1. Primary Prevention of Acute Coronary Events with Lovastatin in Men and Women with Average Cholesterol Levels Results 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:

2. Major Statin Trials 4S WOSCOPS CARE AFCAPS/ LIPID TexCAPS LDL-C
1º Prevention
2º Prevention
Gotto, et. al. AHA Nov ’97 Preliminary Results

3. 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:

4. AFCAPS/TexCAPS Study 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:

5. Primary Endpoint First Acute Major Coronary Event defined as:
Unstable Angina Pectoris*
Fatal or Non-fatal MI
Sudden Cardiac Death *
*Unstable Angina Endpoint Criteria
Clinical history with hospitalization, reversible ischemic ECG changes, + thallium ETT,
cardiac catheterization: > 90% stenosis in major epicardial coronary artery.
JAMA 1998;279:

6. Secondary Endpoints 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 *
JAMA 1998;279:

7. Tertiary Endpoints Total Mortality Non-Cardiovascular Mortality
Fatal and Non-Fatal Cancer
Discontinuation of Medication because of Adverse Effects *
JAMA 1998;279:

8. Baseline Demographics
AFCAPS/TexCAPS NHANES III*
Gender
Women ( 997) % 42%
Race
White % 85%
Hispanic % %
Black % %
Mean Age y.o y.o.
Men (45-73) y.o y.o.
Women (55-73) y.o y.o.
> 65 at Randomization % %
Add overall age - NHANES percentile?
If there were no differences bet groups use this -
otherwise use by group version with an overall column
JAMA 1998;279:

9. Risk Factors AFCAPS/TexCAPS NHANES III* Hypertension 22% 35%
Active Smoker 13% %
NIDDM 2% %
Family History 15% %
HDL-C < 35 mg/dl 35% %
If there were no differences bet groups use this -
otherwise use next with an overall column
JAMA 1998;279:

10. Baseline Lipid Levels Compared with U. S
Baseline Lipid Levels Compared with U.S. Reference Population Based Upon NHANES III
JAMA 1998;279:
1 Percentile ranks from US NHANES III reference population for study population averages
2 Men aged 45-73, and women aged 55-73, without cardiovascular disease

11. Year 1 Lipids Placebo Lovastatin Mean TC 228.1 + 27.7 183.7 + 23.8
Mean LDL-C
Mean HDL-C
Median TG
Ratios
Mean LDL-C/HDL-C
Mean TC/HDL-C
Placebo
Lovastatin
add overall column
fix spacing - group by line
Used Johns Hopkins Lipid Research Laboratory data from second interim analysis (parametric and preparametric (TG) data).
Methods for sd for TG medians - Toukey
Placebo
(N = )
Lovastatin
(N = )
JAMA 1998;279:

12. Percent Change in Lipid Parameters Baseline to Year 1
p-value < for all lovastatin treatment groups
42% 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:

13. Primary Endpoint ~ First Acute Major Coronary Event*
0.06
*Includes unstable angina,
fatal and non-fatal MI &
sudden cardiac death
0.05
Placebo
37% Risk Reduction
(p < 0.001)
0.04
Cumulative Incidence
0.03
Lovastatin
0.02
0.01
0.00 1 2 3 4 5
5+ Years
Years of Follow-up
# At Risk
Lovastatin
N=3304
N=3270
N=3228
N=3184
N=3134
N=1688
Placebo
N=3301
N=3251
N=3211
N=3159
N=3092
N=1644
JAMA 1998;279:

14. Primary Endpoint Risk of First Acute Major Coronary Event by Year
Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac Death
reduced by 37% (p < )
Poster Presentation at the 1998 ACC Meeting, Atlanta GA

15. Lovastatin Reduced the Risk of First Acute Major Coronary Events
> Median
by Age
N=3180
Men
N=5608
Women
N=997
Smokers
N=818
Hypertension
N=1448
Diabetes
N=156
Poster Presentation at the 1998 ACC Meeting, Atlanta GA

16. Lovastatin Reduced the Risk of First Acute Major Coronary Events in All Baseline LDL Tertiles
Poster Presentation at the 1998 ACC Meeting, Atlanta GA

17. AFCAPS/TexCAPS Role of Baseline LDL on Outcomes
Baseline LDL Level (mg/dL)
JAMA 1998;279:

18. AFCAPS/TexCAPS Role of Baseline HDL on Outcomes
JAMA 1998;279:

19. AFCAPS/TexCAPS Role of Baseline HDL on Outcomes
Baseline HDL Level (mg/dL)
JAMA 1998;279:

20. Secondary Endpoint Analyses
Cardiovascular Events*
Fatal and Non-Fatal MI
0.03
0.08
0.07
Placebo
25% Risk Reduction
(p = 0.003)
Placebo
40% Risk Reduction
(p = 0.002)
0.06
0.02
0.05
Cumulative Incidence
Cumulative Incidence
0.04
Lovastatin
Lovastatin
0.03
0.01
0.02
0.01
0.00
0.00 1 2 3 4 5
5+ years 1 2 3 4 5
5+ years
Years of Follow-up
N=3304
N=3260
N=3206
N=3147
N=3088
N=1651
N=3301
N=3242
N=3187
N=3124
N=3045
N=1615
# At Risk
Lovastatin
Placebo
Years of Follow-up
N=3304
N=3281
N=3249
N=3214
N=3174
N=1717
N=3301
N=3270
N=3237
N=3200
N=3148
N=1692
# At Risk
Lovastatin
Placebo
Unstable Angina
Coronary Events*
0.03
0.07
Placebo
32% Risk Reduction
(p = 0.02)
0.06
Placebo
25% Risk Reduction
(p = 0.006)
0.05
0.02
0.04
Cumulative Incidence
Cumulative Incidence
0.03
Lovastatin
0.01
Lovastatin
0.02
0.01
0.00
0.00 1 2 3 4 5
5+ years 1 2 3 4 5
5+ years
Years of Follow-up
Years of Follow-up
N=3304
N=3281
N=3250
N=3217
N=3174
N=1707
N=3301
N=3267
N=3240
N=3205
N=3150
N=1678
# At Risk
Lovastatin
Placebo
N=3304
N=3264
N=3215
N=3160
N=3106
N=1666
N=3301
N=3246
N=3201
N=3141
N=3069
N=1634
# At Risk
Lovastatin
Placebo
JAMA 1998;279:

21. Coronary Revascularizations
0.05
0.04
33% Risk Reduction
(p = 0.001)
Placebo
0.03
Cumulative Incidence
0.02
Lovastatin
0.01
0.00 1 2 3 4 5
5+ Years
Years of Follow-up
N=3304
N=3277
N=3237
N=3192
N=3148
N=1691
N=3301
N=3258
N=3221
N=3174
N=3108
N=1659
# At Risk
Lovastatin
Placebo
JAMA 1998;279:

22. Mortality Placebo Lovastatin Event n=3301 n=3304 P-value
Total Mortality N.S.
Cardiovascular too few*
Non-cardiovascular N.S.
*Too few for survival analyses
JAMA 1998;279:

23. Fatal and Non-Fatal Cancer*
Tertiary Analysis
Fatal and Non-Fatal Cancer*
0.08
*Excludes non-melanoma skin cancer
0.07
P = NS
Placebo
0.06
0.05
Lovastatin
Cumulative Incidence
0.04
0.03
0.02
0.01
0.00 1 2 3 4 5
5+ years
Years of Follow-up
# At Risk
Lovastatin
N=3304
N=3249
N=3188
N=3117
N=3059
N=1626
Poster Presentation
1998 ACC Meeting, Atlanta GA
Placebo
N=3301
N=3234
N=3171
N=3105
N=3043
N=1603

24. Cancer Placebo Lovastatin n=3301 n=3304 P-value
All Fatal and Non-Fatal
Most Frequently Reported
Prostate > 0.99
Melanoma
Colon
Lung
Lymphoma > 0.99
Bladder > 0.99
Breast
please format so that digits line up
this table is optional
p.39
Excludes non-melanoma skin cancer
JAMA 1998;279:

25. Safety ~ Laboratory *Consecutive elevations
#Treatment group differences were not significant
JAMA 1998;279:

26. 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 mg/day.
Lovastatin 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)
treatment with lovastatin neutralizes risk
JAMA 1998;279:

27. Summary of Results Clinical benefit Range 90-235 mg/dl Women
Appeared within the first year of treatment and continued
Was apparent for all LDL-C tertiles
Range mg/dl
Was consistent for subgroups
Women
Risk Factors - Age, DM, HTN, Smokers
Clinical benefit
appears within the first year of treatment and continues
is apparent for all LDL-C tertiles [Range mg/dl]
is consistent for subgroups
Women [54% RR]
Risk Factors [Age, DM, HTN 43%, TOB 59%]
LDL-C mg/dl [30-41% RR]
treatment with lovastatin neutralizes risk
JAMA 1998;279:

28. Conclusions
In conjunction with a prudent diet, regular exercise and risk factor modification
Lovastatin 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
consider - treat to target LDL-C goal < 110 mg/dl -
The magnitude of benefit is comparable to that seen in the secondary prevention setting.
Treatment results in decreased morbidity and in the expansion of potential healthy longevity.
JAMA 1998;279:

29. Conclusions
Lovastatin 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
Significant benefit is apparent across a spectrum of clinical events (from unstable angina through sudden death).
This is the first and only study that has addressed the prospective risk of unstable angina, an event that accounts for close to 50% of the first admission for CAD and results in invasive diagnostic and revascularization procedures for most newly diagnosed cases.
JAMA 1998;279:

30. 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:

31. AFCAPS/TexCAPS Implications
“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:

32. 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