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.
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· 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
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· Total Mortality
· Non-Cardiovascular Mortality
· Fatal and Non-Fatal Cancer
· Discontinuation of Medication because of Adverse Effects
Tertiary Endpoints
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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
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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
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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
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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)
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AFCAPS/TexCAPSRole of Baseline HDL on Outcomes
HDL Level (mg/dL) < 34 35-39 > 40
Events: Placebo Lovastatin
7140
6841
4435
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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)
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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
# At RiskLovastatinPlacebo
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
# At RiskLovastatinPlacebo
Cum
ulat
ive
Inci
denc
e
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Years of Follow-up0 1 2 3 4 5 5+ years
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
# At RiskLovastatinPlacebo
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
# At RiskLovastatinPlacebo
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)
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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
# At RiskLovastatinPlacebo
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
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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
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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
# At RiskLovastatinPlacebo
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Years of Follow-up0 1 2 3 4 5 5+ years
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
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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)
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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
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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
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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
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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