Bài giảng Chiến lược giảm đột tử trong suy tim - TS.BS Tôn Thất Minh

CHIẾN LƯỢC GIẢM ĐỘT TỬ
TRONG SUY TIM

TS.BS Tôn Thất Minh
GĐ Bệnh viện tim tâm đức TP HCM
Hue 07.2019


Disclosure
Presenter’s Name: Ton That Minh
• Employed as Director of Tam Duc Heart Hospital and
lecturer at Pham Ngoc Thach Medicine University
Relevant Nonfinancial Relationships:
• Societies member – VNHA, HCMCA, VN ICA, South ICA

Last 12 month Relevant Financial Relationships:
Receives a financial support for speaking and traveling from
Astra-Zeneca, Medtronic, Biotronic, Boehringer, Sanofi,
MSD, Novartis, Servier, Pfizer.
This presentation is supported by Novartis.
References for this presentation will be provided if
required.


NỘI DUNG
1.
2.
3.
4.

Khái niệm suy tim ổn định

Khuyến cáo phòng ngừa đột tử
ARNI chiến lược giảm đột tử trong suy tim
Kết luận


Suy tim là một bệnh tiến triển
Sự thoái triển cấu trúc và chức năng tim xảy ra ngay
trong giai đoạn sớm
▪ Bệnh nhân suy tim có nguy cơ đột tử trong suốt q trình bệnh (5,6).
▪ Đột tử có tỷ lệ lớn hơn ở bệnh nhân trẻ tử vong với suy tim nhẹ, hơn khi
bệnh suy tim tiến triển (6-8).
HF symptom onset

Risk of
sudden death
Chronic decline

Cardiac
function
and
quality of life

Hospitalizations for acute
decompensation episodes
Disease progression
4
1. Gheorghiade et al. Am J Cardiol. 2005;96:11G–17G; 2. Gheorghiade, Pang. J Am Coll Cardiol. 2009;53:557–73; 3. Lee et al. Am J Med. 2009 122, 162-69; 4. Allen et al.
Circulation. 2012 Apr 17; 125(15): 1928–1952; 5. Ponikowski et al. Eur Heart J. 2016(37):2129-2200;; 6. Al-Khatib et al. Circulation. 2017;000:e000–e000. DOI:
10.1161/CIR.0000000000000549; 7. Bogle et al. J Am Heart Assoc. 2016;5:e002398; 8. Uretsky, Sheahan. J Am Coll Cardiol. 1997;30:1589-1597; Figure adapted from Gheorghiade
et al. 2005

NYHA khơng là chỉ số duy nhất đánh giá tính
ổn định
• Nhóm bệnh nhân ít triệu chứng chưa được chú ý đúng mức
• Đa số bác sĩ suy nghĩ rằng NYHA II / ít triệu chứng khơng phải nhóm
nguy cơ cao
• Triệu chứng chưa được khai thác kỹ để đánh giá
• “bệnh nhân khơng than phiền / ít than phiền có nghĩa là bệnh nhân ổn
định”

Định nghĩa thế nào là một bn suy tim ổn định?
- Triệu chứng ổn định, không xấu đi với NYHA I-II từ lần xuất viện trước?
- Bệnh nhân đã “quen” với thuốc cũ?
- 3 tháng, 6 tháng, 12 tháng... gần đây chưa cần nhập viện?


Khơng có suy tim ổn định:

NYHA II vẫn tiếp tục tử vong
▪ MERIT HF post hoc analysis: the incidence of SCD is higher in patients with less
severe HF (NYHA class II), although total mortality rates increase with higher
NYHA class1

▪ PARADIGM-HF analysis: 44.8% of NYHA class II HF CV deaths were SCDs2
SCD

CHF

NYHA Class II:

Mode of CV death
N=791

Other

70

Death (%)

60

50
40
30
20
10
0
NYHA II

NYHA III

NYHA IV
*Other CV death includes all CV deaths not ascribed to
pump failure or sudden death

A post-hoc analysis from MERIT-HF (n=3991)1
Mean follow up, 1 year
CV, cardiovascular; HF, heart failure; MERIT-HF, Metoprolol
11 CR/XL Randomised Intervention Trial in-Congestive Heart Failure;

NYHA, New York Heart Association; PARADIGM-HF, Prospective
comparison of ARNI with ACEI to Determine Impact on Global
Mortality and morbidity in Heart Failure;SCD, sudden cardiac
death; CHF, congestive heart failure

An analysis from PARADIGM-HF(n=8399)2
Median follow up, 2.3 years

1.MERIT-HF Study Group. Lancet. 1999;353(9169):2001–7;
2. Desai AS et al. Eur Heart J. 2015;36:1990–7


Bệnh nhân suy tim NYHA II có nguy cơ cao
bị đột tử
Sự thoái triển cấu trúc và chức năng tim xảy ra ngay
trong giai đoạn sớm
NYHA class II:
Mode of CV death
N=791

70

Death (%)

60

64
59

50

56

40
30
20
10

Sudden
death
44.8%

33
26

24

15

12

11

Worsening
HF
27.1%

0
NYHA II

NYHA III

Sudden death

WHF

Other CV
death *
28.2%

NYHA IV
Other*

*Other death includes all CV deaths not ascribed to

WHF or sudden death

A post-hoc analysis from MERIT-HF (n=3,991)1
Mean follow up, 1 year

*Other CV death includes all CV deaths not ascribed

to pump failure or sudden death

An analysis from PARADIGM-HF (n=8,399)2
Median follow up, 2.3 years

7

1. MERIT-HF Study Group. Lancet. 1999;353(9169):2001–7; 2. Desai et al. Eur Heart J.

2015;36:1990–7


Phòng ngừa tiên phát đột tử do tim ở BN
bệnh động mạch vành
Primary prevention in pts with IHD,
LVEF ≤40%

MI <40 d
and/or
revascularization
<90 d

EP study
(especially in the
presence of
NSVT)

Yes*

GDM T
(Class I)

No
Reassess LVEF
>40 d after MI
and/or >90 d after
revascularization

WCD

(Class IIb)
No

NYH A
class II or III
LVEF ≤35%

NYH A class I
LVEF ≤30%

Yes
ICD
(Class I)*

LVEF ≤40%
NSV T, inducible
sustained VT on
EP study

Yes

ICD
(Class I)

No

GDM T

Inducible
sustained VT

NYH A
class IV candidate
for advance HF
therapy †

Yes

ICD
(Class IIa)

1. Al-Khatib et al. Circulation. 2017;000:e000–e000. DOI: 10.1161/CIR.0000000000000549

No
ICD should not
be implanted
(Class III:
No Benefit)

Yes

ICD
(Class I)


2016 ESC: Khuyến cáo phòng ngừa đột tử

Recommendations for implantable cardioverter-defibrillator in patients with heart failure
Recommendations

Class

Level

IHD (unless they have had an MI in the prior 40 days)

I

A

DCM

I

B

An ICD is recommended to reduce the risk of sudden death and all-cause mortality in
patients with symptomatic HF (NYHA Class II–III), and an LVEF ≤35% despite ≥3 months
of OMT, provided they are expected to survive substantially longer than one year with
good functional status, and they have:

Recommendations for the management of ventricular tachyarrhythmias in heart failure1
Recommendations

Class

Level

Treatment with beta-blocker, MRA and sacubitril/valsartan reduces the risk of sudden
death and is recommended for patients with HFrEF and ventricular arrhythmias

I

A

1. Ponikowoski et al. Eur Heart J. 2016;37:2129–2200


2017 AHA/ACC/HRS: Khuyến cáo
phòng ngừa đột tử
Recommendations for Primary Prevention of SCD in Patients With Ischemic Heart Disease
Recommendations

Class

Level

1. In patients with LVEF of 35% or less that is due to ischemic heart disease who are at least
40 days’ post-MI and at least 90 days postrevascularization, and with NYHA class II or III HF
despite GDMT, an ICD is recommended if meaningful survival of greater than 1 year is
expected

I

A

2. In patients with LVEF of 30% or less that is due to ischemic heart disease who are at least
40 days’ post-MI and at least 90 days postrevascularization, and with NYHA class I HF despite
GDMT, an ICD is recommended if meaningful survival of greater than 1 year is expected

I

A

Recommendations

Class

Level

In patients with HFrEF (LVEF ≤40%), treatment with a beta blocker, MRA and either an ACEI,
ARB, or an angiotensin receptor neprilysin inhibitor is recommended to reduce SCD
and all-cause mortality

I

A

Recommendations for pharmacological prevention of SCD1

1. Al-Khatib et al. Circulation. 2017;000:e000–e000. DOI: 10.1161/CIR.0000000000000549


Đột tử vẫn còn xảy ra dù BN được đặt
máy ICD
▪ In a review of 320 patient deaths during trials
of ICD systems, the most common
mechanism of sudden death in patients with
an ICD was VT/VF treated with an
appropriate shock followed by EMD1

▪ In an analysis of trials of ICD systems,
greater absolute benefit was found in
patients with ischemic heart disease
compared with dilated cardiomyopathy2

Study or subcategory

Risk ratio
IV, Random, 95% CI

lschemic cardiomyopathy
01 - MADIT
04 - MADIT II
08 - SCD-HeFT
Subtotal (95% CI)

Non-ischemic cardiomyopathy
03 - CAT
05 - AMIOVIRT
06 - DEFINITE
08 - SCD-HeFT
Subtotal (95% CI)

Total (95% CI)
0.1 0.2

0.5

Favours ICD

Mitchell et al. J Am Coll Cardiol. 2002;39:1323– 8; 2. Theuns et al. Europace. 2010;12:1564-70;
Figure on left from Mitchell et al; Figure on right adapted from Theuns et al.

1

2

5

10

Favours control


Nghiên cứu PARADIGM-HF
Randomization
(N=8,442 patients with CHF
[NYHA Class II–IV with LVEF ≤40%] and elevated BNP)

Sacubitril/valsartan 97/103 (200) mg BID

Single-blind run-in period

Enalapril
10 mg BID‡

Sac/val
49/51 (100) mg
BID

Sac/val
97/103 (200) mg
BID

Testing tolerability to target doses of enalapril and
sacubitril/valsartan
2 weeks

1–2 weeks

Double-blind randomized treatment period

Enalapril 10 mg BID

On top of standard HF therapy (excluding ACEi and ARB)

2–4 weeks

Median duration of follow-up 27 months

A washout of more than a day occurred between enalapril and sacubitril/valsartan
dosing and at randomization

Primary outcome: CV death or HF hospitalization
‡Enalapril

5 mg BID for 1–2 weeks followed by enalapril 10 mg BID as an optional starting run-in dose for
patients who are treated with ARB or with a low dose of ACEi.

1. McMurray et al. Eur J Heart Fail. 2013;15:1062-1073; 2. McMurray et al. Eur J Heart Fail. 2014;16:817-825; 3. McMurray et al. N Engl J Med. 2014;371:9931004


PARADIGM-HF: Sacubitril/valsartan giảm
tiêu chí chính
Primary Endpoint: Time to First Occurrence of CV Death or HF Hospitalization

Cumulative probability of event

1.0

Enalapril
Sacubitril/valsartan

0.6

Hazard ratio = 0.80
(95% CI: 0.73–0.87) P<0.0001
0.4

1117 events
914 events

0.2

0
0

180

360

Sacubitril/valsartan 4187

3922

3663

3018

Enalapril

3883

3579

2922

No. at risk

4212

540
720
Days since randomization

1. McMurray, et al. New Engl J Med. 2014;371:993-1004

900

1080

1260

2257

1544

896

249

2123

1488

853

236


Sacubitril/valsartan làm giảm đáng kể
đột tử so với enalapril
Cumulative probability of sudden
death

0.10

311/4187 died
(7.4% patients)

Enalapril
Sacubitril/valsartan

0.08

250/4212 died
(6.0% patients)

Hazard ratio=0.80
(95% CI: 0.68–0.94)
p=0.008

0.06

0.04

0.02

0
0

180

360

540

720

900

1080

Days since randomization
No. at risk
Sacubitril/valsartan
4187
Enalapril
4212

3891
3860

2478
2410

1005
994

1. Desai et al. Eur Heart J 2015;36:1990-7; 2. McMurray, et al. New Engl J Med. 2014;371:993-1004

1260


Lợi ích giảm đột tử của
sacubitril/valsartan độc lập với ICD
▪

▪

▪

ICD and CRT-D use in PARADIGM-HF was 15% and 5%1,2 respectively, similar to that in other
recent HFrEF trials.3,4 While the patients with an ICD had a lower overall risk of sudden death,
their use did not eliminate risk completely
The sacubitril/valsartan treatment effect on sudden death was not influenced by the presence
of defibrillator devices2
Among patients with an ICD, use of sacubitril/valsartan reduced the relative risk of sudden
death by 51% compared with enalapril2

PARADIGM-HF
− ICD

Sudden
death
n (%)

Hazard ratio,
sac/val vs. enalapril
(95% CI)

7.3% (525/7156)

0.82 (0.69–0.98)

Enalapril*

8% (287/3592)

n/a

Sac/val*

6.7% (238/3564)

n/a

+ ICD

2.9% (36/1243)

0.49 (0.25–0.98)

Enalapril*

3.9% (24/620)

n/a

Sac/val*

1.9% (12/623)

n/a

This was a post hoc analysis; * Novartis data on file
1. McMurray et al. 2014. Eur J Heart Fail. 2014;16:817-25; 2. Desai et al. Eur Heart J. 2015;36:1990-7; 3. Swedberg et al. Lancet. 2010;376:875-85; 4. Zannad et al. N Engl J
Med 2011;364:11-21

Sacubitril/valsartan làm giảm nguy cơ đột tử hay ngưng
tim so với enalapril, bất chấp ICD

Sudden Death or Cardiac Arrest

0.12

Sudden Death or Cardiac Arrest in ICD Patients

0.12

Enalapril
0.10

0.10

Sacubitril/valsartan

0.07

0.07

0.05

0.05

0.03

Hazard ratio = 0.77
(95% CI: 0.66–0.92) p=0.002

0

500

1000

Days since randomization

1500

Hazard ratio = 0.54
(95% CI: 0.30–1.00) p=0.05

0.03

0

500

Days since randomization

P-interaction for efficacy of sacubitril/valsartan and ICD = 0.21

Novartis data on file.

1000

1500

Sacubitril/valsartan’s
potential mechanism of
action for the reduction in
sudden deaths


Effects of angiotensin-neprilysin
inhibition as compared to angiotensin
inhibition on ventricular arrhythmias in
reduced ejection fraction patients
under continuous remote monitoring
of implantable defibrillator devices
de Diego et al. Heart Rhythm 2018;15(3):395-402


Study design and patient population
Pre-ARNI
Angiotensin inhibition
(ramipril or valsartan)

9 months

Switch
treatment to
ARNI
36 h ACEi
washout

β-blockers and MRA

Post-ARNI
Sacubitril/valsartan
9 months

Analysis:
• Appropriate shocks
• NSVT
• PVC burden
• Biventricular Pacing %

Patient population:
120 HFrEF patients with ICD or ICD-CRT referred to cardiology HF/arrhythmia
outpatient clinic:
▪ HF symptoms with NYHA class ≥II despite optimal medical therapy, including
initiation and titration of ACEi (ramipril) or ARB (valsartan), β-blockers, and
MRA if tolerated
▪ LVEF ≤40%
▪ Under home monitoring of an ICD
▪ Patients serve as their own control by design

19

1. de Diego et al. Heart Rhythm. 2018;15(3):395-402


Patient characteristics pre- and postintervention (1/3)
▪ Study design ensured patients served as their own controls1

Clinical characteristics
Age (yrs)

Male
Ischemic cardiopathy
Hypertension
Diabetes
Hypercholesterolemia
Renal insufficiency
(filtration rate <60 mL/min)
Rhythm
Sinus rhythm
Paroxysmal AF
Permanent AF

Pre-ARNI (n = 120)

Post-ARNI (n = 120)

P value

69 ± 8
91 (76)
98 (82)
75 (62)
36 (30)
62 (52)
48 (40)

70 ± 8
91 (76)
98 (82)
75 (62)

36 (30)
63 (52)
48 (40)

NS
NS
NS
NS
NS
NS
NS

85 (71)
17 (14)
35 (29)

84 (70)
12 (10)
36 (30)

NS
.07
NS

20

Values are given as mean ± SD, n (%), or %.
1. de Diego et al. Heart Rhythm. 2018;15(3):395-402;

Patient characteristics pre- and postintervention (2/3)
▪ Patients were on OMT throughout the study period

▪ An improvement in NYHA functional class and a reduction in the dose of diuretic
treatment were observed post-ARNI

Medical treatment
β-blocker
Mineraloid antagonist
Antiarrhythmic drug
Oral diuretic
Device
ICD only
ICD + CRT
Primary prevention
Secondary prevention
Clinical data
NYHA functional class
(I–IV)

Pre-ARNI (n = 120)

Post-ARNI (n = 120)

P value

100% ACEi or ARB
98%
97%
30%

75%

100% sacubitril-valsartan
98%
97%
29%
52%

NS
NS
NS
<.03

56%
44%
65%
35%

56%
44%
65%
35%

NS
NS
NS
NS

2.4 ± 0.4

1.5 ± 0.7

<.0002

21

Values are given as mean ± SD, n (%), or %
1. de Diego et al. Heart Rhythm. 2018;15(3):395-402


Patient characteristics pre- and postintervention (3/3)
▪ There was a significant increase in LVEF and LVEDD post-ARNI1, suggesting both
functional and structural improvements in cardiac tissue1-3

▪ Levels of pro-BNP were lowered post-ARNI1, potentially leading to a reduction in
myocardial wall stress and a lower likelihood of ICD shocks1,4
Pre-ARNI (n = 120)

Post-ARNI (n = 120)

P value

Echocardiographic data
LVEF (%)
LVEDD (mm)

30.4 ± 4
61 ± 5

35.1 ± 8

58 ± 6

<.01
<.01

Examination data
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Heart rate average (bpm)

121 ± 38
73 ± 23
67 ± 7

107 ± 39
64 ± 26
64 ± 5

<.02
<.006
<.006

Blood tests
Potassium level (mEq/L)
Pro-BNP (pg/mL)
Glomerular filtration rate (mL/min)

4.4 ± 0.5
1971 ± 1530
55 ± 19

4.7 ± 0.5
1172 ± 955
57 ± 19

<.03
<.01
NS

Values are given as mean ± SD, n (%), or %
1. de Diego et al. Heart Rhythm. 2018;15(3):395-402; 2. Al-Khatib et al. Circulation. 2017;000:e000–e000. DOI:
10.1161/CIR.0000000000000549; 3. Tomaselli , Zipes. Circ Res. 2004;95:754-63; 4. Levine et al. Heart Rhythm 2014;11:1109–
1116

22


Sacubitril/valsartan significantly increased
survival free time from appropriate ICD
shocks, compared with ACEi/ARB
▪ The most common mechanism of sudden death in patients with an ICD was VT/VF treated
with an appropriate shock followed by EMD2

▪ ICD patients suffer from poorer psychological well-being following shocks, which impacts
QoL3-5

Survival free from
appropriate ICD shocks

100

n=120
P<0.02
90

80
Pre-ARNI
Post-ARNI

70
0

3

6

9

Time (months)
Number at risk
ARNI

120

120

120

120

119

119

ACEi/ARB 120

119

119

115

113

113

1, de Diego et al. Heart Rhythm. 2018;15(3):395-402; 2. Mitchell et al. J Am Coll Cardiol. 2002;39:1323– 8; 3. Tomzik et al. Front
Cardiovasc Med. 2015;234. doi: 10.3389/fcvm.2015.00034; 4. Passman, et al. Arch Intern Med 2007;167(20):2226-32.
5. Mark et al. New Engl J Med. 2008;359(10):999-1008; Figure from de Diego et al

23


Sacubitril/valsartan significantly increased
survival free time from VT and NSVT,
compared with ACEi/ARB
100

VT

Survival free from

NSVT and VT

P<0.02
80
60

NSVT
P<0.001

40
20

Pre-ARNI
Post-ARNI
0

3

6

9

Time (months)
Number at risk (VT)
ARNI

120

120

120

120

119

119

ACEi/ARB 120

119

119

115

113

113

Number at risk (NSVT)
ARNI

120

111

103

95

86

82

ACEi/ARB 120

104

90

77

67

59

24

1. de Diego et al. Heart Rhythm. 2018;15(3):395-402


A decrease in PVC burden after
sacubitril/valsartan was associated with an
increase in biventricular pacing %, compared
with ACEi/ARB
100

PVCs/hour

80

78

P<0.0003
n=120
Mean ± SE

60
40

33

Biventricular Pacing %

100
95

0

75

Pre-ARNI

P<0.02
N=53
Mean ± SD

85

80

Angiotensin-neprilysin
inhibition
+β-blocker +MRA
Post-ARNI

95%

90

20

Angiotensin inhibition
+β-blocker +MRA

98.8%

Angiotensin inhibition
+β-blocker + MRA
Pre-ARNI

Angiotensin-neprilysin
inhibition
β-blocker + MRA
Post-ARNI

25

1. de Diego et al. Heart Rhythm. 2018;15(3):395-402