pharmacological management for heart failure and reduced...

2/9/2017

1

Pharmacological Management for Heart Failure and Reduced Ejection Fraction: Reducing

Rehospitalization

Nancy M. Albert PhD, CCNS,

CHFN, CCRN, NE-BC

FAHA, FHFSA, FAAN

Cleveland Clinic

Cleveland Ohio

Disclosures

• Novartis: Consultant, Speaker’s Bureau

Objectives

• Describe pharmacologic properties of two recently approved drugs for HF-rEF

• An angiotensin receptor neprilysin inhibitor

• A selective sinus node If channel inhibitor

• Discuss use of newer agents in conjunction with other HF-rEF medications to improve quality of life and survival, and reduce rehospitalization

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2

Normal HFrEF HFpEF Concentric Remodeling

Thickness Volume

Volume/mass

Eccentric Remodeling Thickness Volume

Volume/mass

Definition & Pathology of Heart Failure

Konstam MA. J Card Fail. 2003;9:1-3; Yancy CW, et al. Circulation. 2013;128:e240-e327; a Images courtesy of Dr. William Little and Dr. Marvin Konstam Aurigemma GP et al. Circulation. 2006;113:296-304.

• A clinical syndrome; it results from any structural or functional impairment of ventricular filling or ejection of blood

Pathophysiology of HFrEF

Left ventricular dysfunction

Coronary disease Cardiomyopathy Cardiac overload

Vasoconstriction Neurohormonal

activation

Peripheral organ blood flow

Skeletal

Blood flow

RBF, Na

retention

LV

dilatation

LV

hypertrophy

Symptoms, fluid retention, death

Arrhythmias

Cardiac remodeling

Heart Failure Pharmacotherapy

Reduces Death

82 78

67

50

60

70

80

90

100

1985-1994 1995-2004 2005-2014

Percentage of Deaths in Heart Failure and Reduced Ejection Fraction (HFrEF) Clinical Trials Caused by

Cardiovascular Disease, 1985-2014

Heart Failure Trials by Decade

Per

cen

tage

of

Dea

ths

P<0.01

Rush CJ et al. JACC Heart Fail. 2015;3(8):603-14.

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3

How Should Novel Medications Be

Incorporated into the Pharmacotherapy of Heart

Failure Patients?

A 32 year old female without significant PMH is flown to your center in refractory cardiogenic shock one week after delivering a healthy baby boy.

She has been newly diagnosed with non-ischemic dilated cardiomyopathy.

Case Presentation

• Developed progressive shock and multi-organ dysfunction • ECMO initiated • After 4 days, clinical status improved

• ECMO is successfully weaned • Remained hospitalized for an additional 2 weeks.

• NOW: 1 month post discharge and you are seeing her in clinic • Current pharmacotherapies:

• Furosemide and warfarin for LV thrombus • Low dose carvedilol • Low dose lisinopril

• She tells you she feels her life has been turned upside down and is frightened about her and baby’s future.

Case Presentation

What is the optimal pharmacotherapy plan?

ECMO, extracorporeal membrane oxygenation; LV, left ventricular

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Pharmacologic Treatment for Stage C HFrEF

HFrEF Stage C NYHA Class I-IV

Treatment:

For NYHA Class II-IV patients, if estimated creatinine >30 mL/min

and K+ <5.0 mEq/dL

For all volume overload, NYHA Class II-IV patients

For persistently symptomatic African Americans, NYHA Class III-IV

Class I, LOE A ACEI or ARB AND

beta blocker

Class I, LOE C Loop diuretics

Class I, LOE A Hydralazine-

nitrates

Class I, LOE A Aldosterone Antagonist

ADD ADD ADD

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

Pooled Analysis: 32 RCT of ACEi

21.9

15.8

10.5

6.5

32.6

22.5

0

5

10

15

20

25

30

35

% o

f p

atients

Total

Mortality

Death due to

CHF Mortality Death or

Hospitalization

Due to CHF

Placebo

ACEI P<0.01

P<0.001

Garg R, Yusuf S. JAMA. 1995;273:1450-1456.

P<0.001

All-cause mortality in 5 pooled trials: OR 0.80 (95% CI, 0.74-0.87; p<0.0001)*

*Flather et al. Lancet 2000;355(9215):1575-1581.

Treatment of 100 patients could prevent 7 major events (death/CHF readmission/MI)

Clinical Effects of ARBs on HF

* Pfeffer MA et al. Lancet 2003;363:759-766. ** Cohn JN et al. N Engl J Med 2001;345:1667-1675.

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Risk-Treatment Mismatch in HF: Major Clinical Challenge

0

10

20

30

40

50

60

70

80

90

Low Risk Average Risk High Risk

ACEI ACEI

or ARB

-Blocker 1 Year

Mortality

Rate

Pati

en

ts (

%)

Use rates in absence of contraindications. For all drug classes, P<.001 for trend.

Lee D, et al. JAMA. 2005;294(10):1240-1247.

At Hospital Discharge 90 Day Follow-Up 1 Year Follow-Up

ACEI ACEI or

ARB -Blocker

Guideline Recommendations and Medications in HF: 2 Issues

“Medications

don’t work in

patients who don’t

take them”

C. Everett Koop

#1.

Teach Back

NEW CONCEPT: Health

information, advice,

instructions, or change

in management

Adherence /

Error reduction

Explain new concept /

Demonstrate new skill

Pt. recalls & comprehends

/ demonstrates skill

mastery

Assess patient

comprehension /

Ask patient to

demonstrate

Clarify & tailor

explanation

Re-assess recall

and comprehension

/ Ask patient to

demonstrate

Arch Intern Med 2003;163:83-90.

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Shared Decision Making

Guideline Recommendations and Medications in HF: 2 Issues

“Medications don’t work in patients

who don’t take them” C. Everett Koop #1.

#2. Health care

providers who fail to order AND who under dose HF medications are not serving their patients best interest

Patients who Survived 1st HF Hospitalization and Claimed a RASi, β-B or Spironolactone

Prescription in 3 mos. (statin, 6 mos) of Discharge

Gislason GH et al. Circulation 2007;116:737-744.

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Mineralocorticoid Receptor Antagonism

Mineralocorticoid receptor expressed in renal tubular cells

• Associated with sodium retention and K+ loss

• Also expressed in vascular smooth muscle cells, endothelial cells, myocardium, brain, kidney, and other tissues (i.e., eyes)

Pitt B, et al. Euro Heart J - Cardiovasc Pharmacotherapy. 2017;3(1):48-57.

Vicious Cycle of MR Activation

AT1R, angiotensin type 1 receptor; ATII, angiotensin II; ACE, angiotensin converting enzyme; ROS, reactive oxygen species; MR, mineralocorticoid receptor

Pitt B, et al. Euro Heart J - Cardiovasc Pharmacotherapy. 2017;3(1):48-57.

Mineralocorticoid Receptor Antagonism Evidence

• RALES1: Spironolactone in advanced NYHA FC III-IV [10% on beta-blocker (BB)]

• 24-month 30% all-cause mortality; 30% in HF hospitalization

• EPHESUS2: Eplerenone in early post-AMI (3-14 days) with LVSD/HF and/or DM [85% on BB]

• 16 month 13% all-cause mortality; in combo CV mortality and HF hospitalization

• EMPHASIS-HF3: chronic stable HF/NYHA class II + Hx CV hospitalization within the past 6 months

• 21 month 37% total mortality and total hospitalizations

1. Pitt B, et al. N Engl J Med .1999;341:709–717; 2. Pitt B, et al. J Am Coll Cardiol. 2005;46:425–431; 3. Zannad F, et al. N Engl J Med 2011;364:11–21.

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Stage C HFrEF Tx: Mineralocorticoid Receptor Antagonists

GDMT

RR

Reduction

in

Mortality

NNT to

Mortality

(Standardized to

36 months)

RR Reduction

in HF

Hospitalization

ACEi / ARB 17% 26 31%

Beta blocker 34% 9 41%

MRA 30% 6 35%

Hydralazine/

nitrate 43% 7 33%

Yancy CW et al. Circulation. 2013;128(16):e240-327.

Contemporary Use of MRA Based on Guideline Recommendations

• Registry- or survey-based studies

• Prescribing rates of ACEi, ARBs, BBs and MRAs among HFREF patients

• Published in 2000-2015

• 23 reports and 83,605 patients

Medication Prescribed, %

Treatment Gap, %

≥ 50% Target Dose, %

ACEi/ARB 79.8 13.1 72, ACEi / 51, ARB

Beta-blocker 81.4 3.9 49

MRA 36.4 16.8 83

Chin KL et al. Heart Fail Rev. 2016;21(6):675-697.

Stage C HFrEF Tx: Mineralocorticoid Receptor Antagonists

Recommended for patients w NYHA class II-IV and • LVEF of ≤ 35%, unless contraindicated

If NYHA class II: • History of prior cardiovascular hospitalization or • Elevated plasma BNP

• Creatinine: ≤ 2.5 mg/dL, men // ≤ 2.0 mg/dL, women or • eGFR >30 mL/min/1.73m2

• Potassium < 5.0 mEq/L • Monitor K+, renal function, & diuretic dosing

• To minimize risk of hyperkalemia and renal insufficiency

I IIa IIb III


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Stage C HFrEF MRA Use; AHA/ACC Guidelines

Recommended to morbidity and mortality after AMI if LVEF ≤ 40% who develop symptoms of HF or Hx diabetes mellitus, unless contraindicated

I IIa IIb III

I IIa IIb III

Harm

Inappropriate use is potentially harmful

• Life-threatening hyperkalemia

• If potassium > 5.0 mEq/L

• Renal insufficiency when:

– Sr. creatinine >2.5 mg/dL/men

• or >2.0 mg/dL/women

– or eGFR <30 mL/min/1.73m2


Mortality in HF-rEF

Although survival rates improved with new therapies, mortality remains at 50% within 5 years of diagnosis

* Standard therapies at the time of the study (except CHARM-Alternative, where background ACE-I was excluded)

ACEI* β-Blocker* MRA* ARB*

Red

uct

ion

in R

R o

f

Mo

rtal

ity

vs. p

lace

bo

16%

SOLVD

34%

CIBIS-II

30%

RALES CHARM

ALT

17% 4.5% ARR; mean FU,

41.4 mo

5.5% ARR; mean FU,

1.3 years

11.0% ARR; mean FU,

24 mo

3.0% ARR; median FU,

33.7 mo

2016 ACC/AHA/HFSA Heart Failure Guideline Update

• Released May 20, 2016

• Focus: Pharmacological Treatment for Stage C HF-rEF recommendations

• Renin-angiotensin system inhibition with:

• Angiotensin converting enzyme inhibitor (ACEi)

• Angiotensin receptor blocker (ARB)

• Angiotensin receptor neprilysin inhibitor (ARNI)

• Ivabradine

Yancy C, Jessup M, et al. Circulation. 2016;134(13):e282-93.

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How Does an ARNI fit into HF-rEF Treatment?

• Angiotensin receptor blocker

• Neprilysin Inhibitor

• Degrades many

endogenous

vasoactive

peptides

Endogenous

vasoactive peptides

(natriuretic peptides, adrenomedullin,

bradykinin, substance P, calcitonin gene-related

peptide)

Inactive metabolites

Neprilysin

Neprilysin Inhibitor

Endogenous vasoactive peptides

(natriuretic peptides, adrenomedullin,

bradykinin, substance P, calcitonin gene-related

peptide)

Neurohormonal activation

Vascular tone

Cardiac fibrosis, hypertrophy

Sodium retention


Neprilysin Neprilysin

inhibition

Renin Angiotensin System Angiotensin I Sodium retention

Volume expansion

Vascular smooth muscle cell growth

Vasoconstriction

LV dysfunction

Myocardial fibrosis, hypertrophy


Neprilysin

Neprilysin

inhibition

ACE

ANG II

ATIR

Aldosterone

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Mechanisms of Progression in Heart Failure

Myocardial or vascular stress or injury

Evolution and progression of heart failure

activity or response to maladaptive mechanisms

activity or response to adaptive

mechanisms

Myocardial or vascular stress or injury

Evolution and progression of heart failure

Mechanisms of Progression in Heart Failure

Angiotensin receptor blocker

Neprilysin inhibitor

activity or response to maladaptive mechanisms

activity or response to adaptive

mechanisms

LCZ696- Valsartan / Sacubitril

Angiotensin Receptor Neprilysin Inhibition


Inhibition of neprilysin

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Prospective comparison of ARNI with ACEI to

Determine Impact on Global Mortality and

Morbidity in Heart Failure trial (PARADIGM-HF)

Designed to replace current use

of ACEi and ARB as the cornerstone of the treatment of heart failure

Aim of the PARADIGM-HF Trial

LCZ696 400 mg daily

Enalapril 20 mg daily

PARADIGM-HF: Entry Criteria

• NYHA class II-IV heart failure

• LV ejection fraction ≤ 40% 35%

• BNP ≥ 150 (or NT-proBNP ≥ 600 pg/mL), but 1/3 lower if hospitalized for heart failure within 12 months

• Any use of ACEi or ARB, but able to tolerate stable dose equivalent to at least enalapril 10 mg/daily for at least 4 weeks

• Guideline recommended use of β-blocker and MRA

• Systolic BP ≥ 95 mmHg, eGFR ≥ 30 ml/min/1.73 m2 and serum K ≤ 5.4 mEq/L at randomization

McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.

PARADIGM-HF: Entry Criteria

• Not entered:

• Patients with a history of angioedema related to previous ACEi or ARB therapy

• Patients taking ACEi concurrently

• Patients with diabetes on aliskiren concurrently

• Excluded if:

• Current acute decompensated HF

• Hx Severe pulmonary disease


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2 weeks 1-2 weeks 2-4 weeks

Single-blind run-in period Double-blind period

(1:1 randomization)

Enalapril

10 mg BID

100 mg BID

200 mg BID

Enalapril 10 mg BID

LCZ696 200 mg BID

PARADIGM-HF: Study Design Randomization

LCZ696


0

16

32

40

24

8

Enalapril (n=4212)

360 720 1080 0 180 540 900 1260

Days After Randomization

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)

4187

4212

3922

3883

3663

3579

3018

2922

2257

2123

1544

1488

896

853

249

236

LCZ696

Enalapril

Patients at Risk

1117

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)


0

16

32

40

24

8

Enalapril (n=4212)

360 720 1080 0 180 540 900 1260


4187

4212

3922

3883

3663

3579

3018

2922

2257

2123

1544

1488

896

853

249

236

LCZ696

Enalapril

Patients at Risk

1117

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)

914

LCZ696 (n=4187)



2/9/2017

14

0

16

32

40

24

8

Enalapril (n=4212)

360 720 1080 0 180 540 900 1260


4187

4212

3922

3883

3663

3579

3018

2922

2257

2123

1544

1488

896

853

249

236

LCZ696

Enalapril

Patients at Risk

1117

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)

914

LCZ696 (n=4187)

HR = 0.80 (0.73-0.87)

P = 0.0000002

Number needed to treat = 21



Enalapril (n=4212)

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)


PARADIGM-HF: Cardiovascular Death

4187

4212

4056

4051

3891

3860

3282

3231

2478

2410

1716

1726

1005

994

280

279

LCZ696

Enalapril

Patients at Risk

360 720 1080 0 180 540 900 1260 0

16

32

24

8

693


Enalapril (n=4212)

LCZ696 (n=4187)

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)


4187

4212

4056

4051

3891

3860

3282

3231

2478

2410

1716

1726

1005

994

280

279

LCZ696

Enalapril

Patients at Risk

360 720 1080 0 180 540 900 1260 0

16

32

24

8

693

558



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Enalapril (n=4212)

LCZ696 (n=4187)

HR = 0.80 (0.71-0.89)

P = 0.00004

Number need to treat = 32

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)


4187

4212

4056

4051

3891

3860

3282

3231

2478

2410

1716

1726

1005

994

280

279

LCZ696

Enalapril

Patients at Risk

360 720 1080 0 180 540 900 1260 0

16

32

24

8

693

558



LCZ696

(n=4187)

Enalapril

(n=4212)

Hazard

Ratio

(95% CI)

P

Value

Primary

endpoint

914

(21.8%)

1117

(26.5%)

0.80

(0.73-0.87) 0.0000002

Cardiovascular

death

558

(13.3%)

693

(16.5%)

0.80

(0.71-0.89) 0.00004

Hospitalization

for heart failure

537

(12.8%)

658

(15.6%)

0.79

(0.71- 0.89) 0.00004

PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its

Components


Effects on Primary Endpoint & Cardiovascular Death, by Subgroups

Primary endpoint

Cardiovascular death


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PARADIGM-HF: All-Cause Mortality

4187

4212

4056

4051

3891

3860

3282

3231

2478

2410

1716

1726

1005

994

280

279

LCZ696

Enalapril

Enalapril (n=4212)

LCZ696 (n=4187)

HR = 0.84 (0.76-0.93)

P<0.0001

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)

Days After Randomization Patients at Risk

360 720 1080 0 180 540 900 1260 0

16

32

24

8

835

711


LCZ696 (n=4187)

Enalapril (n=4212)

P Value

Prospectively identified adverse events

Symptomatic hypotension 588 388 < 0.001

Serum potassium > 6.0 mmol/l 181 236 0.007

Serum creatinine ≥ 2.5 mg/dl 139 188 0.007

Cough 474 601 < 0.001

Discontinuation for adverse event 449 516 0.02

For hypotension 36 29 NS

For hyperkalemia 11 15 NS

For renal impairment 29 59 0.001

Angioedema (adjudicated)

Medications, no hospitalization 16 9 NS

Hospitalized; no airway compromise 3 1 NS

Airway compromise 0 0 ----

PARADIGM-HF: Adverse Events


Paradigm-HF; Outcomes by Age

Jhund PS, et al. Euro Heart J. 2015; 36(38):2576-2584.

8399 patients aged 18-96 years Line of unity LCZ696 to Enalapril Hazard Ratio; grey shading, 95% CI

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≥ 5-point Fall (Deterioration) in KCCQ at 8 months by Age & Tx

Jhund PS, et al. Euro Heart J. 2015; 36(38):2576-2584.

Favorable benefit-risk profile in all age groups

PARADIGM-HF: Benefit with Dose Reduction?

• Dose reduction post randomization:

• Enalapril: 1792 / 4212 = 42.5%

• Sacubitril/valsartan: 1755 / 4187 = 41.9%

• Overall: 3547/ 8442 = 42.0%

• Those w dose reduction had more severe HF at baseline and were:

• Older Less use: BB & MRA

• More Ischemic CM Higher creatinine

• More diabetes Lower systolic BP

• Higher NT-proBNP Higher diuretic use

• Higher NYHA FC III Higher CRT/ICD use

Vardeny et al. J Card Fail. 2015;21(8); Suppl S9.

Vardeny et al. J Card Fail. 2015;21(8); Suppl S9.

PARADIGM-HF: Benefit with Dose Reduction?

LCZ696, mg

Enalapril, mg

Events (N) HR (95% CI)

RRR P Value

200 10 1262 0.79 (0.71, 0.88) 21% <0.001

100-200 5-10 541 0.80 (0.67, 0.94) 20% 0.008

< 100 mg < 5 mg 225 0.76 (0.58, 0.99) 24% 0.043

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In HF-rEF, when compared with recommended

doses of enalapril:

LCZ696 was more effective than enalapril in . . .

• the risk of CV death and HF hospitalization

• the risk of CV death by incremental 20%

• the risk of HF hospitalization by incremental 21%

• all-cause mortality by incremental 16%

• Incrementally symptoms and physical limitations

LCZ696 was better tolerated than enalapril . . .

• Less likely to cause cough, hyperkalemia or renal impairment

• Less likely to be discontinued due to an adverse event

• More hypotension, but no in discontinuations

• Not more likely to cause serious angioedema

PARADIGM-HF: Summary of Findings

10%

ARNI Doubles Effect on Cardiovascular Death of Current Inhibitors of the RAS

20%

30%

40%

ACE inhibitor


0%

% D

ecre

ase i

n M

ort

ali

ty

18%

16%

Effect of ARB vs placebo derived from CHARM-Alternative trial

Effect of ACEi vs placebo derived from SOLVD-Treatment trial

Effect of ARNI vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensin receptor

neprilysin inhibitor

15%

McMurray JJ et al. Eur Heart J. 2015;36:434-439; Claggett B et al. N Engl J Med. 2015;373:2289-2290.

ACC/AHA/HFSA Guideline Update Recommendations for RAS Inhibition with

ACEi or ARB or ARNI (Stage C-HFrEF)

COR LOE Recommendations

I ACEi: A Inhibition of the RAS with ACEi OR ARB OR ARNI in conjunction with evidence-based beta blocker, and aldosterone antagonist in selected patients, is recommended for patients with chronic HFrEF to morbidity and mortality

ARB: A

ARNI: B-R


COR= class of recommendation (Strength); green, IS recommended (Strong) LOE= level of evidence (Quality); A, high qual evidence; B, moderate qual; randomized

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I ACEi: A Use of ACEi is beneficial for patients with prior or current symptoms of chronic HFrEF to morbidity and mortality

ARB: A The use of ARB to morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACE inhibitors because of cough or angioedema

ARNI: B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACEi or ARB, replacement by ARNI is recommended to further morbidity and mortality


COR= class of recommendation (Strength); green, IS recommended (Strong) LOE= level of evidence (Quality); A, high qual evidence; B, moderate qual; randomized




III B-R ARNI should not be administered concomitantly with ACEi or within 36 hours of the last dose of an ACEi

III C-EO ARNI should not be administered to patients with a history of angioedema


COR= class of recommendation (Strength); red, IS HARM LOE= level of evidence (Quality); B, moderate quality; 1 or more randomized trial C-EO, Expert opinion, based on clinical experience

Heart Rate as a Predictor of Death and/or HF Hospitalizations in

Chronic HF (SHIFT placebo group)

Böhm, et al. Lancet. 2010;376(9744):886-894.

Increase in risk by 2.9% per 1 bpm ; 15.6% per 5 bpm

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SHIFT: Baseline Heart Rate Analysis

Böhm M et al. Lancet. 2010; 376(9744):886-894.

Heart Rate and Pathophysiology of HF (All Cause)

• Elevated heart rate directly affects progression of coronary atherosclerosis

• oxygen demand / oxygen supply

Short term: LV function, heart failure

Death (Heart Failure and Sudden) Long term:

Muscarinic

receptor

cAMP

PKA

P P

IK

Norepinephrine Acetylcholine

+ _

If

Ica,L

Ica,T

Beta receptor

Sinus node cell

Heart Rate Control

Verkerk AO et al. Euro Heart J. 2007;28:2472-2478.

If, a hyperpolarization-activated pacemaker current;

Slows diastolic depolarization in the SA node

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Hyperpolarization-activated Cyclic

Nucleotide-gated (HCN4) Channels

Sino-atrial node: 80% HCN4

Ivabradine (Iv): Inhibiting HCN4 (i.e. If current) iNa+ iCa2+

Hyperpolarization-activated Cyclic Nucleotide-gated (HCN4)

Channels

Sino-atrial node: 80% HCN4

Ivabradine (Iv): Inhibiting HCN4 (i.e. If current) iNa+ iCa2+

iCa2+, intracellular calcium; iNa+, intracellular sodium Postea O, Biel M. Nat Rev Drug Discov. 2011;10(12):903-914.

SHIFT Study

• Hypothesis:

• Therapeutic slowing of HR will reduce the risk of cardiovascular outcomes and symptoms (QoL) in patients with

• NYHA functional class II – IV HF

• Systolic dysfunction (EF ≤ 35%)

• HR ≥ 70 bpm in NSR

• Receiving GDMT including maximally tolerated β-B

Heart rate is not just a risk marker but a

modifiable “risk factor” in heart failure

Swedberg K, et al. Euro J Heart Fail. 2010;12:75-81.

Ivabradine 5 mg bid

Matching placebo bid Every 4 months D0 D14 D28 M4

Ivabradine 7.5/ 5/ 2.5 mg bid

according to HR and tolerability

3.5 years

Screening

7 to 30 days

SHIFT Study Design

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

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Patients and follow-up

Study duration:

Median: 22.9 months; Maximum: 41.7 months

6558 randomized

3268 to ivabradine 3290 to placebo

3264 analyzed

1 lost to follow-up 3241 analyzed

2 lost to follow-up

7411 screened

Excluded: 27 Excluded: 26

SHIFT Study Design


SHIFT(Time to first event); N=6505 CV Death or Hospitalization for HF


Number needed to treat for 1 year = 26

- 18%

SHIFT(Time to first event); N=6505 Hospitalization for HF

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

- 26%

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SHIFT(Time to first event); N=6505 Death from HF

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

- 26%

SHIFT: Cumulative incidence of HF Hospitalizations (first and repeated)

0 6 12 18 24 30

Placebo

Ivabradine

40

10

0

IRR (95% CI), 0.75 (0.65;0.87)

P=0.0002

Time (months)

20

30

- 25%

Borer JS, et al. Eur Heart J. 2012;33(22):2813-2820.

Böhm M, et al. Lancet. 2010;376(9744):886-894.

Heart Rate as a Predictor of Death and/or HF Hospitalizations in

Chronic HF (SHIFT based on Day 28 in

the Ivabradine group)

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SHIFT: Other benefits of HR slowing with ivabradine (from pre-

specified protocol sub-studies)

Tardif JC, et al. Eur Heart J 2011; 32:2507-2515.

SHIFT: Other benefits of HR slowing with ivabradine (from pre-

specified protocol sub-studies)

• Significantly greater improvement in HF related QoL by KCCQ with ivabradine than with placebo

• Clinically meaningful with ivabradine; not with placebo

• Magnitude of HQoL improvement was directly related to magnitude of HR reduction

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

Conclusions - Implications

• In patients with chronic HF-rEF (≤35%) in NSR with HR ≥70 bpm and already receiving guideline-suggested Tx, isolated HR reduction outcomes in addition to those achievable with β-blockade, including

• in CV death or HF hospitalizations

• in LV function

• in total hospitalizations

• HQoL

• Benefits occur when ivabradine was ADDED to current recommended therapy

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ACC/AHA/HFSA Guideline Update Recommendations for Ivabradine

(Stage C-HFrEF)


IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for pts. with symptomatic (NYHA class II-III), stable chronic HFrEF (LVEF ≤35%) who are receiving GDEM, inc. β-blocker at maximum tolerated dose, and who are in NSR with a heart rate of 70 bpm or > at rest

Yancy C, Jessup M, et al., Circulation. 2016;134(13):e282-93.

COR= class of recommendation (Strength); yellow, is reasonable/useful (Moderate) LOE= level of evidence (Quality); B, moderate quality; 1 or more randomized trials; GDEM: Guideline-directed evaluation and management

Guideline-Recommended Pharmacologic Treatments

() For select patients

HFrEF Therapy

NYHA Class

1 2 3 4

ACE inhibitor, ARB

ARNI () () () ()

Beta-blocker

Aldosterone antagonist (MRA) ()

Diuretics ()

Digoxin () ()

Ivabradine () ()

Hydralazine / isosorbide dinitrate () () ()


ARNI, angiotensin receptor neprilysin inhibitor; MRA, minerocorticoid receptor antagonist

Case 1: Relatively Stable Patient

Presentation

• 65-year-old woman with chronic HF due to dilated cardiomyopathy

– NYHA FC II, no HF hospitalizations within last year, EF 35%

Examination Notes

• Euvolemic, BP 115/75 mmHg, heart rate 67 bpm

Laboratory Results

• Cr 1.5

• K 4.5

• NT-proBNP 1,200 pg/mL

Medications

• Lisinopril 10 mg 1x daily

• Carvedilol 12.5 mg 2x daily

• Spironolactone 25 mg 1x daily

• Furosemide 40 mg 2x daily

• Would you continue with patient’s current medications or switch to

a different treatment?

• What strategies would you implement to reduce HF hospitalization?

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Case 2: Higher Risk Patient With HF

Presentation

• 72-year-old man with chronic HF due to ischemic heart disease

– NYHA FC III, hospitalized twice for HF in past 6 months, EF 25%

Examination Notes

• JVP 2 cm above clavicle, BP 112/65 mmHg, heart rate 79 bpm

Laboratory Results

• Cr 1.9

• K 4.9

• NT-proBNP 3,200 pg/mL

Medications

• Valsartan 80 mg 2x daily

• Carvedilol 3.125 mg 2x daily

• Unable to tolerate MRA due to

concerns about hyperkalemia

• Furosemide 80 mg 2x daily

• Would you continue current medications or switch to different Tx?

• Which methods should we use to decongest patient prior to

discharge?

Case 3: Putting it All Together 74 yr old AA male with HFrEF

• Complaint: “I can’t catch my breath sometimes”

• Med Hx: Type 2 DM, HTN, CAD, hyperlipidemia, gout, previous anterior wall MI (ejection fraction [EF] 15% post MI); 2 stents; obesity [BMI 32 kg/m2]

• HFrEF Dx: 5 years ago; just moved to your town • EF currently 30%; NYHA FC III; stable • Today’s VS: BP 102/68, HR 86 bpm; Resp 22 bpm

• X-Ray: Marked prominence of pulmonary vascular shadows (bilateral), increased haziness and decreased radiolucency of the lung parachyma (bilateral), increased transverse diameter of the heart

• Objective assessment: apical pulse at 5th ICS; S1 and 2 diminished; S3 at apex; JVP ~12 cm at 90°; firm abdomen; grade 3 systolic murmur; strongest at apex and radiates toward base

Case 3- Putting it All Together

Serum labs • Glucose 132mg/dL

(non-fasting) • BUN 33mg/dL • Creatinine 1.6mg/dL • Albumin 3.1g/dL • Sodium 132mEq/L • Potassium 4.0mEq/L • eGFR 48

Current Medications • Lisinopril 40 mg/d • Carvedilol 25 mg 2x/d • Furosemide 60 mg/d • ASA 81 mg/d • Clopidogrel 75 mg/d • Metformin 500 mg 2x/d • Atorvastatin 40 mg/d • Allopurinol 200 mg/d

74 yr old AA male with HFrEF

• Subjective findings: Lives w wife who purchases and cooks food; does not use salt shaker; favorite foods: fried chicken and soup; eat out most evenings; no exercise; sleeps on 2 pillows “for comfort”; dizzy with position changes

APN medication changes? If yes, what?

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Putting it All Together

Self management

• Diet

• Exercise/activity

• Flu shot

• ETOH/smoking cessation

• Weight loss

• Caution w non-prescription/OTC medications

• Follow-up

• Comorbidities

Medication adherence

• Consider lifestyle

• Discuss value

• Provide resources

pharmacological management for heart failure and reduced...

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