Context.— Although cholesterol-reducing treatment has been shown to reduce fatal
and nonfatal coronary disease in patients with coronary heart disease (CHD),
it is unknown whether benefit from the reduction of low-density lipoprotein
cholesterol (LDL-C) in patients without CHD extends to individuals with average
serum cholesterol levels, women, and older persons.
Objective.— To compare lovastatin with placebo for prevention of the first acute
major coronary event in men and women without clinically evident atherosclerotic
cardiovascular disease with average total cholesterol (TC) and LDL-C levels
and below-average high-density lipoprotein cholesterol (HDL-C) levels.
Design.— A randomized, double-blind, placebo-controlled trial.
Setting.— Outpatient clinics in Texas.
Participants.— A total of 5608 men and 997 women with average TC and LDL-C and below-average
HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort
without cardiovascular disease from the National Health and Nutrition Examination
Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21]
mg/dL) (51st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150
[17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L
(36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th
and 16th percentiles, respectively), and median (SD) triglyceride levels were
1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile).
Intervention.— Lovastatin (20-40 mg daily) or placebo in addition to a low–saturated
fat, low-cholesterol diet.
Main Outcome Measures.— First acute major coronary event defined as fatal or nonfatal myocardial
infarction, unstable angina, or sudden cardiac death.
Results.— After an average follow-up of 5.2 years, lovastatin reduced the incidence
of first acute major coronary events (183 vs 116 first events; relative risk
[RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001),
myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI,
0.43-0.83; P=.002), unstable angina (87 vs 60 first
unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02),
coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95%
CI, 0.52-0.85; P=.001), coronary events (215 vs 163
coronary events; RR, 0.75; 95% CI, 0.61-0.92; P=.006),
and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95%
CI, 0.62-0.91; P=.003). Lovastatin (20-40 mg daily)
reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6%
to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in
safety parameters between treatment groups.
Conclusions.— Lovastatin reduces the risk for the first acute major coronary event
in men and women with average TC and LDL-C levels and below-average HDL-C
levels. These findings support the inclusion of HDL-C in risk-factor assessment,
confirm the benefit of LDL-C reduction to a target goal, and suggest the need
for reassessment of the National Cholesterol Education Program guidelines
regarding pharmacological intervention.
EPIDEMIOLOGICAL observations have demonstrated consistently a strong
positive, continuous, independent, graded relation between plasma total cholesterol
(TC) and the incidence of coronary heart disease (CHD). This relation covers
a wide range of cholesterol concentrations, including those considered normal
or mildly elevated.1-3
In the Multiple Risk Factor Intervention Trial follow-up of screened men,
69% of deaths from CHD in the first 6 years of follow-up occurred in subjects
with TC values between 4.71 and 6.83 mmol/L (182-264 mg/dL).4
In the first 16 years of the Framingham Heart Study, 40% of participants who
developed a myocardial infarction had a TC level between 5.17 and 6.47 mmol/L
(200-250 mg/dL).5
Large end point studies have demonstrated conclusively that effective
cholesterol-lowering treatment can substantially reduce myocardial infarction
and other coronary events. In the Scandinavian Simvastatin Survival Study
the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin
reduced total mortality in patients with CHD by 30% because of a 42% reduction
in deaths from CHD.6 Subsequently, pravastatin
was shown to reduce fatal and nonfatal coronary events in patients with7 and without8 CHD. However,
it is unknown whether benefit from reduction of low-density lipoprotein cholesterol
(LDL-C) in patients without CHD (primary prevention) extends to individuals
with average serum cholesterol levels, women, and older persons.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
targeted a cohort of generally healthy middle-aged and older men and women
with average TC and LDL-C levels and with below-average high-density lipoprotein
cholesterol (HDL-C) levels. The primary end point analysis was the incidence
of first acute major coronary events, defined as fatal or nonfatal myocardial
infarction, unstable angina, or sudden cardiac death. The inclusion of unstable
angina was a unique feature of this study, and its inclusion as a primary
end point reflects the increasing frequency of unstable angina as the initial
presentation of CHD in the United States.9
The design of the study has been described in detail previously.10 In summary, AFCAPS/TexCAPS was a randomized, double-blind,
placebo-controlled primary prevention trial that included 6605 men and women
and was conducted at 2 sites in Texas, Lackland Air Force Base in San Antonio
(n = 3737) and University of North Texas Health Science Center in Fort Worth
(n = 2868).
AFCAPS/TexCAPS was powered to investigate whether long-term lipid lowering
with lovastatin would decrease the rate of first acute major coronary events
compared with placebo during at least 5 years of follow-up in a cohort without
clinical evidence of atherosclerotic cardiovascular disease and with average
TC and LDL-C levels and below-average HDL-C levels. Unstable angina was prospectively
defined and required new-onset exertional angina, accelerated or rest angina,
or both, and at least 1 of the following: (1) electrocardiographic findings
of at least 1-mm ST-segment changes and reversible defect on stress perfusion
study, (2) angiographic findings of at least 90% epicardial vessel stenosis
or at least 50% stenosis in the left main coronary artery (without exercise
testing), or (3) at least 1-mm ST-segment changes with pain on electrocardiographic
stress testing and/or rest electrocardiograph and evidence of at least 50%
stenosis in a major epicardial vessel.
Secondary objectives were to investigate whether long-term treatment
with lovastatin, compared with placebo, would decrease cardiovascular morbidity
and mortality across the spectrum of clinical events by measuring the rates
of 7 secondary end points, including 2 components of the primary end point.
The secondary end points were (1) fatal or nonfatal coronary revascularization
procedures, (2) unstable angina, (3) fatal or nonfatal myocardial infarction,
(4) fatal or nonfatal cardiovascular events, (5) fatal or nonfatal coronary
events, (6) cardiovascular mortality, and (7) CHD mortality.
The tertiary objectives were to investigate safety, that is, whether
long-term treatment with lovastatin, compared with placebo, would result in
similar rates of total mortality, noncardiovascular mortality (with subset
analyses for unintentional or violent death and death from cancer), fatal
and nonfatal cancer (excluding basal cell and squamous cell skin cancers),
and discontinuation of medication because of adverse drug effects.
Participant Recruitment and Follow-up
Men aged 45 to 73 years and postmenopausal women aged 55 to 73 years
who met the lipid entrance criteria and had no prior history, signs, or symptoms
of definite myocardial infarction, angina, claudication, cerebrovascular accident,
or transient ischemic attack were eligible for participation in the study.
Lipid entry criteria (TC, 4.65-6.82 mmol/L [180-264 mg/dL]; LDL-C, 3.36-4.91
mmol/L [130-190 mg/dL]; HDL-C, ≤1.16 mmol/L [45 mg/dL] for men or ≤1.22
mmol/L [47 mg/dL] for women; and triglycerides, ≤4.52 mmol/L [400 mg/dL])
were to be met at both 4 and 2 weeks prior to randomization, with less than
15% difference in LDL-C values. In addition, participants with LDL-C values
between 3.23 and 3.34 mmol/L (125-129 mg/dL) were included when the ratio
of TC to HDL-C was more than 6.0. We excluded volunteers with uncontrolled
hypertension, secondary hyperlipidemia, or type 1 or type 2 diabetes mellitus
that was either managed with insulin or associated with a glycohemoglobin
level of at least 10% (20% above the upper limit of normal). Additionally,
volunteers were excluded if, according to the 1983 Metropolitan Life Insurance
tables, they had a body weight of more than 50% greater than the desirable
limit for height. All participants provided written informed consent.
The Data and Safety Monitoring Board and the institutional review boards
of the 2 participating centers approved the consent form and protocol. The
study was conducted under the supervision of a steering committee. Administrative,
clinical, and data management was performed by a contract research organization
with staff at each site who were under the supervision of the clinical investigator.
All personnel involved in participant care were blinded to treatment assignment
and lipid levels.
Participants who met entrance criteria and completed a 12-week American
Heart Association Step I diet run-in, including a 2-week placebo baseline
run-in, were randomized to treatment with either lovastatin, 20 mg/d, or matching
placebo. Participants in the lovastatin group were titrated to 40 mg/d if
their LDL-C level was more than 2.84 mmol/L (110 mg/dL) at the 3-month study
visit. The blind was maintained by titrating equal numbers of randomly selected
placebo-group participants to 2 tablets daily. Throughout the trial, dietary
reinforcement and other risk factor modification information was provided.
An extensive safety evaluation was performed prior to treatment, at
1 year, and at each subsequent year-end visit. Clinical visits were every
6 weeks for the first year. After 1 year, all randomized participants who
continued the study drug were seen semiannually. Participants who discontinued
use of the study drug were contacted on an annual basis for follow-up by questionnaire,
which included an assessment of possible end point events and cancer occurrence.
End point event information was compiled and adjudicated in the same manner
for all participants, including those who had withdrawn from the study. An
end point committee, blinded to treatment-group assignment and not involved
in participant care, used prespecified criteria to adjudicate all end point
events.
For analyses of changes in lipids, frozen serum samples obtained on
the date of randomization before active treatment (day 1) and at the 1-year
visit (posttreatment) were assayed at a specialized lipid laboratory at Johns
Hopkins University, Baltimore, Md. This laboratory also analyzed lipids for
the National Health and Nutrition Examination Survey (NHANES) III as noted
by Sempos et al11 (also P. S. Bachorik, PhD,
unpublished data, 1997). The laboratory was standardized for lipid and lipoprotein
measurements through the Centers for Disease Control and Prevention–National
Heart, Lung, and Blood Institute Lipid Standardization Program.12
All LDL-C values were calculated based on the Friedewald estimation.13
The size of the sample was designed to provide 90% to 97% power to detect
a 30% to 35% reduction in the number of participants with primary end point
events by treatment with lovastatin. All analyses were performed on an intention-to-treat
basis and all P values were 2-sided. A log-rank test,
with study center and sex as stratification factors, was used to assess the
effect of therapy on the rate of primary end point events. Analyses of relative
reductions in risk resulting from lovastatin therapy were calculated using
the Cox proportional hazards regression model that had study center and sex
as stratification factors. The proportionality assumption was met for all
Cox models. Cumulative incidence and interval estimates were calculated using
the life-table method.
The effect of therapy on percent change in lipid parameters from baseline
to 1 year was assessed using an analysis of variance model that included treatment,
study center, and sex after first examining a model that also included the
treatment-by-center and treatment-by-sex interaction effects. All participants
with data at both baseline and 1 year were included.
The proportions of participants who discontinued therapy because of
adverse events or had clinically important adverse events or laboratory abnormalities
were compared between the 2 treatment groups using the Fisher exact test.
The trial was designed to continue until a total of 320 participants
had experienced a first primary end point event or for a minimum of 5 years
after the last participant was randomized, whichever occurred later. In addition
to the final analysis, 2 interim analyses of the trial were planned for the
points at which 120 and 240 participants, respectively, experienced the first
primary end point event. A group sequential design was used with an early
stopping rule, described previously,10 which
preserved the type I error probability of .05. The critical values for finding
statistical significance for 120, 240, and 320 participants with primary end
points were .003, .016, and .044, respectively.
Early Termination for Efficacy
Following a review of the second interim analysis (data from 267 participants
who had experienced a primary end point event), the Data and Safety Monitoring
Board recommended that the trial be stopped early for efficacy. The voting
members of the steering committee agreed unanimously on July 3, 1997, to accept
the recommendation for early termination. The steering committee required
that the participants and personnel continue to be blinded throughout the
final visit of the study to provide unbiased assessment of all additional
end point and safety information in the final analysis. End point status was
determined for all but 1 active participant within 3 months of the decision
to stop the study (Figure 1).
Beginning May 30, 1990, and ending February 12, 1993, 6605 participants
were randomized to treatment with lovastatin (2805 men and 499 women) or placebo
(2803 men and 498 women). For comparison with the age- and sex-matched US
population without clinical evidence of cardiovascular disease, the NHANES
III percentile is presented for average baseline lipid levels.14
Baseline lipid levels were similar in both treatment groups; combined averages
were as follows: mean (SD) TC, 5.71 (0.54) mmol/L (221 [21] mg/dL) (51st percentile);
mean (SD) LDL-C, 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile); mean
(SD) HDL-C, 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L
(40 [5] mg/dL) for women (25th and 16th percentiles, respectively); and median
(SD) triglycerides, 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile).
The 2 treatment groups were also balanced with respect to baseline demographics,
risk factors, and medications (Table 1).
A more detailed description of the baseline characteristics of the study cohort
in comparison with the US NHANES III reference population is provided elsewhere.15
The mean (SD) duration of follow-up was 5.2 (0.9) years (range, 0.2-7.2
years) for those treated with lovastatin and 5.2 (0.9) years (range, 0.1-7.2
years) in the placebo group. As assessed by pill counts, 99% of participants
adhered to their study regimen for at least 75% of the time that they were
receiving active treatment. Study drug regimens were maintained until trial
termination by 2335 (71%) of the 3304 participants randomized to lovastatin
and by 2081 (63%) of the 3301 randomized to placebo (Figure 1). Participants treated with placebo were more likely to
be withdrawn from the study as a result of developing CHD or starting cholesterol-reducing
medication (generally at the request of their primary care physician). The
frequency of discontinuation for other reasons was similar between treatment
groups.
Lovastatin had a significant effect on changes in lipid levels from
baseline (day 1) to posttreatment as assessed at 1 year (P<.001). Low-density lipoprotein cholesterol levels were reduced
by 25%, TC levels were reduced by 18%, triglyceride levels were reduced by
15%, HDL-C levels were increased by 6%, and the ratios of TC to HDL-C and
LDL-C to HDL-C were decreased by 22% and 28%, respectively. By comparison,
in the placebo group, there were small changes in lipid levels that were not
clinically important
(Figure 2).
Treatment effects were similar in men and women (Table 2).
In the lovastatin group, 1657 participants (50%) were titrated from
20 mg/d to 40 mg/d, and of these, no participant was subsequently back-titrated.
At 1 year, 1216 participants (42%) receiving lovastatin and 86 (3%) receiving
placebo reached the study target for LDL-C values of no more than 2.84 mmol/L
(110 mg/dL); 2334 participants (81%) receiving lovastatin and 350 (12%) receiving
placebo reached an LDL-C level of 3.36 mmol/L (130 mg/dL) or less.
Participants treated with lovastatin experienced a 37% lower incidence
of the first acute major coronary event (primary end point defined as fatal
or nonfatal myocardial infarction, unstable angina, or sudden cardiac death)
than did those treated with placebo (Cox model 95% confidence interval, 21%-50%; P<.001).
A total of 116 participants treated with lovastatin compared with 183
in the placebo group had at least 1 primary end point event. Results of primary
and secondary end point analyses are summarized in Table 3. Participants are counted only once within a specific end
point analysis; however, a participant may be included in more than 1 analysis
in Table 3 if they experienced
different types of end points, experienced an event that is comprised in more
than 1 end point analysis (eg, the secondary end point, unstable angina, is
also a component of the primary end point), or both.
Life-table plots (Figure 3)
illustrate a difference between treatment groups beginning in the first year
of treatment and continuing throughout the remainder of the study. These show
the cumulative incidence and the number of participants at risk. By treatment
year, the average risk reduction in the primary end point (acute major coronary
events) with lovastatin was 43% in the first year and 12%, 30%, 41%, and 49%
in the second, third, fourth, and fifth years, respectively. These yearly
rates were not statistically different from each other.
For the primary end point, the event rate for subjects receiving lovastatin
averaged 7 per 1000 patient-years and was 37% less than the 11 per 1000 patient-years
observed for the placebo group. These rates correspond to cumulative incidences
of 4.0% and 6.8% for the lovastatin and placebo groups, respectively, during
the study period (P<.001).
For secondary end points, treatment with lovastatin resulted in significant,
consistent benefit compared with placebo, including 33% reduction in revascularizations
(P=.001), 32% reduction in unstable angina (P=.02), and 40% reduction in the incidence of fatal or
nonfatal myocardial infarction (P=.002). For coronary
and cardiovascular events (total fatal or nonfatal), treatment with lovastatin
resulted in significant (P=.006 and P=.003, respectively) reductions of 25% compared with placebo. The
category of cardiovascular events included all atherosclerotic cardiovascular
events, as specified by the end point definitions, including stable angina,
thrombotic cerebrovascular accidents, transient ischemic attacks, and peripheral
arterial vascular disorders. For the secondary end points fatal cardiovascular
events and fatal CHD events, there were too few events to perform survival
analysis based on prespecified criteria (Table 3).
Figure 4 summarizes the effect
of treatment on the rate of the first primary end point event for predefined
factors: sex, age (older defined as above the median
by sex: >57 years for men and >62 years for women), history of hypertension,
active cigarette smoking, family history of CHD, baseline LDL-C, and baseline
HDL-C. Treatment group, as well as each of these factors, demonstrated a significant
association with risk (eg, smoking was positively associated with first acute
major coronary events). Baseline triglyceride level (P=.98)
and history of diabetes (P=.34, 155 participants
with diabetes) were not significant predictors of outcome. Within a factor,
the numerical rate of first acute major coronary events was similar among
those treated with lovastatin in the CHD positive-risk subgroup and those
treated with placebo who did not have the CHD risk
factor (eg, lovastatin-treated smokers had rates similar to placebo-treated
nonsmokers).
The effect of treatment with lovastatin on the rate of first acute major
coronary events was numerically greater in women than in men (46% vs 37% reduction
in relative risk); however, the actual number of women who had a primary end
point event was small (20 of 997), and there were no statistical differences
in treatment effects between sexes. None of the subgroups differed significantly
in treatment benefit (eg, treatment benefit was not different for participants
with hypertension compared with participants without hypertension and benefit
was not different for smokers compared with nonsmokers, since none of the
treatment-by-subgroup interactions were significant). There were no significant
interactions between treatment and either LDL-C (P=.99)
or HDL-C (P=.16) when evaluated as continuous variables
in a model with the other associated covariates. No threshold to benefit was
observed in LDL-C and HDL-C ranges studied.
In addition to the protocol-specified rates that considered time to
the first event for withdrawn and active participants, we also analyzed the
total number of events experienced by active and withdrawn participants including
multiple events of the same type (eg, multiple myocardial infarctions experienced
by a participant). There were 142 and 209 acute major coronary events in participants
treated with lovastatin and placebo, respectively, with rates of 8 and 12
per 1000 patient-years, respectively. There were 137 and 195 coronary revascularizations
(8 and 11 per 1000 patient-years) in participants treated with lovastatin
and placebo, respectively. Combining acute major coronary events and coronary
revascularizations, there were 279 and 404 (16 and 23 per 1000 patient-years)
in the lovastatin and placebo groups, respectively. If 1000 men and women
were treated with lovastatin for 5 years, approximately 19 acute major coronary
events (12 myocardial infarctions and 7 presentations of unstable angina)
and 17 coronary revascularizations could be prevented.
Overall, treatment with lovastatin was well tolerated. Mortality and
incidence of fatal and nonfatal cancer (tertiary end points to assess safety)
did not demonstrate any difference between treatment groups. The overall mortality
rate was similar in each group, with 80 deaths among participants treated
with lovastatin and 77 deaths among participants treated with placebo (4.6
and 4.4 per 1000 patient-years in participants treated with lovastatin and
placebo, respectively). The majority of deaths had noncardiovascular causes.
There were 17 deaths from cardiovascular causes among participants treated
with lovastatin and 25 in the placebo group (1.0 and 1.4 per 1000 patient-years
in lovastatin and placebo groups, respectively) and 63 deaths from noncardiovascular
causes among participants treated with lovastatin and 52 in the placebo group
(3.6 and 3.0 per 1000 patient-years among participants treated with lovastatin
and placebo, respectively). There were 4 deaths from trauma, 3 in the placebo
group and 1 in the lovastatin group.
The overall incidence of fatal and nonfatal cancer, excluding nonmelanoma
skin cancers, was 15.1 and 15.6 per 1000 patient-years (252 and 259 cases)
among participants treated with lovastatin and placebo, respectively. The
most frequently reported tertiary end point cancers are summarized in Table 4. The number of participants reporting
nonmelanoma skin cancers, predominantly diagnoses of basal cell and squamous
cell cancers, was 250 (7.6%) in the lovastatin group and 243 (7.4%) in the
placebo group.
The number of participants with any adverse experience that led to discontinuation
was 449 (13.6%) in the group treated with lovastatin and 445 (13.8%) in the
placebo group. Both treatment groups had similar numbers of adverse experiences
that were considered serious (ie, life-threatening, causing death or a permanent
disability, resulting in or prolonging hospitalization, or diagnosis of any
cancer), 1131 (34.2%) and 1126 (34.1%) in the groups treated with lovastatin
and placebo, respectively. One participant from each treatment group was unblinded
after discontinuation of the study drug and before the end of the study. A
placebo-treated patient, who discontinued therapy because of idiopathic hepatitis,
was unblinded because a primary care physician advised beginning lipid-reducing
treatment. Another participant was unblinded when he developed study drug–related
Stevens-Johnson syndrome after approximately 9 months of treatment with lovastatin.
Following appropriate treatment and within 2 weeks of discontinuing lovastatin
use, this participant recovered. No other lovastatin-related, life-threatening,
serious, adverse experiences were reported.
Consecutive elevations of more than 3 times the upper limit of normal
in either aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
were rare, and the incidence was similar in both treatment groups (18 [0.6%]
of 3242 participants and 11 [0.3%] of 3248 receiving lovastatin and placebo,
respectively). (Not all participants had postrandomization tests.) Examining
these elevations by final dose for those who were titrated also revealed no
significant trends. Consecutive elevations of more than 3 times the upper
limit of the normal range in either AST or ALT were reported in 11 (0.7%)
of 1585 participants and 7 (0.4%) of 1657 receiving lovastatin, 20 mg/d, and
lovastatin, 40 mg/d, respectively. (Unlike the other comparisons of randomized
treatment groups, the dose comparisons are of nonrandomized groups.) The number
of participants with any drug-attributable AST elevation above the upper limit
of normal was similar between treatment groups (33 [1.0%] and 34 [1.0%] in
the groups treated with lovastatin and placebo, respectively); however, the
number with any ALT drug-related elevations was significantly (P=.003) higher in the group treated with lovastatin (110 [3.3%] and
70 [2.1%] for lovastatin and placebo, respectively). The percentage of participants
reporting myalgia leading to discontinuation was 0.3% for both treatment groups.
Creatine kinase (CK) elevations greater than 10 times the upper limit
of normal were rare, and the incidence was similar in both treatment groups
(11 [0.7%] of 1586, 10 [0.6%] of 1657, and 21 [0.6%] of 3248 receiving lovastatin,
20 mg/d, lovastatin, 40 mg/d, and placebo, respectively). (Denominators are
participants having postrandomization tests; unlike the other comparisons
of randomized treatment groups, the dose comparisons are of nonrandomized
groups.) There were no cases of myopathy (defined as muscle symptoms accompanied
with CK elevations >10 times the upper limit of normal). There were 3 cases
of rhabdomyolysis; 2 cases occurred in placebo-treated participants, and 1
case occurred in a participant treated with lovastatin following surgery for
prostate cancer.
In AFCAPS/TexCAPS, treatment with lovastatin resulted in a 37% reduction
(P<.001) in the risk for first acute major coronary
events, defined as fatal or nonfatal myocardial infarction, unstable angina,
or sudden cardiac death. The study was originally powered to detect a 30%
difference between the treatment groups after 320 participants had experienced
a primary event; however, the benefit after the second interim analysis (with
267 participants experiencing an event) was of such magnitude that the predefined
conditions for stopping the study were met. The differences between the 2
treatment groups appeared as early as 1 year (40 participants with events
in the placebo group vs 23 treated with lovastatin).
Analysis of secondary end points confirmed that the composite primary
end point was representative of its components: lovastatin therapy significantly
reduced the risk for fatal or nonfatal myocardial infarction by 40% and unstable
angina by 32%. Risk reduction with lovastatin across the spectrum of cardiovascular
events was further confirmed by a 33% risk reduction in the need for revascularizations
(P=.001) and 25% risk reductions in both total cardiovascular
and total coronary events (P≤.006). The number
of deaths in AFCAPS/TexCAPS was low (157 total deaths; 42 cardiovascular deaths,
of which 26 were CHD deaths), and as predicted,10
the study was not adequately powered to detect treatment differences in the
low frequency end points of cardiovascular mortality and CHD mortality.
Primary end point risk reduction with lovastatin was apparent across
all baseline LDL-C tertiles with no threshold to benefit observed across baseline
LDL-C levels (range, 2.33-6.08 mmol/L [90-235 mg/dL]). Benefit was also apparent
within subgroups, including women, men older than the median age (>57 years),
women older than the median age (>62 years), and for participants with additional
CHD risk factors. As observed in secondary prevention trials,6,7
female AFCAPS/TexCAPS participants responded to treatment as well as, if not
better than, male participants. Lovastatin appeared to attenuate (Figure 4) the risk conferred by sex, age,
family history, hypertension, smoking, LDL-C levels, and below-average HDL-C
levels.
AFCAPS/TexCAPS is, to our knowledge, the first primary prevention trial
to demonstrate risk reduction from lipid modification in generally healthy
men and women without clinical evidence of cardiovascular disease and with
average TC and LDL-C levels and below-average HDL-C levels. The baseline means
for TC and LDL-C (5.71 mmol/L [221 mg/dL] and 3.89 mmol/L [150 mg/dL], respectively)
are similar to the average levels for age- and sex-matched individuals without
cardiovascular disease in NHANES III.14 Mean
baseline HDL-C values (0.94 mmol/L [36 mg/dL] for men and 1.03 mmol/L [40
mg/dL] for women) were below the average for the NHANES III reference population;
however, the HDL-C range for the cohort is 0.47 to 1.58 mmol/L (18-61 mg/dL).
Only 17% of AFCAPS/TexCAPS participants would have met current National Cholesterol
Education Program (NCEP) guidelines for drug therapy (TC, ≥6.21 mmol/L
[240 mg/dL]; LDL-C, ≥4.14 mmol/L [160 mg/dL]; and 2 or more risk factors)
and 32% would not have a fasting lipid profile measurement by current NCEP
guidelines (TC, <6.21 mmol/L [240 mg/dL] without 2 or more risk factors).16
Earlier primary CHD prevention studies included only middle-aged men
with very high TC and LDL-C concentrations.8,17,18
In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT),17 the upper age limit was 59 years (mean age, 47.8
years), and the mean TC, LDL-C, and HDL-C concentrations at baseline (prior
to diet therapy) were 7.55 mmol/L (292 mg/dL), 5.59 mmol/L (216 mg/dL), and
1.16 mmol/L (45 mg/dL), respectively. In the Helsinki Heart Study,18 the upper age limit was 55 years (mean age, 47.3
years), and the mean baseline lipid values for TC, LDL-C, and HDL-C were 6.98
mmol/L (270 mg/dL), 4.86 mmol/L (188 mg/dL), and 1.22 mmol/L (47 mg/dL), respectively.
Likewise, the West of Scotland Coronary Prevention Study (WOSCOPS)8 was limited to middle-aged men; the upper age limit
was 64 years (mean age, 55.2 years) and the mean baseline lipid values for
TC, LDL-C, and HDL-C were 7.03 mmol/L (272 mg/dL), 4.97 mmol/L (192 mg/dL),
and 1.14 mmol/L (44 mg/dL), respectively. All of these trials reported statistically
significant reductions in the primary end point of the combined incidence
of nonfatal myocardial infarction and CHD death; the risk reductions were
19% in LRC-CPPT,17 34% in the Helsinki Heart
Study,18 and 31% in WOSCOPS.8
Extrapolation of the results of these 3 trials of middle-aged men with moderate-to-severe
hypercholesterolemia to the general population with lower TC and LDL-C levels,
to women, and to older individuals has remained a matter of debate.19
Results from AFCAPS/TexCAPS are consistent with findings from previous
primary prevention trials with high-risk cohorts8,17,18;
however, treatment with lovastatin in AFCAPS/TexCAPS extends the benefit to
a lower-risk segment of the general population. In contrast with earlier studies,
the AFCAPS/TexCAPS cohort included Hispanics, African Americans, and older
persons (baseline mean age, 58.2 years; upper limit, 73 years; 21% older than
65 years).15 The AFCAPS/TexCAPS trial is also
the first large-scale primary prevention trial of LDL-C reduction to include
a substantial number of women (997 of the 6605 participants randomized). The
cohort was also generally healthy, with only 12% active smokers, 22% with
hypertension, and 2% with diabetes.
Inclusion of unstable angina in the primary end point analysis resulted
from the observations that hospital admissions for diagnostic and surgical
intervention following unstable angina were increasing while myocardial infarction,
as the cause for initial presentation, was decreasing.9
AFCAPS/TexCAPS data indicate that approximately equal numbers of patients
initially present with unstable angina and nonfatal myocardial infarction.
The issue of safety and drug tolerance is particularly important in
primary prevention, where the risks of long-term drug therapy must be considered
in the context of achievable benefit. AFCAPS/TexCAPS provides long-term safety
data on a cohort treated up to 7 years with lovastatin. The withdrawal rate
was comparable to that seen in other primary prevention trials,8,18
and frequency of withdrawal for adverse experiences was similar in the treatment
groups.
The results confirm and, by longer treatment duration, extend those
from the Expanded Clinical Evaluation of Lovastatin (EXCEL) trial,20 in which 8245 participants were studied for 1 year
using regimens representative of the entire lovastatin dosage range. Both
EXCEL and AFCAPS/TexCAPS demonstrated no cases of lovastatin-induced myopathy,
no significant differences between treatment with lovastatin, 20 mg/d, and
placebo in the number of participants experiencing clinically important elevations
in transaminase concentrations (>3 times the upper limit of normal) and CK
elevations (10 times the upper limit of normal). Furthermore, AFCAPS/TexCAPS
provides reassuring data about long-term treatment with lovastatin, cancer
rates, and traumatic deaths, and confirms the safety shown in other large
long-term studies with simvastatin and pravastatin.6-8
The AFCAPS/TexCAPS results indicate that cholesterol reduction with
lovastatin for men and women with average TC and LDL-C levels could potentially
improve quality of life by extending CHD event-free survival and conserving
invasive treatments. The economic impact of treatment requires resource utilization
analyses that consider the cost of long-term treatment, hospitalization, and
the cost of diagnostic and therapeutic intervention.
These findings support and extend the recommendations of the NCEP to
include HDL-C in addition to TC in initial risk-factor assessment, target
LDL-C reduction as the primary goal of therapy, and, if necessary, titrate
treatment to achieve an LDL-C goal level. The benefit seen in all subgroups
and across all tertiles of LDL-C in AFCAPS/TexCAPS occurred with 25% LDL-C
reduction and suggests that treatment with lovastatin could be considered
in asymptomatic participants at relatively low risk for CHD and with average
TC and LDL-C levels (>3.36 mmol/L [130 mg/dL]) and below-average HDL-C levels
(<1.29 mmol/L [50 mg/dL]).
AFCAPS/TexCAPS demonstrates that lovastatin, 20 to 40 mg/d, can reduce
the risk for first acute major coronary events in men and women with average
or mildly elevated TC and LDL-C levels and below-average HDL-C levels. Using
NHANES III survey data,14,15 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. These results support the
inclusion of HDL-C measurement in initial risk-factor assessment and suggest
reassessment of NCEP guidelines regarding pharmacological intervention.
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