Kiểm soát rối loạn lipid máu thế nào để dự phòng đột quỵ

CHOLESTEROL LOWERING AFTER STROKE
What ? When ? How Much & How Long ?

Nguyen Huy Thang, MD

Department of Cerebrovascular Disease


CASE

• BN nữ 67T, nhập viện vì hôn mê

• NIHSS 34, nhập viện lúc 12g trưa
• Thời điểm còn bình thường gần nhất 1g
sáng


CT - CTA


IV rtPA sau 13 giờ tính từ thời điểm BN còn bình thường
NIHSS 8 lúc xuất viện, mRS 3 sau 3 tháng


CASE
• Bệnh sử

–Không có tiền căn đột quỵ, bệnh mạch vành
–Cao huyết áp không điều trị
• Xét nghiệm:
Lipids: TC: 224 mg/dL; LDL-C: 120 mg/dL

TG: 125 mg/dL; HDL-C: 55 mg/dL
Glycemia: 110 mg%, Hba1c 6%


CHOLESTEROL LOWERING AFTER STROKE
What ? When ? How Much & How Long ?


WHAT TO START ?


Non-Statin Cholesterol Lowering
Stroke Risk

Intervention

No of Trials

Risk Ratio

Diet

10

0.99 (0.85-1.15)

Fibrates

11

1.04 (0.92-1.19)

Resins

4

1.03 (0.54-2.00)

N3 Fatty Acids

8

0.91 (0.56-1.48)

Briel et al. Am J Med 2004;117:596


Non-stroke

Stroke

4S
TNT1

LIPID

Coronary
Disease

CARE

MIRACL
GREACE

PROSPER2

WOSCOPS

Non
Coronary
Disease

ALLHAT

JUPITER

HPS2

SPPARCL

ASCOT
CARDS

1Some
2Mixed

patients with prior stroke
primary and secondary CVD patient populations


Heart Protection Study

HPS Collaborative Group Lancet 2002;360:7

• Tuổi 40 - 80 (n= 20,536)
• Nguy cơ bệnh mạch vành cao:
– Tiền sử nhồi máu cơ tim hoặc bệnh mạch vành
– Tắc nghẽn các mạch máu khác
• Đột quỵ (n=3,280)
• Đột quỵ không kèm mạch vành (n=1,820)

– Tiền sử tiểu đường, tăng huyết áp
• Triglyceride > 135 mg/dl
• Điều trị: 2x2 (factorial design)
– Simvastatin 40 mg vs Matching placebo
– Antioxidant vitamins vs Matching placebo


Heart Protection Study
Patients With vs. Without Prior Stroke

24%

HPS Investigators Lancet 2004;363:757


Patient with Event (5)

HPS: No Reduction in Risk of Recurrent Stroke
in Patients With Prior Cerebrovascular Disease

n=406

n=488

Major Vascular Events
*29% RR, P=.001
Heart Protection Study Collaborative Group. Lancet. 2004;363:757–767.

n=169

n=170

Stroke


SPARCL
Study Design
Double-Blind Period

Patient Population
 Stroke or TIA within 1-6 months
4,731
 No history of CHD
Patients

Atorvastatin 80 mg/day
Mean on Rx LDL-C 73 mg/dL

 LDL-C levels ≥100 mg/dL and
≤190 mg/dL
Baseline LDL-C

133 mg/dL

Placebo
Mean on Rx LDL-C 129 mg/dL
540 Primary Endpoints

Primary End Point (n=576)
Time to the First Occurrence of a Fatal or Non-fatal Stroke
Pre-specified adjustment for geographical region, entry event, time since entry event, gender, and baseline age

The SPARCL Investigators. NEJM 2006;355 549


SPARCL Primary Endpoint

Fatal or Non-Fatal Stroke (%)

Time to Fatal or Non-Fatal Stroke
16%
Placebo
Atorvastatin
12%

16%
8%

4%

Adjusted HR (95% CI) = 0.84 (0.71, 0.99),
p = 0.03

0%
0

1

2

3

4

5

6

Years Since Randomization

The SPARCL Investigators. NEJM 2006;355:549

Pre-specified adjustmentfor geographical
region, entry event, time since entry event,
sex, and age.


“ Statin therapy with intensive lipid-lowering effects is
recommended to reduce risk of stroke and

cardiovascular events among patients with ischemic
stroke or TIA ”
(Class I; Level of Evidence B)

WHEN TO START?


WHEN TO START ?
• Heart Protection Study: Thời gian bắt đầu sử
dụng sau Đột Qụy # 4.3 năm

Không ghi

nhận lợi ích của Simvastatin
• SPARCL: 1 – 6 tháng

Giảm 16% nguy cơ ĐQ

• Guidelines: Sự tuân thủ điều trị sẽ tốt hơn nếu

bắt đầu sử dụng trong thời gian nằm viện


HOW MUCH ?


Statins and Hemorrhagic Stroke
Meta-analysis

Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

SPARCL Ischemic and Hemorrhagic Stroke
Post hoc analysis
Fatal and Non-fatal Stroke

Ischemic or Hemorrhagic Stroke (%)

16
Placebo: Ischemic
Atorvastatin: Ischemic
Placebo: Hemorrhagic
Atorvastatin: Hemorrhagic

21%

12
Ischemic: HR (95% CI) = 0.79 (0.66, 0.95)

8

4
Hemorrhagic: HR (95% CI) = 1.68 (1.09, 2.59)

0
0

1

2

3

Years Since Randomization

Goldstein et al. Neurology 2008;70: 2364-2370

4

5

6

Unadjusted HR


SPARCL
Entry Events
Atorvastatin
(N=2365)

Stroke
Ischemic stroke
Hemorrhagic stroke
Not determined

TIA

Placebo
(N=2366)

N

%

N

1655
1595
45
15

70.0
67.4
1.9
0.6

1613
1559
48
6

708

29.9

752

%

68.2
65.9
2.0

0.3

31.8

The SPARCL Investigators. NEJM 2006;355: 549-559


SPARCL Exploratory Analysis
Hemorrhagic Stroke
• Nguy cơ xuất huyết có tăng lên đối với các BN xuất
huyết não?
• Nguy cơ xuất huyết não có liên quan với mức giảm LDLC?
• Các yếu tố khác có liên quan với Nguy cơ xuất huyết
não? Huyết áp, tuổi
Goldstein et al. Neurology 2008;70:2364


SPARCL Multivariable Cox Regression Model
Baseline Characteristics & Time Varying LDL-C

Risk of hemorrhage

OR (95% CI)

p

Hemorrhage as entry event

8.38 (3.78, 18.56)

<0.001

Male sex

2.21 (1.20, 4.09)

0.01

Age (10 yr increments)

1.40 (1.08, 1.81)

0.01

1.26 (0.60, 2.64)
0.97 (0.44, 2.17)
1.37 (0.63, 2.98)

0.77
0.54
0.94
0.43

LDL-cholesterol (quartiles)
52-65 mg/dL
66-92 mg/dL
>93 mg/dL

For atorvastatin-treated patients
Goldstein et al. Neurology 2008;70:2364

SPARCL Multivariable Cox Regression Model
Baseline Characteristics & Time-Varying BP

Risk of hemorrhage

Blood Pressure
Pre-hypertension
Stage 1 hypertension
Stage 2 hypertension

OR (95% CI)

3.18 (0.76, 13.34)
3.49 (0.83, 14.61)
6.19 (1.47, 26.11)

p

0.01
0.11
0.09
0.01

Pre-HTN: SBP 120-139 or DBP 80-89
Stage 1: SBP 140-159 or DBP 90-99
Stage 2: SBP>160 or DBP>100
Goldstein et al. Neurology 2008;70 2364

Time Varying LDL-C and Stroke Risk
HR (95% CI)

p-value

All Stroke
≥0% Increase

1.00

<50% Decrease
≥50% Decrease

0.89 (0.73, 1.08)
0.69 (0.55, 0.87)

0.2253
0.0016

Ischemic Stroke
≥0% Increase

1.00

<50% Decrease
≥50% Decrease

0.90 (0.73, 1.12)
0.67 (0.52, 0.86)

0.3394
0.0018

Hemorrhagic Stroke
≥0% Increase

1.00

<50% Decrease
≥50% Decrease

0.84 (0.50, 1.40)
1.04 (0.61, 1.78)

0.4716
0.8864

Note: Percent change effects from Cox proportional hazards
models with adjustment for gender and baseline age with
reference group = no change or increase

0.4

0.7

1.0

1.3

Hazard Ratio (95% CI)

Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:3198-3204

1.6 1.9 2.2