Primary Prevention of Acute Coronary Events with Lovastatin in Men and Women with Average Cholesterol Levels Results of AFCAPS/TexCAPS John R. Downs, Michael

Primary Prevention of Acute Coronary Events with Lovastatin in Men and Women with Average Cholesterol

LevelsResults of AFCAPS/TexCAPS

John R. Downs, Michael Clearfield, Stephen Weis, Edwin Whitney, Deborah R. Shapiro, Polly A. Beere, Alexandra

Langendorfer, Evan A. Stein, William B. Kruyer, Antonio M. Gotto; for the AFCAPS/TexCAPS Research Group

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Major Statin Trials

LDL-C

1º Prevention 2º Prevention

AFCAPS/TexCAPS

4SWOSCOPS

CARE

LIPID

Gotto, et. al. AHA Nov ’97 Preliminary Results

Objective

· To compare lovastatin with placebo for prevention of the first acute major coronary event:- unstable angina, fatal and non-fatal MI and sudden

cardiac death

in a cohort of men and women without clinically evident atherosclerotic CVD, who have average TC and LDL-C and below-average HDL-C.

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

AFCAPS/TexCAPSStudy Design

· Design:- Randomized, double-blind, placebo-controlled trial

· Setting:- Outpatient clinics in Texas

· Participants:- 5608 men and 997 women with at baseline, average TC (221

mg/dL) and LDL-C (150 mg/dL) and below-average HDL-C (37 mg/dL).

· Intervention:- Lovastatin (20-40 mg daily - to achieve an LDL-C of < 110

mg/dL) or placebo in addition to a low-saturated fat, low-cholesterol diet.

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

· First Acute Major Coronary Event defined as:

- Unstable Angina Pectoris*

- Fatal or Non-fatal MI

- Sudden Cardiac Death

Primary Endpoint

*Unstable Angina Endpoint CriteriaClinical history with hospitalization, reversible ischemic ECG changes, + thallium ETT,cardiac catheterization: > 90% stenosis in major epicardial coronary artery.

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

· Fatal or Non-Fatal Coronary Revascularization

· Fatal or Non-Fatal MI· Unstable Angina· Fatal or Non-Fatal Cardiovascular

Events· Fatal or Non-Fatal Coronary Events· Cardiovascular Mortality· CHD Mortality

Secondary Endpoints

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

· Total Mortality

· Non-Cardiovascular Mortality

· Fatal and Non-Fatal Cancer

· Discontinuation of Medication because of Adverse Effects

Tertiary Endpoints

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Baseline Demographics AFCAPS/TexCAPS NHANES III*

Gender

Women ( 997) 15% 42%

Race

White - 89% 85%

Hispanic - 7% 7%

Black - 3% 8%

Mean Age 58 + 7 y.o. 60 + 8 y.o.

Men (45-73) 57 + 7 y.o. 57 + 8 y.o.

Women (55-73) 63 + 5 y.o. 64 + 5 y.o.

> 65 at Randomization 21% 33%

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Risk Factors

AFCAPS/TexCAPS NHANES III*

Hypertension 22% 35%

Active Smoker 13% 26%

NIDDM 2% 4%

Family History 15% 9%

HDL-C < 35 mg/dl 35% 13%

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Baseline Lipid LevelsCompared with U.S. Reference Population Based Upon

NHANES III

Lipid Level(mg/ dL)

Wilford HallAvg + SD(mg/ dL)N=6605

NHANESPercentile1

U.S. NHANES Ref.Population2

Mean + SD(mg/ dL)

Mean TCMean LDLMean HDL Men WomenMedian TG

221 + 21150 + 17

36 + 540 + 5

158 + 76

5160

251663

225 + 45142 + 3750 + 16

140 + 120

1 Percentile ranks from US NHANES III reference population for study population averages2 Men aged 45-73, and women aged 55-73, without cardiovascular disease

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Year 1 Lipids

Mean TC

Mean LDL-C

Mean HDL-C

Median TG

Ratios

Mean LDL-C/HDL-C

Mean TC/HDL-C

Placebo

228.1 + 27.7

156.4 + 24.5

37.5 + 7.9

162.8 + 82.1

4.3 + 1.1

6.3 + 2.5

Lovastatin

183.7 + 23.8

114.6 + 20.1

39.3 + 8.0

142.8 + 72.8

3.0 + 0.8

4.8 + 1.0

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Percent Change in Lipid Parameters Baseline to Year 1

0.9 1.5 1.2

-2.3

1.7 1.6

-18.4-25

6

-15

-21.8-28

-40

-30

-20

-10

0

10

20

30

Per

cent

Placebo

Lovastatin, avg dose 30 mg

p-value < 0.001 for all lovastatin treatment groups42% of lovastatin patients achieved LDL-C goal of < 110 mg/dL (placebo 3%)81% of lovastatin patients achieved LDL-C goal of < 130 mg/dL (placebo 12%)

TC LDL HDL TG TC/HDL LDL/HDL

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Primary Endpoint ~ First Acute Major Coronary Event*

N=3304 N=3270 N=3228 N=3184 N=3134 N=1688

Lovastatin

N=3301 N=3251 N=3211 N=3159 N=3092 N=1644

Placebo

# At RiskLovastatinPlacebo

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Years of Follow-up0 1 2 3 4 5 5+ Years

Cum

ula

tive In

cidence

37% Risk Reduction(p < 0.001)

*Includes unstable angina, fatal and non-fatal MI &sudden cardiac death

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Primary EndpointRisk of First Acute Major Coronary Event by Year

40

66

100

135

183

2346

7091

116

0

50

100

150

200

250

1 2 3 4 5+ yearsYears Since Randomization

Cum

ulat

ive

Num

ber

of P

artic

ipan

tsw

ith E

vent

s

Placebo (n=3301)Lovastatin (n=3304)

Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac Death reduced by 37% (p < 0.0008)

Poster Presentation at the 1998 ACC Meeting, Atlanta GA

Lovastatin Reduced the Risk of First Acute Major Coronary Events

-37

-46

-31

-58

-38-42

-70

-60

-50

-40

-30

-20

-10

0

Per

cent R

isk R

educt

ion

Poster Presentation at the 1998 ACC Meeting, Atlanta GA

MenN=5608

WomenN=997

> Medianby AgeN=3180

SmokersN=818

HypertensionN=1448

DiabetesN=156

Lovastatin Reduced the Risk of First Acute Major Coronary Events in All Baseline LDL Tertiles

-34 -36-41

-60

-50

-40

-30

-20

-10

0

90.4-141.9 142.0-156.8 156.9-235.4

Per

cent C

han

ge

Relative Risk Reduction

Baseline LDL TertilesPoster Presentation at the 1998 ACC Meeting, Atlanta GA

54 52

77

3733

46

0

10

20

30

40

50

60

70

80

90

< 142, n=2210 143-156, n=2195 > 157, n=2199

Nu

mb

er o

f E

ven

ts

Placebo

Lovastatin

AFCAPS/TexCAPSRole of Baseline LDL on Outcomes

Baseline LDL Level (mg/dL)

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

AFCAPS/TexCAPSRole of Baseline HDL on Outcomes

HDL Level (mg/dL) < 34 35-39 > 40

Events: Placebo Lovastatin

7140

6841

4435

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

71 68

4440 41

35

0

10

20

30

40

50

60

70

80

< 34 35-39 > 40

Nu

mb

er o

f E

ven

ts

Placebo

Lovastatin

AFCAPS/TexCAPSRole of Baseline HDL on Outcomes

Baseline HDL Level (mg/dL)

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Secondary Endpoint AnalysesFatal and Non-Fatal MI

N=3304 N=3281 N=3249 N=3214 N=3174 N=1717N=3301 N=3270 N=3237 N=3200 N=3148 N=1692


0.00

0.01

0.02

0.03

Years of Follow-up0 1 2 3 4 5 5+ years

Lovastatin

Placebo

Cum

ulat

ive

Inci

denc

e 40% Risk Reduction(p = 0.002)

25% Risk Reduction(p = 0.003)

Cardiovascular Events*

N=3304 N=3260 N=3206 N=3147 N=3088 N=1651N=3301 N=3242 N=3187 N=3124 N=3045 N=1615


Cum

ulat

ive

Inci

denc

e

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08


Lovastatin

Placebo

N=3304 N=3281 N=3250 N=3217 N=3174 N=1707N=3301 N=3267 N=3240 N=3205 N=3150 N=1678


Years of Follow-up

Unstable Angina

Cum

ulat

ive

Inci

denc

e

0.00

0.01

0.02

0.03

0 1 2 3 4 5 5+ years

Lovastatin

Placebo 32% Risk Reduction(p = 0.02)

N=3304 N=3264 N=3215 N=3160 N=3106 N=1666N=3301 N=3246 N=3201 N=3141 N=3069 N=1634


Coronary Events*

Cum

ulat

ive

Inci

denc

e

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Years of Follow-up

0 1 2 3 4 5 5+ years

Lovastatin

Placebo 25% Risk Reduction(p = 0.006)

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Coronary Revascularizations

N=3304 N=3277 N=3237 N=3192 N=3148 N=1691N=3301 N=3258 N=3221 N=3174 N=3108 N=1659


Lovastatin

Placebo

0.00

0.01

0.02

0.03

0.04

0.05

Years of Follow-up0 1 2 3 4 5 5+ Years

33% Risk Reduction(p = 0.001)

Cum

ulat

ive

Inc

iden

ce

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Placebo LovastatinEvent n=3301 n=3304

P-value

Total Mortality 77 80 N.S.

Cardiovascular 25 17 too few*

Non-cardiovascular 52 63 N.S.

Mortality

*Too few for survival analyses

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Tertiary AnalysisFatal and Non-Fatal Cancer*

N=3304 N=3249 N=3188 N=3117 N=3059 N=1626

Lovastatin

N=3301 N=3234 N=3171 N=3105 N=3043 N=1603

Placebo


0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08


Cum

ulat

ive

Inci

denc

e

P = NS

*Excludes non-melanoma skin cancer

Poster Presentation 1998 ACC Meeting, Atlanta GA

Placebo Lovastatin

n=3301 n=3304P-value

All Fatal and Non-Fatal 259 252 .75

Most Frequently ReportedProstate 108 109 > 0.99Melanoma 27 14 0.04Colon 20 25 .55

Lung 17 22 .52 Lymphoma 11 12 >

0.99Bladder 11 12 > 0.99

Breast 9 13 .52

Cancer

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Safety ~ Laboratory

PlaceboN=3248

Lovastatin20 mg

N=1585

Lovastatin40 mg

N=1657

ALT and/ or AST > 3x ULN*#

11 (0.3%) 11 (0.7%) 7 (0.4%)

CPK > 10x ULN# 21 (0.6%) 11 (0.7%) 10 (0.6%)

*Consecutive elevations#Treatment group differences were not significant

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Summary of Results· Men and women who are free of clinical evidence of

atherosclerotic CVD, with average TC and LDL-C but below average HDL-C can obtain significant benefit from LDL-C reduction with lovastatin 20-40 mg/day.

· Lovastatin 20-40 mg/day, (mean dose 30 mg/day) significantly reduced the risk of:

· The first acute major coronary event - by 37 % (p<0.001)

· MI - by 40% (p=0.002)· Unstable angina - by 32% (p=0.02)· Coronary revascularization - by 33 % (p=0.001)

- Was generally well-tolerated (13.6% discontinuation rate compared with 13.8% for placebo)

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Summary of Results

· Clinical benefit - Appeared within the first year of treatment and

continued- Was apparent for all LDL-C tertiles

· Range 90-235 mg/dl- Was consistent for subgroups

· Women· Risk Factors - Age, DM, HTN, Smokers

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Conclusions

· In conjunction with a prudent diet, regular exercise and risk factor modification

Lovastatin 20-40 mg/day could be used to lower the risk of the first acute major coronary event

- for primary prevention candidates - · men > 45 years, women > 55 years· HDL < 50 mg/dl· LDL > 130 mg/dl

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Conclusions

· Lovastatin 20-40 mg/day reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C and below-average HDL-C

· These findings support the inclusion of HDL-C in risk-factor assessment and confirm the benefit of LDL-C reduction to a target goal

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Conclusions

· Treatment was beneficial for women, and persons with any active risk factor and appeared to neutralize the risk conferred by HTN, smoking and low HDL

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

AFCAPS/TexCAPSImplications

· “Using NHANES III survey data, approximately 8 million Americans without documented cardiovascular disease meet the age and lipid criteria of AFCAPS/TexCAPS.”

· “Assuming that only 17% of the reference population would qualify for drug treatment by current NCEP guidelines, we estimate that 6 million Americans currently not recommended for drug treatment may benefit from LDL-C reduction with lovastatin.”

JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622

Cost Analysis (AFCAPS/TexCAPS)· Cost of hospitalizations, procedures, etc.*

- Placebo group = $2,100- Lovastatin group = $1,513- Savings = $587 per patient during study

· Cost of lovastatin therapy (retail price x days on drug)- $4,700

· Cost per day of lovastatin (offset by savings)- $2.44

*Does not include loss of income, non-medical expenses, etc.Gotto, ACC, Atlanta, GA 1998

Documents

Primary Prevention of Acute Coronary Events with Lovastatin in Men and Women with Average Cholesterol Levels Results of AFCAPS/TexCAPS John R. Downs, Michael