Transcript *Out of the Water* An update on emerging heart failure therapies

“Out of the Water”
An update on emerging heart failure
therapies
Robert Mohapatra, MD, MPH, FACC
September 10, 2016
Disclosures
• Honarariums received for participating in
speaker programs for Novartis and Amgen
Heart Failure – A Growing Global
Concern
Prevalence and Incidence
 Overall 2.1% prevalence: 5.1M heart failure
patients in 20101
 825,000 people ≥ 45 years of age are newly
diagnosed each year with HF1
 15M heart failure patients in the ESC
51-member countries2
Mortality
– For AHA/ACC stage C/D patients
diagnosed
with HF:
• 30% will die in the first year.3-5
• 60% will die within 5 years.5
• Overall 2-3% prevalence2
HF prevalence in the US is projected to increase 46% from 2012 to 2030,
resulting in > 8M people ≥ 18 years of age with HF.6
1.
2.
3.
4.
5.
6.
AHA 2014 Statistics at a Glance, 2014
The European Society of Cardiology, ESC HF Guideline, 2008
Curtis et al, Arch Intern Med, 2008.
Roger et al. JAMA, 2004.
Cowie et al, EHJ, 2002.
Heidenreich PA et al. Circ Heart Failure 2013.
Heart Failure Is Associated with High
Hospitalization and Readmission Rates
•
In 2010, there were 1 million hospitalizations in
the US with HF as the principal diagnosis1
–
•
Average length of hospital stay
–
–
•
Hospitalization rate did not change significantly
from 20001
Approximately 5 days (US)2
11 days (Europe)3
HF is also associated with high readmission
rates:
–
~25% all-cause readmission within 30 days
and ~50% within 6 months4,5
Graph from www.health.org.uk. Bridging the gap: Heart Failure, 2010.
Data from Organization for Economic Cooperation and Development, 2009.
1.
2.
3.
4.
5.
CDC NCHS National Hospital Discharge Survey, 2000-2010
Yancy et al. JACC, 2006.
Cleland et al. EuroHeart, 2003.
Krumholz HM, et al. Circ Cardiovas Qual Outcomes 2009.
Wexler DJ, et al. Am Heart J 2001.
Economic Burden of HF Will Continue to
Rise Through 2030*
The AHA estimates that the total medical costs for HF are projected to increase
to $70B by 2030  a 2-fold increase from 2013.1
• 50% of the costs are attributed to hospitalization.2
Graph: Heidenreich PA, et al. Circulation Heart Failure 2013.
*Study projections assumes HF prevalence remains constant and continuation of current hospitalization practices
1. Heidenreich PA, et al. Circulation Heart Failure 2013.
2. Yancy CW, et al. Circulation 2013.
Economic Risks of HF Readmissions in
the US
Medicare’s Hospital Readmissions Reduction program penalizes hospitals that
have above average all-cause readmissions within 30 days following HF
discharge.
22.7%
national average 30-day
readmissions rate1,2
Percent withholding of all inpatient Medicare payments will increase to up to 3% by
2015 and beyond.3
Fiscal Year
2013
2014
2015+
% payment withholding
up to 1%
up to 2%
up to 3%
1. Dharmarajan K, et al. JAMA. 2013;309(4):355-363.
2. Linden A, Adler-Milstein J. Health Care Finance Rev. 2008;29(3):1-11.
3. CMS Hospitals Readmissions Reductions Program of the Patient Protection and Affordable Care Act (PPACA), 2010.
Worsening Heart Failure Leading to HF Hospitalizations Contributes
to Disease Progression
With each subsequent HF-related admission, the patient leaves the hospital with a
further decrease in cardiac function.
Graph adapted from: Gheorghiade MD, et al. Am J. Cardiol. 2005
Sacubitril/Valsartan
®
(Entresto )
HFrEF Pathophysiology
The SNS and RAAS Are Overexpressed
SNS2,4
 Neurohormonal activation
via SNS and RAAS signaling
may exacerbate the failing
heart and trigger lethal
ventricular arrhythmias1,2
α1, β1, β2
receptors
Epinephrine
Norepinephrine
HF SYMPTOMS &
PROGRESSION
Vasoconstriction
RAAS activity
Heart rate
Contractility
 The RAAS and SNS are
overexpressed1,2,4
RAAS2,3,4
Ang II
AT1R
Vasoconstriction
Blood pressure
Sympathetic tone
Vasopressin
Aldosterone
Hypertrophy
Fibrosis
Ang II, angiotensin II; AT1R, angiotensin II type 1 receptor; HF, heart failure; NPs, natriuretic peptides; SNS, sympathetic nervous system;
RAAS, renin-angiotensin-aldosterone system.
1. Tomaselli GF, Zipes DP. Circ Res. 2004;95(8):754-763. 2. Kemp CD, Conte JV. Cardiovasc Pathol. 2012;21(5):365-371. 3. Mangiafico S et al. Eur Heart J.
2013;34:886-893. 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
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HFrEF Pathophysiology
Role of Endogenous Compensatory Peptides
Endogenous Compensatory
Peptides (ECPs)2-4
NPR-A, NPR-B, B2, calcitonin
receptor-like receptor
SNS1,4
NPs, Bradykinin, ADM
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
α1, β1, β2
receptors
Epinephrine
Norepinephrine
HF SYMPTOMS &
PROGRESSION
Vasoconstriction
RAAS activity
Heart rate
Contractility
RAAS1,2,4
Ang II
 The effects of RAAS and SNS are balanced by the
counterregulatory effects of ECPs, including NPs,
bradykinin, and adrenomedullin2-4
AT1R
Vasoconstriction
Blood pressure
Sympathetic tone
Vasopressin
Aldosterone
Hypertrophy
Fibrosis
ADM, adrenomedulin; Ang II, angiotensin II; AT1R, angiotensin II type 1 receptor; ECPs, endogenous compensatory peptides; HF, heart failure;
NPs, natriuretic peptides; SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system.
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.
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HFrEF Pathophysiology
Existing Therapies
Endogenous Compensatory
Peptides2-4
NPR-A, NPR-B, B2, calcitonin
receptor-like receptor
α1, β1, β2
receptors
Epinephrine
Norepinephrine
NPs, Bradykinin, ADM
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
1,4 1
SNS
SNS
β-blockers5
Vasoconstriction
RAAS activity
Heart rate
Contractility
HF SYMPTOMS &
PROGRESSION
RAAS inhibitors
(ACEI, ARB, MRA)5
1,2,4
1,22,4
RAAS
RAAS
RAAS
Ang IIII
AT1R
Vasoconstriction
Blood pressure
Sympathetic tone
Vasopressin
Aldosterone
Hypertrophy
Fibrosis
ACEI, angiotensin-converting enzyme inhibitor; ADM, adrenomedulin; Ang II, angiotensin II; ARB, angiotensin II receptor blocker; AT1R, angiotensin II type 1
receptor; ECPs, endogenous compensatory peptides; HF, heart failure; MRA, mineralocorticoid receptor antagonists; NPs, natriuretic peptides; SNS,
sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system.
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. Mann DL. Management of Patients with Heart Failure with Reduced Ejection Fraction. In:
Mann DL et al, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Elsevier; 2015
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Sacubitril/Valsartan
Effects of Sacubitril/valsartan in HFrEF
Endogenous Compensatory
Compensatory
Endogenous
2-4
Peptides2-4
Peptides
NPR-A, NPR-B, B2, calcitonin
receptor-like receptor
SNS1,4
Epinephrine
Norepinephrine
NPs, Bradykinin,
Bradykinin, ADM
NPs,
ADM
Vasodilation
Vasodilation
Blood pressure
Blood
pressure
Sympathetic tone
Sympathetic
tone
Natriuresis/diuresis
Natriuresis/diuresis
Vasopressin
Aldosterone
Vasopressin
Fibrosis
Aldosterone
Hypertrophy
Fibrosis
Hypertrophy
+
HF SYMPTOMS &
PROGRESSION
Vasoconstriction
RAAS activity
Heart rate
Contractility
1,2
RAAS
1,2,4
RAAS
Enhance the beneficial
effects of endogenous
compensatory peptides
Neprilysin
Inhibitor
Sacubitril/
valsartan5
α1, β1, β2
receptors
Suppress deleterious
effects of RAAS
ARB
Ang II
Ang II
AT1R
AT1R
Vasoconstriction
Vasoconstriction
Blood pressure
Blood pressure
Sympathetic
tone
Vasopressin
Sympathetic tone
Aldosterone
Vasopressin
Hypertrophy
Aldosterone
Fibrosis
Hypertrophy
Fibrosis
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.
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Sacubitril/Valsartan
Components and Indication
Sacubitril/valsartan is a combination of a
neprilysin inhibitor and an Ang II receptor blocker
Neprilysin
Inhibitor
ARB
 Sacubitril/valsartan is indicated to reduce the risk of cardiovascular (CV) death and
hospitalization for HF in patients with chronic HF (CHF; NYHA class II–IV) with
reduced ejection fraction (HFrEF)
 Sacubitril/valsartan is usually administered in conjunction with other HF therapies, in
place of an ACEi or other ARB
NYHA, New York Heart Association.
Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
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Sacubitril/Valsartan
Effect on BNP and NT-proBNP
⬆ proBNP secretion
⬆ Myocardial
wall tension
in HF
Vasoactive
peptidea with
cardioprotective
effects
Sacubitril/
valsartan
NT-proBNP
BNP
Neprilysin
Inactive
(inert) marker
of HF
Neprilysin inhibition has
no effect on NT-proBNP
Sacubitril/Valsartan Increases
BNP Levels
Inactive
fragments
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.
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Sacubitril/Valsartan
Patient Selection
 Patients with
• Chronic HFrEF
• NYHA Class II – IV
PI Indication Statement
 Sacubitril/valsartan is indicated to reduce the risk of CV death and
hospitalization for HF in patients with chronic HFrEF (NYHA class II–IV)
 Sacubitril/valsartan is usually administered in conjunction with other HF
therapies, in place of an ACEI or other ARB
Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
15
Sacubitril/Valsartan
Contraindications for Use
Sacubitril/valsartan is contraindicated:
 In patients with hypersensitivity to any component
 In patients with a history of angioedema related to previous ACEI or ARB
therapy
 With concomitant use of ACEIs. It cannot be administered within 36 hours
of switching from or to an ACEI
 With concomitant use of aliskiren in patients with diabetes
Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
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PARADIGM-HF Trial
Key Findings
PARADIGM-HF
Study Design
Phase 3 Trial to Examine the Efficacy of Sacubitril/Valsartan vs Enalapril in Patients With HFrEF1,2
N=8442 patients with chronic HF
(NYHA class II–IV with LVEF ≤40%) and elevated BNP
Single-blind run-in period
Double-Blind Randomized Treatment Period
Randomization
Sac/val 97/103 mg BID
Enalaprila
10 mg BID
Sac/valb
49/51 mg BID
Sac/valb
97/103 mg BID
Enalapril 10 mg BID
Testing tolerability to target doses of enalapril and sac/val
2 weeks
1–2 weeks
2–4 weeks
On top of standard HF therapy,
excluding ACEIs and ARBs3
Median duration of follow-up: 27 months
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
 Primary outcome: To demonstrate superiority of sacubitril/valsartan over enalapril in
reducing composite of death from CV causes or a first hospitalization for HF
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.
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.
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PARADIGM-HF
Baseline Characteristics
Characteristic*
Age, years
Female, n (%)
Ischemic cardiomyopathy, n (%)
LVEF (%)
NYHA functional class, n (%)
II
III
SBP, mm Hg
Heart rate, BPM
NT-proBNP, median, pg/mL (IQR)
BNP, median, pg/mL (IQR)
History of DM, n (%)
Treatments at randomization, n (%)
Diuretics
Digitalis
Beta-blockers
MRAs
ICD
CRT
Sac/Val (N=4187)
63.8 ± 11.5
879 (21.0)
2506 (59.9)
29.6 ± 6.1
Enalapril (N=4212)
63.8 ± 11.3
953 (22.6)
2530 (60.1)
29.4 ± 6.3
2998 (71.6)
969 (23.1)
122 ± 15
72 ± 12
1631 (885–3154)
255 (155–474)
1451 (34.7)
2921 (69.3)
1049 (24.9)
121 ± 15
73 ± 12
1594 (886–3305)
251 (153–465)
1456 (34.6)
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)
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.
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PARADIGM-HF
Primary Endpoint: Time to First Occurrence of CV Death or HF Hospitalization
The difference in favor of sacubitril/valsartan was seen early in the trial and at each interim
analysis
Cumulative Probability of the
Combined Endpoint of CV Death or
HF Hospitalization
1.0
Enalapril
0.6
Sac/val
HR: 0.80 (95% CI: 0.73–0.87)
P<0.001
20% Relative Risk Reduction
0.4
1117 events
914 events
0.2
0
0
180
360
540
720
900
1080
1260
896
853
249
236
Days Since Randomization
No. at risk
Sac/val
Enalapril
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
CI, confidence interval; HR, hazard ratio.
McMurray JJ et al. N Engl J Med. 2014;371:993-1004.
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PARADIGM-HF
Summary of Key Findings
Sac/Val
N=4187
n (%)
Enalapril
N=4212
n (%)
HR (95% CI)
P Value
914 (21.8)
1117 (26.5)
0.80 (0.73–0.87)
<0.0001
CV death as first event
377 (9.0)
459 (10.9)
HF hospitalization as first event
537 (12.8)
658 (15.6)
CV deathb
558 (13.3)
693 (16.5)
0.80 (0.71–0.89)
HF hospitalizations
537 (12.8)
658 (15.6)
0.79 (0.71–0.89)
711 (17.0)
835 (19.8)
0.84 (0.76–0.93)
Endpoint
Primary composite endpoint of CV
death or HF hospitalization
Number of patients with eventsa
All-cause mortality
0.0009
aAnalyses
of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity.
subjects who had HF hospitalization prior to death.
Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
bIncludes
21 21
PARADIGM Adverse Effects
Sac/Val
Enalapril
N=4203
n (%)
N=4229
n (%)
Hypotension
18
12
Hyperkalemia
12
14
Cough
9
13
Dizziness
6
5
Renal failure/acute renal failure
5
5
Adverse Reactions Occurring ≥5%

In the PARADIGM-HF trial, the incidence of angioedema was 0.1% in both the enalapril and
sacubitril/valsartan run-in periods. In the double-blind period, the incidence of angioedema was
higher in patients treated with sacubitril/valsartan than enalapril (0.5% and 0.2%, respectively). The
incidence of angioedema in Black patients was 2.4% with sacubitril/valsartan and 0.5% with enalapril

Orthostasis was reported in 2.1% of patients treated with sacubitril/valsartan compared to 1.1% of
patients treated with enalapril during the double-blind period of
PARADIGM-HF. Falls were reported in 1.9% of patients treated with sacubitril/valsartan compared to
1.3% of patients treated with enalapril
Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
22
2016
ACC/AHA/HFSA
Focused
Update
Pharmacological Treatment for Stage C HFrEF: Recommendations
Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor
or ARB or ARNI
COR
LOE
Recommendations
ACE: A
ARB: A
I
ARNI: B-R
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.
“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.
2016
ACC/AHA/HFSA
Focused
Update
Pharmacological Treatment for Stage C HFrEF: Recommendations
Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB
or ARNI (cont’d)
COR
LOE
I
ARNI: B-R
Recommendations
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.
“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.
Sacubitril/Valsartan
Available Dosages
 Sacubitril/valsartan is available as film-coated tablets for oral administration. It is
available in the following dosages:
24 mg of sacubitril and
26 mg of valsartan
49 mg of sacubitril and
51 mg of valsartan
97 mg of sacubitril and
103 mg of valsartan
 These doses should be utilized when prescribing sacubitril/valsartan.*
24/26 mg
49/51 mg
97/103 mg
*In clinical studies sacubitril/valsartan doses were refered to as 50mg, 100mg and
200mg (24/26mg, 49/51mg and 97/103mg), respectively
Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
25
Sacubitril/Valsartan
Dosing Guidelines1,2
ARB
ACEI
 Choose the initial dose of sacubitril/valsartan* based on current treatment and titrate to the target dose
 Dosing in clinical trials was based on the total amount of both components of sacubitril/valsartan; 24/26 mg, 49/51 mg, and 97/103 mg were
referred to as 50 mg, 100 mg, and 200 mg, respectively
 Clinicians should use the available doses when prescribing (24/26mg, 49/51mg and 97/103mg) to help avoid errors in dispensing
>10 mg of enalapril or therapeutically
equivalent doses of another ACEI:
• Lisinopril >10
• Ramipril >5 mg
≤10 mg of enalapril or therapeutically
equivalent doses of another ACEI:
• Lisinopril ≤10 mg
• Ramipril ≤5 mg
Start sac/val at the recommended dose of 49/51
Stop
mg BID
ACEI
36 hours
before
Double the dose after
starting Start sac/val at the
2 to 4 weeks to
sac/val recommended dose of
49/51 mg BID, as
>160 mg of valsartan or therapeutically equivalent doses
of another ARB:
• Losartan >50 mg
• Olmesartan >10 mg
≤160 mg of valsartan or therapeutically equivalent doses
of another ARB:
• Losartan ≤50 mg
• Olmesartan ≤10 mg
Not currently taking ACEIs or ARBs
24/26 mg BID
tolerated by the patient
Start sac/val at the recommended dose of 49/51
mg BID
Start sac/val at the
recommended dose of
24/26 mg BID
Double the dose after 2
to 4 weeks to
49/51 mg BID, as tolerated
by the patient
Start sac/val at the
recommended dose of
24/26 mg BID
Double the dose after 2
to 4 weeks to
49/51 mg BID, as tolerated
by the patient
Double the dose
of sac/val after 2
to 4 weeks, as
tolerated by the
patient, to reach
the target
maintenance
dose of
97/103 mg BID
BID, twice daily; sac/val, sacubitril/valsartan.
*Sacubitril/valsartan may be taken with or without food. Sacubitril/valsartan is not scored, and should not be broken in half or crushed.
1. Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
2. Senni M et al. Presented at ESC-HF Congress; May 23, 2015; Seville, Spain.
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Corlanor ® (Ivabradine)
-Has been used in Europe since 2005.
-Was initially approved for treatment of Chronic,
stable angina, in patients intolerant to beta
blockers or for those on beta blockers with resting
heart rate greater than 70.
-Was approved in Europe for use in Chronic
systolic heart failure in 2012.
Was approved for use in United States in April
2015
Corlanor® (ivabradine) Indication
• Corlanor® is indicated to reduce the risk of
hospitalization for worsening heart failure in patients
who meet all of the following conditions
• Stable, symptomatic chronic heart failure with
left ventricular ejection fraction ≤ 35%
– In sinus rhythm with resting heart rate ≥ 70 bpm
– On maximally tolerated doses of beta-blockers or
have a contraindication to beta-blocker use
bpm, beats per minute.
Corlanor® (ivabradine) Prescribing Information, Amgen.
Corlanor ® (Ivabradine, cont’d)
• Approved based on SHIFT study which studied
the rationale that a higher resting heart rate is
associated with a worse prognosis in patients
with chronic heart failure
• This finding was first seen in retrospective
analysis of the CHARM study, which found that
higher resting heart rates were associated with
higher likelihood of admission for heart failure
• Has unique mechanism of action which lowers
heart rate without lowering blood pressure
Corlanor® (ivabradine) Blocks the HCN Channel in the Sinus
Node which Reduces Heart Rate
Adapted from: Postea O, et al. Nature Reviews. 2011;10:903-914.
Adapted from: DiFrancesco D, et al. Drugs. 2004;64:1757-1765.
Corlanor® (ivabradine) Prescribing Information, Amgen.
SHIFT Study
Corlanor® (ivabradine) Pivotal Study
– SHIFT
Systolic Heart failure treatment with the If inhibitor ivabradine
Trial
SHIFT Study
SHIFT Study Design
Randomized, double-blind, parallel-group study to assess the effect of ivabradine in addition to
guidelines-based treatment in 6,558 patients with HF, conducted from October 2006 through March 2010.
• Subjects ≥ 18 years
• NYHA Class II, III, or IV
and in stable condition for
≥ 4 weeks
• LVEF ≤ 35%
• Optimal stable Standard
of Care (SOC) therapy,
including maximally
tolerated doses of betablockers
Randomization
• In sinus rhythm and had a
resting HR ≥ 70 bpm
• Hospitalization for
worsening HF within
≤ 12 months
14 day run-in
HF, heart failure; HR, heart rate; LVEF, left ventricular ejection fraction.
Swedberg K, et al. Lancet. 2010;376:875-885.
Ivabradine 5 mg twice daily for 2 weeks
(n = 3,268)

Ivabradine 7.5/5.0/2.5 mg twice daily according
to HR and tolerability*
Placebo twice daily (n = 3,290)
Median follow-up duration: 22.9 months
(interquartile range = 18 to 28 months)
SHIFT Study
Primary and Secondary Endpoints
•Primary Endpoint
• Composite of the first
occurrence of either CV
death or hospital admission
for worsening HF
CV, cardiovascular.
Swedberg K, et al. Lancet. 2010;376:875-885.
Corlanor® (ivabradine) Prescribing Information, Amgen.
•Secondary Endpoints
• CV death (component of the primary
composite endpoint)
• Hospitalization for worsening HF
(component of the primary composite
endpoint)
SHIFT Study
Ivabradine Titration
Starting dose
5 mg twice daily
Titration Period: D14 & D28
Follow-up Period: Every 4 months
< 50 bpm or patient
experiencing signs or
symptoms related to
bradycardia
50 to 60 bpm
> 60 bpm
2.5 mg twice daily
5 mg twice daily
7.5 mg twice daily
Treatment was discontinued if heart rate remained below 50 bpm or
symptoms of bradycardia persisted after dose reduction.
D, day.
Swedberg K, et al. Lancet. 2010;376:875-885.
Corlanor® (ivabradine) Prescribing Information, Amgen.
Primary Composite Endpoint
Time to First Event of Hospitalization for Worsening HF or CV Death
Composite Endpoint (%)
Patients With Primary
40
Placebo + SOC
(937 events)
Hazard Ratio 0.82
95% CI (0.75–0.90)
ARR = 4.2%
P < 0.0001
30
18% Relative Risk
Reduction
Ivabradine + SOC
(793 events)
20
10
The treatment effect reflected only a reduction in the risk of
hospitalization for worsening HF; there was no favorable
effect on the mortality component of the primary endpoint.
0
0
6
12
18
Time (months)
Primary Composite Endpoint: Time to CV Death or First Hospitalization for Worsening HF.
ARR, absolute risk reduction; CI, confidence interval; SOC, standard of care.
Corlanor® (ivabradine) Prescribing Information, Amgen.
Swedberg K, et al. Lancet. 2010;376:875-885
24
30
36
Secondary Endpoint
CV Death at Any Time
Patients With CV Death (%)
40
Hazard Ratio 0.91
95% CI (0.80–1.03)
ARR = 1.1%
In the overall treatment population, Corlanor®
had no statistically significant benefit on
cardiovascular death
30
Placebo + SOC
(491 events)
20
9% Relative Risk
Reduction
Ivabradine + SOC
(449 events)
10
0
0
6
12
18
Time (months)
CI, confidence interval; CV, cardiovascular; SOC, standard of care.
Swedberg K, et al. Lancet. 2010;376:875-885.
24
30
Secondary Endpoint
Hospitalization for Worsening HF at Any Time
For Worsening HF (%)
Patients With First Hospitalization
40
Hazard Ratio 0.74
95% CI (0.66–0.83)
ARR = 4.7%
30
Placebo + SOC
(672 events)
26% Relative Risk
Reduction
20
Ivabradine + SOC
(514 events)
10
0
0
6
12
18
Time (months)
Swedberg K, et al. Lancet. 2010;376:875-885.
24
30
Adverse Events
Adverse Drug Reactions with Rates ≥ 1.0% Higher on
Ivabradine than Placebo
Ivabradine
N = 3,260
Placebo
N = 3,278
Bradycardia
10%
2.2%
Hypertension
(Blood pressure increased)
8.9%
7.8%
Atrial Fibrillation
8.3%
6.6%
Phosphenes (Visual brightness)
2.8%
0.5%
Adverse Events
Corlanor® (ivabradine) Prescribing Information, Amgen.
Ivabradine, summary
 SHIFT study showed beneficial effect on HF hospitalization, but not
mortality
 Benefits were greater in those intolerant/on low doses of beta
blockers along with those with higher resting heart rates
 2016 Updated ACC/AHA/HFSA guidelines: Class IIa recommendation
 Ivabradine can be beneficial to reduce HF hospitalization for
patients with:
 symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%)
who are receiving GDMT, including a beta blocker at maximum
tolerated dose
 who are in sinus rhythm with a heart rate of 70 bpm or greater at
rest
CardioMEMS™ HF System
Pulmonary Artery
Pressure Sensor
Patient Electronics
System
CardioMEMS™
HF System Website
Time Course of Decompensation
Physiologic Markers of Acute Decompensation
Graph adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009.
CardioMEMS™ HF System
The pulmonary artery pressure sensor
is implanted via a right heart
catheterization procedure via femoral vein
approach.
Target location for pulmonary artery
pressure sensor
CardioMEMS™ HF System
The pulmonary artery pressure sensor is
implanted via a right heart catheterization
procedure via femoral vein approach.
Target location for pulmonary artery pressure sensor
CHAMPION Clinical Trial: The Effect of Pulmonary Artery PressureGuided Therapy on HF Hospitalizations vs. Standard of Care
Patients with moderate NYHA class III HF for at least 3 months, irrespective of
LVEF
and a HF hospitalization within the past 12 months were included in the study.
550 Pts with CardioMEMS™ HF System Implants
All Pts Take Daily readings
Treatment
270 Pts
Management Based on
PA Pressure +Traditional Info
26 (9.6%) Exited
< 6 Months
15 (5.6%) Death
11 (4.0%) Other
Abraham WT, et al. Lancet, 2011.
Control
280 Pts
Management Based on
Traditional Info
Primary Endpoint: Rate of HF Hospitalization
Secondary Endpoints:
 Change in PA Pressure at 6 months
 No. of patients admitted to hospital for HF
 Days alive outside of hospital
 QOL
26 (9.6%) Exited
< 6 Months
20 (7.1%) Death
6 (2.2%) Other
CHAMPION Clinical Trial
Patients managed with PA pressure data had significantly fewer
HF hospitalizations as compared to the control group.
Abraham WT, et al. Lancet, 2011.
CHAMPION CLINICAL Trial: Both Primary Safety Endpoints and All
Secondary Endpoints Were Met at 6 months
Primary Safety
Endpoints
Device-related or system-related complications
Pressure-sensor failures
Control
(n = 280)
3 (1%)
3 (1%)
Total 8 (1%)*
P-value
< 0.0001
0
0
< 0.0001
-156
33
0.008
Number and proportion of patients hospitalized
for HF (%)
55 (20%)
80 (29%)
0.03
Days alive and out of hospital for HF (mean ±
SD)
174.4 ±
31.1
172.1 ± 37.8
0.02
Quality of life (Minnesota Living with Heart
Failure Questionnaire, mean ± SD)
45 ± 26
51±25
0.02
Change from baseline in PA mean pressure
(mean AUC [mm Hg x days])
Secondary
Endpoints
Treatment
(n = 270)
* Total of 8 DSRCs including 2 events in Consented not implanted patients (n = 25)
Abraham WT, et al. Lancet, 2011.
Cardiomems ™ approval
• Approved by the FDA in May, 2014 for the
indication of reduction of heart failure
hospitalization
• Indication for implantation is NYHA class III
heart failure and hospitalization for CHF within
last year
LCS experience with Cardiomems ™
• 11 patients have been implanted thus far
• One patient has been admitted to the hospital
with HF
Insurance Coverage
• Novitas, which contracts with Medicare to
determine local coverage, declined to reimburse
Cardiomems ™ in February of 2016
• Select private insurers have continued to
reimburse Cardiomems ™
• A national decision from CMS is expected by the
end of the year
Telehealth
• What is Telehealth?
– The use of digital /communication technology to
provide healthcare
– Examples of telehealth include phone calls, use of
media such as tablets to transmit vital signs
including weight, BP, HR, and O2 saturation
– ECG’s can be transmitted with some telehealth
programs
– Other telehealth programs utilize video conferencing
Telehealth
• There have been dozens of studies which have
examined different approaches using telehealth
with HF patients
• A meta analysis published in 2015 reviewing 41
randomized trials found minimal benefit in
reduction of HF admissions (8% relative risk
reduction, NNT to prevent HF admission was 52)
(Ann Fam Med 2015:13:6 562-571)
TELE-HF Trial: Telemonitoring of Weight and
Symptoms Do Not Reduce Readmission or Death
•
Randomized study of 1653 patients
•
Primary endpoint: Readmission for any reason or death from any cause within 180 days
after enrollment
•
Control group = Standard-of-care (no telemonitoring)
•
Treatment group = telemonitoring of symptoms and weight
•
Results: No difference in number of deaths, readmissions or days in hospital
p = 0.39
60
% of Patients
50
Telemonitoring of Symptoms
and Weight group
40
30
p = 0.86
20
10
0
Re-hospitalization
Chaudhry SI, et al. N Engl J Med, 2010.
Death
Standard-of-care Group
TIM-HF Trial: Telemonitoring of Weight
and Blood Pressure Do Not Reduce
Readmission or Mortality
• Randomized study of 710 patients
• Primary Endpoint: Total Mortality
• Control Group: Standard-of-care (no telemonitoring)
• Treatment Group: Telemonitoring of weight and BP information
• Results: No difference in all-cause death or HF hospitalizations
Telemonitoring
n = 354 (%)
Usual care
n = 356 (%)
HR
(95% CI)
p
All-cause mortality
15.3
15.4
0.97 (0.67-1.41)
0.87
Cardiovascular-related
mortality
11.3
12.9
0.86 (0.56-1.31)
0.49
54.2
50.3
1.12 (0.91-1.37)
0.29
End Point
Koehler F et al, Circulation 2011
All-cause readmission
Cardio-oncology
• Emerging field in cardiology which pertains to
the cardiovascular effects of chemotherapy and
radiation treatments on cancer patients
• Utilizes techniques such as strain imaging with
echocardiography which can help identify
patients that are at risk