n eng j med, august 5, 1999 vol. 341:410-418

Gemfibrozil for the Secondary Prevention of Gemfibrozil for the Secondary Prevention of Coronary Heart Disease in MenCoronary Heart Disease in Men

with Low Levels of High-Density Lipoprotein with Low Levels of High-Density Lipoprotein CholesterolCholesterol

VA-HIT VA-HIT Rubins, HB, et al, for the Veterans Affairs High-Density Rubins, HB, et al, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study GroupLipoprotein Cholesterol Intervention Trial Study Group

N Eng J Med, August 5, 1999 Vol. 341:410-418N Eng J Med, August 5, 1999 Vol. 341:410-418

VA-HIT: BackgroundVA-HIT: Background

• It is generally accepted that lowering LDL cholesterol in It is generally accepted that lowering LDL cholesterol in patients with CHD is beneficial.patients with CHD is beneficial.

• Few data exist, however, to guide the treatment of Few data exist, however, to guide the treatment of patients whose primary lipid abnormality is low HDL.patients whose primary lipid abnormality is low HDL.


VA-HIT: HypothesisVA-HIT: Hypothesis

• Treatment of men with CHD whose primary lipid Treatment of men with CHD whose primary lipid abnormality is low HDL-C will reduce the endpoint of abnormality is low HDL-C will reduce the endpoint of CHD death and non-fatal M.I. CHD death and non-fatal M.I.

• Gemfibrozil is the drug most likely to favorably affect Gemfibrozil is the drug most likely to favorably affect HDL-C and triglycerides with the HDL-C and triglycerides with the least least effect on LDL-effect on LDL-cholesterol.cholesterol.


VA-HIT: Study DesignVA-HIT: Study Design• 2,531 men with coronary heart disease2,531 men with coronary heart disease

– average age: 64yrsaverage age: 64yrs– 90% white, 57% with hypertension, 25% diabetic, 61% prior MI, 22% current 90% white, 57% with hypertension, 25% diabetic, 61% prior MI, 22% current

smokerssmokers

• Double-blind trial comparing:Double-blind trial comparing:– Gemfibrozil 1200 mg/dGemfibrozil 1200 mg/d– placeboplacebo

• HDL HDL << 40 mg/dL (average: ~ 32 mg/dL) 40 mg/dL (average: ~ 32 mg/dL)• LDL-C LDL-C << 140 mg/dL (average: ~ 111 mg/dL) 140 mg/dL (average: ~ 111 mg/dL) • TG < 300 mg/dL (average: ~ 161 mg/dL)TG < 300 mg/dL (average: ~ 161 mg/dL)


• Primary endpoint: nonfatal MI or death from coronary heart Primary endpoint: nonfatal MI or death from coronary heart diseasedisease

• Secondary endpoints: stroke, death from any cause, TIA, Secondary endpoints: stroke, death from any cause, TIA, revascularization procedures, carotid endarterectomy, and revascularization procedures, carotid endarterectomy, and hospitalization for unstable angina or CHF.hospitalization for unstable angina or CHF.

• Median follow-up 5.1 yearsMedian follow-up 5.1 years

VA-HIT: Study DesignVA-HIT: Study Design


VA-HIT: Mean Plasma Lipid Changes, Year OneVA-HIT: Mean Plasma Lipid Changes, Year One

166

32

113

177 170

113

34

115

0

50

100

150

200

250

TC LDL HDL TG

Lip

opro

tein

, mg/

dL

PlaceboGemfibrozil

166

32

113

177 170

113

34

115

0

50

100

150

200

250

TC LDL HDL TG

Lip

opro

tein

, mg/

dL

PlaceboGemfibrozil


6% increasep<0.001

31% decreasep<0.001

4% decreasep<0.001

P=NS

VA-HIT: Lipid EffectsVA-HIT: Lipid Effects

0

50

100

150

200

0 1 2 3 4 5

Years

Tot

al C

hole

ster

ol (

mg/

dl)

Placebo

Gemfibrozil0

50

100

150

200

0 1 2 3 4 5

Years

Tot

al C

hole

ster

ol (

mg/

dl)

Placebo

Gemfibrozil30

31

32

33

34

35

0 1 2 3 4 5

YearsH

DL

-C (m

g/dl

)

Placebo

Gemfibrozil

30

31

32

33

34

35

0 1 2 3 4 5

YearsH

DL

-C (m

g/dl

)

Placebo

Gemfibrozil


0

50

100

150

200

0 1 2 3 4 5

Years

LD

L-C

(mg/

dl)

PlaceboGemfibrozil

0

50

100

150

200

0 1 2 3 4 5

Years

LD

L-C

(mg/

dl)

PlaceboGemfibrozil

0

50

100

150

200

0 1 2 3 4 5

YearsT

G (m

g/dl

)

PlaceboGemfibrozil

0

50

100

150

200

0 1 2 3 4 5

YearsT

G (m

g/dl

)

PlaceboGemfibrozil

VA-HIT: Lipid EffectsVA-HIT: Lipid Effects


VA-HIT: ResultsVA-HIT: Results

• Increased HDL 6%Increased HDL 6%• Decreased TG 31%Decreased TG 31%• Decreased TC 4%Decreased TC 4%• No change in LDLNo change in LDL• Primary event (death from CHD or nonfatal M.I.) occurred in: Primary event (death from CHD or nonfatal M.I.) occurred in:

– 275 of 1267 patients on placebo (21.7%)275 of 1267 patients on placebo (21.7%)– 219 of 1264 patients on gemfibrozil (17.3%)219 of 1264 patients on gemfibrozil (17.3%)



• Primary endpoint:Primary endpoint:– 22 % risk reduction in nonfatal MI or death from CHD (p=0.006)22 % risk reduction in nonfatal MI or death from CHD (p=0.006)

• Secondary endpoints:Secondary endpoints:– 24% risk reduction in CHD death, nonfatal MI and confirmed stroke 24% risk reduction in CHD death, nonfatal MI and confirmed stroke

combined (p< 0.001)combined (p< 0.001)– 22% risk reduction in CHD death (p = 0.07)22% risk reduction in CHD death (p = 0.07)– 23% risk reduction in nonfatal MI (p = 0.02)23% risk reduction in nonfatal MI (p = 0.02)– 25% risk reduction in confirmed stroke (p = 0.10)25% risk reduction in confirmed stroke (p = 0.10)– 59% risk reduction in TIA (p<0.001)59% risk reduction in TIA (p<0.001)– 65% risk reduction in carotid endarterectomy (p<0.001)65% risk reduction in carotid endarterectomy (p<0.001)


• There was no significant difference in rates of coronary There was no significant difference in rates of coronary revascularization, hospitalization for unstable angina, death revascularization, hospitalization for unstable angina, death from any cause, and cancer between patients randomized to from any cause, and cancer between patients randomized to gemfibrozil or placebo.gemfibrozil or placebo.

• Gemfibrozil was generally well tolerated. Dyspepsia occurred Gemfibrozil was generally well tolerated. Dyspepsia occurred in 40% of patients taking gemfibrozil and 34% of patients taking in 40% of patients taking gemfibrozil and 34% of patients taking placebo (p=0.002)placebo (p=0.002)

• The beneficial effects of gemfibrozil did not become apparent The beneficial effects of gemfibrozil did not become apparent until 2 years after randomization.until 2 years after randomization.



VA-HIT:VA-HIT:Primary Endpoint ResultsPrimary Endpoint Results

17.3

21.7

0

5

10

15

20

25

Gemfibrozil Placebo

17.3

21.7

0

5

10

15

20

25

Gemfibrozil Placebo

22% Relative Risk Reduction (p = 0.006)

Non

fata

l M.I

. or

CH

D D

eath

, %


VA-HIT: Results by Baseline HDL-CVA-HIT: Results by Baseline HDL-CDeath due to CHD, Nonfatal MI or Confirmed StrokeDeath due to CHD, Nonfatal MI or Confirmed Stroke

28

2321

18

0

10

20

30

40

HDL <31.5 mg/dl HDL >31.5 mg/dl

% W

ith

Eve

nt

PlaceboGemfibrozil28

2321

18

0

10

20

30

40

HDL <31.5 mg/dl HDL >31.5 mg/dl

% W

ith

Eve

nt

PlaceboGemfibrozil

30% risk reductionp=0.003 24% risk reduction

p=0.03


VA-HIT: Results by Baseline LDL-C VA-HIT: Results by Baseline LDL-C Death due to CHD, Nonfatal MI or Confirmed StrokeDeath due to CHD, Nonfatal MI or Confirmed Stroke

29

2524

2724

2019

211919

0

5

10

15

20

25

30

35

LDL <112 LDL >112 LDL<104 LDL104-121 LDL >121

% W

ith E

vent

PlaceboGemfibrozilP< 0.04

P< 0.003

P< 0.46

P< 0.008

P< 0.02


VA-HIT: Results by Prespecified SubgroupVA-HIT: Results by Prespecified SubgroupCHD Death, Nonfatal MI, or Confirmed StrokeCHD Death, Nonfatal MI, or Confirmed Stroke

262629

2629

24212022

2022

19

0

10

20

30

40

Age <66 Age >66 White Non-White FamilyHistory

No FamilyHistory

% W

ith E

vent

PlaceboGemfibrozil

262629

2629

24212022

2022

19

0

10

20

30

40

Age <66 Age >66 White Non-White FamilyHistory

No FamilyHistory

% W

ith E

vent

PlaceboGemfibrozil

Risk Reduction (%): 22 26 24 27 25 24Risk Reduction (%): 22 26 24 27 25 24 P value: 0.04 0.007 0.002 0.20 0.11 0.004P value: 0.04 0.007 0.002 0.20 0.11 0.004



262623

36

2724

1822

18

28

18

28

0

10

20

30

40

50

Smoker Non-Smoker Diabetes No Diabetes Hypertension NoHypertension

% W

ith E

vent

PlaceboGemfibrozil

262623

36

2724

1822

18

28

18

28

0

10

20

30

40

50

Smoker Non-Smoker Diabetes No Diabetes Hypertension NoHypertension

% W

ith E

vent

PlaceboGemfibrozil

Risk Reduction (%): -16 34 24 24 17 34Risk Reduction (%): -16 34 24 24 17 34 P value: 0.41 0.001 0.05 0.009 0.09 0.002P value: 0.41 0.001 0.05 0.009 0.09 0.002



2725

2826

19

31

1922

17

21

16

24

0

10

20

30

40

Prior MI No Prior MI ASA use No ASA use BB use No BB use

% W

ith E

vent

PlaceboGemfibrozil

2725

2826

19

31

1922

17

21

16

24

0

10

20

30

40

Prior MI No Prior MI ASA use No ASA use BB use No BB use

% W

ith E

vent

PlaceboGemfibrozil

Risk Reduction (%): 27 19 20 42 14 31Risk Reduction (%): 27 19 20 42 14 31 P value: 0.002 0.17 0.02 0.007 0.24 0.001P value: 0.002 0.17 0.02 0.007 0.24 0.001


VA-HIT:VA-HIT:ConclusionsConclusions

• The results of this study suggest that raising HDL cholesterol The results of this study suggest that raising HDL cholesterol and lowering levels of TG, without lowering LDL cholesterol and lowering levels of TG, without lowering LDL cholesterol level, reduces major coronary events in patients whose primary level, reduces major coronary events in patients whose primary lipid abnormality is a low HDL cholesterol levellipid abnormality is a low HDL cholesterol level

• A 6% increase in HDL and a 31% decrease in TG resulted in A 6% increase in HDL and a 31% decrease in TG resulted in 24% decrease in CHD death, nonfatal MI and stroke combined.24% decrease in CHD death, nonfatal MI and stroke combined.


n eng j med, august 5, 1999 vol. 341:410-418

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