Tối ưu hóa quản lý đa yếu tố nguy cơ tim mạch giải pháp viên phối hợp

Nội dung Các hướng dẫn điều trị rối loạn lipid Các hướng dẫn điều trị tăng HA hiện hành Đa yếu tố nguy cơ tim mạch -Tần suất -Lợi ích của kiểm soát yếu tố nguy cơ Một số nghiên cứu viên

HEE HWANG, MD

Department of Pediatric Neurology Center for Medical Informatics, SNUBH

TỐI ƯU HÓA QUẢN LÝ ĐA YẾU TỐ NGUY CƠ TIM MẠCH:

GIẢI PHÁP VIÊN PHỐI HỢP

Wonjae Lee, MD MBA International Healthcare Center/Cardiovascular Center

Seoul National University Bundang Hospital

Nội dung

Các hướng dẫn điều trị rối loạn lipid

Các hướng dẫn điều trị tăng HA hiện hành

Đa yếu tố nguy cơ tim mạch

- Tần suất

- Lợi ích của kiểm soát yếu tố nguy cơ Một số nghiên cứu viên phối hợp

Ca lâm sàng

Nguy cơ tử vong do tim mạch tăng gấp đôi với mỗi 20/10 mmHg huyết áp tăng

1 Chobanian AV et al JAMA 2003;289:2560-2572 Lewington S et al Lancet 2002;360:1903-1913

SBP = systolic blood pressure; DBP = diastolic blood pressure

*Individuals aged 40-69 years, starting at blood pressure 115/75 mm Hg

Lợi ích giảm nguy áp là bao nhiêu?

Phân tích gộp

• MEDLINE search

• Included RCT with a minimum of 1000 Pts-yrs f/u

Tác động của giảm HA tâm thu 10mmHg

1 Lancet 2016; 387: 957–67

↓SBP 10mmHg ↓ 20% Major CV events ↓ 17% Coronary heart disease ↓ 27% Stroke

↓ 28% HF ↓ 13% All-cause mortality

Baseline BP

SPRINT: điều trị chuẩn vs điều trị tích cực

1 SPRINT Research Group, NEJM 2015

Average SBP: 121 mmHg (2.9 meds) vs 134 mmHg (1.9 meds)

SPRINT: kết cục chính

1 SPRINT Research Group, NEJM 2015

Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)

Number Needed to Treat (NNT)

to prevent a primary outcome = 61 (319 events)

Number of

Participants

Primary outcome: CVD composite: first occurrence of Myocardial infarction (MI), Acute coronary syndrome (non-MI ACS), Stroke,

Acute decompensated heart failure (HF), Cardiovascular disease death

Kiểm soát tích cực huyết áp có thể giảm tử vong

Lower rates of heart attack, heart failure, and other cardiovascular events

Lower risk of death

Lower Blood Pressure Target : Dramatic Results

1 SPRINT Research Group, NEJM 2015

Chiến lược điều trị tăng huyết áp

1 //

Stage1 hypertension 130-139 or 80-89 Initial therapy

(ASCVD >10%) Stage2 hypertension 140-159 or 90-99 Dual-therapy

Stage2 hypertension ≥160 or ≥100 Dual-therapy

disease, chronic kidney disease

Thấp hơn là tốt hơn?

1 Kang et al Eur Heart J 2018 Dec 6

Patient: 290,600 subjects from the NHIS Health Screening Cohort who are not taking anti-hypertensive medication

Outcomes: MACE

Tăng huyết áp không được kiểm soát tốt

Dịch tể học cho thấy LDL-C cao có liên quan đến bệnh tim mạch và các biến cố tử vong

cholesterol or LDL-C resulted in more CV events

1 Kannel WB, et al Ann Intern Med 1971;74:1-12 2 MRFIT Research Group Prev Med 1986;15:254–273

Gánh nặng bệnh tật của xơ vữa động mạch

SATURN Substudy Baseline Percent Atheroma Volume Quartiles and Major Adverse CV Events

CV = cardiovascular; MACE = major adverse cardiovascular events; PAV = percent atheroma volume

Adapted from: Puri R, et al Eur Heart J 2013;34:3182-3190

7.9%

5.7%

Giảm LDL-C làm giảm gánh nặng bệnh tật do xơ vữa động mạch

1 LDL-C = low-density lipoprotein cholesterol; PAV = percent atheroma volume

Puri R, et al Am Heart J 2016;176:83-92

CAMELOT Placebo

STRADIVARIUS Placebo REVERSAL

Atorvastatin 80 mg

ASTEROID Rosuvastatin 40 mg

SATURN Rosuvastatin 40 mg SATURN Atorvastatin 80 mg

ILLUSTRATE Atorvastatin + placebo Progression

Regression

The ESTABLISH Study

Giảm LDL mạnh đi kèm với thoái triển mãng xơ vữa

LDL-C=low-density lipoproteins cholesterol; PAV = percent atheroma volume; CI = confidence interval

1 Nicholls et al JAMA 2007;297:499-508

• LDL-C is an independent predictors of atheroma regression.

• Substantial atheroma regression was observed in patients with levels of LDL-C less than the mean (87.5 mg/dL) during treatment.

Lipids: một yếu tố nguy cơ có thể thay đổi được của nhồi máu cơ tim cấp

INTERHEART: 9 modifiable factors account for 90% of first-MI risk worldwide, N = 15,152 patients and 14,820 controls in 52

countries.1 *Proportional reduction in population disease that would occur if exposure to a risk factor were reduced to an

alternative ideal exposure scenario

(eg no tobacco use).2 PAR = population attributable risk, adjusted for all risk factors

1 Yusuf S, et al Lancet 2004:364;937-952 2 2 World Health Organization https://www.who.int/healthinfo/global

_burden_disease/metrics_paf/en/ Accessed February 1, 2019

Psychosocial Smoking Lipids

Population Attributable Risk*

Tỷ lệ bệnh nhân CHD và ACS không đạt được LDL-C < 70 mg/dL

Gitt AK, et al Atherosclerosis 2017;266:158-166

CHD and ACS Patients Achieving Target LDL-C in Multinational, Prospective,

Observational DYSIS II Study, 2012–2013

29.4 30.6

11.1 18.9

25.7

6.2

0 10 20 30 40

All patients Patients on

treatment Patients not on treatment

CHD cohort (n = 6,794) ACS cohort (n = 3,867)

* Treatments included statin monotherapy, statins plus cholesterol absorption inhibitor, statins plus fibrates, statins plus omega-3 fatty acids, statins plus

ASCOT: cộng dồn tần suất NMCT không tử vong và tử vong do bệnh tim mạch vành

Sever PS, et al Lancet 2003;361:1149-1158

Thiết kế nghiên cứu IMPROVE-IT

ACS, acute coronary syndrome; CV, cardiovascular; MI, myocardial infarction; UA, unstable angina;

N Engl J Med 2015;372:2387-97;

Standard Medical & Interventional Therapy

Patients stabilized post ACS ≤ 10 days:

LDL-C 1.3*-3.2† mM/L (or 1.3*-2.6** mM/L if prior lipid-lowering RX)

Primary Endpoint: CV death, MI, hospital admission for UA, coronary

revascularization (≥ 30 days after randomization), or stroke

Standard Medical & Interventional Therapy

Duration: Minimum 2 ½-year follw-up

(at least 5,250 events)

 Double-blind, randomized trial, n=18,144

Giảm thêm 24% khi phối hợp với ezetimibe dẫn đến giảm thêm 6.4% biến cố bệnh tim mạch

N Engl J Med 2015;372:2387-97

Thiết kế nghiên cứu FOURIER

Giảm thêm 59% với evolucomab dẫn đến giảm thêm 15% biến cố tim mạch

Tổng quan của phòng ngừa tiên phát và thứ phát

enhancers and coronary artery calcium score

if uncertain

Risk discussion for statin benefit: Use risk enhancers Lifestyle:

selective moderate statin

Lifestyle and risk discussion Assess lifetime

risk

Maximally tolerated statin Moderate-

intensity statin

High-intensity statin

Moderate- intensity statin

N

N

Y

If LDL-C ≥ 100 mg/dL: Adding ezetimibe is reasonable

↓

If LDL-C

≥ 100 mg/dL:

PCSK9i may be considered

Aim for LDL-C lowering 30%–49%

If multiple ASCVD risk factors 50–75 years of age:

High-intensity statin

Aim for LDL-C lowering

≥ 50%

Aim for LDL-C lowering 30%–49%

Stable ASCVD Very high–risk

If LDL-C ≥ 70 mg/dL: Adding ezetimibe is reasonable

↓

If LDL-C

≥ 70 mg/dL or non–HDL-C

≥ 100 mg/dL:

Adding PCSK9i

is reasonable following risk discussion

High- or moderate- intensity statin

If high-intensity statin: Aim for LDL-C lowering

≥ 50%

If intensity statin: Aim for LDL-C lowering 30%–40%

moderate-History of multiple major ASCVD events

2018 ACC/AHA Guidelines: Tăng cholesterol nguyên phát nặng

J Am Coll Cardiol 2018 doi: 10.1016/j.jacc.2018.11.003

Extremely high LDL-C (≥ 190 mg/dL)

requires immediate intervention

with high-intensity statins, without

risk assessment†

Age 30–75 years with HeFH and LDL-C ≥ 100 mg/dL and maximal statin and ezetimibe therapy, consider addition of PCSK9 inhibitor‡

Age 40–75 years with baseline LDL-C ≥ 220 mg/dL and with LDL-C

≥ 130 mg/dL on maximal statin and ezetimibe therapy, consider addition of PCSK9 inhibitor§

Primary Severe Hypercholesterolemia (LDL-C ≥ 190 mg/dL [≥ 4.9 mmol/L]) Recommendations

DM and age 40–75 years

Moderate-intensity statin‡

DM and age 40–75 years

Risk assessment to consider high-intensity statin†

Age > 75 years

Clinical assessment, risk discussion

Primary Severe Hypercholesterolemia Prevention

LDL-C ≥ 190 mg/dL (≥ 4.9 mmol/L)

No risk assessment; high-intensity statin†

Age 40–75 years

• And LDL-C ≥ 70–189 mg/dL without DM – 10-year ASCVD risk percent begins risk discussion

2018 ACC/AHA Guidelines: Statin cường đột cao phòng

ngừa thứ phát biến cố lâm sàng của ASCVD*

J Am Coll Cardiol 2018 doi: 10.1016/j.jacc.2018.11.003

Secondary ASCVD Prevention

In those with very high–risk ASCVD on maximal statin therapy, LDL-C ≥ 70 mg/dL

is the point at which to initiate non-statin therapy to intensify lipid-lowering

Clinical ASCVD Healthy lifestyle ASCVD not at very high risk†

≥70 mg/dL (≥1.8 mmol/L), may add ezetimibe

Initiation of moderate- or high-intensity statin

Continuation of high-intensity statin

If on maximal statin therapy and LDL-C ≥ 70 mg/dL (≥ 1.8 mmol/L), may add ezetimibe

If PCSK9i is consi dered, add ezetimi

be before PCSK9i

to maximal statin

Dashed arrow: RCT-supported efficacy, but less cost-effective

High-intensity statin

(Goal  LDL-C ≥ 50%)

Age > 75 years

Very high–risk ASCVD†

High-intensity or maximal statin

If on maximal LDL-C–lowering therapy and LDL-C ≥ 70 mg/dL (≥ 1.8 mmol/L) or non–HDL-C ≥ 100 mg/dL (≥ 2.6 mmol/L),

may add PCSK9i Age ≤ 75 years

Đánh giá và phân tầng nguy cơ tim mạch tạo thuận lợi trong quyết định điều trị

Mach F, et al Eur Heart J 2019 doi:10.1093/eurheartj/ehz455 [Epub ahead of print.]

People with any of the following:

• Documented ASCVD , either clinical or

unequivocal on imaging Documented

ASCVD includes previous ACS (MI or

unstable angina), stable angina , coronary

revascularization (PCI, CABG, and other

arterial revascularization procedures),

stroke and TIA, and PAD Unequivocally

documented ASCVD on imaging includes

those findings that are known to be

predictive of clinical events, such as

significant plaque on coronary angiography

or CT scan (multivessel coronary disease

with two major epicardial arteries having >

50% stenosis ), or on carotid ultrasound

• DM with target organ damage,a or at least

three major risk factors, or early onset of

T1DM of long duration (> 20 years)

• Severe CKD (eGFR < 30 mL/min/1.73 m2)

• A calculated SCORE ≥ 10% for 10-year risk

T2DM < 50 years) with

DM duration < 10 years, without other risk factors

• Calculated SCORE ≥ 1%

and < 5% for 10-year risk

of fatal CVD

• Calculated SCORE < 1% for 10-year risk of fatal CVD

Các hướng dẫn điều trị năm 2019 khuyến cáo giảm LDL-C càng thấp càng tốt

Mach F, et al Eur Heart J 2019 doi:10.1093/eurheartj/ehz455 [Epub ahead of print.]

LDL-C < 1.8 mmol/L (< 70 mg/dL)

AND

≥ 50% LDL-C reduction from baselineb

Moderate risk < 3.0 mmol/L (116 mg/dL) LDL-C < 2.6 mmol/L (< 100 mg/dL)

Low risk < 3.0 mmol/L (116 mg/dL) LDL-C < 3.0 mmol/L (< 116 mg/dL)

Can thiệp điều trị bằng thuốc bắt đầu bằng statin cường

độ cao và tăng liều nếu cần

Mach F, et al Eur Heart J 2019 doi:10.1093/eurheartj/ehz455 [Epub ahead of print.]

High-intensity statin should be prescribed up to the

highest tolerated dose to reach the goals set for the

For patients who cannot tolerate the recommended statin dose due to adverse events, or for those who do not reach their LDL-

C goal, the addition of non-statin lipid-lowering therapy to

maximally tolerated statin is recommended

High-intensity statin regimen

• A dose of statin that, on average, reduces LDL-C by ≥ 50%

Moderate-intensity statin regimen

Can thiệp điều trị: Statin + Ezetimibe + PCSK9i

Mechanism of action representations are for illustrative purposes only and not meant to imply clinical efficacy mAb = monoclonal

Statins

Upregulation of LDL-R expression

↓ Cholesterol synthesis

↑ LDL-R on hepatocyte surface

↑ LDL clearance ↓ Circulating LDL-C

Free circulating PCSK9

LDL degradation

LDL-R recycling

LDL particle

Tích hợp các cơ chế tế bào của bệnh tim mạch

Park KH et al J Korean Med Sci 2015 Sep;30(9):1213-25

Hypertension and Dyslipidemia are the critical Oxidative Stress factors causing Atherosclerosis and Cardiovascular Disease

Hypertension Dyslipidemia

Oxidative stress

Endothelial dysfunction Reduced NO bioavailability

Progression of Atherosclerosis and Cardiovascular

disease

Bệnh đồng mắc không ngừng tăng ở Hàn Quốc

Dyslipidemia fact sheets in Korea, 2018

4,667,226

HTN with comorbidities

3,551,873

HTN only vs.

Tác động nhân lên của nhiều yếu tố nguy cơ tim mạch

Hypertension: Physiopathology and Treatment New York, NY: McGraw-Hill Book Company;1977:888-910

Bệnh tim mạch với đa yếu tố nguy cơ

1 Mancia G, et al 2013 ESH/ESC Guidelines for the management of arterial hypertension Eur Heart J 2013;34:2159-2219

2 Kannel WB Risk Stratification in Hypertension: New Insights From the Framingham Study Am J Hypertens 2000;13:3S-10S

Hypertension

Abnormal cholesterol + Hypertension

Diabetes + Abnormal cholesterol + Hypertension

Smoking + Diabetes + Abnormal cholesterol + Hypertension

Heart damage + Smoking + Diabetes + Abnormal cholesterol + Hypertension

10-Year Probability of

Event (%)

Probability Of a Coronary Heart Disease According

to the Presence of Risk Factors

in Men Aged 45 Years2

Tác động gộp của giảm cholesterol và giảm huyết áp trong dân số

Emberson J, et al Eur Heart J 2004;25:484-91

Amlodipine giảm nguy cơ các biến cố tim mạch chính

Tiwaskar M, et al Amlodipine in the Era of New Generation Calcium Channel Blockers J Assoc Physicians India 2018;66:59-64

No of Events Odds Ratio (95% CI)

Trial Intervention No of Patient

(0.35-OR 0.52 1.41)

(0.19-OR 0.80 (0.34- 1.84)

OR 0.58 0.92)

(0.36-OR 1 18 3.04)

(0.46-ALLHAT Lisinopril 9054 457 796 612 2514 618

Amlodipine 9048 377 798 706 2432 603

OR 0.82 0.94)

(0.71-OR 0.99 1.08)

(0.90-OR 1.17 (1.04- 1.31)

OR 0.96 1.03)

OR 0.97 1.09)

(0.74-OR0.85 0.99)

(0.73-OR 1.15 (0.99- 1.33)

OR 0.96 1.05)

(0.89-OR 1.01 1.18)

(0.86-IDNT Amlodipine 567 15 27 93 161 37

Irbesartan 579 28 44 60 172 52

OR 0.53 1.01)

(0.28-OR 0.61 1.00)

(0.37-OR 1.70 (1.20- 2.40)

OR 0.94 1.21)

(0.73-OR 0.71 1.10)

(0.46-CASE J Amlodipine 2349 47 18 16 134 15

Candesartan 2354 60 17 20 134 11

OR 0.78 1.15)

(0.53-OR 1.06 2.06)

(0.55-OR 0.80 (0.41- 1.55)

OR 1.00 1.28)

(0.78-OR 1.37 2.99)

(0.63-AASK, The African American Study of Kidney Disease and Hypertension; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; IDNT, Irbesartan diabetic nephropathy trial; VALUE Valsartan Antihypertensive Long-Term Use Evaluation; CASE J, Candesartan

Antihypertensive Survival Evaluation in Japan; MI, Myocardial Infarction; CHF, Congestive Heart Failure; MACE, Major Adverse Cardiovascular Events

Amlodipine giảm nguy cơ các biến cố tim mạch chính

No of Events Odds Ratio (95% CI)

Trial Intervention No of Patien

ts Stroke MI CHF MACE CV Mortality

Amlodipine v

s Diuretic ALLHAT Chlorthalidone 15255 675 1362 870 3941 996

Amlodipine 9048 377 798 706 2432 603

OR 0.94 1.07) OR 1.00 (0.91-1.11) OR 1.40 (1.26-1.55) OR 1.06 (0.99-1.12) OR 1.02 (0.92-1.14) ACCOMPLI

(0.83-SH Amlodipine 5744 112 125 100 552 107

HCTZ 5762 133 159 96 679 134

OR 0.84 1.09) OR 0.78 (0.62-0.99) OR 1.05 (0.79-1.39) OR 0.80 (0.71-0.90) R 0.80 (0.62-1.03) Amlodipine v

(0.66-ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm; ACCOMPLISH, The Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension trial; HCTZ, hydrochlorothiazide; MI, Myocardial Infarction; CHF, Congestive

Heart Failure; MACE, Major Adverse Cardiovascular Events

Tiwaskar M, et al Amlodipine in the Era of New Generation Calcium Channel Blockers J Assoc Physicians India 2018;66:59-64