Suy tim mạn: GÓC NHÌN TỪ ACC 2017, PGS TS Châu Ngọc Hoa Bộ môn Nội ĐHYD Tp HCM

Ivabradine approval timeline • 2005 approved in EU for angina • 2012 approved in EU for heart failure • 2015 approved in US for heart failure to reduce the risk for hospitalization fo

PGS TS Châu Ngọc Hoa

Bộ môn Nội ĐHYD Tp HCM Suy tim mạn:

GÓC NHÌN TỪ ACC 2017

ACC Focused update on HF, 2017

Two New Pharmacological Therapies Approved by FDA for Heart Failure

• Ivabradine (April 15, 2015)

• Sacubitril/Valsartan (July 7, 2015)

WHO, WHEN AND

Ivabradine approval timeline

• 2005 approved in EU for angina

• 2012 approved in EU for heart failure

• 2015 approved in US for heart failure

to reduce the risk for hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with LVEF ≤35%, who are in sinus rhythm with a resting heart rate of ≥70 beats per minute (bpm) and are taking maximally tolerated doses of beta-blockers or have a contraindication to beta-blockers

Ivabradine

Blocks I f channel

Slows heart rate

Few if any other CV effects

SHIFT Trial

> 6500 HF patients (NYHA II-IV) LVEF < 35%

Resting HR > 70 BPM Primary endpoint: composite of CV death/HF hospitalization

On maximally tolerated beta-blocker

SHIFT: primary outcome

Ivabradine in HF

Up-titrate beta blocker dose as much as possible

Add on therapy to beta blocker; not replacement

Does not lower blood pressure

Contraindicated in atrial fibrillation

Benefit greater in patients with higher baseline heart rate

Startingdose(mg) Targetdose(mg)

ACEI

Enalapril 2.5b.i.d 10-20b.i.d

Lisinopril 2.5-5.0o.d 20-35o.d

Beta-blocker

Bisoprolol 1.25o.d 10o.d

Carvedilol 3.125b.i.d 25-50b.i.d

Metoprololsuccinate 12.5/25o.d 200o.d

MRA

Eplerenone 25o.d 50o.d

Spironolactone 25o.d 25-50o.d

I f Inhibitor

Ivabradine 5b.i.d 7.5b.i.d

Can we reach and maintain „target” dose

CIBIS-ELD – 883 elderly HF patients;

The primary endpoint: tolerability, defined as reaching and maintaining guideline-

recommended target doses after 12 weeks treatment

Dungen HD, et al Eur J Heart Fail 2011:13:670–680

Trials Targetdose (mg) Time to reach target/max tolerated dose

ACEI

Enalapril SOLVD 10b.i.d Notspecified

Lisinopril ATLAS 35o.d 4weeks

Beta-blocker

Bisoprolol CIBISII 10o.d 11weeks

Carvedilol COPERNICUS 25b.i.d 6weeks

Metoprololsuccinate MERITHF 200o.d 6weeks

Nebivolol SENIORS 10o.d 6weeks

MRA

Eplerenone EMPHASIS-HF 50o.d 4weeks

I f Inhibitor

Ivabradine SHIFT 7.5b.i.d 2weeks

1- The SOLVD Investigators N Engl J Med 1991;325:293-302 2- Packer M, et al Circulation 1999;100:2312-2318 3- CIBIS-II study group.

Lancet 1999;353:9-13 4- Packer M, et al Circ 2002;106:2194-2199 5- Merit-HF study group Lancet 1999;353:2001- 2007 6- Zannad F, et al.

N Engl J Med 2011:364:11-21 7- Swedberg K, et al Lancet 2010;376: 875-885

Uptitration target in stable HF patients

2 weeks

Reasons for non-reaching target dose

CIBIS-ELD: RCT aimed to reach guideline-recommended target doses

883 HF patients, NYHA II-IV, >65 y, no contraindication or intolerance to BB

Dungen HD, et al Eur J Heart Fail 2011:13:670–680

Treatment Effect of Ivabradine

Komajda M, et al. Eur Heart J. 2013;34 (Abst Suppl), 610

Placebo, renal dysfunction

Ivabradine,renal dysfunction

Placebo, no renal dysfunction

Ivabradine, no renal dysfunction

Voors A, et al. Eur Heart J. 2013;34 (Abst Suppl)

Effect of early treatment of Ivabradine with BBs vs BB alone in patients hospitalized for WHF: randomized ETHIC study

Hidalgo FJ et al Int J Cardiol 2016;217:7-11

n=71 patients hospitalized for WHF

Effect of early treatment of Ivabradine with BBs vs BB alone in patients hospitalized for WHF: randomized ETHIC study

n=71 patients hospitalized for WHF

Effect of early treatment of Ivabradine with BBs vs BB alone in patients hospitalized for WHF: randomized ETHIC study

n=71 patients hospitalized for WHF

Background

Romans used a non-Digoxin cardiac

glycoside derived from sea onion

Used sporadically in Middle Ages but

popularized in 18 th century

Used for dropsy and recognized to

decrease edema and slow HR

Withering in 1785 published an

account of 156 patients successfully

treated including Erasmus Darwin

“That it has a power over the motion of the heart, to a degree yet unobserved

in any other medicine, and this power may be converted to salutary ends”

Withering, 1775

All-cause death HF hospitalization Composite outcome

23780 pts with HFrEF, 4194 (18%) receiving Digoxin

All-cause death HF hospitalization Composite outcome

All-cause death Composite outcome

Conclusions

• Digoxin was associated with decreased risk of HF

hospitalization in HFrEF with permanent AF

• Digoxin was associated with increased risk of death in

HFrEF with sinus rhythm or concomitant paroxysmal AF

• Digoxin was neutral for other patient categories and outcomes

The human face of heart failure

Two New Pharmacological Therapies Approved by FDA for Heart Failure

• Ivabradine (April 15, 2015)

• Sacubitril/Valsartan (July 7, 2015)

Over 1 million hospitalizations for HF

annually in US and in Europe

33

M o r t a l i t y i n H F r E F r e m a i n s h i g h

d e s p i t e n e w t h e r a p i e s t h a t i m p r o v e s u r v i v a l

▪ Survival rates in chronic HF have improved with the introduction of new therapies 1

▪ However, significant mortality remains – ~50% of patients die within 5 years of diagnosis 6–8

16%

(4.5% ARR; mean follow up of 41.4 months)

RALES 4

17%

(3.0% ARR; median follow up of 33.7 months)

Alternative 5

• Quality of life for patients with HF

is: 1

– Worse than those with diabetes

– Similar to those with Parkinson’s

disease or motor neuron disease

• Patients may require assistance

with daily activities such as

taking their medication 2,3

– Caregiver burden can be

substantial 3,4

Quality of life is worse in patients with HF than in

those suffering from other chronic conditions

1 Calvert et al Eur J Heart Fail 2005;7:243–51;

2 Boyd et al Eur J Heart Fail 2004;6:585–591;

3 Clark et al J Adv Nurs 2008;61:373–83;

4 Saunders West J Nurs Res 2008;30:943–59

HF=heart failure;

NYHA=New York Heart Association

Mean EQ-5D in patients with NYHA class III/IV HF compared with

general population & other chronic diseases 1

EQ-5D Index score

General population General population age 65–74

HF patients NYHA III/IV

Type 2 diabetes Mild motor neuron disease Moderate motor neuron disease Parkinson’s disease

Hospitalized after ischemic stroke 3-month assessment post-stroke Non–small cell lung cancer

HFrEF SYMPTOMS

&

PROGRESSION

Overactivation of RAAS & SNS is detrimental in HFrEF

and underpins the basis of therapy

1 McMurray et al Eur Heart J 2012;33:1787–847; Figure References: Levin et al N Engl J Med 1998;339:321–8; Nathisuwan

& Talbert Pharmacotherapy 2002;22:27–42; Kemp & Conte Cardiovascular Pathology 2012;365–71;

Schrier & Abraham N Engl J Med 2009;341:577–85

ACEI: angiotensin-converting-enzyme inhibitor; Ang: angiotensin; ARB: angiotensin receptor blocker; AT1R: angiotensin II type 1

receptor; MRA: mineralocorticoid receptor antagonist; NPs: natriuretic peptides; NPRs: natriuretic peptide receptors; RAAS:

renin-angiotensin-aldosterone system; SNS: sympathetic nervous system

Epinephrine Norepinephrine α1, β1, β2

receptors

Vasoconstriction

RAAS activity Vasopressin Heart rate Contractility

Sympathetic nervous system

Ang II AT1R

Vasoconstriction

Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis

Renin-angiotensin- aldosterone-system

Natriuretic peptide system 1

• The crucial importance of the RAAS is supported by the beneficial effects

of ACEIs, ARBs and MRAs1

• Benefits of β-blockers indicate that the SNS also plays a key role1

▪ Wall stress as a result of volume

expansion or pressure overload

induces the synthesis of

precursors of NPs 2

▪ The NP system consists mainly

of three peptides: ANP, BNP and

CNP 7

• ANP is produced primarily in

the atrial myocardium

• BNP is produced primarily in

the ventricular myocardium

• CNP predominates in brain,

kidney, vascular endothelial

cells and plasma

The NP system 6

NT-proBNP (aa1-aa76) (aa77-aa108) BNP 1–32

7–32

DPP-IV Meprin A

proBNP (aa1-aa108)

Cleavage Pre-proBNP

Natriuretic peptides are cleared by NPR-C and neprilysin

ANP: atrial natriuretic peptide; Ang: angiotensin; AT1: angiotensin II type 1; BNP: B-type natriuretic peptide; cGMP: cyclic guanosine monophosphate;

CNP: C-type natriuretic peptide; GTP: guanosine triphosphate; HF: heart failure; NP: natriuretic peptide; NPR: natriuretic peptide receptor; RAAS: renin-angiotensin-aldosterone system Levin et al N Engl J Med 1998;339;321–8; Gardner et al Hypertension 2007;49:419–26; Molkentin J Clin Invest 2003;111:1275–77; Nishikimi et al Cardiovasc Res 2006;69:318–28; Guo et al Cell Res 2001;11:165–80; Von Lueder et al Circ Heart Fail 2013;6:594–605; Yin et al Int J Biochem Cell 2003;35:780–3; Mehta & Griendling Am J Physiol Cell Physiol 2007;292:C82–97

Signaling cascades

Neprilysin has many substrates that are metabolized

with differing levels of affinity

Metabolism of natriuretic and other vasoactive peptides* by NEP 1–9

1 Erdos, Skidgel FASEB J 1989;3:145–51; 2 Levin et al N Engl J Med 1998;339;321–8; 3 Stephenson et al Biochem J 1987;243:183–7; 4 Lang et al Clin Sci 1992;82:619–23; 5 Kenny et al Biochem J 1993;291:83–8; 6 Skidgel et al Peptides 1984;5:769–76; 7 Abassi et al Metabolism 1992;41:683–5; 8 Murphy et al Br J Pharmacol 1994;113:137–42; 9 Jiang et al Hypertens Res 2004;27:109–17; 10 Langenickel & Dole Drug Discovery Today: Ther Strateg 2012;9:e131–9;

11 Richards et al J Hypertens 1993;11:407–16; 12 Ferro et al Circulation 1998;97:2323–30

Ang II

Adrenomedullin Ang I

NEP

Inactive fragments

or metabolites

Implications for NEP inhibition

Ang=angiotensin; ANP=atrial natriuretic peptide;

BNP=B-type natriuretic peptide;

CNP=C-type natriuretic peptide; NEP=neprilysin;

NP=natriuretic peptide; RAAS=renin angiotensin

▪ NEP inhibitors: natriuretic and other vasoactive peptides enhancement

Evolution of pharmacologic approaches in HF:

Neprilysin inhibition as a new therapeutic strategy in patients with HF1

SNS

RAAS

Vasoconstriction

Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis

Ang II AT1R

HF SYMPTOMS &

PROGRESSION

INACTIVE FRAGMENTS

α1, β1, β2 receptors

Vasoconstriction

RAAS activity Vasopressin Heart rate Contractility

Neprilysin inhibitors

RAAS inhibitors (ACEI, ARB, MRA)

β-blockers

1 McMurray et al Eur J Heart Fail 2013;15:1062–73; Figure references: Levin et al N Engl J Med 1998;339:321–8; Nathisuwan & Talbert Pharmacotherapy 2002;22:27–42; Kemp & Conte Cardiovascular Pathology 2012;365–371;

Schrier & Abraham N Engl J Med 2009;341:577–85

ACEI=angiotensin-converting-enzyme inhibitor; Ang=angiotensin;

ARB=angiotensin receptor blocker; AT1 = angiotensin II type 1; HF=heart

failure; MRA=mineralocorticoid receptor antagonist; NEP=neprilysin;

NP=natriuretic peptide; NPRs=natriuretic peptide receptors;

RAAS=renin-40

Primary endpoint: death from CV causes or first hospitalization for HF

CI: confidence interval; CV: cardiovascular; HF: heart failure

McMurray et al N Engl Med 2014;371:993–1004

0.2

0 180 360 540 720 900 1,080 1,260

4,187 3,922 3,663 3,018 2,257 1,544 896 249 4,212 3,883 3,579 2,922 2,123 1,488 853 236

Days since randomization

Who, When, and How

to Transition to

Sacubitril/Valsartan

Sacubitril/Valsartan was studied in mild-moderate HF

Do not wait for patients to deteriorate!

Data is lacking for inpatients and the ACE/ARB nạve Stop ACE 36 hours prior to starting sacubitril/valsartan

Go low and slow with dose titration

Dose Selection and Titration

Monitor for Adverse Effects

High Risk: Older, lower SBP, higher Cr, higher NT-proBNP, worse NYHA

Hypotension Check BP and for symptoms of hypotension

Hyperkalemia Check serum K + before dose change

Renal Dysfunction Check serum Cr before dose change

Biomarkers BNP falsely elevated Follow NT-proBNP

Populations, trials and guidelines

All patients

Clinical trial inclusion/

exclusion criteria

Clinical trial –

actual patients

randomized

Guidelines

47