Statin trong phng nga bin c ng mch vnh

PGS.TS Trng Quang Bnh HYD TP HCM

Ganh nang toan cau cua benh ly tim mach

Nam 2002: T vong do benh tim mach chiem 1/3 so t vong toan cau (17 trieu) 80% ganh nang nay se e tren vai cua cac quoc gia co thu nhap thap en trung bnh
D tnh vao nam 2020: Benh M vanh va ot qu :nguyen nhan gay t vong va thng tat hang au tren toan the gii T vong do benh tim mach se tang en 20 trieu

=> Cham soc y te cho benh tim mach rat hao ton
International Cardiovascular Disease Statistics 2005; AHA

Risk Factors for Atherothrombosis

Hypercoagulable states Life-style (e.g., Homocysteinaemia smoking, diet, Hyperlipidaemia lack of exercise) Insulin resistance Diabetes Obesity Hypertension Genetics Infection? Age

Atherosclerosis
Gender

Atherothrombotic Manifestations (MI, Ischemic Stroke, Vascular Death)

American Heart Association. Heart and Stroke Facts: 1997 Statistical Supplement; Wolf. Stroke 1990;21(suppl 2):II4II-6; Laurila et al. Arterioscler Thromb Vasc Biol 1997;17:2910-2913; Grau et al. Stroke 1997;28:1724-1729; Graham et al. JAMA 1997;277:1775-1781; Brigden. Postgrad Med 1997;101(5):249-262.

Cholesterol and atherosclerosis

LDL-C is strongly associated with an increased risk of atherosclerosis and CVD events HDL-C has a protective effect for the risk of atherosclerosis and CHD.
1% decrease in LDL-C reduces CHD risk by 1%1

1% change in HDL-C associated with 1-3% reduction in CHD risk2-5

1.Grundy SM et al. Circulation. 2004; 110: 22739. 2.Gordon DJ, Probstfield JL, Garrison JD et al. Circulation 1989; 79: 8-15. 3.Boden W. American Journal of Cardiology 2000; 86 (suppl): 19L-22L. 4.Manninen V, Elo O, Frick MH et al. JAMA 1988; 260:641-651. 5.Rubins HB, Robins S, Collins D et al. N Engl J Med 1999; 341:410-418

Key Statin Trials and Spectrum of Risk

CHD/high cholesterol 4S CHD/average to high cholesterol LIPID CHD/low to average cholesterol PROVE-IT MI/low to average cholesterol CARE Increasing MI/low to average cholesterol IDEAL absolute CHD CHD or diabetes/low to average cholesterol HPS risk TNT CHD/low to average cholesterol CARDS Diabetes + 1 other risk factor/low to average cholesterol PROSPER CHD or risk factors/average cholesterol WOSCOPS no MI/high cholesterol ALLHAT-LLT some CHD/average cholesterol ASCOT-LLA >3 risk factors/low to average cholesterol AFCAPS/TexCAPS No CHD/average cholesterol JUPITER No CHD/low to normal cholesterol

Nghien cu 4S: m ng cho ATP III

Trc NC 4S, statin:

* Giam t vong do benh MV, cha giam t vong chung.

NC 4S (Scandinavian Simvastatin Survival Study), 1994:

* Giam t vong do benh MV va t vong chung 30%.

NC 4S la NC au tien tra li chnh thc ve tac dung co li cua

statin trong ieu tr RLLP mau.

NC 4S co anh hng ln cho khuyen cao ATP III

6

HPS = Heart Protection Study

NC tien cu, ngau nhien, so sanh cheo (simvastatin vi gia dc). cac bien co tim mach cho oi tng co nguy c cao.

Muc tieu NC: Simvastatin co lam giam ty le t vong va Tieu ch chnh: Ty le t vong chung, Ty le cac bien co

tim mach gay t vong va khong gay t vong.

Thi gian theo doi trung bnh : 5 nam

Heart Protection Study

(Nghien cu keo dai 5 nam)

Simvastatin 40 mg
Nguy c BMV

Simvastatin 40 mg

Giam 26% nguy c BMV

Giam 22% nguy c BMV

60

100

LDL-C (mg/dL)

Heart Protection Study Collaborative Group. Lancet 2002;360:722.

TNT Trial
10,003 benh nhan benh M vanh on nh Tuoi 35-75 , LDL t 130 - 250 mg/dL, triglyceride 600 mg/dL 19% la n, tuoi trung bnh 60.3 Tat ca c dung atorvastatin 10 mg trong 8 tuan au

Atorvastatin 80 mg n=4,995

Atorvastatin 10 mg n=5,006

Primary Endpoint: Bien co tim mach chnh : t vong do benh M vanh ,NMCT khong t vong, ngng tim c hoi sc, ot qu gay t vong hoac khong t vong . Theo doi 4.9 nam.

TNT Trial: Primary endpoint

Primary Composite of CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke
Hazard Ratio [HR]=0.78 p<0.001

IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering)

8888 patients, 80 years or less with prior MI

randomised to atorvastatin 80 mg/d (n = 4439), or simvastatin 20 mg/d (n = 4449), with a median follow-up of 4.8 years.

Primary endpoint was occurrence of a major

coronary event (coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation).

11

IDEAL
Major coronary event in 463 on simvastatin (10.4%) and

411 on atorvastatin (9.3%) P = 0.07 (not significant); nonfatal MI in 321 (7.2%) and 267 (6.0%) (P = 0.02).

No differences in cardiovascular or all-cause mortality. Patients with MI may benefit from intensive lowering of

LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions.

12

PROVE-IT
The Pravastatin or Atorvastatin Evaluation and Infection Therapy trial (PROVE-IT/TIMI-22)
4162 Patients with acute coronary syndrome

within the preceeding 10 days.

Aggressive lipid-lowering using atorvastatin 80

mg/day versus using pravastatin 40 mg/day.

13

PROVE-IT likely benefits

Atorvastatin 80 mg: additional 18%

reduction in nonfatal MI and CHD death beyond treatment with pravastatin 40 mg.

Extrapolation of the event rate:

approximate additional 22% reduction in major CHD events in the atorvastatin group at 5 years.

14

On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials

30 4S - Pl 25 Rx - Statin therapy Pl Placebo Pra pravastatin Atv - atorvastatin

Secondary Prevention

20

4S - Rx

LIPID - Pl 15 LIPID - Rx CARE - Rx HPS - Rx TNT Atv80 PROVE-IT Atv 5 TNT Atv10 PROVE-IT - Pra CARE - Pl HPS - Pl

10

0 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) 200 (5.2)

LDL-C achieved mg/dL (mmol/L)

Rosenson RS. Exp Opin Emerg Drugs 2004;9(2):269-279, LaRosa JC et al. N Engl J Med 2005;352:1425-1435.

MCAEs (%)
18 16

MCAEs (30 days)

P=0.002

15.9

14
12 10 8 6 4 2 0

6.7

Rosuvastatin

Control

Why Is LIPS Unique?

In previous secondary prevention trials
PCI in subpopulations only multiple previous PCIs allowed PCI in distant past allowed LIPS is the first prospective secondary prevention statin trial with cardiac outcomes (time to first MACE) as the primary endpoint to exclusively study the post-PCI population

PCI, percutaneous coronary intervention; MACE, major adverse cardiac event.

Primary Endpoint: MACE-Free Survival Time

100 Subjects free from MACEs (%) 90

Risk reduction = 22%

Fluvastatin 80 Placebo 70 0 0.0 0.5
P=0.0127

Subjects at risk (% survival) Fluvastatin Placebo 844 (100.0) 833 (100.0)

1.0 1.5 2.0 2.5 3.0 Years post randomization 703 (84.2) 686 (83.6) 666 (80.9) 642 (78.8) 647 (80.2) 610 (76.1)

3.5

4.0

250 (78.3) 228 (72.6)

MACE, major adverse cardiac event. Serruys PW. Presented at: ACC 51st Annual Scientific Session; March 20, 2002; Atlanta, GA.

A large number of clinical events occur in those with below average cholesterol levels
Total Cholesterol Distribution: CHD vs Non-CHD Population Framingham Heart Study26-Year Follow-up
No CHD

35% of CHD Occurs in People with TC<5.0 mmol/L

CHD

6.5

7.7

Total Cholesterol (mmol/L)

Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 1996 Reprinted with permission from Elsevier Science.

Key statin trials on Primary prevention studies

WOSCOPS (1995) AFCAPS/TexCAPS (1998) ALLHAT-LLA (2002) ASCOT-LLA (2003) JUPITER (2008)

Subjects with No Previous MI but Raised Cholesterol

Number of events Outcomes
placebo (n=3293) pravastatin (n=3302) RRR (%) p-value

Cardiovascular Endpoints: WOSCOPS

Nonfatal MI/CHD death* CHD death Nonfatal MI PCTA/CABG Stroke All cardiovascular deaths Total mortality#

248 52 204 80 51 73 135

174 38 143 51 46 50 106

31 28 31 37 11 32 22

<0.001 ns <0.001 0.009 ns 0.033 0.051

* primary endpoint # study not powered to detect differences in this endpoint RRR relative risk reduction
Shepherd J et al. N Engl J Med 1995;333:13011307.

Nonfatal MI and CHD Death: WOSCOPS

12 10 8 6 4 2 0 1 2 3 4 5 6

placebo (n=3293) pravastatin (n=3302)

31% relative risk reduction p<0.001

Years

Shepherd J et al. N Engl J Med 1995;333:13011307.

AFCAPS/TexCAPS
6605 patients. Average TC and LDL-C levels (Mean TC 5.71
mmol/L, LDL-C 3.89 mmol/L, mean HDL-C level 0.94 mmol/L and median (SD) TG levels were 1.78 (0.86) mmol/L).

Without clinically evident atherosclerotic cardiovascular disease

Fatal/Nonfatal MI, Sudden Cardiac Death, Unstable Angina: AFCAPS/TexCAPS

0.07
Cumulative incidence 0.06 0.05 0.04 0.03 0.02 0.01

placebo lovastatin

37% relative risk reduction p<0.001

0.00
0.0 1 2 3 4 5 >5 Years of follow-up

Downs JR et al. JAMA 1998;279:16151622.

Statin and Usual Care in Hypertensive Patients with Average Cholesterol Levels: ALLHAT-LLT
Number of events

Outcomes
All-cause mortality CVD deaths Non-CVD deaths Cause unknown Fatal CHD and nonfatal MI All stroke Heart failure
RR relative risk

usual care (n=5185)

641 300 302 39 421 231 248

pravastatin (n=5170)
631 295 302 34 380 209 243

RR

p-value

0.99 0.99 1.01 0.88 0.91 0.91 0.99

0.88 0.91 0.92 0.58 0.16 0.31 0.89

ALLHAT Collaborative Research Group. JAMA 2002;288:29983007.

ALLHAT
Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C.

The results may be due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention.

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

19,342 hypertensive patients (40-79 years with at least three other CV risk factors randomised to one of two antihypertensive regimens.

(Hypertension but no CAD)

10,305 with TC of 6.5 mmol/L or less randomised to additional atorvastatin 10 mg or placebo- ASCOT-LLA.

(Average cholesterol)

ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm - RESULTS continued Nonfatal MI and fatal CHD
Proportion of patients (%) 4

2 1

HR=0.64 (95% CI=0.500.83) P=0.0005 Placebo

0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years after randomization

Atorvastatin

Sever et al. Lancet 2003;361:114958.

JUPITER - Objective

The primary objective: Long-term rosuvastatin 20 mg decreases the rate of first major cardiovascular events compared with placebo in patients with low to normal LDL-C + elevated CRP levels

Ridker PM. Circulation 2003; 108: 22922297

JUPITER study design

No history of CAD men 50 yrs women 60 yrs LDL-C <130 mg/dL CRP 2.0 mg/L

Rosuvastatin 20 mg (n=8901)
Placebo

run-in

Placebo (n=8901)

Visit: Week:

1 6

2 4

3 0

4 13

6-monthly

Final

Lead-in/ eligibility

Randomisation

Lipids CRP Tolerability

Lipids CRP Tolerability

Lipids CRP Tolerability HbA1C

Median follow-up 1.9 years

CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA1c=glycated haemoglobin Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER - Primary Endpoint

Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization
0.08

Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001

Placebo

44%

Cumulative Incidence

0.06

0.04

Rosuvastatin 20 mg

NNT for 2y = 95 5y* = 25

0.00 0
Number at Risk Rosuvastatin Placebo 8,901 8,901 8,631 8,621 8,412 8,353 6,540 6,508

0.02

Follow-up (years)
3,893 3,872 1,958 1,963 1,353 1,333 983 955 544 534 157 174

*Extrapolated figure based on Altman and Andersen method

Ridker P et al. N Eng J Med 2008;359: 2195-2207

Nghin cu Phng nga th pht 1994 1996 1998 2002 2004 4S CARE LIPID HPS TNT

Thuc

S bnh nhn

Simvastatin Pravastatin Pravastatin Simvastatin Atorvastatin

4,444 4,159 9,014 20,536 10,000

Phng nga tin pht

1995 WOSCOPS Pravastatin 6,595 31%

1998
2003

AFCAPS/TexCAPS
ASCOT-LLA

Lovastatin
Atorvastatin

6,605
10,305

37%
36%

2005

JUPITER

Rosuvastatin

17,802

44%

Ket luan
Statin la thuoc hieu qua trong phong nga bien co M vanh hau nh tat ca cac dang lam sang cua benh. iem noi bat trong nhng nam gan ay la phong nga tien phat cho nhng oi tng nguy c benh M vanh khong cao

Chan thanh cam n s chu y cua quy v