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
2/9/2017
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.
2/9/2017
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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5
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.
2/9/2017
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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
Yancy CW et al. Circulation. 2013;128(16):e240-327.
2/9/2017
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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
Yancy CW et al. Circulation. 2013;128(16):e240-327.
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.
2/9/2017
10
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
Inactive metabolites
Neprilysin Neprilysin
inhibition
Renin Angiotensin System Angiotensin I Sodium retention
Volume expansion
Vascular smooth muscle cell growth
Vasoconstriction
LV dysfunction
Myocardial fibrosis, hypertrophy
Inactive metabolites
Neprilysin
Neprilysin
inhibition
ACE
ANG II
ATIR
Aldosterone
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11
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
Angiotensin receptor blocker
Inhibition of neprilysin
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12
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
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
2/9/2017
13
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
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
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 (
%)
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
0
16
32
40
24
8
Enalapril (n=4212)
360 720 1080 0 180 540 900 1260
Days After Randomization
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)
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
2/9/2017
14
0
16
32
40
24
8
Enalapril (n=4212)
360 720 1080 0 180 540 900 1260
Days After Randomization
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
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
Enalapril (n=4212)
Kap
lan
-Meie
r E
sti
mate
of
Cu
mu
lati
ve R
ate
s (
%)
Days After Randomization
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
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
Enalapril (n=4212)
LCZ696 (n=4187)
Kap
lan
-Meie
r E
sti
mate
of
Cu
mu
lati
ve R
ate
s (
%)
Days After Randomization
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
PARADIGM-HF: Cardiovascular Death
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
2/9/2017
15
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 (
%)
Days After Randomization
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
PARADIGM-HF: Cardiovascular Death
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
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
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
Effects on Primary Endpoint & Cardiovascular Death, by Subgroups
Primary endpoint
Cardiovascular death
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
2/9/2017
16
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
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
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
McMurray JJV et al. New Engl J Med. 2014;371(11):993-1004.
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
Angiotensin receptor blocker
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
Yancy C, Jessup M, et al. Circulation. 2016;134(13):e282-93.
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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ACC/AHA/HFSA Guideline Update Recommendations for RAS Inhibition with
ACEi or ARB or ARNI (Stage C-HFrEF)
COR LOE Recommendations
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
Yancy C, Jessup M, et al. Circulation. 2016;134(13):e282-93.
COR= class of recommendation (Strength); green, IS recommended (Strong) LOE= level of evidence (Quality); A, high qual evidence; B, moderate qual; randomized
ACC/AHA/HFSA Guideline Update Recommendations for RAS Inhibition with
ACEi or ARB or ARNI (Stage C-HFrEF)
COR LOE Recommendations
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
Yancy C, Jessup M, et al. Circulation. 2016;134(13):e282-93.
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
Swedberg K, et al. Lancet. 2010;376: 875-885.
SHIFT(Time to first event); N=6505 CV Death or Hospitalization for HF
Swedberg K, et al. Lancet. 2010;376: 875-885.
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)
COR LOE Recommendations
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 () () ()
Yancy CW et al. Circulation. 2013;128(16):e240-327.
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