cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina...

Cholesterol-Lowering Therapy in Cholesterol-Lowering Therapy in Women and Elderly Patients with Women and Elderly Patients with Myocardial Infarction or Angina Myocardial Infarction or Angina

PectorisPectorisFindings From the Scandinavian Simvastatin Survival Findings From the Scandinavian Simvastatin Survival

Study (4S)Study (4S)

Tatu A. Miettinen, MD; Kalevi Pyorala, MD; Anders G. Olsson, Tatu A. Miettinen, MD; Kalevi Pyorala, MD; Anders G. Olsson, MD; Thomas A. Musliner, MD; Thomas J. Cook, MD; Ole MD; Thomas A. Musliner, MD; Thomas J. Cook, MD; Ole

Faergeman, MD; Kare Berg, MD; Terje Pedersen, MD; John Faergeman, MD; Kare Berg, MD; Terje Pedersen, MD; John Kjekshsus, MD; for the Scandinavian Simvastatin Survival Kjekshsus, MD; for the Scandinavian Simvastatin Survival

StudyStudy

Circulation. 1997;96:4211-4218Circulation. 1997;96:4211-4218

Women and Elderly in 4SWomen and Elderly in 4S

827 women (age range 35-70 years) 827 women (age range 35-70 years) who comprised 19% of the total study who comprised 19% of the total study population (407 in the simvastatin population (407 in the simvastatin group and 420 in the placebo group).group and 420 in the placebo group).

1021 patients 1021 patients >> 65 years of age 65 years of age comprised 23% of the total population comprised 23% of the total population (518 in the simvastatin group and 503 (518 in the simvastatin group and 503 in the placebo group).in the placebo group).


Women and Elderly Substudy in 4S Women and Elderly Substudy in 4S -Between-Treatment Changes in Lipid Parameters--Between-Treatment Changes in Lipid Parameters-

TCTC LDLLDL HDLHDL TrigsTrigs


-25

-35

8

-10

-26

-37

7

-15

-26

-34

7

-16

-50

-40

-30

-20

-10

0

10

20

% R

edu

ctio

n

Total populationWomenElderly

Kaplan-Meier Survival Curves for Women and Kaplan-Meier Survival Curves for Women and Men in the 4S Trial Men in the 4S Trial - Major CHD Event -- Major CHD Event -

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6

Years after Randomization

Pro

port

ion w

ithout

Majo

r CH

D E

vent

SimvastatinPlacebo

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6


SimvastatinPlacebo

FemalesFemales MalesMales


P=0.01P=0.01 P<0.00001P<0.00001

Kaplan-Meier Survival Curves for Patients Kaplan-Meier Survival Curves for Patients >> 65 65 years of age, and patients < 65 years of age in years of age, and patients < 65 years of age in

the 4S Trial the 4S Trial - Major CHD Event -- Major CHD Event -

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6


SimvastatinPlacebo

Age < 65 YearsAge < 65 Years AgeAge >>65 Years


P<0.00001P<0.00001 P<0.001P<0.001

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6


Pro

port

ion w

ithout

Majo

r CH

D E

vent

SimvastatinPlacebo

P<0.00001P<0.00001

Kaplan-Meier Survival Curves for Women and Kaplan-Meier Survival Curves for Women and Men in the 4S Trial Men in the 4S Trial - Revascularization -- Revascularization -

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6


Pro

port

ion w

ithout

Revasc

ula

riza

tion

SimvastatinPlacebo

0.75

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6


SimvastatinPlacebo

FemalesFemales MalesMales


P=0.01P=0.01 P<0.00001P<0.00001


the 4S Trial the 4S Trial - Revascularization -- Revascularization -

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6


Pro

port

ion w

ithout

Revasc

ula

riza

tion

SimvastatinPlacebo

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6


SimvastatinPlacebo



P<0.00001P<0.00001 P<0.001P<0.001


the 4S Trial the 4S Trial - All Cause Mortality -- All Cause Mortality -

0.75

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6


Pro

port

ion A

live

SimvastatinPlacebo

0.75

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6


SimvastatinPlacebo



P<0.01P<0.01 P<0.01P<0.01

Clinical End Points in 4S SubpopulationsClinical End Points in 4S Subpopulations-Women--Women-

Event category S; n=407 P; n=420 RR 95% CIP

value

All-cause mortalityCHD mortalityMajor coronary eventsNonfatal MIAny acute CHD-relatedend-point eventAny atherosclerosis-related end-point eventRevascularizationprocedure

28146053

97

111

21

25179183

134

154

42

1.160.860.660.64

0.72

0.71

0.51

0.68-1.990.42-1.740.48-0.910.47-0.98

0.55-0.93

0.56-0.91

0.30-0.86

0.580.67

0.0120.011

0.014

0.006

0.012


Number of Patients

Clinical Endpoints in 4S Clinical Endpoints in 4S Subpopulations -Subpopulations -

- Women -- Women -

16

-14

-34 -36-28 -29

-49

-70

-50

-30

-10

10

30

Rel

ativ

e R

isk

Red

uct

ion (

%)


Total Total MortalityMortality

CHDCHDMortalityMortality

MCEMCE Nonfatal Nonfatal MIMI

Any acuteAny acuteCHD-relatedCHD-related

end-pointend-pointeventevent

Any Any atherosclerosis-atherosclerosis-

relatedrelatedend-point eventend-point event

RevascularizationRevascularizationprocedureprocedure

P=0.58P=0.58

P=0.67P=0.67

P=0.012P=0.012 P=0.011P=0.011P=0.014P=0.014 P=0.006P=0.006

P=0.012P=0.012

Women Substudy in 4S Women Substudy in 4S Decrease in Hospital Bed Days for all CVDecrease in Hospital Bed Days for all CV

0

1000

2000

3000SimvastatinPlacebo

1457 days1457 days 2391 days2391 days

39% Decrease39% Decreasep < 0.05p < 0.05


Clinical End Points in 4S PopulationsClinical End Points in 4S Populations-Age -Age >>65 y-65 y-


value


6744

12289

176

204

51

9673

168122

238

271

80

0.660.570.660.67

0.66

0.67

0.59

0.48-0.900.39-0.830.52-0.840.51-0.88

0.55-0.81

0.56-0.81

0.41-0.84

0.0090.003

<0.0010.004

<0.001

<0.001

0.003


Number of Patients

Clinical Endpoints in 4S Clinical Endpoints in 4S SubpopulationsSubpopulations- Age - Age >>65 y -65 y -

-34

-43

-34 -33 -34 -33

-41

-60

-40

-20

0

20

Rel

ativ

e R

isk

Red

uct

ion (

%)










P=0.009P=0.009 P=0.003P=0.003 P<0.001P<0.001 P=0.004P=0.004 P<0.001P<0.001 P<0.001P<0.001 P=0.003P=0.003

Clinical End Points in 4S PopulationsClinical End Points in 4S Populations-Age <-Age <65 y-65 y-


value


11567

309263

532

592

201

160116454379

689

751

303

0.720.580.660.67

0.75

0.76

0.65

0.57-0.910.43-0.780.57-0.760.58-0.79

0.67-0.84

0.68-0.84

0.54-0.77

0.007<0.001<0.001<0.001

<0.001

<0.001

<0.001


Number of Patients

Clinical Endpoints in 4S Clinical Endpoints in 4S SubpopulationsSubpopulations- Age <- Age <65 y -65 y -

-28

-42

-34 -33

-25 -24

-35

-50

-25

0

25

Rel

ativ

e R

isk

Red

uct

ion (

%)










P=0.007P=0.007 P<0.001P<0.001 P<0.001P<0.001 P<0.001P<0.001 P<0.001P<0.001 P<0.001P<0.001 P<0.001P<0.001

Elderly Substudy in 4S Elderly Substudy in 4S Decrease in Hospital Bed Days for all CVDecrease in Hospital Bed Days for all CV

2000

3000

4000SimvastatinPlacebo

2776 days2776 days 3843 days3843 days

28% Decrease28% Decreasep < 0.01p < 0.01


Discussion - WomenDiscussion - Women Differences in baseline characteristics for women Differences in baseline characteristics for women

compared with men in 4S included a lower compared with men in 4S included a lower proportion of prior MI, more nonsmokers, more proportion of prior MI, more nonsmokers, more baseline diagnoses of HTN, greater use of nitrates & baseline diagnoses of HTN, greater use of nitrates & CCBs and fewer prior coronary revascularization CCBs and fewer prior coronary revascularization procedures.procedures.

Females were slightly older than males and they had Females were slightly older than males and they had higher HDL levels with comparable LDL levels.higher HDL levels with comparable LDL levels.

Some of these differences undoubtedly contributed Some of these differences undoubtedly contributed to the lower incidence of CHD mortality and nonfatal to the lower incidence of CHD mortality and nonfatal CHD events in women compared with men.CHD events in women compared with men.


Discussion - WomenDiscussion - Women 4S is the first clinical trial to convincingly 4S is the first clinical trial to convincingly

demonstrate that cholesterol-lowering demonstrate that cholesterol-lowering therapy reduces the risk of major coronary therapy reduces the risk of major coronary events in women with preexisting CHD.events in women with preexisting CHD.

The magnitude of the reduction (34%) was The magnitude of the reduction (34%) was similar to that observed in men.similar to that observed in men.

Small numbers of CHD and total deaths in Small numbers of CHD and total deaths in women precluded meaningful assessment of women precluded meaningful assessment of simvastatin effects on all-cause or CHD simvastatin effects on all-cause or CHD mortality in women.mortality in women.


Discussion - ElderlyDiscussion - Elderly The most notable baseline differences The most notable baseline differences

between the age subgroups were fewer between the age subgroups were fewer smokers and greater numbers of patients smokers and greater numbers of patients entered on basis of MI in older versus entered on basis of MI in older versus younger patientsyounger patients

Because of the randomization process, Because of the randomization process, however, between-treatment group however, between-treatment group differences for the age subpopulations were differences for the age subpopulations were minor and did not significantly affect the minor and did not significantly affect the resultsresults


Discussion - ElderlyDiscussion - Elderly 4S is also the first clinical trial to clearly demonstrate 4S is also the first clinical trial to clearly demonstrate

that cholesterol-lowering therapy reduces the risk of that cholesterol-lowering therapy reduces the risk of all-cause mortality (34%) and major coronary events all-cause mortality (34%) and major coronary events (34%) in CHD patients (34%) in CHD patients >>65 years of age.65 years of age.

The observed RR reduction in both mortality The observed RR reduction in both mortality categories, as well as for other secondary and categories, as well as for other secondary and tertiary CHD end points were as great as, or greater tertiary CHD end points were as great as, or greater than those seen in younger patients.than those seen in younger patients.

Because mortality and CHD event rates increased Because mortality and CHD event rates increased with age, the absolute reductions in deaths and with age, the absolute reductions in deaths and events were substantially greater for patients events were substantially greater for patients >>65 65 compared with those < 65 years of age.compared with those < 65 years of age.


ConclusionsConclusions Cholesterol lowering with simvastatin produced similar Cholesterol lowering with simvastatin produced similar

reductions in relative risk for MCE in women compared reductions in relative risk for MCE in women compared with men and in elderly (with men and in elderly (>>65 years of age) compared 65 years of age) compared with younger patients.with younger patients.

There were too few female deaths to assess the effects There were too few female deaths to assess the effects on mortality in women.on mortality in women.

Because mortality rates increased substantially with Because mortality rates increased substantially with age, the absolute risk reduction for both all-cause age, the absolute risk reduction for both all-cause mortality and CHD mortality in simvastatin-treated mortality and CHD mortality in simvastatin-treated subjects was approximately twice as great in the older subjects was approximately twice as great in the older patients.patients.


cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina...

Documents

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years circulation

s populations age

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cause mortality age

women age range

elderly patients