Statins in the Primary and Secondary Prevention of CAD Prof. M. Ishaq Karachi Institute of Heart...

Statins in the Primary and Secondary Statins in the Primary and Secondary

Prevention of Prevention of

CADCAD

Prof. M. IshaqProf. M. Ishaq

Karachi Institute of Heart DiseasesKarachi Institute of Heart Diseases

Mortality from CVD and CHD in selected countries

Rate per 100,000 population (Men aged 35–74 years)

0

500

1000

1500

Russia Finland England/Wales

Italy Japan

CVD deaths CHD deaths

(Adapted from 1998 World Health Statistics)

Poland NewZealand

USA Spain

Elevated Serum Cholesterol Levels Elevated Serum Cholesterol Levels are Linked to Increased Risk of CHDare Linked to Increased Risk of CHD

CH

D d

eath

rat

e (p

er 1

000

men

in

6 y

ear

s)

Serum cholesterol (mg/dL)

18

16

14

12

10

8

6

4

2

0

140 160 180 200 220 240 260 280 300

ReferencesMartin et al. Lancet 1986;2:933–6

• Coronary heart disease risk increases progressively as serum cholesterol levels rise above 181 mg/dL (4.68 mmol/L)

(Adapted from Verschuren et al, 1995)

35

30

25

20

15

10

5

0

De

ath

rate

fro

m C

HD

/100

0 m

en

2.60 3.25 3.90 4.50 5.15 5.80 6.45 7.10 7.75 8.40 9.05

Serum total cholesterol (mmol/L)

Northern Europe

United States

Southern Europe, inland

Southern Europe, Mediterranean

Japan

Serbia

Relationship of serum cholesterol to mortality

(Seven Countries Study)

Total Cholesterol Distribution: Total Cholesterol Distribution: CHD vs Non-CHD PopulationCHD vs Non-CHD Population

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

35% of CHD 35% of CHD Occurs in People Occurs in People with TC<200 with TC<200 mg/dLmg/dL

150 200

Total Cholesterol (mg/dL)

250 300

No CHD

CHD

Framingham Heart Study—26-Year Follow-up

Cholesterol – a modifiable risk factor?

In the USA:– 97 million people have total cholesterol

200 mg/dl (5.2 mmol/L)

– 38 million people have total cholesterol

240 mg/dl (6.2 mmol/L)

10% reduction in total cholesterol results in:– 15% reduction in CHD mortality (p<0.001)

– 11% reduction in total mortality (p<0.001)

Total cholesterol is a modifiable CV risk factor

LDL-C is the primary target to prevent CHD

Intensity of intervention depends on total CV risk

Classification of dyslipidaemiasFredrickson (WHO) classification

Phenotype

I

IIa

IIb

III

IV

V

Lipoprotein

elevated

Chylomicrons

LDL

LDL and VLDL

IDL

VLDL

VLDL and

chylomicrons

Atherogenicity

None seen

+++

+++

+++

+

+

Prevalence

Rare

Common

Common

Intermediate

Common

Rare

LDL – low-density lipoprotein; IDL – intermediate-density lipoprotein; VLDL – very low-density lipoprotein.

(High-density lipoprotein (HDL) cholesterol levels are not considered in the Fredrickson classification).

Serum

cholesterol

Normal to

Normal to

Normal to

Serum

triglyceride

Normal

(Adapted from Yeshurun et al, 1995)

Pathogenesis of atherosclerotic plaques

Protective response results in production of cellular adhesion molecules

Monocytes and T lymphocytes attach to ‘sticky’ surface of endothelial cells

Migrate through arterial wall to subendothelial space

Lipid-rich foam cells

Endothelial damage

Macrophages take up oxidised LDL cholesterol

Normal

Fatty streak

Lipid rich plaque

Complex plaque

Thrombus

Lipid core

Fibrous capFoam cells

Development of Atherosclerotic Development of Atherosclerotic PlaquesPlaques

LDL cholesterol (mg/dL)<100 Optimal100-129 Near optimal/above optimal130-159 Borderline high160-189 High190 Very high

HDL cholesterol (mg/dL)<40 Low60 High

NCEP ATP III Lipid andNCEP ATP III Lipid andLipoprotein ClassificationLipoprotein Classification

NCEP ATP III guidelines. JAMA. 2001;285:2486-2497.

NCEP ATP III classification

• Diabetes: CHD risk equivalent• Framingham projections of 10-year CHD risk

SALIENT Features of NCEP ATP IIISALIENT Features of NCEP ATP III

NCEP ATP III guidelines. JAMA. 2001;285:2486-2497.

Focus on Multiple Risk FactorsFocus on Multiple Risk Factors

• Optimal LDL cholesterol <100 mg/dL: changed from 100 mg/dL• Categorical low HDL cholesterol <40 mg/dL: raised from <35 mg/dL

Modification of Lipid and Lipoprotein ClassificationModification of Lipid and Lipoprotein Classification

• Complete lipoprotein profile preferred (TC, LDL, HDL, TG)• Secondary option: fasting TC and HDL; proceed to lipoprotein

profile if TC >200 mg/dL or HDL <40 mg/dL

New Recommendations for Screening/DetectionNew Recommendations for Screening/Detection

CHD or CHD <100 100 >100 to 130 risk equivalent†

2+ risk factors <130 130 >130 to 160

0-1 risk factor <160 160 >160 to 190

NCEP ATP III LDL Cholesterol GoalsNCEP ATP III LDL Cholesterol Goalsand Therapy Recommendationsand Therapy Recommendations

*Authorities disagree on when to initiate drug therapy.†This category refers to patients without clinically evident CHD, but who have a similar risk for CHD events (eg, patients with diabetes, multiple risk factors, or other forms of atherosclerotic disease, such as peripheral artery disease).NCEP ATP III guidelines. JAMA. 2001;285:2486-2497.

Initiate therapeutic lifestyle changesGoal

Initiate drug therapy*

LDL cholesterol level (mg/dL)

ATP III Treatment Recommendations for ATP III Treatment Recommendations for CHD and CHD Risk EquivalentsCHD and CHD Risk Equivalents

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

No treatment No treatment recommended because recommended because “no evidence”“no evidence”

LDL-C LDL-C <100<100 mg/dL mg/dL

Options:Options: TLC aloneTLC aloneFibrateFibrateStatinStatin

LDL-C LDL-C 100–129100–129 mg/dL mg/dL

Lifestyle and statinLifestyle and statinLDL-C LDL-C 130130 mg/dL mg/dL

NCEP-ATP III Metabolic SyndromeNCEP-ATP III Metabolic Syndrome• Some patients have a variety of risk factors that constitute a condition

named metabolic syndrome• The ATP III guidelines recognise metabolic syndrome as a secondary target of

risk-reduction therapy after LDL-C lowering

*on treatment

References1. NCEP Expert Panel. JAMA 2001;285:2486–97

Risk factor of metabolic syndrome Defining level

Abdominal obesity (waist circumference) Men Women

>102 cm (> 40 in) > 88 cm (> 35 in)

TGs 1.7 mmol/L ( 150 mg/dL)

HDL-C Men Women

< 1.1 mmol/L (< 40 mg/dL) < 1.3 mmol/L (< 50 mg/dL)

Blood pressure 130/85 mmHg*

Fasting glucose 6.1 mmol/L ( 110 mg/dL)

First-line agentsFirst-line agents

HMG CoA reductase inhibitorHMG CoA reductase inhibitor

Fibric acid derivativeFibric acid derivative

Second-line agentsSecond-line agents

Bile acid binding resinsBile acid binding resins

Nicotinic acidNicotinic acid

Pharmacologic Agents for Treatment Pharmacologic Agents for Treatment of Dyslipidemiaof Dyslipidemia

American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.

In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred.

Effect on lipoprotein

LDL HDL Triglyceride

Mechanism of Action of Statins Mechanism of Action of Statins Cholesterol Synthesis PathwayCholesterol Synthesis Pathway

acetyl CoA

HMG-CoA

mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

farnesyl pyrophosphate

squalene

cholesterol

dolicholsubiquinones

HMG-CoA synthase

HMG-CoA reductase

Squalene synthase

X Statins

Clinical Pharmacokinetics of StatinsClinical Pharmacokinetics of Statins

References1. Adapted from Corsini et al. Pharmacol Ther 1999;84:413–428.

Parameter Atorvastatin

Fluvastatin

Lovastatin

Pravastatin

Simvastatin

Fraction absorbed (%)

30 98 30 34 60–80

Cmax (ng/mL) 27–66 448 10–20 45–55 10–34

Hepatic extraction (%)

> 70 > 68 > 70 46–66 78–87

MetabolismCYP3A4 CYP2C9 CYP3A4 Sulfation CYP3A4

Systemic metabolites

Active Inactive Active Inactive Active

Clearance (L/hr/kg)

0.25 0.97 0.26–1.1 0.81 0.45

Based on 40 mg oral dose

Major coronary events

Coronary deaths

Cardiovascular deaths

All-cause deathsP

rop

ort

ion

al r

isk

red

uc

tio

n (

%)

References1. LaRosa et al. JAMA 1999;282:2340–6

6

–31%–29%

–27%

–21%

–35

–30

–25

–20

–15

–10

–5

0

Proven Mortality Benefits Of Proven Mortality Benefits Of Lowering LDL-CLowering LDL-C

• A 28% reduction in LDL-C significantly reduces cardiovascular events in hypercholesterolaemic patients

Change in LDL-C and Non-HDL-C by Change in LDL-C and Non-HDL-C by Statins after 54 Weeks of TherapyStatins after 54 Weeks of Therapy

-50

-40

-30

-20

-10

0

10

20

Ballantyne CM et al. Am J Cardiol 2001;88:265-269.

Mean Mean DoseDose

Average baseline LDL-C: 178 mg/dLAverage baseline LDL-C: 178 mg/dLAverage baseline non-HDL-C: 216 mg/dLAverage baseline non-HDL-C: 216 mg/dL

24 mg24 mg 42 mg42 mg 52 mg52 mg 23 mg23 mg

Atorvastatin(n=1,888)

Fluvastatin(n=474)

Pravastatin(n=461)

Simvastatin(n=462)

––4242––3838

––3535––2929

––3232 ––2626––3636

––3232

LDL-C Non-HDL-C

Perc

ent

Change

Perc

ent

Change

Elevated TG Levels Increase the Risk Elevated TG Levels Increase the Risk Of CHDOf CHD

Percentage increase in relative risk associated with 1 mmol/L (equivalent to 88 mg/dL) increase of TG when adjusted for HDL-C and other risk factors

ReferencesHokanson et al. J Cardiovascular Risk 1996;3:213–9

• An increase in TG levels significantly increases the risk of cardiovascular disease

Incr

ease

in

ris

k (%

)

14

37

0

10

20

30

40

Men Women

Combination of Risk Factors Increases Combination of Risk Factors Increases The Risk of Cardiovascular EventsThe Risk of Cardiovascular Events

Men: smoking, SBP > 160 mmHgMen: No risk factorsWomen: smoking, SBP > 160 mmHgWomen: No risk factors

References1. Pyorala et al. Eur Heart J 1994; 15:1300–31

• Risk factors in addition to LDL-C levels include cigarette smoking, hypertension, age and low HDL-C level• A combination of risk factors increases the risk of cardiovascular events

Plasma total cholesterol (mg/dL)

0

5

10

15

20

25

30

200 250 300

10-y

ear

risk

of

CH

D e

ven

ts (

%)

Major Statin TrialsMajor Statin Trials

Primary prevention trials:

—AFCAPS/TexCAPS (lovastatin) - 36% reduction in first

coronary events

—WOSCOPS (paravastatin) - 31 % reduction in fatal and non-

fatal MI

Secondary prevention trials:

—4S (simvastatin) - relative risk of death reduced by 30%,

42% reduction in coronary death

—CARE (paravastatin) - CHD death and non-fatal MI reduced

by 24%

—LIPS: The latest trial in PCI presented at the ACC meting

Major Statin Trials (contd.)Major Statin Trials (contd.)

Angiographic trial:

— LCAS (fluvastatin) - Significantly less lesion progression and

fewer new lesions in treated patients with improvement in

myocardial blood flow by PET

Post-CABG/PTCA trial:

— FLARE (fluvastatin) - 63% reduction in death and MI with

fluvastatin

Severe atherosclerosis trial:

— LiSA (fluvastatin) - 71% reduction in major adverse cardiac events

(MACE)

— lower incidence of angina pectoris attacks

— decreased use of antianginal drug in fluvastatin group

Key Statin Trials and Spectrum of Key Statin Trials and Spectrum of Risk Risk

4S4S11

LIPIDLIPID22

CARECARE33

WOSCOPSWOSCOPS44

AFCAPS/TexCAPSAFCAPS/TexCAPS55

CHD/high cholesterol

CHD/average to high cholesterol

CHD/average cholesterol

No MI/high cholesterol

No CHD/average cholesterol

Secondaryprevention

Primaryprevention

Increasing risk

TC, total cholesterol, CD, cardiac death; MI, myocardial infarction; NA, not available*including silent MI + resuscitated cardiac arrest; **including unstable angina; #including fatal MI

Statins Reduce the Risk of Cardiac Death and Statins Reduce the Risk of Cardiac Death and Myocardial InfarctionMyocardial Infarction

References1. Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–92. Heart Protection Study Collaborative Group. Lancet 2002;6:7–223. Shepherd et al. NEJM 1995;333:1301–74. Sacks et al. NEJM 1996;335:1001–9 5. LIPID study group. NEJM 1998;339:1349–57

6. Shepherd et al. Lancet 2002;360:1623–30 7. ALLHAT Collaborative Research Group J Am Med Assoc 2002;288:2998–30078. Sever et al. Lancet 2003;361:1149–589. Downs et al. JAMA 1998;279:1615–2210. Serruys et al. JAMA 2002;287:3215–2211. Holdaas. Lancet 2003;361:2024–31

Trial Sample size

LDL-C CD + MI annual

rate

CD + MI % of

reduction

CD % of reductio

nmmol/L baseline

mmol/L change

% change

4 S1 4444 4.9 1.7 -35 5.2* 34 42

HPS2 20536 3.4 1.0 -30 2.3 27 18

WOSCOPS3 6595 5.0 1.3 -26 1.5 32 33

CARE4 4159 3.6 1.0 -28 2.6 24 20

LIPID5 9014 3.9 0.9 -25 2.6 24 24

PROSPER6 5804 3.8 1.0 -27 3.8 19 24

ALL-HAT7 10355 3.8 0.6 -30 1.7 9 0

ASCOT-LLA8 10305 3.4 1.0 -29 0.9 36 NA

AFCAPS/Tex CAPS9

6605 3.9 1.0 -25 1.0** 32 33

LIPS10 1677 3.4 0.9 -27 1.8 31 47

ALERT11 2102 4.1 1.0 -32 2 35 38

√

Statin Evidence: Expanding Benefits

Acute coronary event

4S

CARE/LIPID

4 mo

No history of CAD Unstable CAD

3 mo

t = 0

6 mo

Stable CAD

Secondary preventionPrimary prevention

AFCAPS / TexCAPS/WOSCOPS

MIRACL

Hypertension

ASCOT-LLA

HPS

S6

Statins Lower LDL-C Levels and Statins Lower LDL-C Levels and Cardiovascular Event Rate in Cardiovascular Event Rate in Secondary Prevention of CHDSecondary Prevention of CHD

LIPS, Lescol® Intervention Prevention Study (Lescol®) 1

CARE, Cholesterol And Recurrent Events study (pravastatin)2

4S, Scandinavian Simvastatin Survival Study (simvastatin)3

LIPID, Long-term Intervention with Pravastatin in Ischaemic Disease study (pravastatin)4

Statin

0

5

10

15

20

25

30

90 100 110 120 130 140 150 160 170 180 190 200

LDL-C achieved (mg/dL)

PlaceboCARE

CARELIPID

LIPID

4S

4S

Eve

nt

rate

(%

)

LIPS

LIPS

References1. Serruys et al. JAMA 2002;287:3215–222. Sacks et al. N Eng J Med 1996;335:1001–93. Scandinavian Simvastatin Survival Group. Lancet 1994;344:1383–94. LIPID Study Group. N Eng J Med 1998;339:1349–57 √

heart protection studyheart protection study

08-JUN-2008-ZCR-2007-MEA-(PK)-1193-SS

High-Risk Patient Groups in Which Statin High-Risk Patient Groups in Which Statin Therapy Was Not Prospectively Tested Therapy Was Not Prospectively Tested

Prior Prior to the Heart Protection Studyto the Heart Protection Study

• Patients with diabetes– With coronary heart disease (CHD)– Without CHD

• Patients with previous stroke

• Patients with peripheral vascular disease

• Patients with low cholesterol

• Elderly

• Women

Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; MRC/BHF Heart Protection Study Collaborative Group Eur Heart J 1999;20:725-741.

• Increased 5-year risk of CHD death because of– Diabetes mellitus or treated hypertension – Cerebrovascular or peripheral vascular disease– MI or other CHD

• Age 40–80 years

• Men and women

• Total cholesterol 3.5 mmol/L (135 mg/dl)

• Statin not considered clearly indicated or contraindicated by patients’ primary physicians

Heart Protection StudyHeart Protection Study

Patient Inclusion CriteriaPatient Inclusion Criteria

Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; MRC/BHF Heart Protection Study Collaborative Group Eur Heart J 1999;20:725-741.

• 20,536 high-risk patients

Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; MRC/BHF Heart Protection Study Collaborative Group Eur Heart J 1999;20:725-741; HPS Group communication.

Heart Protection StudyHigh-Risk Patient Groups

CHD7414

Diabetes2912

Othervasculardiseases

3168

19811070

3991

*Patients could be in more than one vascular event category.**Includes coronary and noncoronary revascularizations.

Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22.

Impact of Simvastatin in Heart Protection Impact of Simvastatin in Heart Protection StudyStudy

Major Vascular EventsMajor Vascular Events

Vascular event*

Major coronary eventNonfatal MICoronary death

Stroke

Revascularization**

ANY MAJOR VASCULAR EVENT

27% risk reductionp<0.0001




Simvastatin Placebo

better better

0.4 0.6 0.8 1.0 1.2 1.4

Risk ratio and 95% CI


% o

f p

atie

nts

10

20

30

0Placebo

(n=10,267)

25.2%

Simvastatin(n=10,269)

19.8%

2585 Patients with Events 2033

Patients with Events

RR=24%

p<0.0001



*Includes coronary and noncoronary revascularizations


% o

f p

atie

nts

0

15

5

10

Placebo (n=10,267)Simvastatin (n=10,269)

RR=27%p<0.0001

Major coronary event

11.8%

8.7%

Stroke

5.7%

4.3%

Revascularization*

11.7%

9.1%RR=25%p<0.0001

RR=24%p<0.0001



Number of patientswith event

1212 898 585 444 1205 939

*Patients could be in more than one disease category.


Impact of Simvastatin on Major Vascular Impact of Simvastatin on Major Vascular EventsEvents

By Prior CHD StatusBy Prior CHD Status




Prior CHD With prior MINo prior MI, with other CHD

No prior CHD*Cerebrovascular diseasePeripheral vascular diseaseDiabetes

ALL PATIENTS

Baseline feature

Simvastatin Placebo

better better

0.4 0.6 0.8 1.0 1.2 1.4

Risk ratio and 95% CI

Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; HPS Group communication.

Impact of Simvastatin on Major Vascular EventsImpact of Simvastatin on Major Vascular Events

Patients with DiabetesPatients with Diabetes—Five-Year Risk—Five-Year Risk%

of

pat

ien

ts

0

10

20

30

40

All patients with diabetes

n=2985 n=2978

With diabetes,with prior CHD

n=1009 n=972

With diabetes,without prior CHD

n=1976 n=2006

25.1%

20.2%

37.8%

33.4%

18.6%

13.8%

RR=23%p<0.0001

PlaceboSimvastatin

• In more than 20,000 patients at high risk for CHD

– Simvastatin significantly reduced the risk of major vascular events in high-risk patients

• With or without prior CHD

• Regardless of baseline cholesterol levels

– Simvastatin significantly reduced the risk of major vascular events in patients with diabetes with or without prior CHD

– Simvastatin 40 mg had a long-term tolerability profile comparable to placebo


Heart Protection StudyHeart Protection Study Major Medical ConclusionsMajor Medical Conclusions

Safety of Statin TherapySafety of Statin Therapy

• Statin monotherapy is generally well tolerated over the long term and has a low incidence of adverse events1

• Statin treatment is associated with a small risk of muscular adverse effects, or myopathies– In rare cases, myopathy may proceed to muscle cell

breakdown, or rhabdomyolysis, a potentially fatal condition– The risk of muscular toxicity with statin therapy is very low,

but is increased in high-risk groups (e.g. the elderly, patients with CHD, diabetic patients)

– These patients typically take multiple medications and are therefore at risk of drug interactions with statins

• Elevations in liver enzymes >3 times upper limit of normal range are experienced by 1–2% of patients. Such elevations have been reported in all lipid-lowering drugs

References1. Corsini. Cardiovasc Drug Therapy 2003;17:265–852. Friday. Exp Biol Med 2003;228:769–78 √

CONCLUSIONCONCLUSION

• Total cholesterol levels are linearly related to CHD mortality• HDL and triglycerides are also independent risk factors for CHD• ATP III suggests aggressive treatment of dylipidemia.• Reduction in LDL- and increase in HDL-levels significantly reduce

morbidity/mortality• Only one-third of treated patients reach LDL-target• Cholesterol lowering is beneficial for both Primary and Secondary

Prevention of CHD

• Recent data suggest that statin benefit independent of baseline LDL Levels.

2

“Safety and efficacy of statins have revolutionized the treatment of dyslipidaemia and statins have therefore become an essential step in the management of all subsets of CHD, Strokes & peripheral vascular disease”

Thank you for your attention

Statins in the Primary and Secondary Prevention of CAD Prof. M. Ishaq Karachi Institute of Heart...

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