NeprilysinSacubitril/

valsartanNeprilysin inhibition has

no effect on NT-proBNP

Slide has animation

Sacubitril/Valsartan

Increases BNP Levels

Page 17: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

ENTRESTO®

Effects on Neprilysin and RAAS

cGMP=cyclic guanosine monophosphate; RAAS=renin-angiotensin-aldosterone

system; SNS=sympathetic nervous system

Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Schrier & Abraham. N Engl J Med 2009;341:577–85;Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9

Increases effects of endogenous

compensatory peptides

Vasodilation

Natriuretic and diuretic effects

Proliferation

Hypertrophy

SNS outflow/sympathetic tone

Aldosterone secretion

Detrimental effects of vascular

remodeling

Suppressing RAAS-mediated

effects

Vasoconstriction

Sodium and water retention

Ventricular hypertrophy/remodeling

Aldosterone secretion

Cardiac fibrosis

Sympathetic tone

Systemic vascular resistance

ENTRESTO

17

Neprilysin Inhibition RAAS Suppression

Page 18: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

PARADIGM-HF TRIAL

KEY FINDINGS

Page 19: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

2 weeks Median duration of follow-up: 27 months

Randomization

Enalapril 10 mg BID

Sac/val 97/103 mg BID

Sac/valb

97/103 mg BID

On top of standard HF therapy,

excluding ACEIs and ARBs3

Testing tolerability to target doses of enalapril and sac/val

Sac/valb

49/51 mg BID

Enalaprila

10 mg BID

1–2 weeks 2–4 weeks

Single-blind run-in period

Double-Blind Randomized Treatment Period

19

Primary outcome: To demonstrate superiority of sacubitril/valsartan over enalapril in reducing composite of death from CV causes or a first hospitalization for HF

PARADIGM-HFStudy Design

1. Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015. 2. McMurray JJ et al. Eur J Heart

Fail. 2013;15(9):1062-1073. 3. McMurray JJ et al. N Engl J Med. 2014;371(11):993-1004.

N=8442 patients with chronic HF (NYHA class II–IV with LVEF ≤40%) and elevated BNP

BID, twice daily; BNP, brain natriuretic peptide; NYHA, New York Heart Association. aEnalapril 5 mg BID for 1–2 weeks followed by enalapril 10 mg BID was an optional starting run-in dose for patients treated with ARBs or with a low dose of ACEI.bDosing in clinical trials was based on the total amount of both components of sac/val; 24/26 mg, 49/51 mg, and 97/103 mg were referred to as 50 mg, 100 mg,

and 200 mg, respectively. Sac/val was formerly known as LCZ696 in clinical trials.

Phase 3 Trial to Examine the Efficacy of Sacubitril/Valsartan vs Enalapril in Patients With HFrEF1,2

A 36 hour washout was required after single blind enalapril run-in and also at end of entresto single blind run-in

prior to being randomized

Page 20: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

20

PARADIGM-HFBaseline Characteristics

BPM, beats per minute; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; IQR, interquartile range; SBP, systolic blood pressure. *Mean ± standard deviation, unless stated.McMurray JJ et al. N Engl J Med. 2014;371:993-1004.

Characteristic* Sac/Val (N=4187) Enalapril (N=4212)

Age, years 63.8 ± 11.5 63.8 ± 11.3

Female, n (%) 879 (21.0) 953 (22.6)

Ischemic cardiomyopathy, n (%) 2506 (59.9) 2530 (60.1)

LVEF (%) 29.6 ± 6.1 29.4 ± 6.3

NYHA functional class, n (%)

II

III

2998 (71.6)

969 (23.1)

2921 (69.3)

1049 (24.9)

SBP, mm Hg 122 ± 15 121 ± 15

Heart rate, BPM 72 ± 12 73 ± 12

NT-proBNP, median, pg/mL (IQR) 1631 (885–3154) 1594 (886–3305)

BNP, median, pg/mL (IQR) 255 (155–474) 251 (153–465)

History of DM, n (%) 1451 (34.7) 1456 (34.6)

Treatments at randomization, n (%)

Diuretics

Digitalis

Beta-blockers

MRAs

ICD

CRT

3363 (80.3)

1223 (29.2)

3899 (93.1)

2271 (54.2)

623 (14.9)

292 (7.0)

3375 (80.1)

1316 (31.2)

3912 (92.9)

2400 (57.0)

620 (14.7)

282 (6.7)

Page 21: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

21

PARADIGM-HFPrimary Endpoint: Time to First Occurrence of CV Death or HF Hospitalization

CI, confidence interval; HR, hazard ratio. McMurray JJ et al. N Engl J Med. 2014;371:993-1004.

Enalapril

Sac/val

1.0

0.6

0.4

0.2

0

0 180 360 540 720 900 1080 1260

1117 events

914 events

HR: 0.80 (95% CI: 0.73–0.87)

P<0.001

20% Relative Risk Reduction

Cum

ula

tive

Pro

bab

ilit

y o

f th

e

Com

bin

ed E

ndpoin

t of

CV

Dea

th o

r

HF

Hosp

ital

izat

ion

No. at risk

Sac/val 4187 3922 3663 3018 2257 1544 896 249

Enalapril 4212 3883 3579 2922 2123 1488 853 236

Days Since Randomization

The difference in favor of sacubitril/valsartan was seen early in the trial and at each

interim analysis

Page 22: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

22

PARADIGM-HFSummary of Key Findings

aAnalyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity.bIncludes subjects who had HF hospitalization prior to death.Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.

22

Endpoint

Sac/Val

N=4187

n (%)

Enalapril

N=4212

n (%)

HR (95% CI) P Value

Primary composite endpoint of

CV death or HF hospitalization

CV death as first event

HF hospitalization as first event

914 (21.8)

377 (9.0)

537 (12.8)

1117 (26.5)

459 (10.9)

658 (15.6)

0.80 (0.73–0.87) <0.0001

Number of patients with eventsa

CV deathb

HF hospitalizations

558 (13.3)

537 (12.8)

693 (16.5)

658 (15.6)

0.80 (0.71–0.89)

0.79 (0.71–0.89)

All-cause mortality 711 (17.0) 835 (19.8) 0.84 (0.76–0.93) 0.0009

Page 23: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

PARADIGM-HFProspectively defined safety events

• Fewer patients in the Entresto group than in the enalapril group stopped their study

medication because of an AE (10.7 vs 12.3%, p=0.03)

Event, n (%)

Entresto

(n=4187)

Enalapril

(n=4212) p-value‡

Hypotension

Symptomatic 588 (14.0) 388 (9.2) <0.001

Symptomatic with SBP <90 mmHg 112 (2.7) 59 (1.4) <0.001

Elevated serum creatinine

≥2.5 mg/dL 139 (3.3) 188 (4.5) 0.007

≥3.0 mg/dL 63 (1.5) 83 (2.0) 0.10

Elevated serum potassium

>5.5 mmol/L 674 (16.1) 727 (17.3) 0.15

>6.0 mmol/L 181 (4.3) 236 (5.6) 0.007

Cough 474 (11.3) 601 (14.3) <0.001

Angioedema (adjudicated by a blinded expert committee)

No treatment or use of antihistamines only 10 (0.2) 5 (0.1) 0.19

Catecholamines or glucocorticoids without hospitalization 6 (0.1) 4 (0.1) 0.52

Hospitalized without airway compromise 3 (0.1) 1 (<0.1) 0.31

Airway compromise 0 0 ---

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

23

Page 24: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

PARADIGM-HF Effects of ENTRESTO® on BNP

Wk

0

Wk

4

Mth

8

Wk

-10

Wk

-8

Enalapril

Run-in*

Entresto

Run-in* Enalapril

Entresto

*Patients in both groups received the same single-blind treatment

Geo

met

ric

Mea

n

(nm

ol/

L)

Packer M et al. Circulation. 2014;131:54–61.

"BNP, but not NTproBNP, is a neprilysin substrate, and therefore BNP levels will increase as levels of

active drug increase; whereas levels of NTproBNP will show the effects of the drug on the heart"

Entresto ® (sacubitril/valsartan) [full prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; July 2015.

24

Page 25: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

PARADIGM-HF: Effects of ENTRESTO® on NT-proBNP

Enalapril

Entresto

Wk

0

Wk

4

Mth

8

Wk

-10

Wk

-8

*Patients in both groups received the same single-blind treatment

Geo

met

ric

Mea

n

(nm

ol/

L)

Enalapril

Run-in*

Entresto

Run-in*

Packer M et al. Circulation. 2014;131:54–61.

"BNP, but not NTproBNP, is a neprilysin substrate, and therefore BNP levels will increase as levels of

active drug increase; whereas levels of NTproBNP will show the effects of the drug on the heart"

Entresto ® (sacubitril/valsartan) [full prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; July 2015.

25

Page 26: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

2016 ACC/AHA/HFSA Focused UpdatePharmacological Treatment for Stage C HFrEF: Recommendations

COR LOE Recommendations

I

ACE: A The clinical strategy of inhibition of the renin-angiotensin

system with ACE inhibitors (Level of Evidence: A), OR

ARBs (Level of Evidence: A), OR ARNI (Level of

Evidence: B-R) in conjunction with evidence-based beta

blockers, and aldosterone antagonists in selected

patients, is recommended for patients with chronic

HFrEF to reduce morbidity and mortality.

ARB: A

ARNI: B-R

Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB

or ARNI

“In ARNI, an ARB is combined with an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides,

bradykinin, adrenomedullin, and other vasoactive peptides. In an RCT that compared the first approved ARNI,

valsartan/sacubitril, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either

ACE inhibitor or ARB, the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization

significantly, by 20%. The benefit was seen to a similar extent for both death and HF hospitalization and was

consistent across subgroups. The use of ARNI is associated with the risk of hypotension and renal insufficiency

and may lead to angioedema, as well.”

ARNI, angiotensin receptor-neprilysin inhibitor

Yancy CW, et.al. , 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update

of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, Journal of the American College of Cardiology (2016),

doi: 10.1016/ j.jacc.2016.05.011.

Page 27: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

2016 ACC/AHA/HFSA Focused Update

Pharmacological Treatment for Stage C HFrEF: Recommendations

COR LOE Recommendations

I ARNI: B-R

In patients with chronic symptomatic HFrEF NYHA class

II or III who tolerate an ACE inhibitor or ARB, replacement

by an ARNI is recommended to further reduce morbidity

and mortality.

Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or

ARB or ARNI (cont’d)

“In patients with mild-to-moderate HF (characterized by either [1] mildly elevated natriuretic peptide levels, BNP

[B-type natriuretic peptide] >150 pg/mL or NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥600 pg/mL;

or [2] BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with a prior hospitalization in the preceding 12 months) who

were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNI

(valsartan/sacubitril, 200* mg twice daily, with the ARB component equivalent to valsartan 160 mg),

hospitalizations and mortality were significantly decreased with the valsartan/sacubitril compound compared with

enalapril.”

*Dosing in clinical trials was based on the total amount of both components of sacubitril/valsartan, i.e., 24/26 mg, 49/51 mg, and

97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.

ARNI, angiotensin receptor-neprilysin inhibitor

Yancy CW, et.al. , 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update

of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, Journal of the American College of Cardiology (2016),

doi: 10.1016/ j.jacc.2016.05.011.

Page 28: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

2016 ACC/AHA/HFSA Focused Update

Pharmacological Treatment for Stage C HFrEF: Recommendations

COR LOE Recommendations

III: Harm B-R

ARNI should not be administered concomitantly with

ACE inhibitors or within 36 hours of the last dose of an

ACE inhibitor.

III:

HarmC-EO

ARNI should not be administered to patients with a

history of angioedema.

Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB

or ARNI (cont’d)

• Oral neprilysin inhibitors when used in combination with ACE inhibitors can lead to angioedema -

concomitant use is contraindicated and should be avoided

• An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor.

• In patients with a history of angioedema there is a concern that treatment with an ARNI will increase

the risk of a recurrence of angioedema

ARNI, angiotensin receptor-neprilysin inhibitor

Yancy CW, et.al. , 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update

of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, Journal of the American College of Cardiology (2016),

doi: 10.1016/ j.jacc.2016.05.011.

Page 29: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Stroke risk in patients with HFrEF

• Meta-analysis of 4 trials. 22,904 patients with myocardial

infarction without A Fib

• Follow up of 1.9 years. 660 patients had a stroke. (2.9%)

• Final stroke risk model

• Older age

• Killip Class 3 or 4 MI

• eGFR < 45 ml/min/1.73 m2

• Hypertension history

• History of previous stroke

Page 30: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical
Page 31: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

João Pedro Ferreira et al. JACC 2018;71:727-735

2018 American College of Cardiology Foundation

Page 32: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

João Pedro Ferreira et al. JACC 2018;71:727-735

2018 American College of Cardiology Foundation

Page 33: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Pulmonary vein isolation for HF + AF

• Atrial fibrillation and heart failure commonly occur

together, with atrial fibrillation increasing the risk for stoke,

hospitalization for heart failure and death.

Page 34: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Pulmonary vein isolation for HF + AF

• Atrial fibrillation and heart failure commonly occur

together, with atrial fibrillation increasing the risk for stoke,

hospitalization for heart failure and death.

• Rhythm control with antiarrhythmic drugs is not superior

to rate control in patients with atrial fibrillation.

Page 35: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Pulmonary vein isolation for HF + AF

• Atrial fibrillation and heart failure commonly occur

together, with atrial fibrillation increasing the risk for stoke,

hospitalization for heart failure and death.

• Rhythm control with antiarrhythmic drugs is not superior

to rate control in patients with atrial fibrillation.

• Catheter ablation is well-established as a treatment for

atrial fibrillation in patients with normal LV function, and

there is some evidence of benefit in patients with heart

failure.

Page 36: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

CASTLE-AF. Catheter ablation vs standard

conventional therapy in patients with LV dysfunction

and atrial fibrillation.

• Patients with paroxysmal or chronic atrial fibrillation and

• LV EF < 35%

• AICD

• Standard therapy for HF

Randomized to:

• Pulmonary vein isolation - 179 patients

• Medical therapy (rate/rhythm control) - 184 patients

Page 37: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Kaplan–Meier Curves Comparing Survival Free of the Primary End Point (Death from Any

Cause or Admission for Worsening Heart Failure) and Its Two Components in the Two Trial Groups.

Marrouche NF et al. N Engl J Med 2018;378:417-427

Outcomes of CASTLE-AF. NEJM Feb 1, 2018

Page 38: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Primary and Secondary Clinical End Points.

Marrouche NF et al. N Engl J Med 2018;378:417-427

Page 39: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Underutilization of CAD Testing among

patients hospitalized with new onset HF• Retrospective cohort study of 67,161 patients with new

onset HF

• Only 17.5% had testing for ischemic CAD during index

hospitalization, increasing to 27.4% at 90 days

• Only 2.1% underwent revascularization during index

hospitalization, increasing to 4.3% at 90 days

• ACC/AHA 2013 guidelines designate Class IIa indication

to noninvasive and invasive assessment of ischemic CAD

in HF patients.

Page 40: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical
Page 41: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Iron deficiency in heart failure

• 2017 ACC/AHA/HSA guidelines state

• IV iron may be reasonable in selected NYHA functional class II to III

patients with HF (recommendation level II-B)

• 2016 ESC guidelines recommend (II-A) IV iron in

symptomatic HFrEF to alleviate symptoms and imptrove

functional status

Page 42: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Bruno M.L. Rocha et al. JACC 2018;71:782-793

2018 American College of Cardiology Foundation

Page 43: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Sleep disordered breathing

• Most patients with HF have sleep disordered breathing

(SDB) with central (rather than obstructive) sleep apnea

becoming the predominant form in patients with more

severe disease.

• Cyclical apnea and hypopnea are associated with

• Sleep disturbance

• Hypoxemia

• Hemodynamic changes

• Sympathetic activation

• Worse prognosis

• Randomized trials of treatment of central sleep apnea

show possibility of harm

Page 44: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Martin R. Cowie, and Angela M. Gallagher JCHF

2017;5:715-723

2017 American College of Cardiology Foundation

Page 45: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Treatment of central sleep apnea

• Acetazolamide

• Theophylline

• Adaptive servo ventilation

Page 46: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Treatment of central sleep apnea

• Acetazolamide

• Theophylline

• Adaptive servo ventilation

Page 47: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Take home points

• Entresto (sacubitril/valsartan)

• Consider stroke risk for post-MI cardiomyopathy and

normal sinus rhythm

• Catheter ablation for atrial fibrillation and LVEF < 35%

• Test for coronary artery disease in new onset heart failure

Page 48: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

HFPEF, PRT 2

Page 49: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Impaired flow pattern and low e’ in male with dyspnea, from Penicka M, Heart, 2014

Page 50: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical
Page 51: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical
Page 52: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Stepwise approach to the diagnosis of heart failure with preserved EF in elderly

ambulatory patients with equivocal symptoms. Penicka M, Heart 2014;100: 68-76

Page 53: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Pathophysiology of HFpEF

• Breathlessness is the predominant symptom due to

elevated left ventricular diastolic pressure.

• Focus on abnormalities in active relaxation and passive

stiffness

• Extracellular matrix

• Interstitial fibrosis

• Cardiomyocyte itself

• Incomplete relaxation of myocardial strips

• Increased myocardial stiffness

Page 54: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Pathophysiology of HFpEF

• A new paradigm – Paulus & Tschope – comorbidities such

as obesity, diabetes and COPD lead to a systemic pro-

inflammatory state that induces coronary microvascular

endothelial inflammation.

• This inflammation and resultant oxidative stress cause

stiff myocytes and interstitial fibrosis.

• Although hypertension is commonly felt to cause HFpEF

by afterload excess, this model changes the emphasis to

inflammation

Page 55: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Date of download:

5/14/2014

Copyright © The American College of Cardiology.

All rights reserved.

From: A Novel Paradigm for Heart Failure With Preserved Ejection Fraction: Comorbidities Drive Myocardial

Dysfunction and Remodeling Through Coronary Microvascular Endothelial Inflammation

J Am Coll Cardiol. 2013;62(4):263-271. doi:10.1016/j.jacc.2013.02.092

Myocardial Dysfunction and Remodeling in HFPEF and HFREF

In HFPEF, myocardial dysfunction and remodeling are driven by endothelial inflammation and oxidative stress. In HFREF, oxidative

stress originates in the cardiomyocytes because of ischemia, infection, or toxic agents. ROS trigger cardiomyocyte autophagy,

apoptosis, or necrosis. The latter attracts leukocytes. Dead cardiomyocytes are replaced by fibrous tissue. cGMP = cyclic guanosine

monophosphate; HFREF = heart failure with reduced ejection fraction; other abbreviations as in Figure 1.

Figure Legend:

Page 56: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Pathophysiology of HFpEF

• Vascular abnormalities

• Arterial stiffness increases with aging and is amplified by

hypertension, diabetes and renal disease

• With an increase in arterial stiffness, the ejected pressure

wave is reflected back to the heart, altering systolic

pressure load and diastolic function, increasing hydraulic

work and myocardial oxygen consumption

• This leads to impaired LV reserve function, labile systemic

hypertension, diminished coronary flow reserve and

increased diastolic filling pressures, leading to

breathlessness.

Page 57: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Increased ventriculoarterial stiffness means that older adults have

greater dependence of BP on preload

Page 58: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Pathophysiology of HFpEF

• The end systolic stiffness of the LV and the arteries

increases with aging, especially in women, who are

disproportionately represented in HFpEF

• Women also develop more concentric LVH in the setting

of pressure overload compared to men.

• With exercise, the patient with HFpEF has a limited

vasodilator response to activity.

• These patients often have marked systemic hypertension

with exercise stress.

Page 59: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Treatment of HFpEF

• Pharmacologic management of HFpEF

• Agents in investigational trials

• Sildenafil (RELAX Trial)

• Aldosterone antagonists (TOPCAT Trial)

• Angiotensin-receptor neprilipsin inhibitor ARNI (PARAMOUNT Trial)

• In each case, the information for each trial shows no

benefit of treatment.

Page 60: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

More on TOPCAT

Patients Sites Pt/site/mo Mortality

Overall 3,445 233 0.22 4.2-4.6

N & S Am 1,767 188 0.14 6.5-7.7

East. Eur. 1,676 45 0.56 2.0-2.3

Page 61: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Diuretic Treatment in HF

Page 62: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Mechanisms of Loop Diuretic Action and Resistance.

Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975

Page 63: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Pharmacokinetic and Pharmacodynamic Properties of Loop Diuretics.

Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975

Page 64: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Nephron Remodeling as a Mechanism of Diuretic Resistance.

Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975

Page 65: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Causes of Diuretic Resistance.

Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975

Page 66: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

HFPEF PART 3

Page 67: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Stepped-Care Pharmacologic Approach.

Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975

Page 68: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS

• 74 year old female with symptoms of progressive dyspnea and exercise intolerance since February, 2014. No ankle edema.• She tries to exercise on her stationary bike for 10 minutes per day

• PMHx

• Atrial fib, on warfarin, labetalol

• Hypothyroid, on replacement

• Hyperlipidemia

• COPD and restrictive lung disease

• Mitral regurgitation, moderate on 11/25/09

• Exam

• 132/62, HR 58 and irreg.

• Weight 181, Height 5’ 6,” BMI 29.2

• No JVD

• Trace ankle edema

Page 69: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS

Page 70: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS, Prior study.

Page 71: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS

Page 72: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS

Page 73: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS

Page 74: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS, mitral inflow

Page 75: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS

Echocardiogram features

• Estimated RVSP (PA systolic pressure) 45 mm Hg

• Septal e’ 7.6 cm/s

• E/e’ 14.7

• Mitral valve deceleration time 201

Page 76: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS

• Your diagnosis?

A) Atrial fibrillation with tachycardia cardiomyopathy

B) Diastolic heart failure (HFpEF)

C) Non cardiac dyspnea due to lung disease

D) Deconditioning

E) Labile hypertension

Page 77: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

One more case: BS

• You would order

A) CXR

B) BNP

C) Add furosemide, increase until dyspnea resolved

D) Start sildenafil

E) Cardiac rehabilitation exercise, paid by medicare

Page 78: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Exercise and HFpEF

Page 79: Heart Failure with reduced Ejection fractionHEART FAILURE WITH REDUCED EJECTION FRACTION STATE OF THE ART Felix J. Rogers, DO, FACOI February 28, 2018. ... • Anticoagulation •Electromechanical

Exercise in HFpEF