Modern Management of Cholesterol in the High-Risk Patient.

Modern Management of Cholesterol in the High-Risk Patient

Overview PresentationOverview Presentation

• Who are at risk Who are at risk – Secondary preventionSecondary prevention– Primary prevention - Diabetes Mellitus type 2Primary prevention - Diabetes Mellitus type 2

• Lowering CholesterolLowering Cholesterol– Secondary preventionSecondary prevention– Primary preventionPrimary prevention

• Beyond cholesterol loweringBeyond cholesterol lowering• How low should we goHow low should we go• GuidelinesGuidelines

Priorities for Lipid loweringPriorities for Lipid lowering

• Secondary preventionSecondary prevention

• Patients with diabetes mellitus type 2Patients with diabetes mellitus type 2

• Patients with genetic dyslipidemia'sPatients with genetic dyslipidemia's

• Patients with multiple Patients with multiple rriskisk factorsfactors

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SECONDARY PREVENTION


Consequences of CHDConsequences of CHD

• 50 % of all MI’s in patients with previous MI

• 70 % of all fatal MI’s in patients with previous MI

• 4 -7 x increased risk of MI compared to people

without CHD

Mortality in Hypercholesterolemic Men With CHD

LDL cholesterol levelLDL cholesterol level

55

1010

1515

2020

De

ath

s p

er

10

00

pe

rso

n-y

ea

rsD

ea

ths

pe

r 1

00

0 p

ers

on

-ye

ars

25 X25 X

12 X12 X

CHDCHD>160 mg/dl>160 mg/dl(4.1 mmol/l)(4.1 mmol/l)

19.1519.15

CHDCHD<130 mg/dl<130 mg/dl(3.4 mmol/l)(3.4 mmol/l)

1.641.64

No CHDNo CHD<130 mg/dl<130 mg/dl(3.4 mmol/l)(3.4 mmol/l)

0.770.77

TikkanenJ. et al. N Engl J Med 1990:322(24):1700 - 1707TikkanenJ. et al. N Engl J Med 1990:322(24):1700 - 1707

168-191 (168-191 (4.3-4.9)4.3-4.9)180 180 (4.6)(4.6)

192-217 192-217 (4.9-5.5)(4.9-5.5)204 204 (5.2)(5.2)

>218 >218 (5.6)(5.6)245 245 (6.3)(6.3)

<167 <167 (4.2)(4.2)149 149 (3.7)(3.7)

Serum cholesterol mg/dl Serum cholesterol mg/dl (mmol/l)(mmol/l)

RangeRangeMeanMean

Cu

mu

lati

ve

in

cid

en

ce

of

AM

I p

er

Cu

mu

lati

ve

in

cid

en

ce

of

AM

I p

er

10

0,0

00

sc

ree

ne

d s

ub

jec

ts i

n 3

yr.

10

0,0

00

sc

ree

ne

d s

ub

jec

ts i

n 3

yr.

100100

00

400400

200200

300300

500500

MenMenWomenWomen

Cholesterol/AMI Link in Low TC Population

Wakugami K., et al. Jpn Cir J. 1998;52:7-14Wakugami K., et al. Jpn Cir J. 1998;52:7-14


PRIMARY PREVENTION


Diabetes Mellitus type 2


‘With an excess of fat diabetes begins and from an excess of

fat diabetics die…’

Elliott P. Joslin MD 1927

National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.

Atherosclerosis in DiabetesAtherosclerosis in Diabetes

• ~80% of all diabetic mortality~80% of all diabetic mortality– 75% from coronary atherosclerosis75% from coronary atherosclerosis

– 25% from cerebral or peripheral vascular disease25% from cerebral or peripheral vascular disease

• >75% of all hospitalizations for diabetic >75% of all hospitalizations for diabetic

complicationscomplications

• >50% of patients with newly diagnosed >50% of patients with newly diagnosed

type 2 diabetes have CHDtype 2 diabetes have CHD


1818

1616

1414

1212

1010

88

66

44

22

00menmen womenwomen

Framingham study: Framingham study: DM type 2 and cardiovascular mortalityDM type 2 and cardiovascular mortality

Annual cardiovascular Annual cardiovascular mortality per 1000 personsmortality per 1000 persons

DM+DM+

Kannel et al, JAMA 241: 2035 - 38 1979Kannel et al, JAMA 241: 2035 - 38 1979

DM -DM -


MRFIT: DM type 2 and CVD mortalityMRFIT: DM type 2 and CVD mortality

Stamler J et al. Diabetes Care 16(2): 434 - 444, 1993Stamler J et al. Diabetes Care 16(2): 434 - 444, 1993

00

2020

4040

6060

8080

100100

120120

140140

160160

< 4.7< 4.7 4.7-5.14.7-5.1 5.2-5.75.2-5.7 5.8-6.25.8-6.2 6.3-6.76.3-6.7 6.8-7.26.8-7.2 7.37.3 mmol/lmmol/l

CV

mort

ality

per

CV

mort

ality

per

10.0

00 p

ers

on

years

10.0

00 p

ers

on

years

DiabetesDiabetesNo diabetesNo diabetes

total cholesteroltotal cholesterol

04/19/23 17:53P0168.PFIZER.Lipitor.Slide_Kit.A.dh07UKPDS BMJ 1998UKPDS BMJ 1998

Impact of CHD Risk Factors in Patients with DM type 2 Impact of CHD Risk Factors in Patients with DM type 2

% risk increase% risk increase

HbAHbA1C1C per 1 % per 1 % +11+11

Systolic bloodSystolic blood pressure per 10 mm Hg.pressure per 10 mm Hg. +15+15

HDL-cholesterol per 0.1 mmol/lHDL-cholesterol per 0.1 mmol/l -15 -15

LDL-cholesterol per 1 mmol/lLDL-cholesterol per 1 mmol/l +57+57

8 year CV mortality in Finnish DM (n=1059) and 8 year CV mortality in Finnish DM (n=1059) and non-DM (n=1378) subjects following MInon-DM (n=1378) subjects following MI

non DMnon DM DM DMMI +MI + MI -MI - MI + MI + MI -MI -

CV events (%)CV events (%) 18.818.8 3.53.5 4545 20.220.2

Strokes (%)Strokes (%) 7.27.2 1.91.9 19.519.5 10.310.3

Haffner et. al. NEJM July 23 1998 (Vol 339: 229-334)Haffner et. al. NEJM July 23 1998 (Vol 339: 229-334)

Kannel WB. Am Heart J. 1985;110:1100-1107.Abbott RD et al. JAMA. 1988;260:3456-3460.

Women, Diabetes, and CHDWomen, Diabetes, and CHD

• Diabetic women are at high risk for CHDDiabetic women are at high risk for CHD• Diabetes eliminates relative cardioprotective effect Diabetes eliminates relative cardioprotective effect

of being premenopausalof being premenopausal– risk of recurrent MI in diabetic women is three times that of risk of recurrent MI in diabetic women is three times that of

nondiabetic womennondiabetic women

• Age-adjusted mean time to recurrent MI or fatal Age-adjusted mean time to recurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic womenfor nondiabetic women

Diabetes Mellitus and Reduction of CHD in the USDiabetes Mellitus and Reduction of CHD in the US

-21%

-1%

-13%

15%

-36%

-13%

-27%

23%

-44%

-17%

-20%

11%

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

30%

Red

uct

ion m

ort

alit

y

Total mortality CVD mortality CHD mortality

Men no DMMen DM +Women no DMWomen DM +

197119719639 individuals (670 DM+)9639 individuals (670 DM+)

Age: 35 – 74 yearsAge: 35 – 74 years

9 year follow-up9 year follow-up

198219828463 individuals (637 DM+)8463 individuals (637 DM+)

Age: 35 – 74 yearsAge: 35 – 74 years

8 year follow-up8 year follow-up

K. Gu, et al. JAMA 1999; 281:1291 K. Gu, et al. JAMA 1999; 281:1291

Overview PresentationOverview Presentation

• Who are at riskWho are at risk– Secondary preventionSecondary prevention– Primary prevention - Diabetes Mellitus type 2Primary prevention - Diabetes Mellitus type 2

• Lowering CholesterolLowering Cholesterol– Secondary preventionSecondary prevention– Primary preventionPrimary prevention

• Beyond cholesterol loweringBeyond cholesterol lowering• How low should we goHow low should we go• GuidelinesGuidelines

22.622.6

15.9/13.215.9/13.2

7.97.9

2.82.8

Pla

ceb

o M

I ra

te p

er 1

00

sub

ject

s p

er

5 ye

ars

Pla

ceb

o M

I ra

te p

er 1

00

sub

ject

s p

er

5 ye

ars

WOS : NEJM 1995; 333 : 1301-1307CARE : NEJM 1996; 335 : 1001-1009LIPID : NEJM 1998; 339: 1349-13574S : Lancet 1994; 344 : 1383-1389TexCAPS: JAMA 1998; 279: 1615-1622

Major HMG-CoA TrialsMajor HMG-CoA Trials

CARECAREn=4,159n=4,159

TC 5.4 mmol/lTC 5.4 mmol/l

LIPIDLIPIDn=9,014n=9,014


WOSWOSn=6,595 TC 7.0 mmol/ln=6,595 TC 7.0 mmol/l

4S4Sn=4,444n=4,444


With CHD +With CHD +high cholesterolhigh cholesterol

With CHD +With CHD +normal cholesterolnormal cholesterol

Without CHD +Without CHD +high cholesterolhigh cholesterol

TexCAPSTexCAPSn=6,605 TC 5.7 mmol/ln=6,605 TC 5.7 mmol/l

Without CHD +low HDL

‘‘Numbers Needed to Treat’Numbers Needed to Treat’Major Coronary Events (MACE)Major Coronary Events (MACE)

LD

L c

ho

lest

ero

l

Low

High

4-Snnt 13

LIPIDnnt 26

CAREnnt 33

AFCAPSnnt 59

WOSnnt 43

0

5

10

15

20

25

Atorvastatin Angioplasty/UC

*p=0.048 vs an adjusted significance level of p=0.045 atorvastatin vs angioplasty/UC.

% of patientswith an

ischemic event

13%

21%

-36% difference*

(p = 0.048)

Ischemic Events

n = 22 of 164 n = 37 of 177

Pitt B et al. N Engl J Med. 1999;341:70-76.

0

5

10

15

20

0-6 months >6-18 months

% of patientswith an

ischemic event

Atorvastatin

7%6%

Angioplasty/UC

10%11%

Pitt B et al. N Engl J Med. 1999;341:70-76.

46% difference24% difference

AVERT: Incidence of First Ischemic Event by Time AVERT: Incidence of First Ischemic Event by Time

0

5

10

15

20

25

0 6 12 18

p=0.027Cumulative incidence

(%)

Time since randomization (months)

Time to First Ischemic Event

Data on file. Parke-Davis, Morris Plains, NJ, Study 981-068.

Atorvastatin (n=164)

Angioplasty/UC (n=177)

Acute coronary eventAcute coronary event

WOSCOPSWOSCOPSAFCAPSAFCAPS

Primary prevention Secondary prevention

00 3 m3 m 6 m6 m 9 m9 m 1 y1 y 2 y2 y 3 y3 y 4 y4 y

4 S

CARE

LIPID

MIRACL : unstable a.p. and non-Q infarctMIRACL : unstable a.p. and non-Q infarctFLORIDA: AMI ( ischemie)FLORIDA: AMI ( ischemie)A-Z: standard vs. aggressive careA-Z: standard vs. aggressive care

Start of Statin Therapy in Secondary Prevention

Ischaemic StrokeIschaemic Stroke

placeboplacebo treated treated reductionreduction

Primary preventionPrimary preventionWoscopWoscop 5151 4646 10%10%

Secondary preventionSecondary preventionCARECARE 7878 5454 31%31%4S4S 9898 7070 30%30%

Hebert et al JAMA 1997; 278: 313 - 21

Ischaemic Stroke Reduction in Statin TrialsIschaemic Stroke Reduction in Statin Trials

-15

-32*

-27*

-40

-30

-20

-10

0

Crouse JR et al. Arch Intern Med. 1997;157:1305-1310.

*P=0.001.†95% confidence interval of percentage of relative reduction.

Effects of Statins on Stroke Events: A Meta-analysisof Primary- and Secondary-Prevention Trials

Relativereduction

in rates (%)

1° Prevention (-42 to -27)†

2° Prevention (13-45)†

Combined (11-40)†

-1 0 1

Cholesterol Reduction and StrokeCholesterol Reduction and StrokePre Statin Trials (1965 - 1992)Pre Statin Trials (1965 - 1992)

InterventionCholestyramine

Niacin

Diet

Diet

Diet

Gemfibrozil

Clofibrate and Niacin

Clofibrate

Clofibrate

Multiple

Multiple

Summary Odds ratio (N)

Fatal Stroke - Clofibrate (3)

Fatal Stroke - Other (11)

Fatal Stroke - All (13)

Total Stroke All

Odds Ratio of Stroke

Cholesterol Reduction and the Risk for Stroke in Men. David Atkins et al. Ann. Intern. Med. 1993;119:136-145

Modern Management of Cholesterol in the High-Risk Patient.

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Transcript of Modern Management of Cholesterol in the High-Risk Patient.