Bài giảng Suy tim mạn: Góc nhìn từ ACC 2017

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 
ON IVABRADINE 
WHY ADD 
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 If 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 
CV death 
40 
or hospitalization for HF (%) 
HR= 0.82 
p<0.0001 Placebo 
30 
20 
10 
Months 
12 18 24 6 
lvabradine 
Swedberg K., et al. Lancet.2010;376:875-885 
SHIFT: HF hospitalization 
Hospitalization for HF (%) 
30 
HR= 0.74 
Placebo 
20 
10 
Months 
6 12 18 24 30 
Swedberg K, et al. Lancet. 2010;376:875-885. 
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 
Ramipril 2.5o.d 5b.i.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 
IfInhibitor 
Ivabradine 5b.i.d 7.5b.i.d 
Target doses as defined in the ESC guidelines 
 Can we reach and maintain „target” dose 
in „real-life” elderly HF patients with comorbidities ? 
 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 
IfInhibitor 
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. 
Up-titration period as defined in the landmark trials 
Uptitration target in stable HF patients 
. 
Dose 
Beta-blockers 
6 weeks 
ACEIs 
4 weeks 
MRAs 
4 weeks 
Ivabradine 
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. 
Yes but  
My Patient  
- is too old 
- has low blood pressure 
- has COPD 
- has renal impairment 
- is too sick 
Treatment Effect of Ivabradine 
According to Blood Pressure 
Komajda M, et al. Eur Heart J. 2013;34 (Abst. Suppl), 610. 
N at risk 
COPD (pl) 
COPD (iva) 
NCOPD (pl) 
NCOPD (iva) 
372 
358 
2892 
2883 
298 
312 
2570 
2616 
250 
266 
2239 
2334 
209 
216 
1852 
1957 
110 
124 
979 
1067 
0 6 12 18 24 
Patients (%) 
 50 
 45 
 40 
 35 
 30 
 25 
 20 
 15 
 10 
 5 
 0 Time (months) 
Effect of ivabradine on composite of 
 CV death or HF hospitalization 
 COPD (placebo) 
 COPD (ivabradine) 
 Non-COPD (placebo) 
 Non-COPD (ivabradine) 
Tavazzi L, et al. Eur Heart J. 2013;34 (Abst. Suppl), 652. 
0 6 12 18 24 30 
Patients (%) 
 50 
 40 
 30 
 20 
 10 
 0 
Time (months) 
Effect of ivabradine on composite of CV 
 death or HF hospitalization 
 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). 
N at risk 
RD (pl) 
RD (iva) 
NRD (pl) 
NRD (iva) 
799 
780 
2293 
2288 
706 
720 
2119 
2166 
612 
612 
1847 
1963 
488 
489 
1551 
1662 
261 
273 
820 
906 
95 
104 
343 
339 
Effect of early treatment of Ivabradine with BBs vs BB alone in 
patients hospitalized for WHF: randomized ETHIC study 
LV
EF
, 
%
Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11 
n=71 patients hospitalized for WHF 
P=0.039 
Greater improvement in LVEF 
29.8 
32.9 
44.8 
29.9 
31.9 
38.1 
10.
19.
28.
37.
46.
55.
Admission Dicharge 4 months FU
Ivabradine + BB BB alone
P=0.039 
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 
1469 
463 
259 
1061 
671 
554 
100
475
850
1225
1600
Admission Dicharge 4 months FU
Ivabradine + BB BB alone
Better reduction in BNP 
P=0.02 
B
N
P
, p
g/
m
l 
Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11 
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 
Better HR control 
87.3 
70.1 
60.6 
88.4 
73.9 
67.8 
50.
60.
70.
80.
90.
100.
Admission Dicharge 4 months FU
Ivabradine + BB BB alone
H
R
, b
p
m
Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11 
Background 
Romans used a non-Digoxin cardiac 
glycoside derived from sea onion 
Used sporadically in Middle Ages but 
popularized in 18th 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 
Background 
Inhibits Cardiac isoform of Na/K ATPase which 
indirectly increases intracellular Ca 
concentration 
• Increased cardiac output in low output states 
without increased oxygen consumption 
• Decreases PCWP 
• Improves baroreceptor sensitivity in the carotid 
which may decrease RAAS activation 
• Increases AV node refractory period by increasing 
vagal tone 
tea++ 
\ 
tTN-C --- t1notropy 
Ca" binding 
All-cause death HF hospitalization Composite outcome 
23780 pts with HFrEF, 4194 (18%) receiving Digoxin 
All-cause death Composite outcome HF hospitalization 
HF hospitalization 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 
 Hypertension 
 Angina 
 Diabetes 
 Atrial fibrillation 
 Prostatic disease 
 Depression 
 Cognitive impairment 
 Arthritis 
 Cachexia 
 Renal impairment 
 Parkinson’s disease 
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 
Mor ta l i t y i n HF rE F rema ins h i gh 
desp i t e new the rap ies t ha t imp rove su rv i va l 
▪ Survival rates in chronic HF have improved with the introduction of new therapies1 
▪ However, significant mortality remains – ~50% of patients die within 5 years of diagnosis6–8 
16% 
(4.5% ARR; mean 
follow up of 41.4 
months) 
SOLVD1,2 34% 
(5.5% ARR; mean follow 
up 
of 1.3 years) 
CIBIS-II3 
R
e
d
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ti
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n
 i
n
 r
e
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 r
is
k
 o
f 
m
o
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a
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 v
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 p
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30% 
(11.0% ARR; mean 
follow up of 24 
months) 
RALES4 
17% 
(3.0% ARR; median 
follow up of 33.7 
months) 
CHARM-
Alternative5 
ACEI* β-blocker* MRA* ARB* 
• 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 medication2,3 
– Caregiver burden can be 
substantial3,4 
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 diseases1 
0. 0.23 0.45 0.68 0.9 1.13
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 
NPRs NPs 
Vasodilation 
Blood pressure 
Sympathetic tone 
Natriuresis/diuresis 
Vasopressin 
Aldosterone 
Fibrosis 
Hypertrophy 
Natriuretic peptide system1 
• 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 NPs2 
▪ The NP system consists mainly 
of three peptides: ANP, BNP and 
CNP7 
• 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 system6 
NT-proBNP 
(aa1-aa76) 
BNP1–32 
(aa77-aa108) 
BNP3–32 
BNP7–32 
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 
GTP 
GTP 
cGMP 
Inactive peptides 
ANP/CNP 
ANP BNP 
NPR-A 
CNP 
NPR-B 
Inactive NP 
fragments 
ANP/CNP/BNP 
NPR-C 
Ang II 
AT1 receptor 
Internalization 
Receptor 
recycling 
Neprilysin 
Vasodilation 
Cardiac fibrosis/hypertrophy 
 Natriuresis/diuresis 
Vasoconstriction 
 Cardiac fibrosis/hypertrophy 
 Sodium/water retention 
NP signaling and effects 
RAAS 
over-activation in 
HF 
NP degradation and clearance 
Neprilysin has many substrates that are metabolized 
with differing levels of affinity 
Metabolism of natriuretic and other vasoactive peptides* by NEP1–9 
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 
Relative 
affinity 
for NEP 
ANP and CNP 
Endothelin 
Substance P 
Bradykinin 
Ang II 
Adrenomedullin 
Ang I 
NEP 
Inactive 
fragments 
or metabolites 
Implications for NEP inhibition 
▪ NEP substrates can have opposing 
biological actions10 
▪ Overall effect is dependent upon 
the net effect on NEP metabolism 
of individual substrates10 
▪ Benefits in enhancing NP system 
may be offset by increased Ang II11 
▪ Needs to be complemented by 
simultaneous RAAS 
suppression2,11,12 
*Not an exhaustive list of all neprilysin substrates; the most relevant substrates for cardiovascular physiology are listed 
BNP 
Ang=angiotensin; ANP=atrial natriuretic peptide; 
BNP=B-type natriuretic peptide; 
CNP=C-type natriuretic peptide; NEP=neprilysin; 
NP=natriuretic peptide; RAAS=renin angiotensin 
aldosterone system 
▪ 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 
NP system 
Vasodilation 
Blood pressure 
Sympathetic tone 
Natriuresis/diuresis 
Vasopressin 
Aldosterone 
Fibrosis 
Hypertrophy 
NPRs NPs 
Epinephrine 
Norepinephrine 
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-
angiotensin-aldosterone system; SNS=sympathetic nervous system 
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. 
C
u
m
u
la
ti
v
e
 p
ro
b
a
b
il
it
y
0.4 
0 
1.0 
0.6 
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 
LCZ696 
Enalapril 
No. at risk 
Hazard ratio = 0.80 
(95% CI: 0.73–0.87) 
p<0.001 
Enalapril LCZ696 
Days since randomization 
Who, When, and How 
to Transition to 
Sacubitril/Valsartan 
1) 
2) 
3) 
4) 
5) 
Sacubitril/Valsartan was studied in mild-moderate HF. 
Do not wait for patients to deteriorate! 
Data is lacking for inpatients and the ACE/ARB naïve. 
Stop ACE 36 hours prior to starting sacubitril/valsartan. 
Go low and slow with dose titration. 
Dose Selection and Titration 
High Dose 
ACE/ARB 
49-51 mg 
BID 
Consider 
Low Dose 
ACE/ARB 
24-26 mg 
BID 
ACE/ARB_ 
Start 
,_Cons_ider v l No ACE/ARB J 
Monitor for Adverse Effects 
 High Risk: Older, lower SBP, higher Cr, higher NT-proBNP, worse NYHA 
class, diabetes (from Vardeny EJHF 2016) 
 Wait at least 2-4 weeks before doubling the dose. 
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