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. Khái niệm suy tim ổn định

2. Khuyến cáo phòng ngừa đột tử

3. ARNI chiến lược giảm đột tử trong suy tim

4. Kết luận

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

Suy tim là một bệnh tiến triển

▪ Bệnh nhân suy tim có nguy cơ đột tử trong suốt quá 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).

Chronic declineCardiac

function

and

quality of life

Risk of

sudden death

Disease progression

Hospitalizations for acute

decompensation episodes

HF symptom onset

4

Sự thoái triển cấu trúc và chức năng tim xảy ra ngaytrong giai đoạn sớm

NYHA không là chỉ số duy nhất đánh giá tínhổn 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 không phải nhóm

nguy cơ cao

• Triệu chứng chưa được khai thác kỹ để đánh giá

• “bệnh nhân không than phiền / ít than phiền có nghĩa là bệnh nhân 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?

Định nghĩa thế nào là một bn suy tim ổn định?

A post-hoc analysis from MERIT-HF(n=3991)1

Mean follow up, 1 year

An analysis from PARADIGM-HF(n=8399)2

Median follow up, 2.3 years

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

CV, cardiovascular; HF, heart failure; MERIT-HF, Metoprolol

11 CR/XL Randomised Intervention Trial in-Congestive HeartFailure;

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

1.MERIT-HF Study Group. Lancet. 1999;353(9169):2001–7;

2. Desai AS et al. Eur Heart J. 2015;36:1990–7

NYHA Class II:

Mode of CV death

N=79170

60

50

40

30

20

10

0NYHA II NYHA III NYHA IV

De

ath

(%)

SCD CHF Other

*Other CV death includes all CV deaths not ascribed to

pump failure or sudden death

Không có suy tim ổn định:

Bệnh nhân suy tim NYHA II có nguy cơ caobị đột tử

7

Sự thoái triển cấu trúc và chức năng tim xảy ra ngaytrong giai đoạn sớm

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

Mean follow up, 1 yearAn analysis from PARADIGM-HF (n=8,399)2

Median follow up, 2.3 years

NYHA class II:

Mode of CV death

N=791

6459

33

12

26

56

24

1511

0

10

20

30

40

50

60

70

NYHA II NYHA III NYHA IV

Dea

th (

%)

Sudden death WHF Other*

*Other CV death includes all CV deaths not ascribed

to pump failure or sudden death

Other CV death *28.2%

Worsening HF

27.1%

Sudden death44.8%

*Other death includes all CV deaths not ascribed to

WHF or sudden death

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

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

Primary prevention in pts with IHD,EP study

(especially in the

presence of

NSVT)

Induciblesustained VT

ICD

(Class I)

Yes* No

No

MI <40 d

and/or

revascularization

<90 d

GDM T

(Class I)

ICD

(Class I)*

ICD

(Class I)

ICD

(Class IIa)

ICD should not

be implanted

(Class III:

No Benefit)

GDM T

WCD

(Class IIb)

Reassess LVEF

>40 d after MI

and/or >90 d after

revascularization

YesYes

Yes

NYH A class INYH A

class II or III NSV T, inducible

sustained VT on

EP study

NYH A

class IV candidate

for advance HF

therapy†

No Yes No

LVEF ≤30%LVEF ≤35%

LVEF ≤40%

LVEF ≤40%

2016 ESC: Khuyến cáo phòng ngừa đột tử

Recommendations for implantable cardioverter-defibrillator in patients with heart failure

Recommendations Class Level

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:

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

DCM I B

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

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 arrhythmiasI A

2017 AHA/ACC/HRS: Khuyến cáophòng 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

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

Recommendations for pharmacological prevention of SCD1

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

Đột tử vẫn còn xảy ra dù BN được đặtmáy 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

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.

▪ 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

Non-ischemic cardiomyopathy

Subtotal (95% CI)

03 - CAT

05 - AMIOVIRT

08 - SCD-HeFT

06 - DEFINITE

Total (95% CI)

0.1 0.2 0.5 1 2 5 10

Favours ICD Favours control

IV, Random, 95% CI

Risk ratio

lschemic cardiomyopathy

Subtotal (95% CI)

01 - MADIT

04 - MADIT II

08 - SCD-HeFT

Nghiên cứu PARADIGM-HF

Primary outcome: CV death or HF hospitalization

2 weeks Median duration of follow-up 27 months

Randomization

(N=8,442 patients with CHF

[NYHA Class II–IV with LVEF ≤40%] and elevated BNP)

Enalapril 10 mg BID

Sacubitril/valsartan 97/103 (200) mg BID

Sac/val

97/103 (200) mg

BID

On top of standard HF therapy (excluding ACEi and ARB)Testing tolerability to target doses of enalapril and

sacubitril/valsartan

Sac/val

49/51 (100) mg

BID

Enalapril

10 mg BID‡

1–2 weeks 2–4 weeks

Single-blind run-in period

Double-blind randomized treatment period

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

dosing and at randomization

‡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;371:993-

1004

PARADIGM-HF: Sacubitril/valsartan giảmtiêu chí chính

Days since randomizationNo. at risk

Sacubitril/valsartan

Enalapril

Cu

mu

lati

ve

pro

ba

bil

ity o

f e

ve

nt

1.0

0.6

0.4

0.2

0

0 180 360 540 720 900 1080 1260

Enalapril

Sacubitril/valsartan

4187

4212

3922

3883

3663

3579

3018

2922

2257

2123

1544

1488

896

853

249

236

1117 events

914 events

Hazard ratio = 0.80

(95% CI: 0.73–0.87) P<0.0001

Primary Endpoint: Time to First Occurrence of CV Death or HF Hospitalization

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

Sacubitril/valsartan làm giảm đáng kểđột tử so với enalapril

Hazard ratio=0.80

(95% CI: 0.68–0.94)

p=0.008

Enalapril

Sacubitril/valsartan

0 180 360 540 720 900 1080 1260

0

0.02

0.04

0.06

0.08

0.10

Days since randomizationNo. at risk

Sacubitril/valsartan 4187 3891 2478 1005

Enalapril 4212 3860 2410 994

Cu

mu

lati

ve

pro

ba

bil

ity o

f s

ud

de

n

de

ath

311/4187 died

(7.4% patients)

250/4212 died

(6.0% patients)

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

▪ 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

Lợi ích giảm đột tử củasacubitril/valsartan độc lập với ICD

PARADIGM-HF

Sudden

death

n (%)

Hazard ratio,

sac/val vs. enalapril

(95% CI)

− ICD 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 ngưngtim so với enalapril, bất chấp ICD

0.10

0.07

0.05

0.12

0.03

10005000 1500

Days since randomization

Sudden Death or Cardiac Arrest

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

Hazard ratio = 0.77

(95% CI: 0.66–0.92) p=0.002

0.10

0.07

0.05

0.12

0.03

10005000 1500

Days since randomization

Sudden Death or Cardiac Arrest in ICD Patients

Hazard ratio = 0.54

(95% CI: 0.30–1.00) p=0.05

Enalapril

Sacubitril/valsartan

Novartis data on file.

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

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

9 months

Angiotensin inhibition

(ramipril or valsartan) 36 h ACEi

washout9 months

Switch

treatment to

ARNI

β-blockers and MRA

Sacubitril/valsartanAnalysis:

• Appropriate shocks

• NSVT

• PVC burden

• Biventricular Pacing %

Pre-ARNI Post-ARNI

Study design and patient population

Patient characteristics pre- and post-intervention (1/3)

Pre-ARNI (n = 120) Post-ARNI (n = 120) P value

Clinical characteristics

Age (yrs)

Male

Ischemic cardiopathy

Hypertension

Diabetes

Hypercholesterolemia

Renal insufficiency

(filtration rate <60 mL/min)

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

Rhythm

Sinus rhythm

Paroxysmal AF

Permanent AF

85 (71)

17 (14)

35 (29)

84 (70)

12 (10)

36 (30)

NS

.07

NS

Values are given as mean ± SD, n (%), or %.

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

20

▪ Study design ensured patients served as their own controls1

Patient characteristics pre- and post-intervention (2/3)

Pre-ARNI (n = 120) Post-ARNI (n = 120) P value

Medical treatment

β-blocker

Mineraloid antagonist

Antiarrhythmic drug

Oral diuretic

100% ACEi or ARB

98%

97%

30%

75%

100% sacubitril-valsartan

98%

97%

29%

52%

NS

NS

NS

<.03

Device

ICD only

ICD + CRT

Primary prevention

Secondary prevention

56%

44%

65%

35%

56%

44%

65%

35%

NS

NS

NS

NS

Clinical data

NYHA functional class

(I–IV)

2.4 ± 0.4 1.5 ± 0.7 <.0002

Values are given as mean ± SD, n (%), or %

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

21

▪ 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

Patient characteristics pre- and post-intervention (3/3)

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

▪ 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

Sacubitril/valsartan significantly increased survival free time from appropriate ICD shocks, compared with ACEi/ARB

231, 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

▪ 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

Number at risk

ARNI 120

120

120

119

120

119

120

115

119

113

119

113ACEi/ARB

100

90

80

70

0 3 6 9

Time (months)

P<0.02

n=120

Su

rviv

al fr

ee f

rom

ap

pro

pri

ate

IC

D s

ho

cks

Pre-ARNI

Post-ARNI

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

24

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

Number at risk (VT)

ARNI 120

120

120

119

120

119

120

115

119

113

119

113ACEi/ARB

Number at risk (NSVT)

ARNI 120

120

111

104

103

90

95

77

86

67

82

59ACEi/ARB

100

80

60

40

20

0 3 6 9

NSVT

VT

Time (months)

Su

rviv

al fr

ee f

rom

NS

VT

an

d V

T

P<0.02

P<0.001

Pre-ARNI

Post-ARNI

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

25

80

60

40

20

100

0

PV

Cs/h

our

P<0.0003

n=120

Mean ± SE

33

78

Angiotensin inhibition

+β-blocker +MRA

Angiotensin-neprilysin

inhibition

+β-blocker +MRA

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

Angiotensin-neprilysin

inhibition

β-blocker + MRA

95

90

85

80

100

75

P<0.02

N=53

Mean ± SD

Angiotensin inhibition

+β-blocker + MRA

95%

98.8%

Biv

en

tric

ula

r P

acin

g %

Pre-ARNIPre-ARNI

Post-ARNIPost-ARNI

Optimization of medical therapy is necessary to improve outcomes in HF patients, whether or not they have an ICD

Summary (1/2)

• In patients with HFrEF (LVEF ≤40%), OMT is recommended to reduce sudden death and all-cause mortality– If LVEF remains <35% after OMT, guideline recommendations advise the

use of ICD in symptomatic patients

• Despite OMT and use of ICD, many patients remain at a high risk of sudden death (especially NYHA class II patients)

• In PARADIGM-HF:– 44.8% of NYHA class II HF CV deaths were sudden deaths

– Sacubitril/valsartan decreased the risk of sudden death by 20% vs enalapril

– For patients on an ICD, sacubitril/valsartan showed a 51% relative risk reduction vs enalapril

• Sacubitril/valsartan has a class IA recommendation for the pharmacological prevention of sudden death (as part of triple therapy)

27

Summary (2/2)

• deDiego et al (2018) have shown that, in patients with

an ICD and remote monitoring, switching ACEi/ARB to

sacubitril/valsartan significantly decreases:

– Ventricular arrhythmias

– ICD shocks

– PVC burden

And significantly increases:

– Biventricular pacing percentage

• This mechanistic study provides a potential explanation

for the observed reduction in sudden death seen in

PARADIGM-HF

28

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