Context.— The Lifestyle Heart Trial demonstrated that
intensive lifestyle changes may lead to regression of coronary
atherosclerosis after 1 year.
Objectives.— To determine the feasibility of patients to
sustain intensive lifestyle changes for a total of 5 years and the
effects of these lifestyle changes (without lipid-lowering drugs) on
coronary heart disease.
Design.— Randomized controlled trial conducted from 1986 to
1992 using a randomized invitational design.
Patients.— Forty-eight patients with moderate to severe
coronary heart disease were randomized to an intensive lifestyle change
group or to a usual-care control group, and 35 completed the 5-year
follow-up quantitative coronary arteriography.
Setting.— Two tertiary care university medical centers.
Intervention.— Intensive lifestyle changes (10% fat whole
foods vegetarian diet, aerobic exercise, stress management training,
smoking cessation, group psychosocial support) for 5 years.
Main Outcome Measures.— Adherence to intensive lifestyle
changes, changes in coronary artery percent diameter stenosis, and
cardiac events.
Results.— Experimental group patients (20 [71%] of 28
patients completed 5-year follow-up) made and maintained comprehensive
lifestyle changes for 5 years, whereas control group patients (15
[75%] of 20 patients completed 5-year follow-up) made more moderate
changes. In the experimental group, the average percent diameter
stenosis at baseline decreased 1.75 absolute percentage points after 1
year (a 4.5% relative improvement) and by 3.1 absolute percentage
points after 5 years (a 7.9% relative improvement). In contrast, the
average percent diameter stenosis in the control group increased by 2.3
percentage points after 1 year (a 5.4% relative worsening) and by 11.8
percentage points after 5 years (a 27.7% relative worsening)
(P=.001 between groups. Twenty-five cardiac
events occurred in 28 experimental group patients vs 45 events in 20
control group patients during the 5-year follow-up (risk ratio for any
event for the control group, 2.47 [95% confidence interval,
1.48-4.20]).
Conclusions.— More regression of coronary
atherosclerosis occurred after 5 years than after 1 year in the
experimental group. In contrast, in the control group, coronary
atherosclerosis continued to progress and more than twice as many
cardiac events occurred.
THE LIFESTYLE Heart Trial was the first randomized clinical
trial to investigate whether ambulatory patients could be motivated to
make and sustain comprehensive lifestyle changes and, if so, whether
the progression of coronary atherosclerosis could be stopped or
reversed without using lipid-lowering drugs as measured by
computer-assisted quantitative coronary arteriography. This study
derived from earlier studies that used noninvasive
measures.1,2
After 1 year, we found that experimental group participants were able
to make and maintain intensive lifestyle changes and had a 37.2%
reduction in low-density lipoprotein (LDL) cholesterol levels and a
91% reduction in the frequency of anginal episodes.3
Average percent diameter stenosis regressed from 40.0% at baseline to
37.8% 1 year later, a change that was correlated with the degree of
lifestyle change. In contrast, patients in the usual-care control group
made more moderate changes in lifestyle, reduced LDL cholesterol levels
by 6%, and had a 165% increase in the frequency of reported anginal
episodes. Average percent diameter stenosis progressed from 42.7% to
46.1%.
Given these encouraging findings, we extended the study for an
additional 4 years to determine (1) the feasibility of patients
sustaining intensive changes in diet and lifestyle for a much longer
time, and (2) the effects of these changes on risk factors, coronary
atherosclerosis, myocardial perfusion, and cardiac events after 4
additional years.
The design, recruitment, and study population were previously
described.3-5 In brief, we recruited men and women
with coronary atherosclerosis documented by
quantitative coronary arteriography.
We identified 193 patients as potentially eligible for our study who
agreed to undergo quantitative coronary angiography. Following
angiography, 93 patients remained eligible and were randomly
assigned to experimental or control groups using a randomized
invitational design to minimize crossover, ethical concerns,
nocebo effects, and dropout. Of these 93 patients who were eligible, 53
were randomly assigned to the experimental group and 40 to the
usual-care control group. Patients were then contacted and invited to
participate in the study; 28 (53%) and 20 (50%) agreed to participate
in the experimental and control groups, respectively. The primary
reason for refusal in the experimental group was not wanting to undergo
intensive lifestyle changes and/or not wanting a second coronary
angiogram; control patients refused primarily because they did not want
to undergo a second angiogram. To detect possible selection biases, we
collected data on age, marital status, reported angina, history of
myocardial infarction, height, weight, number of diseased lesions, and
stenosis severity for all patients who were randomized into the study
but refused to participate. We did not exclude any experimental group
patients who volunteered even if we doubted their ability to adhere to
the lifestyle program. All patients who volunteered were followed up
using the intention-to-treat principle.
After 1 year, 7 patients did not provide angiographic data, and the
reasons for loss to follow-up have been reported.3 Of the
remaining 41 patients at baseline most had severe coronary
atherosclerosis: 28 had 3-vessel disease, 12 had 2-vessel disease,
and 1 had 1-vessel disease. Two of these patients whose
angiographic data were not usable after 1 year agreed to undergo
quantitative coronary arteriography after 5 years; these results are
included in the baseline to 5-year comparisons.
Four experimental and 4 control patients who had an angiogram at
1 year did not have a third angiogram after 5 years. Three of these 4
patients in the experimental group refused a third angiogram (patients
only volunteered for a 1-year study that was subsequently extended),
and 1 died between years 1 and 4; of the 4 control group patients who
did not undergo a third angiogram, 1 died, 2 underwent
revascularization of the arterial lesions under study, and 1
developed Parkinson disease and became too ill to be safely tested.
Cine arteriograms made in San Francisco, Calif, were sent to the
University of Texas Medical School, Houston, for blinded quantitative
analyses as previously described in detail.4
All results, except lesion changes at 1 year (18 experimental and 15
control subjects) and cardiac events after 5 years (all 28 experimental
and 20 control subjects), are based on the total of 35 patients (20
experimental and 15 control subjects) who had both baseline and 5-year
angiograms. From these 35 patients, there were 224 lesions studied at
baseline, of which 24 were 100% occluded and were excluded a priori
from the lesion-change analyses per the study protocol. Of the
remaining 200 lesions, 14 were lost to the 4-year follow-up, as
follows: in the experimental group, 2 lesions were excluded due to
technical failure during the angiogram and 2 had views that did not
match; in the control group, views did not match for 3 lesions, 3
lesions were excluded due to technical failure, 1 was excluded due to
angioplasty, and 3 were excluded due to coronary artery bypass surgery.
Of the 186 lesions available for analysis at 4 years, 109 were from the
experimental group and 77 were from the control group.
The 1-year original study and the 4-year extension were approved by the
committees on human research at California Pacific Medical Center and
University of California, San Francisco, and each patient signed a
written consent form after being fully informed of the study
requirements.
Patients completed a 3-day diet diary at baseline and after 1 and 5
years to assess nutrient intake and dietary adherence.6
Methods of lipid assays were the same as previously
reported.3 These 3-day diet diaries were analyzed with a
software package (CBORD Diet Analyzer; CBORD Group Inc; Ithaca, NY)
using the US Department of Agriculture database. Also, patients were
asked to complete a questionnaire reporting the frequency and duration
of exercise and of each stress management technique. Information from
these sources was quantified into continuous scores using an a priori
determined formula. The adherence measure was a continuous score
reflecting daily intake of cholesterol (in milligrams), fat (in
grams), frequency and duration of exercise, frequency and duration
of stress management techniques, and smoking. A score of 1.0 equalled
100% adherence but scores could be greater than 1.0 if participants
exceeded the recommended intensive lifestyle changes.
The technicians responsible for performing all medical tests were
blinded to patient group assignment. Also, different personnel
implemented the lifestyle intervention, conducted the tests, and
computed statistical analyses, although the dietitian was made aware of
the nutrient analysis to monitor patients' safety and adherence.
Quantitative coronary arteriograms were blindly analyzed without
knowledge of group assignment.
Experimental group patients were prescribed an intensive lifestyle
program that included a 10%-fat vegetarian diet, moderate aerobic
exercise, stress management training, smoking cessation, and group
psychosocial support previously described in detail.3,7-10
Patients were encouraged to avoid simple sugars and to emphasize the
intake of complex carbohydrates and other whole foods. Only 1 patient
in the experimental group was actively smoking at baseline, and she
quit at entry. Control group patients were asked to follow the advice
of their personal physicians regarding lifestyle changes.
We decided a priori to use percent diameter stenosis as the primary
dependent variable. Statistical methods to compare the 2 groups were
previously described.3 Analysis of adherence variables and
risk factor levels used time-structured repeated measures in which
levels from all 3 measurement times (baseline, 1 year, and 5 years)
were
included in a single regression model. Statistical
significances of group differences were obtained for baseline levels,
1-year changes, and 5-year changes using F tests. All repeated measures
analyses were implemented using PROC MIXED under SAS version
6.08.11 Analysis of lesion data used a repeated measures
model in which the repeated measures were baseline or change values for
multiple lesions within each subject. Change scores were used for the
baseline to 1-year and baseline to 5-year follow-up periods, and
analysis of baseline levels, 1-year changes, and 5-year changes were
done separately. Again, F tests provided by SAS PROC MIXED were used to
test significance of differences between groups with respect to
baseline levels, 1-year changes, and 5-year changes. The SAS PROC MIXED
linear regression, which allowed for dependence in data, was used to
determine the relationship between adherence and percent diameter
stenosis changes. Relative rates for cardiac events were analyzed and
tested by Poisson regression using exact tests (Stata 5.0, College
Station, Tex).
Baseline Comparisons
of Volunteers With Refusals
Those who declined the invitation to be in the study were similar to
those who volunteered in all available data except those who
volunteered were more likely to have a history of angina (87% vs 65%;
P=.02), a greater number of lesions (4.5 vs
3.5; P=.04), and slightly more severely
stenosed lesions (2.3 vs 2.0 on a 3-point scale;
P=.05).
Baseline Comparisons
of Experimental Group
With Control
Group
Analyses across the 35 volunteers at baseline for whom 4-year lesion
data were available showed no significant differences between the
experimental group and the control group in demographic
characteristics, history of myocardial infarction, angioplasty, bypass
surgery, lesion number, lesion stenosis, dietary fat or cholesterol
intake, exercise and stress management practice, blood pressure,
exercise capacity, and psychosocial measures (Table 1, Table 2, Table 3).
Among the many comparisons, only a few differed significantly
(P<.05). More women were randomly assigned to the control
group (4) than to the experimental group (1); this fact accounted for
half the weight difference (10 kg) between the 2 groups and most of the
height difference (6 cm).
Experimental group patients had a slightly larger body mass index
(measured as the weight in kilograms divided by the square of the
height in meters) (28.4 vs 25.4 kg/m2;
P=.03) and had lower high-density lipoprotein
(HDL) cholesterol levels (1.04 mmol/L [40.1 mg/dL] vs 1.36 mmol/L
[52.4 mg/dL]; P=.04), which was also
reflected in lower apolipoprotein A-I levels (3.45 mmol/L [133.1
mg/dL] vs 4.08 mmol/L [157.5 mg/dL];
P=.03). The lower body mass index in the
control group may be due to the larger number of women in the control
group. Other lipid values, including ratios of total cholesterol to HDL
and LDL to HDL, did not differ significantly at baseline (Table 4).
In the experimental group, adherence to all aspects of the
program was excellent during the first year and good after 5 years,
whereas control group patients maintained more moderate changes during
the 5 years consistent with conventional guidelines (Table 2). The
percentage of daily energy (calories) provided by fruits, vegetables,
whole grains, soy, other legumes, nonfat dairy, and alcohol was
comparable at 1 year and at 5 years. In the experimental group, fat
intake decreased from approximately 30% to 8.5%, cholesterol from
211 to 18.6 mg/d, energy from 8159 to 7724 J (1950-1846 cal), protein
from 17% to 15%, and carbohydrates increased from 53% to 76.5%. In
the control group, fat intake decreased from
30% to 25%, cholesterol from 212.5 to 138.7 mg/d, energy from 5.49 to
3.59 J (1711-1573 cal), protein from 19% to 18%, and carbohydrates
increased from 51% to 52%. Since patients volunteered originally only
for a 1-year study, there was a significant decrease in meeting
attendance after 1 year for 4 of the patients. Walking was the
recommended form of exercise, but some patients jogged or did more
strenuous exercise.
Patients in the experimental group lost 10.9 kg (23.9 lbs) at 1 year
and sustained a weight loss of 5.8 kg (12.8 lbs) at 5 years, whereas
weight in the control group changed little from baseline. In the
experimental group, LDL cholesterol levels decreased by 40% at 1 year
and remained 20% below baseline at 5 years. In the control group, LDL
cholesterol levels decreased by 1.2% at 1 year and by 19.3% at 5
years. There were no statistically significant differences in LDL
levels between the 2 groups at 5 years, primarily because 9 (60%)
of 15 control patients took lipid-lowering drugs between year 1 and
year 5 of the study. None of the experimental group patients took
lipid-lowering drugs during the 5 years of the study. Fourteen patients
in the experimental group and 11 patients in the control group took
aspirin during the study.
Triglycerides did not change significantly in either group.
Apolipoprotein A-I did not change in the experimental group, but it
increased in the control group (P=.04).
High-density lipoprotein levels and blood pressure did not differ
between the 2 groups.
Experimental group patients had a 91% reduction in reported frequency
of angina after 1 year and a 72% reduction after 5 years (Table
5). In contrast, control group patients had a
186% increase in reported frequency of angina after 1 year and a 36%
decrease in frequency after 5 years. The decrease in angina in the
control group after 5 years was in large part because 3 of the 5
patients who reported an increase in anginal episodes from baseline to
1 year underwent coronary angioplasty between years 1 and 5.
Because of this reduction in angina in control group patients who
underwent revascularization, the between-group differences were no
longer significant after 5 years (Table 5).
All detectable lesions that matched at baseline and 5-year follow-up
and were not 100% occluded at baseline were included in the analyses
(n=186). At baseline, there were no significant
differences between the experimental and control groups in any measure
of lesion severity (Table 3). In the experimental group, the average
percent diameter stenosis at baseline decreased 1.75 absolute
percentage points after 1 year (a 4.5% relative improvement) and by
3.1 absolute percentage points after 5 years (a 7.9% relative
improvement). In contrast, the average percent diameter stenosis in the
control group increased by 2.3 percentage points after 1 year (a 5.4%
relative worsening) and by 11.8 percentage points after 5 years (a
27.7% relative worsening). These between-group differences were
statistically significant after both 1 year and 5 years
(P=.02 and P=.001,
respectively, Figure 1).
Figure 2 shows the experimental group changes in
percent diameter stenosis from baseline to 5 years according to
tertiles of adherence to the lifestyle intervention. As seen at 1
year,3 there was also a strong correlation between
adherence and percent diameter stenosis after 5 years in a
dose-response relationship; the tertile of patients that was most
adherent to the program had the most regression, the tertile with
intermediate adherence had less regression, and the tertile with the
least adherence halted the progression of disease without regression
(P=.04). Of interest is that this relationship
was not related to age or disease severity. There was no significant
relationship between adherence and lesion changes in the control group,
perhaps because many of these patients began taking lipid-lowering
drugs, which may have confounded the ability to detect a possible
relationship. Indeed, we found significant correlations between changes
in lipid levels (LDL and total cholesterol) and changes
in lesions in both groups. These correlations
remained significant when examining either the lipid values at 5 years
or the change in lipid values from baseline to 5 years.
As a secondary analysis, we examined the results in control group
patients who began taking lipid-lowering drugs during the study.
Percent diameter stenosis progressed from 45.7% to 51.7%, a change of
6.0 absolute percentage points. In the control patients who did not
take lipid-lowering drugs the disease progressed from 40.7% to 59.7%,
a much greater change of 19.0 absolute percentage points. (No
experimental group patients took lipid-lowering drugs during the
study.)
The change in body mass index from baseline to 1 year
(r=−0.85; P<.001) and from
baseline to 5 years (r=−0.72;
P=.001) was significantly correlated with the
change in percent diameter stenosis in the control group only. In other
words, those who gained weight were more likely to show progression of
atherosclerosis.
Data on cardiac events were obtained from all 48 patients. Cardiac
events included myocardial infarction, coronary angioplasty, coronary
artery bypass surgery, cardiac-related hospitalizations, and
cardiac-related deaths. At 5 years, there were more cardiac events in
the control group (45 events for 20 patients, or 2.25 events per
patient) than the experimental group (25 events for 28 patients, or
0.89 events per patient) (Table 6). Control group
patients were more likely to have undergone coronary angioplasty and
bypass surgery and/or to have been hospitalized for cardiac-related
problems than were experimental group patients.
The primary end point of this study, chosen a priori, was percent
diameter stenosis. On average, there was more reduction (continued
improvement) after 5 years than after 1 year in experimental group
patients who were asked to make intensive lifestyle changes. In
contrast, control group patients showed much more progression
(continued worsening) in average percent diameter stenosis after 5
years than after 1 year, even though more than half of the control
group patients were prescribed lipid-lowering medications during the
course of the study. Although the sample size was relative
small,12 these differences were statistically significant
at both 1 year and 5 years. These findings support the feasibility of
intensive lifestyle changes in delaying, stopping, or reversing the
progression of coronary artery disease in ambulatory patients over
prolonged periods.
We found more than twice as many cardiac events per patient in the
control group than in the experimental group. These findings are
consistent with other clinical trials showing that even small changes
in percent diameter stenosis are often accompanied by marked reductions
in cardiac events.13-16 Other studies have demonstrated how
quickly the coronary artery endothelium stabilizes in response to
lipid-lowering drugs.17,18
Although there was some reduction in adherence to the intensive
lifestyle intervention between years 1 and 5 in the experimental group,
long-term adherence remained remarkably high in this sample of
self-selected patients. The level of lifestyle change, even at 5 years,
is greater than in any other published study of ambulatory populations.
These results are especially encouraging because these patients
initially volunteered to participate for only 1 year when they entered
the study.
The experimental group reduced LDL cholesterol levels by 40% at
1 year and by 20% after 5 years; these reductions are comparable with
those achieved with lipid-lowering drugs in an ambulatory
population.19 In contrast, the Step II diet reduces LDL
cholesterol by only 5% or less.20,21
High-density lipoprotein levels decreased and triglycerides increased
in experimental group patients overall, although the ratio of LDL to
HDL was improved. Recent reports assert that this phenomenon, which is
often seen in very low-fat diets, may be harmful.22,23
However, patients in the Lifestyle Heart Trial showed even more
regression of coronary atherosclerosis after 5 years than after 1 year
as well as significantly decreased cardiac events. Low
HDL cholesterol levels due to reduced fat intake
are the result of a decreased transport rate rather than the increased
catabolism that is responsible for most cases of low HDL cholesterol
levels in persons consuming a typical Western diet.24
Populations consuming low-fat, plant-based diets have low HDL
cholesterol levels and low rates of coronary heart disease. Our data
provide evidence using quantitative coronary arteriography in this
population that diet-induced lowering of HDL cholesterol does not
confer the same risk of atherosclerosis as do low HDL cholesterol
levels in Americans consuming a high-fat diet.25
Experimental group patients whose triglycerides increased during the
first year were asked to minimize their intake of simple carbohydrates,
and triglyceride levels decreased between year 1 and year 5.
The experimental group's marked reduction in frequency, severity, and
duration of angina after 1 year was sustained at similar levels after 5
years. This long-term reduction in angina is comparable with that
achieved following coronary artery bypass surgery or angioplasty and
helps to maintain long-term adherence.26 Between-group
differences in most measures of chest pain were not statistically
significant after 5 years because there was a large variability in
angina and control group patients who were the most symptomatic
underwent revascularization.
When we began this study, we believed that the younger patients
with milder disease would be more likely to show regression, but we did
not find this to be true. Instead, we found that the primary
determinant of change in percent diameter stenosis in the experimental
group was neither age nor disease severity but adherence to the
recommended changes in diet and lifestyle. This relationship of
adherence to percent diameter stenosis in the experimental group was
found after 1 year3 and also after 5 years in a
dose-response relationship. Coronary artery minimum diameter remained
stable in the experimental group but markedly narrowed in the control
group during the 5 years of the study. At 5 years, the differences
between the experimental and control groups were statistically
significant for both percent diameter stenosis and minimum diameter,
even though control group patients reported risk reduction behavior
consistent with a Step II diet of the National Cholesterol Education
Program and the American Heart Association: they consumed an average of
25% of energy (calories) from fat and exercised an average of 3.5
times per week. These data are consistent with other studies indicating
that moderate changes in diet and lifestyle may not be sufficient to
stop the progression of coronary atherosclerosis unless combined with
lipid-lowering drugs.27
After 5 years, the normal diameter (the segment of least narrowing
proximal to the minimum diameter) decreased slightly in the
experimental group but widened slightly in the control group. A slight
decrease in normal diameter, at least up to a point, may improve
myocardial perfusion by streamlining flow—decreasing the forward flow
losses that occur when going from a larger to a sharply reduced lumen
diameter.4 Conversely, the slight increase in the normal
diameter and reduction in the minimum diameter seen in control group
patients increased the entry angle, further reducing blood flow. These
theoretical considerations are consistent with the substantially
increased myocardial perfusion in the experimental group and decreased
myocardial perfusion in the control group that we measured using
cardiac positron emission tomography scans.5
A much earlier study by Morrison28 found that
moderate reductions in fat and cholesterol intake improved cardiac
survival: after 12 years, all of the control group patients had died
compared with only 62% of experimental group patients in a
nonrandomized trial. More recently, an important study by Esselstyn et
al29 reported that a similar diet plus lipid-lowering drugs
in 11 patients caused regression of 11 lesions and stabilization in the
remaining 14 lesions after 5.5 years. Although there was no control
group, those who were adherent to the diet reported substantially fewer
cardiac events than those who were not adherent.29
Like all clinical trials, our study has limitations. Although the study
participants were a diverse group, they may not be representative of
the general population of patients with coronary heart disease. Half of
the patients who underwent quantitative coronary arteriography in the
participatory hospitals did not meet all of the inclusion and exclusion
criteria and were not invited to participate in the study. Also, half
of the patients who were invited declined to enroll in the study.
Nevertheless, it is encouraging that 50% of the patients who
were contacted agreed to volunteer despite the requirement for repeated
arteriography and that experimental group patients were able to make
and maintain comprehensive lifestyle changes. The angiographic
measures lost to follow-up may have affected the treatment and control
groups differently, although there are no data to suggest that this
occurred. In addition, there is a possibility of differential loss of
lesions in patients, although no evidence indicates that this occurred;
in both groups, there were 14 lesions that were lost to follow-up.
Also, 4 lesions were lost in the control group to bypass surgery or
angioplasty; since these lesions were worsening sufficiently to require
revascularization, the exclusion of these lesions from analysis would
make between-group differences more difficult to detect. We recently
completed a multicenter demonstration project to assess the
practicality and cost-effectiveness of this intervention in a larger
sample of economically and geographically diverse patients with
coronary heart disease.30
Although we did not use lipid-lowering drugs in the experimental
group, their value has been demonstrated in studies that have been
published since the Lifestyle Heart Trial began. We do not know if
experimental group patients may have demonstrated even more improvement
by including lipid-lowering drugs.14-16 Patients in the
control group who were not prescribed lipid-lowering drugs during the
study showed more than 3 times as much progression in percent diameter
stenosis as those who were. No experimental group patients took
lipid-lowering drugs during the study, yet they showed better results
than control group patients who were taking these drugs. Lipid-lowering
drugs are expensive,
compliance is difficult to achieve,31 and
long-term safety is unknown.32 In practice, patients may be
offered a range of therapeutic options, including comprehensive
lifestyle changes, lipid-lowering drug therapy, and revascularization,
either separately or in combination.
In summary, these ambulatory patients were able to make and
maintain comprehensive changes in diet and lifestyle for 5 years and
showed even more regression of coronary atherosclerosis after 5 years
than after 1 year as measured by percent diameter stenosis. In
contrast, patients following more conventional lifestyle
recommendations showed even more progression of coronary
atherosclerosis after 5 years than after 1 year, and had more than
twice as many cardiac events as patients making comprehensive lifestyle
changes.
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