primary prevention of acute coronary events with lovastatin in men and women with average...
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Primary Prevention of Acute Coronary Events with Lovastatin in Men and Women with Average Cholesterol Levels Results of AFCAPS/TexCAPS. - PowerPoint PPT PresentationTRANSCRIPT
Primary Prevention of Acute Coronary Primary Prevention of Acute Coronary Events with Lovastatin in Men and Events with Lovastatin in Men and Women with Average Cholesterol Women with Average Cholesterol
LevelsLevelsResults of AFCAPS/TexCAPSResults of AFCAPS/TexCAPS
John R. Downs, Michael Clearfield, Stephen Weis, Edwin John R. Downs, Michael Clearfield, Stephen Weis, Edwin Whitney, Deborah R. Shapiro, Polly A. Beere, Alexandra Whitney, Deborah R. Shapiro, Polly A. Beere, Alexandra
Langendorfer, Evan A. Stein, William B. Kruyer, Antonio M. Langendorfer, Evan A. Stein, William B. Kruyer, Antonio M. Gotto; for the AFCAPS/TexCAPS Research GroupGotto; for the AFCAPS/TexCAPS Research Group
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Major Statin TrialsMajor Statin Trials
LDL-CLDL-C
1º Prevention1º Prevention 2º Prevention2º Prevention
AFCAPS/AFCAPS/TexCAPSTexCAPS
4S4SWOSCOPSWOSCOPS
CARECARE
LIPIDLIPID
Gotto, et. al. AHA Nov ’97 Preliminary ResultsGotto, et. al. AHA Nov ’97 Preliminary Results
ObjectiveObjective
To compare lovastatin with placebo for prevention To compare lovastatin with placebo for prevention of the first acute major coronary event:of the first acute major coronary event: unstable angina, fatal and non-fatal MI and sudden unstable angina, fatal and non-fatal MI and sudden
cardiac deathcardiac death
in a cohort of men and women without clinically in a cohort of men and women without clinically evident atherosclerotic CVD, who have average TC evident atherosclerotic CVD, who have average TC and LDL-C and below-average HDL-C.and LDL-C and below-average HDL-C.
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
AFCAPS/TexCAPSAFCAPS/TexCAPSStudy DesignStudy Design
Design:Design: Randomized, double-blind, placebo-controlled trialRandomized, double-blind, placebo-controlled trial
Setting:Setting: Outpatient clinics in TexasOutpatient clinics in Texas
Participants:Participants: 5608 men and 997 women with at baseline, average TC (221 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) and LDL-C (150 mg/dL) and below-average HDL-C (37 mg/dL).mg/dL).
Intervention:Intervention: Lovastatin (20-40 mg daily - to achieve an LDL-C of < 110 mg/dL) 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.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 First Acute Major Coronary Event defined as:Event defined as:
Unstable Angina Pectoris* Unstable Angina Pectoris* Fatal or Non-fatal MI Fatal or Non-fatal MI
Sudden Cardiac DeathSudden Cardiac Death
Primary EndpointPrimary Endpoint
*Unstable Angina Endpoint Criteria*Unstable Angina Endpoint CriteriaClinical history with hospitalization, reversible ischemic ECG changes, + thallium ETT,Clinical history with hospitalization, reversible ischemic ECG changes, + thallium ETT,cardiac catheterization: > 90% stenosis in major epicardial coronary artery.cardiac catheterization: > 90% stenosis in major epicardial coronary artery.
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Fatal or Non-Fatal Coronary Fatal or Non-Fatal Coronary RevascularizationRevascularization
Fatal or Non-Fatal MIFatal or Non-Fatal MI Unstable AnginaUnstable Angina Fatal or Non-Fatal Cardiovascular Fatal or Non-Fatal Cardiovascular
EventsEvents Fatal or Non-Fatal Coronary EventsFatal or Non-Fatal Coronary Events Cardiovascular MortalityCardiovascular Mortality CHD MortalityCHD Mortality
Secondary EndpointsSecondary Endpoints
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Total MortalityTotal Mortality Non-Cardiovascular MortalityNon-Cardiovascular Mortality
Fatal and Non-Fatal CancerFatal and Non-Fatal Cancer
Discontinuation of Medication Discontinuation of Medication because of Adverse Effectsbecause of Adverse Effects
Tertiary EndpointsTertiary Endpoints
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Baseline DemographicsBaseline Demographics AFCAPS/TexCAPSAFCAPS/TexCAPS NHANES III* NHANES III*
GenderGenderWomen ( 997)Women ( 997) 15% 15% 42% 42%
RaceRaceWhite -White - 89%89% 85% 85%Hispanic -Hispanic - 7%7% 7% 7%Black - Black - 3%3% 8% 8%
Mean AgeMean Age 58 58 ++ 7 y.o. 7 y.o. 60 60 ++ 8 y.o. 8 y.o.Men (45-73)Men (45-73) 57 57 ++ 7 y.o. 7 y.o. 57 57 ++ 8 y.o. 8 y.o.Women (55-73)Women (55-73) 63 63 ++ 5 y.o. 5 y.o. 64 64 ++ 5 y.o. 5 y.o.>> 65 at Randomization 65 at Randomization 21%21% 33% 33%
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Risk FactorsRisk Factors AFCAPS/TexCAPSAFCAPS/TexCAPS NHANES III*NHANES III*
Hypertension Hypertension 22%22% 35% 35%
Active SmokerActive Smoker 13%13% 26% 26%
NIDDMNIDDM 2%2% 4% 4%
Family HistoryFamily History 15%15% 9% 9%
HDL-C < 35 mg/dl HDL-C < 35 mg/dl 35%35% 13% 13%
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Baseline Lipid LevelsBaseline Lipid LevelsCompared with U.S. Reference Population Based Upon Compared with U.S. Reference Population Based Upon
NHANES IIINHANES 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
11 Percentile ranks from US NHANES III reference population for study population averages Percentile ranks from US NHANES III reference population for study population averages22 Men aged 45-73, and women aged 55-73, without cardiovascular disease Men aged 45-73, and women aged 55-73, without cardiovascular disease
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Year 1 LipidsYear 1 Lipids
Mean TCMean TC
Mean LDL-CMean LDL-C
Mean HDL-CMean HDL-C
Median TGMedian TG
RatiosRatios
Mean LDL-C/HDL-C Mean LDL-C/HDL-C
Mean TC/HDL-C Mean TC/HDL-C
PlaceboPlacebo
228.1 228.1 ++ 27.7 27.7156.4 156.4 ++ 24.5 24.537.5 37.5 ++ 7.9 7.9
162.8 162.8 ++ 82.1 82.1
4.3 4.3 ++ 1.1 1.16.3 6.3 ++ 2.5 2.5
LovastatinLovastatin
183.7 183.7 ++ 23.8 23.8114.6 114.6 ++ 20.1 20.1
39.3 39.3 ++ 8.0 8.0142.8 142.8 ++ 72.8 72.8
3.0 3.0 ++ 0.8 0.84.8 4.8 ++ 1.0 1.0
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Percent Change in Lipid Parameters Percent Change in Lipid Parameters Baseline to Year 1Baseline 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
Perc
ent
PlaceboLovastatin, 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/HDLTC LDL HDL TG TC/HDL LDL/HDL
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Primary Endpoint ~ First Acute Major Coronary Event*Primary Endpoint ~ First Acute Major Coronary Event*
N=3304 N=3270 N=3228 N=3184 N=3134 N=1688
LovastatinLovastatin
N=3301 N=3251 N=3211 N=3159 N=3092 N=1644
PlaceboPlacebo
# At RiskLovastatinPlacebo
0.000.00
0.010.01
0.020.02
0.030.03
0.040.04
0.050.05
0.060.06
Years of Follow-upYears of Follow-up00 11 22 33 44 55 5+ Years5+ Years
Cum
ulat
ive
Incid
ence
Cum
ulat
ive
Incid
ence
37% Risk Reduction37% Risk Reduction(p < 0.001)(p < 0.001)
*Includes unstable angina, *Includes unstable angina, fatal and non-fatal MI &fatal and non-fatal MI &sudden cardiac deathsudden cardiac death
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Primary EndpointPrimary EndpointRisk of First Acute Major Coronary Event by YearRisk of First Acute Major Coronary Event by Year
4066
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 o
f Par
ticip
ants
with
Eve
nts
Placebo (n=3301)Lovastatin (n=3304)
Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac DeathFatal & Non-fatal MI, Unstable Angina, Sudden Cardiac Death reduced by 37% (p < 0.0008)reduced by 37% (p < 0.0008)
Poster Presentation at the 1998 ACC Meeting, Atlanta GAPoster Presentation at the 1998 ACC Meeting, Atlanta GA
Lovastatin Reduced the Risk of First Acute Lovastatin Reduced the Risk of First Acute Major Coronary EventsMajor Coronary Events
-37-46
-31
-58
-38-42
-70
-60
-50
-40
-30
-20
-10
0
Perc
ent R
isk
Redu
ction
Poster Presentation at the 1998 ACC Meeting, Atlanta GAPoster Presentation at the 1998 ACC Meeting, Atlanta GA
MenMenN=5608N=5608
WomenWomenN=997N=997
> Median> Medianby Ageby AgeN=3180N=3180
SmokersSmokersN=818N=818
HypertensionHypertensionN=1448N=1448
DiabetesDiabetesN=156N=156
Lovastatin Reduced the Risk of First Acute Major Lovastatin Reduced the Risk of First Acute Major Coronary Events in All Baseline LDL TertilesCoronary 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
Perc
ent C
hang
e
Relative Risk Reduction
Baseline LDL TertilesBaseline LDL TertilesPoster Presentation at the 1998 ACC Meeting, Atlanta GAPoster Presentation at the 1998 ACC Meeting, Atlanta GA
54 52
77
37 33
46
0102030405060708090
< 142, n=2210 143-156, n=2195 > 157, n=2199
Num
ber
of E
vent
s
PlaceboLovastatin
AFCAPS/TexCAPSAFCAPS/TexCAPSRole of Baseline LDL on OutcomesRole of Baseline LDL on Outcomes
Baseline LDL Level (mg/dL)Baseline LDL Level (mg/dL)
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
AFCAPS/TexCAPSAFCAPS/TexCAPSRole of Baseline HDL on OutcomesRole 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 4135
01020304050607080
< 34 35-39 > 40
Num
ber
of E
vent
s
PlaceboLovastatin
AFCAPS/TexCAPSAFCAPS/TexCAPSRole of Baseline HDL on OutcomesRole of Baseline HDL on Outcomes
Baseline HDL Level (mg/dL)Baseline HDL Level (mg/dL)
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Secondary Endpoint AnalysesSecondary Endpoint AnalysesFatal and Non-Fatal MIFatal 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
LovastatinLovastatin
PlaceboPlacebo
Cum
ulat
ive
Inci
denc
eC
umul
ativ
e In
cide
nce 40% Risk Reduction40% Risk Reduction
(p = 0.002)(p = 0.002)
25% Risk Reduction25% Risk Reduction((p = 0.003)p = 0.003)
Cardiovascular Events*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
LovastatinLovastatin
PlaceboPlacebo
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 AnginaUnstable Angina
Cum
ulat
ive
Inci
denc
e
0.00
0.01
0.02
0.03
0 1 2 3 4 5 5+ years
LovastatinLovastatin
PlaceboPlacebo 32% Risk Reduction32% Risk Reduction(p = 0.02)(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*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
LovastatinLovastatin
PlaceboPlacebo 25% Risk Reduction25% Risk Reduction(p = 0.006)(p = 0.006)
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Coronary RevascularizationsCoronary 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 Reduction33% Risk Reduction(p = 0.001)(p = 0.001)
Cum
ulat
ive
Inci
denc
e
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
PlaceboPlacebo Lovastatin LovastatinEventEvent n=3301 n=3301 n=3304 n=3304
P-valueP-value
Total MortalityTotal Mortality 77 77 80 80 N.S. N.S.
CardiovascularCardiovascular 25 25 17 17 too few* too few*
Non-cardiovascular 52Non-cardiovascular 52 63 63 N.S. N.S.
MortalityMortality
*Too few for survival analyses*Too few for survival analyses
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Tertiary AnalysisTertiary AnalysisFatal and Non-Fatal Cancer*Fatal 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*Excludes non-melanoma skin cancer
Poster Presentation Poster Presentation 1998 ACC Meeting, Atlanta GA1998 ACC Meeting, Atlanta GA
PlaceboPlacebo LovastatinLovastatin
n=3301n=3301 n=3304n=3304P-valueP-value
All Fatal and Non-FatalAll Fatal and Non-Fatal 259259 252252 .75.75Most Frequently ReportedMost Frequently Reported
ProstateProstate 108108 109109 > > 0.990.99MelanomaMelanoma 2727 1414 0.040.04ColonColon 2020 2525 .55 .55
LungLung 1717 2222 .52.52 LymphomaLymphoma 1111 1212 > >
0.990.99BladderBladder 1111 1212 > > 0.990.99
BreastBreast 9 9 1313 .52.52
CancerCancer
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Safety ~ LaboratorySafety ~ Laboratory
PlaceboN=3248
Lovastatin20 mg
N=1585
Lovastatin40 mg
N=1657ALT 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*Consecutive elevations##Treatment group differences were not significantTreatment group differences were not significant
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Summary of ResultsSummary of Results Men and women who are free of clinical evidence of Men and women who are free of clinical evidence of
atherosclerotic CVD, with average TC and LDL-C but below atherosclerotic CVD, with average TC and LDL-C but below average HDL-C can obtain significant benefit from LDL-C average HDL-C can obtain significant benefit from LDL-C reduction with lovastatin 20-40 mg/day.reduction with lovastatin 20-40 mg/day.
Lovastatin 20-40 mg/day, (mean dose 30 mg/day) significantly Lovastatin 20-40 mg/day, (mean dose 30 mg/day) significantly reduced the risk ofreduced the risk of::
The first acute major coronary event The first acute major coronary event - - by 37 % (p<0.001)by 37 % (p<0.001) MI - by 40% (p=0.002)MI - by 40% (p=0.002) Unstable angina - by 32% (p=0.02)Unstable angina - by 32% (p=0.02) Coronary revascularization - by 33 % (p=0.001)Coronary revascularization - by 33 % (p=0.001)
Was generally well-tolerated (13.6% discontinuation rate Was generally well-tolerated (13.6% discontinuation rate compared with 13.8% for placebo)compared with 13.8% for placebo)
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Summary of ResultsSummary of Results
Clinical benefit Clinical benefit Appeared within the first year of treatment and continuedAppeared within the first year of treatment and continued Was apparent for all LDL-C tertilesWas apparent for all LDL-C tertiles
Range 90-235 mg/dlRange 90-235 mg/dl Was consistent for subgroupsWas consistent for subgroups
WomenWomen Risk Factors - Age, DM, HTN, SmokersRisk Factors - Age, DM, HTN, Smokers
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
ConclusionsConclusions In conjunction with a prudent diet, regular In conjunction with a prudent diet, regular
exercise and risk factor modification exercise and risk factor modification Lovastatin 20-40 mg/day could be used to lower Lovastatin 20-40 mg/day could be used to lower the risk of the first acute major coronary eventthe risk of the first acute major coronary event for primary prevention candidates - for primary prevention candidates -
men men >> 45 years, women 45 years, women >> 55 years 55 years HDL HDL << 50 mg/dl 50 mg/dl LDL LDL >> 130 mg/dl 130 mg/dl
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
ConclusionsConclusions
Lovastatin 20-40 mg/day reduces the risk for the Lovastatin 20-40 mg/day reduces the risk for the first acute major coronary event in men and first acute major coronary event in men and women with average TC and LDL-C and below-women with average TC and LDL-C and below-average HDL-Caverage HDL-C
These findings support the inclusion of HDL-C in These findings support the inclusion of HDL-C in risk-factor assessment and confirm the benefit of risk-factor assessment and confirm the benefit of LDL-C reduction to a target goalLDL-C reduction to a target goal
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
ConclusionsConclusions
Treatment was beneficial for women, and Treatment was beneficial for women, and persons with persons with anyany active risk factor and active risk factor and appeared to neutralize the risk conferred appeared to neutralize the risk conferred by HTN, smoking and low HDLby HTN, smoking and low HDL
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
AFCAPS/TexCAPSAFCAPS/TexCAPSImplicationsImplications
““Using NHANES III survey data, approximately 8 Using NHANES III survey data, approximately 8 million Americans without documented million Americans without documented cardiovascular disease meet the age and lipid cardiovascular disease meet the age and lipid criteria of AFCAPS/TexCAPS.”criteria of AFCAPS/TexCAPS.”
““Assuming that only 17% of the reference population Assuming that only 17% of the reference population would qualify for drug treatment by current NCEP would qualify for drug treatment by current NCEP guidelines, we estimate that 6 million Americans guidelines, we estimate that 6 million Americans currently not recommended for drug treatment may currently not recommended for drug treatment may benefit from LDL-C reduction with lovastatin.”benefit from LDL-C reduction with lovastatin.”
JAMA 1998;279:1615-1622JAMA 1998;279:1615-1622
Cost Analysis (AFCAPS/TexCAPS)Cost Analysis (AFCAPS/TexCAPS) Cost of hospitalizations, procedures, etc.*Cost of hospitalizations, procedures, etc.*
Placebo group = $2,100Placebo group = $2,100 Lovastatin group = $1,513Lovastatin group = $1,513 Savings = $587 per patient during studySavings = $587 per patient during study
Cost of lovastatin therapy (retail price x days on Cost of lovastatin therapy (retail price x days on drug)drug) $4,700$4,700
Cost per day of lovastatin (offset by savings)Cost per day of lovastatin (offset by savings) $2.44$2.44
*Does not include loss of income, non-medical expenses, etc.*Does not include loss of income, non-medical expenses, etc.Gotto, ACC, Atlanta, GA 1998Gotto, ACC, Atlanta, GA 1998