Đột phá trong điều trị suy tim- Các nhóm thuốc mới

GS.TS. Huỳnh Văn Minh Bộ Môn Nội Trường Đại học Y Dược Huế Trung Tâm Tim mạch BV Đại học Y Dược Huế

Mở đầu

Tần suất Suy tim theo phân bố vùng trên thế giới theo WHO 2004

Ca mới / năm

Vùng

Africa

0.5 M

America

0.8 M

Mediterranean

0.4 M

Europe

1.3 M

Southeast Asia

1.4 M

West Pacific

1.3 M

World

5.7 M

GBD - WHO 2004

Incidence of congestive heart failure due to rheumatic heart disease, hypertensive , heart disease, ischemic heart disease or inflammatory heart diseases

Tần suất và tỉ lệ mắc Suy tim tại Đông Nam Á

Quốc gia

Tần suất

Tỉ lệ

South Korea 2004

--

1/1000

Japan 2004

1.6%

--

Hong Kong

0.5%

3.4/1000

China

--

--

Taiwan

5.5%

2.7/1000

Thailand

--

--

Philippines

--

--

Indonesia

--

--

Malaysia

6.7%

--

Singapore

6.3%

Australia 2005

30,000 /year

Các tiến bộ & nghiên cứu hiện nay trong điều trị suy tim Progress in HFrEF Therapy

Điều trị suy tim HFrEF giai đoạn C và D

Yancy C, et al. JACC, 2016

CÁC NHÓM THUỐC GiẢM TỬ VONG TRONG SUY TIM EF GiẢM

Suy tim trong thời kỳ COVID-19 !

Recommendations

1. Study sponsors and sites should exercise the option of following patients using telephone follow-up procedures, until the COVID-19 pandemic abates.

2. Diagnostic procedures, such as echocardiography, and some study interventions such as the implantation of an investigational study device should be delayed until the COVID-19 pandemic abates, due to the absence of safety concerns or overwhelming evidence benefit.

3. Trials under development or with central IRB capability are encouraged to consider central IRB use.

4. Statistical consideration should account for asymmetric enrollment by geography, and analysis of results before and after a pre-specified date on which

COVID-19 had a significant influence on trial conduct.

5. Specific issues regarding adjudication definitions in light of COVID-19 infection should be adjusted in the clinical events committee manuals of operation.

6. Encourage maintenance of the patient screening architecture for HF clinical trials so that screening may be quickly escalated again once the pandemic subsides, in as much as this can be accomplished safely and remotely.

7. Consider geographically targeting sites for initiation that are less likely to be influenced by the pandemic.

Các nhóm thuốc mới trong điều trị suy tim

1

Tần số tim là một yếu tố nguy cơ của suy tim

Bohm, M et al Lancet 2010

Tác dụng ức chế của Ivabradine lên kênh hyperpolarization-activated

cyclic nucleotide-gated (HCN).

Mitchell A. Psotka, and John R. Teerlink Circulation.

Copyright © American Heart Association, Inc. All rights reserved.

2016;133:2066-2075

SHIFT Trial: Increased Risk of CV Death and HF Nghiên cứu SHIFT: Sự gia tăng nguy cơ tử vong tim mạch Hospitalization With Increased Heart Rate in SR in và nhập viện theo tần số tim HF

Mục tiêu nguyên phát: ( Tử vong TM và nhập viện do suy tim nặng

Cumulative frequency (%)

40

HR = 0.82 (0.75-0.90)

Placebo

P < 0.0001

18%

30

Ivabradine

20

10

0

0

6

12

18

24

30 Months

www.shift-study.com

Swedberg K, et al. Lancet. 2010;376(9744):875-885

2

Vericiguat: tăng hoạt tính của sGC để cải thiện chức năng của cơ tim và mạch máu

Thiết kế nghiên cứu VICTORIA

The VICTORIA study was a randomised, parallel-group, placebo-controlled, double-blind, event-driven, international phase III trial investigating the effect of vericiguat in patients with HFrEF

2.5 mg OD 5 mg OD 10 mg OD

1:1

Placebo OD with sham up-titration at Weeks 2

and 4

Eligibility criteria ­ HFrEF (LVEF <45%) ­ NYHA Class II-IV ­  BNP: ≥300 pg/ml SR; ≥500 pg/ml +AF ­ NT-proBNP: ≥1000 pg/ml; SR ≥1600 pg/ml +AF ­ eGFR: ≥15 ml/min/1.73 m2

Week 0 Week 2 Week 4 Week 16

Q16W

(15% cap: 15-30 ml/min/1.73 m2) ­ HF hospitalisation within 6 months or

IV diuretic treatment for HF within 3 months

Primary endpoint: Time to first occurrence of the composite of CV death and HF hospitalisation

Secondary endpoints: ­ Time to CV death ­ Time to first HF hospitalisation ­ Time to total HF hospitalisations (first and recurrent) ­ Time to all-cause mortality ­ Time to composite all-cause mortality or HF hospitalisation

Exploratory endpoints included changes in KCCQ and EQ-5D from baseline and the relationships among treatment effect, baseline biomarkers and genetic variation

AF, atrial fibrillation; BNP, B-type natriuretic peptide; CV, cardiovascular; eGFR, estimated glomerular filtration rate; EQ-5D, EuroQol 5-dimension; IV, intravenous; KCCQ, Kansas City Cardiomyopathy Questionnaire; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NT- proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; OD, once daily; SR, sinus rhythm

1. Armstrong PW et al. JACC Heart Fail. 2018;6:96-104; 2. Armstrong PW et al. N Engl J Med. 2020;382:1883-1893

Vericiguat giảm có ý nghĩa nguy cơ tuyệt đối suy tim

Time to CV death or first HF hospitalisation

§ Median treatment duration for

primary endpoint: 10.8 months

Vericiguat Placebo

Giảm 4.2%

§ Annual event rate for vericiguat vs placebo per 100 patient-years was 33.6% versus 37.8%, respectively

p=0.02

0.55 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15

HR=0.90 (95% CI: 0.82-0.98) ARR=4.2% per year Annual NNT=24*

4

8

12

20

24

32

36

0.10 0.05 0.00 0

Number of subjects at risk

28 16 Months since randomisation

Vericiguat

2526

2099

1621

1154

826

577

125

348

1

0

Placebo

2524

2053

1555

1097

772

559

110

324

0

0

*Calculations: Annual NNT = 100/4.2 = 24

ARR, absolute risk reduction; CI, confidence interval; CV, cardiovascular; HF, heart failure; HFH, heart failure hospitalisation; HR, hazard ratio; NNT, number needed to treat

Armstrong PW et al. N Engl J Med. 2020;382:1883-1893

Tóm tắt tác dụng Vericiguat trong suy tim HFrEF

Cơ chế tác dụng1,2

Quần thể bệnh nhân2

Vericiguat enhances the cGMP pathway leading to improved myocardial and vascular function in HF

VICTORIA included patients with symptomatic chronic HF (LVEF <45%) who had a previous worsening HF event despite currently available HF therapies2

Hiệu quả

An toàn2 § Overall AE profile of vericiguat comparable to placebo

§ Vericiguat significantly reduced the annualised absolute risk of the VICTORIA composite outcome of time to HFH or CV death by 4.2%2

§ Rates of symptomatic hypotension and syncope were similar to placebo § No decreases in eGFR

§ The effect of vericiguat on the primary outcome was consistent across most prespecified subgroups2

§ Vericiguat reduced the primary endpoint and its

components across a range of NT-proBNP up to 8000 pg/ml3

§ Despite decreases in SBP and DBP occurring Early In the titration phase, no further clinically relevant reductions in BP were subsequently observed

AE, adverse event; BP, blood pressure; CV, cardiovascular; cGMP, cyclic guanosine monophosphate; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HF, heart failure; HFH, heart failure hospitalisation; HFrEF, heart failure with reduced ejection fraction; SBP, systolic blood pressure; sGC, soluble 1. Gheorghiade M et al. Heart Fail Rev. 2013;18:123; 2. Armstrong PW et al. N Engl J Med. 2020;382:1883-1893; 3. Ezekowitz JA et al. HFA. 2020 guanylate cyclase; NT-proBNP, N-terminal pro-brain natriuretic peptide

Tác dụng của nhóm thuốc LCZ696 lên hệ NP và hệ 3

RAAS

NP system

RAS

Pathophysiological response Physiological response

Ang II

– –

NPs

N

e

p

rily

-

X

-

AT1 receptor

sin X

LCZ696 (an ARNI)

Inactive fragments

Vasodilation

Vasoconstriction

BP

BP

Sympathetic tone

Sympathetic tone

HF symptoms/ progression

Aldosterone

Aldosterone

Fibrosis

Fibrosis

Hypertrophy

Hypertrophy

Natriuresis/diures

is

18

Ferro et al. Circulation 1998;97:2323–30; Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Schrier et al. Kidney Int 2000;57:1418–25; Schrier & Abraham. N Engl J Med 1999;341:577–85; Stephenson et al. Biochem J. 1987;241:237–47 Langenickel , Dole. Drug Discov Today: Ther Strategies 2014, in press.

Kết quả nghiên cứu PARADIGM-HF

Significant Reduction in Primary Endpoints (CV death or heart failure hospitalization), CV Death and All-Cause Mortality

McMurray et al. N Engl J Med 2014; 371(11):993-1004.

Sacubitril/valsartan trong suy tim cấp

Serious Composite Clinical Endpoint

Death, HF re-hosp, LVAD, Transplant listing

20

16.8%

enalapril

HR = 0.54; 95% CI 0.37, 0.79 P = 0.001

N = 441

NNT = 13

10

9.3%

sacubitril/valsartan N = 440

0

0 7 14 24 28

35 42 49 56

Days since Randomization

Velazquez EJ et al. NEJM 2018

Thuốc ức chế SGLT2 trong suy tim mạn

4

2019

2020

2021

DAPA-HF1 Dapagliflozin

EMPEROR-Reduced2 Empagliflozin

SOLOIST-WHF4 Sotagliflozin

N~2800 patients with HFrEF,

N~4500 patients with

N~4000 (HF+ T2DM

with or without DM)

HFrEF, with or without

all EF; pre-discharge)

CV death of HHF

DM)

CV death or hHF

WHF or CV death

EMPEROR-Preserved3 Empagliflozin

DELIVER5 Dapagliflozin

N~4100 HF patient with

N~4500 HF patients with

LVEF>40% with or without T2DM

CV death or HHF

LVEF>40% with or without T2DM) WHF or CV death

1. https://clinicaltrials.gov/ct2/show/NCT03036124; 2. https://clinicaltrials.gov/ct2/show/

2. NCT03057977; 3. https://clinic . 4. https://clinicaltrials.gov/ct2/show/NCT03521934

Cơ chế tác dụng của thuốc ức chế SGLT-2

Abhinav Sharma et al. JCHF 2018;6:813-822

©2018 by American College of Cardiology

Nghiên cứu liên quan SGLT2 inhibition

EMPA-REG CANVAS DECLARE

N 7020 10,142 17,160

SGLT2i Empagliflozin Canagliflozin Dapagliflozin

T2DM with T2DM with established CVD T2DM with established CVD

Patients

established CVD or multiple CV risk factors or multiple CV risk factors

a) CV death, MI, stroke a) CV death, MI, stroke Primary

CV death, MI, stroke

b) albuminuria b) CV death or hHF Outcome

a) HR: 0.86; P=0.016 a) HR 0.93; P = 0.17 HR: 0.86

Primary result P=0.04 b) HR 0.73; (0.67 - 0.79) b) HR 0.83 ; P = 0.005

Heart Failure

HR 0.65 (0.50 - 0.85) HR 0.67 (0.52 - 0.87) HR 0.73 (0.61- 0.88)

hospitalization

DAPA-HF: Tác dụng Dapagliflozin trong suy tim có hoặc

không ĐTĐ

Effect on Primary Endpoint of Cardiovascular Death and Serious Heart Failure Events

Nghiên cứu EMPA-REG

Nhập viện do suy tim HR 0.65

(95% CI 0.50, 0.85)

Giảm nguy cơ 35%

p=0.0017

Cumulative incidence function. HR, hazard ratio

Median follow-up, 3.6 years

Fitchett D et al. Eur Heart J 2016; 37, 1526-1534

Điều trị suy tim ở bệnh nhân Đái tháo đường

Abhinav Sharma et al. JCHF 2018;6:813-822

©2018 by American College of Cardiology

5

Omecamtiv Mecarbil (OM) Nhóm hoạt hóa chọn lọc Myosin tim

Mechanochemical Cycle of Myosin

OM stabilizes myosin in the Pre- Powerstroke State, increasing the entry rate of myosin into the tightly-bound, force-producing state with actin “More hands pulling on the rope”

Increases duration of systole

Increases stroke volume

No increase in myocyte calcium

No change in dP/dtmax

Malik FI, et al. Science 2011; 331:1439-43. Shen YT, et al. Circ Heart

Fail 2010;3:522-7.

Planelles-Herrero VJ, et al. Nat Commun 2017;8:190.

No increase in MVO2

Teerlink JR, et al. J Am Coll Cardiol HF 2020;8:329-340.

Cơ chế tác dụng Omecamtiv Mecarbil

Omecamtiv mecarbil binds to myosin, stabilizing myosin in a pre-primed position and increasing the number of myosin heads available for contraction

Omecamtiv  mecarbil

S1 Domain

Malik et al. Science 2011

11 Teerlink et al. JACC Heart Fail 2020

COSMIC-HF: tăng chức năng thất trái

SET

Stroke Volume

LVEF

LVEDD

SET, systolic ejection time; LVEF, left ventricular ejection fraction; LVEDD left ventricular end diastolic diameter

Teerlink et al.

Lancet 2016

13

Proprietary and Confidential - not for distribution

COSMIC-HF: Tác dụng dược động học

Decreases in Heart Rate and Brain Natriuretic Peptide

Reductions in NT­proBNP  persisted 4 weeks after  omecamtiv mecarbil was  stopped (p = 0.0006)

NT-proBNP, N-terminal of the prohormone brain natriuretic peptide

Teerlink et al. Lancet 2016

14

Proprietary and Confidential - not for distribution

6

Thiếu sắt và suy tim

• Tần suất thiếu sắt trong suy tim

>40-50%

- Ferritin <100 ng/mL

- Ferritin 100-300 ng/mL + transferrin saturation [TSAT] <20%

• Ở bệnh nhân có và không thiếu máu

Jankowska EA et al. Eur Heart J. 2013 Mar;34(11):816-29.

Iron Deficiency in HF Thiếu sắt trong suy tim

Impact of IV Iron in HFrEF

Thiếu sắt trong suy tim EF giảm

Nghiên cứu CONFIRM-HF

+33 ± 11 m

Reduction in HF hosp HR 0.39 (0.19-0.82) P = 0.009

Improvements in NYHA class, PGA, QoL, with FCM was detected with statistical significance observed from Week 24 onwards

Ponikowski et al. Eur Heart J. 2015

Chuyền sắt trong điều trị suy tim

Tác dụng giảm nguy cơ và tử vong của các loại thuốc

trong suy tim EF giảm

Nguy cơ

tương đối

None

- -

Tử vong 2 năm 35%

ACEI or ARB

23%

27%

Beta Blocker

35%

18%

Aldosterone Ant

30% 13%

ARNI (replacing ACEI/ARB)

16% 10.9%

17%

9.1%

SGLT2 inhibitor

Cumulative risk reduction if all evidence-based medical therapies are used:

Relative risk reduction 74.0%, Absolute risk reduction: 25.9%, NNT = 3.9

Updated from Fonarow GC, et al. Am Heart J 2011;161:1024-1030 and Lancet 2008;372:1195-1196.

Ích lợi của phối hợp thuốc trong điều trị suy tim

All cause Mortality

CVD Mortality

HR

HR

(95% Credible Interval)

(95% Credible Interval)

ARNI+BB+MRA vs Placebo

ARNI+BB+MRA vs Placebo 0.36 (0.16;0.71)

0.38 (0.2;0.65)

0.41 (0.19;0.82)

ACEI+BB+MRA+IVA vs Placebo 0.41 (0.21;0.7)

ACEI+BB+MRA+IVA vs Placebo

0.45 (0.25;0.75)

ACEI+BB+MRA vs Placebo

ACEI+BB+MRA vs Placebo

0.44 (0.27;0.67)

0.47 (0.24;0.82)

0.48 (0.24;0.86)

ACEI+ARB+BB vs Placebo

ARB+BB vs Placebo

0.5 (0.19;1.12)

ACEI+ARB+BB vs Placebo

ARB+BB vs Placebo

0.52 (0.32;0.8)

0.56 (0.31;0.95)

0.58 (0.34;0.95)

ACEI+MRA vs Placebo

BB vs Placebo

0.56 (0.37;0.75)

ACEI+MRA vs Placebo

0.58 (0.36;0.9)

ACEI+BB vs Placebo

0.62 (0.27;1.32)

ACEI+BB vs Placebo

0.58 (0.42;0.73)

BB vs Placebo

ACEI+ARB vs Placebo

0.8 (0.43;1.33)

ACEI+ARB vs Placebo

0.83 (0.52;1.23)

ACEI vs Placebo

0.81 (0.6;1.04)

ACEI vs Placebo

0.84 (0.67;1.01)

ARB vs Placebo

0.85 (0.51;1.28)

ARB vs Placebo

0.89 (0.61;1.27)

0

2

0

2

1 HR

1 HR

46

Komajda M, et al. Eur J Heart Fail 2018.

Zeitler, E.P. et al. J Am Cardiol HF. 2020; 8 (4): 251-64.

KẾT LUẬN

• Suy tim là một biến chứng phổ biến, là gánh

nặng cho kinh tế xã hội.

• Việc điều trị trong những thập niên gần đây

đã có những đột phá với sự ra đời các nhóm thuốc mới.

• Tuy vậy vẫn còn nhiều hạn chế nhất đinh do đó những nghiên cứu vẫn còn mở ra đặc biệt việc phối hợp với các phương tiện ./.

Chân thành cám ơn sự theo dõi quí Đại biểu