primary prevention of acute coronary events with lovastatin in men and women with average...

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

primary prevention of acute coronary events with lovastatin in men and women with average...

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