Clinical Trial Results. org SAGE Trial Prakash Deedwania, MD; Peter H. Stone, MD; C. Noel Bairey Merz, MD; Juan Cosin-Aguilar, MD; Nevres Koylan, MD; Don

Clinical Trial Results . orgClinical Trial Results . org

SAGE TrialSAGE Trial

Prakash Deedwania, MD; Peter H. Stone, MD; C. Noel Bairey Merz, MD; Prakash Deedwania, MD; Peter H. Stone, MD; C. Noel Bairey Merz, MD; Juan Cosin-Aguilar, MD; Nevres Koylan, MD; Don Luo, PhD; Juan Cosin-Aguilar, MD; Nevres Koylan, MD; Don Luo, PhD;

Pamela Ouyang, MBBS; Ryszard Piotrowicz, MD; Pamela Ouyang, MBBS; Ryszard Piotrowicz, MD; Karin Schenck-Gustafsson, MD, PhD; Philippe Sellier, MD; Karin Schenck-Gustafsson, MD, PhD; Philippe Sellier, MD;

James H. Stein, MD; Peter L Thompson, MD; Dan Tzivoni, MDJames H. Stein, MD; Peter L Thompson, MD; Dan Tzivoni, MD

Published in CirculationPublished in Circulation

February 13, 2007February 13, 2007

Effects of Intensive Versus Moderate Lipid-Lowering Therapy on Myocardial Ischemia in Older Patients With Coronary Heart Disease:

Results of the Study Assessing Goals in the Elderly (SAGE)

Effects of Intensive Versus Moderate Lipid-Lowering Therapy on Myocardial Ischemia in Older Patients With Coronary Heart Disease:

Results of the Study Assessing Goals in the Elderly (SAGE)


SAGE Trial: BackgroundSAGE Trial: Background

• Atherosclerosis is a progressive disease and therefore Atherosclerosis is a progressive disease and therefore coronary artery disease (CAD) is most prevalent in older coronary artery disease (CAD) is most prevalent in older persons.persons.

• The risk of CAD events can reduced by lowering low-The risk of CAD events can reduced by lowering low-density lipoprotein cholesterol (LDL-C), for which statins density lipoprotein cholesterol (LDL-C), for which statins are the preferred drug.are the preferred drug.

• However, no studies to date have assessed intensive However, no studies to date have assessed intensive versus moderate statin therapy in older patients with stable versus moderate statin therapy in older patients with stable coronary syndromes.coronary syndromes.

• Atherosclerosis is a progressive disease and therefore Atherosclerosis is a progressive disease and therefore coronary artery disease (CAD) is most prevalent in older coronary artery disease (CAD) is most prevalent in older persons.persons.

• The risk of CAD events can reduced by lowering low-The risk of CAD events can reduced by lowering low-density lipoprotein cholesterol (LDL-C), for which statins density lipoprotein cholesterol (LDL-C), for which statins are the preferred drug.are the preferred drug.

• However, no studies to date have assessed intensive However, no studies to date have assessed intensive versus moderate statin therapy in older patients with stable versus moderate statin therapy in older patients with stable coronary syndromes.coronary syndromes.

Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707.Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707.


SAGE Trial: BackgroundSAGE Trial: Background

• The purpose of the SAGE study was to compare The purpose of the SAGE study was to compare the effects of intensive versus moderate statin the effects of intensive versus moderate statin therapy on the reduction of myocardial ischemia, therapy on the reduction of myocardial ischemia, as assessed by ambulatory ECG, in older men and as assessed by ambulatory ECG, in older men and women with stable CAD.women with stable CAD.

• The purpose of the SAGE study was to compare The purpose of the SAGE study was to compare the effects of intensive versus moderate statin the effects of intensive versus moderate statin therapy on the reduction of myocardial ischemia, therapy on the reduction of myocardial ischemia, as assessed by ambulatory ECG, in older men and as assessed by ambulatory ECG, in older men and women with stable CAD.women with stable CAD.



SAGE Trial: Study DesignSAGE Trial: Study Design

Primary Efficacy Parameter: Absolute change from baseline in total duration of Primary Efficacy Parameter: Absolute change from baseline in total duration of myocardial ischemia on 48-hour Holter Monitormyocardial ischemia on 48-hour Holter Monitor

Secondary Efficacy Parameters: (1) absolute change in total duration of Secondary Efficacy Parameters: (1) absolute change in total duration of ischemia from baseline to month 3; from baseline to month 3 and to month 12: ischemia from baseline to month 3; from baseline to month 3 and to month 12: (2) the % change in total duration of ischemia, (3) the absolute and % change in (2) the % change in total duration of ischemia, (3) the absolute and % change in no. of ischemic episodes, (4) the % change in ischemic burden, (5) the no. of ischemic episodes, (4) the % change in ischemic burden, (5) the proportion of patients who were totally free of ischemia, and (6) the % change in proportion of patients who were totally free of ischemia, and (6) the % change in the levels of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-the levels of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein B.C), triglycerides, and apolipoprotein B.

Primary Efficacy Parameter: Absolute change from baseline in total duration of Primary Efficacy Parameter: Absolute change from baseline in total duration of myocardial ischemia on 48-hour Holter Monitormyocardial ischemia on 48-hour Holter Monitor

Secondary Efficacy Parameters: (1) absolute change in total duration of Secondary Efficacy Parameters: (1) absolute change in total duration of ischemia from baseline to month 3; from baseline to month 3 and to month 12: ischemia from baseline to month 3; from baseline to month 3 and to month 12: (2) the % change in total duration of ischemia, (3) the absolute and % change in (2) the % change in total duration of ischemia, (3) the absolute and % change in no. of ischemic episodes, (4) the % change in ischemic burden, (5) the no. of ischemic episodes, (4) the % change in ischemic burden, (5) the proportion of patients who were totally free of ischemia, and (6) the % change in proportion of patients who were totally free of ischemia, and (6) the % change in the levels of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-the levels of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein B.C), triglycerides, and apolipoprotein B.

Atorvastatin80 mg/dn=377

Atorvastatin80 mg/dn=377

Pravastatin40 mg/dn=374

Pravastatin40 mg/dn=374

893 ambulatory CAD patients 65-85 years with ≥ 1 MI that lasted ≥ 3 minutes during 48-hour ambulatory ECG at screening

Prospective. Randomized. Double-blind. Double-dummy. Multi-Center. International. Mean follow-up 12 months

893 ambulatory CAD patients 65-85 years with ≥ 1 MI that lasted ≥ 3 minutes during 48-hour ambulatory ECG at screening

Prospective. Randomized. Double-blind. Double-dummy. Multi-Center. International. Mean follow-up 12 months

RR

3 and 12 mos. follow-up3 and 12 mos. follow-up



CharacteristicCharacteristic AtorvastatinAtorvastatin(n= 446)(n= 446)

PravastatinPravastatin(n= 445)(n= 445)

Age, yAge, y 72.4 72.4 ± 5.1± 5.1 72.6 72.6 ± 5.2± 5.2

Weight**, kgWeight**, kg 77.4 ± 13.277.4 ± 13.2 75.1 ± 11.575.1 ± 11.5

Body Mass Index**, kg/mBody Mass Index**, kg/m22 27.4 ± 4.027.4 ± 4.0 26.8 ± 3.526.8 ± 3.5

Cholesterol, mg/dLCholesterol, mg/dL Total Total LDLLDL HDLHDL

225.8 ± 36.1225.8 ± 36.1147.5 ± 30.1147.5 ± 30.145.5 ± 11.545.5 ± 11.5

221.9 ± 35.9221.9 ± 35.9144.0 ± 31.5144.0 ± 31.546.4 ± 11.146.4 ± 11.1

Triglycerides, mg/dlTriglycerides, mg/dl 164.4 ± 71.5164.4 ± 71.5 157.1 ± 78.0157.1 ± 78.0

Apolipoprotein B 100**, mg/dLApolipoprotein B 100**, mg/dL 143.6 ± 25.4143.6 ± 25.4 139.3 ± 26.3139.3 ± 26.3

Duration of ischemia, minDuration of ischemia, min 113.5 ± 122.0113.5 ± 122.0 124.3 ± 145.3124.3 ± 145.3

No. of ischemia eventsNo. of ischemia events 3.9 ± 3.83.9 ± 3.8 3.9 ± 3.83.9 ± 3.8

Men (%) Men (%) 307 (68.8)307 (68.8) 312 (70.1)312 (70.1)

White (%)White (%) 433 (97.1)433 (97.1) 430 (96.6)430 (96.6)

SAGE Trial: Baseline CharacteristicsSAGE Trial: Baseline Characteristics

**Denotes statistical significance**Denotes statistical significance



SAGE Trial: Primary Efficacy EndpointSAGE Trial: Primary Efficacy Endpoint

113.5

81.470.8

0

20

40

60

80

100

120

140

113.5

81.470.8

0

20

40

60

80

100

120

140

Atorvastatin

(n=408)

Atorvastatin

(n=408)

124.3

75.3 78.7

0

20

40

60

80

100

120

140124.3

75.3 78.7

0

20

40

60

80

100

120

140

Pravastatin

(n=396)

Pravastatin

(n=396)

BaselineBaseline Month 3Month 3 Month 12Month 12

• The total duration of The total duration of myocardial ischemia myocardial ischemia at month 12 was at month 12 was significantly reduced significantly reduced from baseline in both from baseline in both atorvastatin- and atorvastatin- and pravastatin-treated pravastatin-treated patients.patients.

• There was no There was no significant difference significant difference between atorvastatin between atorvastatin and pravastatin.and pravastatin.

To

tal

du

rati

on

of

Myo

card

ial

Isch

emia

(m

in)

To

tal

du

rati

on

of

Myo

card

ial

Isch

emia

(m

in)

Mean total duration of myocardial Mean total duration of myocardial ischemia over 48 hoursischemia over 48 hours

P<0.001P<0.001 P<0.001P<0.001



SAGE Trial: Secondary Efficacy and Lipid Parameters

SAGE Trial: Secondary Efficacy and Lipid Parameters

• There were no significant differences between atorvastatin There were no significant differences between atorvastatin and pravastatin for any of the secondary efficacy and pravastatin for any of the secondary efficacy parameters at month 3 or month 12. parameters at month 3 or month 12.

• Compared with pravastatin 40 mg/d, atorvastatin 80 mg/d Compared with pravastatin 40 mg/d, atorvastatin 80 mg/d produced significantly greater decreases in total produced significantly greater decreases in total cholesterol, LDL-C, triglycerides, and apolipoprotein B at cholesterol, LDL-C, triglycerides, and apolipoprotein B at month 3 and at month 12 (all P<0.001). month 3 and at month 12 (all P<0.001).

• Levels of HDL-C increased in both groups, with significantly Levels of HDL-C increased in both groups, with significantly larger increases in the pravastatin group at month 3 larger increases in the pravastatin group at month 3 (p<0.001) and 12 (p=0.009) than in the atorvastatin group.(p<0.001) and 12 (p=0.009) than in the atorvastatin group.

• There were no significant differences between atorvastatin There were no significant differences between atorvastatin and pravastatin for any of the secondary efficacy and pravastatin for any of the secondary efficacy parameters at month 3 or month 12. parameters at month 3 or month 12.

• Compared with pravastatin 40 mg/d, atorvastatin 80 mg/d Compared with pravastatin 40 mg/d, atorvastatin 80 mg/d produced significantly greater decreases in total produced significantly greater decreases in total cholesterol, LDL-C, triglycerides, and apolipoprotein B at cholesterol, LDL-C, triglycerides, and apolipoprotein B at month 3 and at month 12 (all P<0.001). month 3 and at month 12 (all P<0.001).

• Levels of HDL-C increased in both groups, with significantly Levels of HDL-C increased in both groups, with significantly larger increases in the pravastatin group at month 3 larger increases in the pravastatin group at month 3 (p<0.001) and 12 (p=0.009) than in the atorvastatin group.(p<0.001) and 12 (p=0.009) than in the atorvastatin group.



-40.9

-56.3

-32.1

2.25.8

-39.6

-21.3

-55.4

-32.4

5.5 7.6

-21.9

-60

-50

-40

-30

-20

-10

0

10

20

-40.9

-56.3

-32.1

2.25.8

-39.6

-21.3

-55.4

-32.4

5.5 7.6

-21.9

-60

-50

-40

-30

-20

-10

0

10

20

SAGE Trial: Lipid ParametersSAGE Trial: Lipid Parameters

TotalTotal LDLLDL HDLHDL

Least Squares Mean Percent Changes in Lipid Least Squares Mean Percent Changes in Lipid Parameters from BaselineParameters from Baseline

p=0.009p=0.009

p<0.001p<0.001

p<0.001p<0.001

AtorvastatinAtorvastatin AtorvastatinAtorvastatin

AtorvastatinAtorvastatin

PravastatinPravastatin PravastatinPravastatin

PravastatinPravastatin

Month 3Month 3

Month 12Month 12


LS

mea

n p

erce

nt

chan

ge

LS

mea

n p

erce

nt

chan

ge


-28.4

-45.6

-25.1-26.3

-7

-44.8

-24.5

-10.6

-60

-50

-40

-30

-20

-10

0

10

20

-28.4

-45.6

-25.1-26.3

-7

-44.8

-24.5

-10.6

-60

-50

-40

-30

-20

-10

0

10

20

SAGE Trial: Lipid ParametersSAGE Trial: Lipid Parameters

TriglyceridesTriglycerides Apolipoprotein B 100Apolipoprotein B 100

Least Squares Mean Percent Changes in Least Squares Mean Percent Changes in Lipid Parameters from BaselineLipid Parameters from Baseline

p<0.001p<0.001

p<0.001p<0.001

AtorvastatinAtorvastatin AtorvastatinAtorvastatinPravastatinPravastatin PravastatinPravastatin

Month 3Month 3

Month 12Month 12


LS

mea

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erce

nt

chan

ge

LS

mea

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erce

nt

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4.0%

1.3%

0%

2%

4%

6%

8%

10%

4.0%

1.3%

0%

2%

4%

6%

8%

10%

11.2%

8.1%

0%

10%

20%

11.2%

8.1%

0%

10%

20%

n =36n =36

Inci

den

ce

(%)

Inci

den

ce

(%)

n =50n =50

Atorvastatin880 mg/d

Atorvastatin880 mg/d

Pravastatin 40 mg/d

Pravastatin 40 mg/d

SAGE Trial: MACE and All-Cause MortalitySAGE Trial: MACE and All-Cause Mortality

Major Adverse Cardiovascular Events (MACE)

Major Adverse Cardiovascular Events (MACE)

Atorvastatin 80 mg/d

Atorvastatin 80 mg/d

Pravastatin 40 mg/d

Pravastatin 40 mg/d

All-Cause Mortality All-Cause Mortality

n =6n =6 n =18n =18

• There was a There was a favorable trend for favorable trend for fewer atorvastatin fewer atorvastatin patients to patients to experience MACE experience MACE than pravastatin than pravastatin patients (HR 0.71; patients (HR 0.71; 95% CI, 0.46, 1.09, 95% CI, 0.46, 1.09, p=0.114).p=0.114).

• A significant 77% A significant 77% reduction in all-reduction in all-cause mortality cause mortality was observed with was observed with atorvastatin atorvastatin relative to relative to pravastatin (HR, pravastatin (HR, 0.33, 95% CI, 0.13, 0.33, 95% CI, 0.13, 0.83; p=0.014). 0.83; p=0.014).

• There was a There was a favorable trend for favorable trend for fewer atorvastatin fewer atorvastatin patients to patients to experience MACE experience MACE than pravastatin than pravastatin patients (HR 0.71; patients (HR 0.71; 95% CI, 0.46, 1.09, 95% CI, 0.46, 1.09, p=0.114).p=0.114).

• A significant 77% A significant 77% reduction in all-reduction in all-cause mortality cause mortality was observed with was observed with atorvastatin atorvastatin relative to relative to pravastatin (HR, pravastatin (HR, 0.33, 95% CI, 0.13, 0.33, 95% CI, 0.13, 0.83; p=0.014). 0.83; p=0.014).



SAGE Trial: LimitationsSAGE Trial: Limitations

• It is possible that reductions in ischemia did not differ It is possible that reductions in ischemia did not differ significantly between the 2 treatment groups because significantly between the 2 treatment groups because ambulatory ischemia is not an adequately sensitive ambulatory ischemia is not an adequately sensitive measure of change in cardiovascular event risk.measure of change in cardiovascular event risk.

• The study may have been underpowered to detect The study may have been underpowered to detect differences between the 2 treatment groups.differences between the 2 treatment groups.

• The number of events for the mortality analysis was The number of events for the mortality analysis was small and was analyzed post-hoc.small and was analyzed post-hoc.

• It is possible that reductions in ischemia did not differ It is possible that reductions in ischemia did not differ significantly between the 2 treatment groups because significantly between the 2 treatment groups because ambulatory ischemia is not an adequately sensitive ambulatory ischemia is not an adequately sensitive measure of change in cardiovascular event risk.measure of change in cardiovascular event risk.

• The study may have been underpowered to detect The study may have been underpowered to detect differences between the 2 treatment groups.differences between the 2 treatment groups.

• The number of events for the mortality analysis was The number of events for the mortality analysis was small and was analyzed post-hoc.small and was analyzed post-hoc.



SAGE Trial: SummarySAGE Trial: Summary

• After comparing the effects of intensive versus After comparing the effects of intensive versus moderate statin therapy in older individuals, this moderate statin therapy in older individuals, this study found that both regimens were equally study found that both regimens were equally effective in the reduction of the frequency and effective in the reduction of the frequency and duration of myocardial ischemia.duration of myocardial ischemia.

• Intensive atorvastatin therapy improved lipids and Intensive atorvastatin therapy improved lipids and reduced all-cause death more effectively than did reduced all-cause death more effectively than did moderate pravastatin.moderate pravastatin.

• After comparing the effects of intensive versus After comparing the effects of intensive versus moderate statin therapy in older individuals, this moderate statin therapy in older individuals, this study found that both regimens were equally study found that both regimens were equally effective in the reduction of the frequency and effective in the reduction of the frequency and duration of myocardial ischemia.duration of myocardial ischemia.

• Intensive atorvastatin therapy improved lipids and Intensive atorvastatin therapy improved lipids and reduced all-cause death more effectively than did reduced all-cause death more effectively than did moderate pravastatin.moderate pravastatin.



SAGE Trial: SummarySAGE Trial: Summary

• Also considering a trend toward reductions in MACE Also considering a trend toward reductions in MACE with atorvastatin versus pravastatin, these results with atorvastatin versus pravastatin, these results support the concept that mechanisms of ischemic support the concept that mechanisms of ischemic events, which are related to oxygen supply and events, which are related to oxygen supply and demand, may differ from acute coronary events, demand, may differ from acute coronary events, which are related to plaque stability.which are related to plaque stability.

• These findings, together with the greater These findings, together with the greater cardiovascular risk in the elderly population, suggest cardiovascular risk in the elderly population, suggest that intensive statin therapy should be considered in that intensive statin therapy should be considered in the elderly population. the elderly population.

• Also considering a trend toward reductions in MACE Also considering a trend toward reductions in MACE with atorvastatin versus pravastatin, these results with atorvastatin versus pravastatin, these results support the concept that mechanisms of ischemic support the concept that mechanisms of ischemic events, which are related to oxygen supply and events, which are related to oxygen supply and demand, may differ from acute coronary events, demand, may differ from acute coronary events, which are related to plaque stability.which are related to plaque stability.

• These findings, together with the greater These findings, together with the greater cardiovascular risk in the elderly population, suggest cardiovascular risk in the elderly population, suggest that intensive statin therapy should be considered in that intensive statin therapy should be considered in the elderly population. the elderly population.


Documents

Clinical Trial Results. org SAGE Trial Prakash Deedwania, MD; Peter H. Stone, MD; C. Noel Bairey Merz, MD; Juan Cosin-Aguilar, MD; Nevres Koylan, MD; Don