© 1997 American Heart Association, Inc.
Articles |
Cholesterol Reduction and Clinical Benefit
Are There Limits to Our Expectations?
From the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden.
Correspondence to Gunnar Fager, MD, PhD, the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail Gunnar.Fager{at}Wlab.Wall.gu.se
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Abstract |
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 Top Abstract IntroductionMethodsResults and DiscussionReferences |
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Abstract Encouraging intervention trials drive our expectations toward more aggressive cholesterol-lowering therapies, lower target levels, and less severe hypercholesterolemia. Available studies may predict which patients, degrees of total cholesterol (TC) reduction, and baseline and target levels of TC provide the most clinical benefit. Data were pooled from seven primary and nine secondary controlled trials with major coronary heart disease (CHD) events as primary endpoints. The analysis showed that we can expect large reductions in CHD from TC reduction in primary and secondary prevention. However, the reduction is much larger in subjects with high TC and/or previous CHD events. The percent reduction in CHD increased exponentially with increasing percent TC reductions, which predicted >70% of the change in CHD. Consequently, we cannot expect cost-effective clinical benefits from mean reductions in TC >15 (LDL cholesterol >20)%. The TC level at the study endpoint correlated with CHD incidence irrespective of the study group and explained almost 45% of CHD incidence. The relationship was progressive and leveled off at a TC level below about 150 mg/dL (3.9 mmol/L) (LDL cholesterol
110 mg/dL
[2.8 mmol/L]). Little extra clinical benefit can be expected
from further reductions. We can expect an average 2% reduction in CHD
events per percent reduction in TC. We can also expect a 2-fold greater
clinical benefit among subjects with high initial TC levels than among
those with low levels. Finally, we can expect that the
cholesterol-attributable risk is reset to that predicted by
the TC level achieved within 4 to 6 years.
Key Words: cholesterol • coronary heart disease • hypolipidemic drugs • hyperlipidemia • prevention
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Introduction |
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TopAbstractIntroductionMethodsResults and DiscussionReferences |
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The conventional risk factors of hyperlipidemia, smoking, and hypertension are the main causes of premature atherosclerotic CHD in prospective population studies.1 2 3 4 This is true for men and women although women generally develop their symptoms about 10 years later than men.
Within a number of populations, the risk of CHD increases exponentially with increasing levels of TC.5 Moreover, the incidence of CHD varies in a similar way also among populations in relation to their mean TC levels.
TC predicts about half of the CHD incidence and up to half of the
incidence occurs among subjects who lack conventional risk
factors3 (see also Fig 3
). Consequently, this
group is not easily accessible for dedicated preventive measures.
Should we then expect that cholesterol-lowering alone could
reduce CHD by more than about 50%?
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, British Regional Heart Study2; 
, The
Pooling Project3; 
, Gothenburg Prospective
Study4). The log-transformed regression equation ([log
incidence]=0.1752x[TC (mg/dL)]-0.2385,
R2=0.67, P=.0002) was used to
construct the regression curve.The reduction by 24 to 35% in the incidence of CHD shown in the recent primary6 and secondary7 8 intervention trials with hydroxymethylglutaryl-CoA reductase inhibitor (statin) therapy in hypercholesterolemia is impressive. Furthermore, non-CHD mortality did not increase in these trials. This suggests that about two-thirds of the predictable CHD incidence can be reversed with maintained safety by a 20 to 35% reduction in LDL cholesterol (corresponding to about a 15 to 25% reduction in TC).
Extrapolation from these results drives our expectations toward more aggressive cholesterol-lowering therapies and toward lower target levels among subjects with less and less severe hypercholesterolemia. Registrations of new potent drugs and increased dosages of old drugs fuel these trends. However, increasing cost-consciousness and cost-containment put definite limits on such trends.
Previous meta-analyses have weighted the importance for the conclusions of quantitative and qualitative properties of the individual trials.9 10 11 12 Large trials have been given a larger weight than small trials. However, a small, well-performed trial may provide more reliable results than a larger trial. Various quality rankings are subjective as well as biased. However, discrepancies between individual trials act as conservative confounders, which blunt rather than strengthen statistical conclusions. Other obvious confounders, which generate different CHD incidences, are age and sex. More or less arbitrary adjustments of CHD incidences for age and/or sex have been used to improve the possibilities of conclusive results. However, adjustments may introduce new biases. Consequently, significant relationships, which emerge from unweighted unadjusted meta-analyses in spite of confounders, may provide robust conclusions.
Therefore, the aim of this overview was (1) to equally value all studies fulfilling defined minimum criteria, (2) to regard every trial as an independent and closed entity, (3) to use published data straightforwardly without statistical weightings or adjustments, and (4) to analyze where the most clinical benefit could be expected from cholesterol-lowering regimens.
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Methods |
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TopAbstractIntroductionMethodsResults and DiscussionReferences |
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Published data from 16 randomized cholesterol-lowering trials were derived from the literature.6 7 8 13 14 15 16 17 18 19 20 21 22 23 24 25 Trials were included only if cholesterol-lowering and major CHD events (CHD death and fatal myocardial infarction) were primary objectives (Table 1
). Trials were excluded if monitoring of
progression of atherosclerosis was the major objective
or if they only reported mortality data. One intervention study was
excluded due to its mixed primary and secondary
cohort.26 Trials were included irrespective of
whether6 7 8 14 15 16 18 19 20 21 22 23 24 25 or
not13 17 they showed a relationship between
cholesterol-lowering treatment and CHD outcomes.
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Seven studies were primary6 13 14 15 16 17 18 and nine were
secondary7 8 19 20 21 22 23 24 25 prevention trials (Table 2). Six studies used dietary intervention
to reduce TC.14 15 17 19 20 21 Three of these also
aimed to control tobacco smoking and
hypertension.14 15 17 Clofibrate
with25 or without13 22 23 24
nicotinic acid was used in five studies. In one of
these,24 nicotinic acid and clofibrate were used
in different arms, but the results were combined in this
analysis. Cholestyramine was used in one
study,16 gemfibrozil in
one,18 pravastatin in
two,6 8 and simvastatin in
one.7 For the purpose of this analysis,
however, the type of cholesterol-lowering regimen was
disregarded.
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Whenever possible, only definite CHD deaths and nonfatal myocardial
infarction have been included as major CHD events in this
analysis (Table 1
). Consequently, the CHD incidences used here
occasionally19 21 23 differ from the reported
total incidence. Minor variations in CHD event definitions were
otherwise ignored.
All studies reported mean TC at baseline and either percent reduction
to study endpoint or percent or absolute difference between control and
treatment groups at the end of study. Reported percent values were used
to calculate absolute levels at endpoint (achieved TC) when necessary.
The achieved TC level in the intervention group was defined as treated
TC (Table 2). In the control group, the corresponding estimate was
denoted control TC. Control TC rather than baseline TC was chosen as
reference because the control group was reasonably stable only in some
studies.6 7 8 13 15 24 25 The studies were
regarded as intention-to-treat studies. The WOSCOPS
trial6 only published on-treatment reductions in
TC of 20%, but a 5% lower intention-to-treat effect has been
communicated orally (Table 2). Therefore, it was set to 15% in this
analysis.
The mean follow-up times were 6.2 (range 4.9 to 10) years in primary
prevention trials and 4.4 (3.3 to 6.2) years in secondary prevention
trials (Table 2). The projected total numbers of PYE were almost
355 000 in the control groups and 348 000 in the intervention groups
with about 12% in secondary prevention trials. Altogether 4456 major
CHD events (54% in primary prevention) were registered in the control
groups and 3642 (59% in primary prevention) in the treatment groups.
In the control groups, the average incidences of major CHD events in
secondary prevention trials were almost six times that in primary
prevention trials.
For comparison, three prospective epidemiological studies, which reported definite CHD mortality and nonfatal myocardial infarctions in strata of baseline TC in essentially healthy populations, were included in this analysis.2 3 4 These studies had mean durations of 7.1 to 8.6 years and covered almost 176 500 PYE. One study2 included a small number (6%) of myocardial infarction patients, but this was disregarded. Another4 contained diabetic subjects, who could be excluded.
Handling of Pooled Data
The percent difference between control and treatment groups
(reduction) in major CHD events (
CHD%) in the nine largest
(n>2000) trials was plotted against percent difference (reduction) in
TC (TC%). The regressions for these trials and for all trials were
calculated separately on log-transformed data. Curves derived from the
regression equations were introduced in the plot.
The observed incidences of major CHD events in the control and treated groups were plotted against the corresponding TC values at the end of each trial. The two data points of each study were joined. The regressions including control as well as intervention group data were calculated on log-transformed values for primary and secondary prevention trials separately and the equations obtained were used to calculate the fitted curves.
A standardized benefit (CHD%:TC%) was constructed from the data
in Table 2 to show which cumulative or additional percentage of CHD
reduction could be expected per percent reduction in TC in strata of
relative TC reductions or of reference (ie, control) TC values.
The observed CHD incidences were compared with incidences estimated from the nonintervened prospective studies by level of TC achieved in primary prevention trials. More precisely, the achieved TC values were introduced into the regression equation obtained from pooled data of the three prospective studies to give estimated incidences. The estimated and observed incidences in the control groups were first compared, and then the corresponding comparison was made for the intervention groups. For the secondary prevention trials, a different approach was used, since appropriate data from corresponding prospective trials are not available. Here, the results from control groups of the trials were used as nonintervened data to calculate the regression equation, and then the estimated incidences in the treated groups were calculated as above. A ratio between observed and estimated CHD incidences of 1 would suggest that the most clinical benefit had been recovered during the study period and that TC levels achieved by therapeutic interventions equaled spontaneous TC levels in predictive value.
Statistical Procedures
Descriptive statistics were calculated according to standard
procedures. In the main analysis, differences in CHD incidences
between study groups were tested with two-way ANOVA with studies as
covariates. Paired data were tested using Student's paired
t tests. Relationships were investigated with linear
regression analysis with logarithmic transformations as
indicated. Values in parentheses denote 95% confidence intervals
throughout this article. A value of P
.05 (two-tailed
tests) was regarded as statistically significant.
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Results and Discussion |
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TopAbstractIntroductionMethodsResults and DiscussionReferences |
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Main Results
In the primary prevention trials, ANOVA of the incidences of major CHD events showed significant differences between control and intervention groups (P=.021) as well as between individual studies (P=.011). The mean incidence in the control groups was 10.0 (6.7 to 13.2) and in the intervention groups 7.6 (5.3 to 9.9) events per 1000 PYE.
Also, in the secondary prevention trials, ANOVA showed similar differences between control and intervention groups (P=.012) and between individual studies (P=.005). The mean incidence in the control groups was 59.2 (44.1 to 74.3) and in intervention groups 46.9 (36.9 to 57.0) events per 1000 PYE.
Percent Changes in Total Cholesterol and Major CHD
Events
Evidently, the difference between studies was partly due to
confounders inherent in protocol- and cohort-specific discrepancies.
However, the studies achieved widely varying degrees of TC reductions
and had very different cholesterol-attributable risks.
Indeed, CHD% increased with increasing averages in TC% (Fig 1). Type of trial (primary or secondary
prevention), type of therapy, and other differences between trials
seemed not to matter much in this regard. This suggested a rather
robust relationship between the degrees of TC and CHD reductions.
Furthermore, trials reporting no significant difference in major CHD
events also showed no difference in TC between the study
groups.13 17 Only trials with TC% of >7
reported significant reductions in major CHD events.
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CHD% leveled off exponentially with increasing TC%. The
regression was highly significant for the nine large trials
(R2=0.73, P=.003) (Fig 1) and
suggested that >70% of the variation in CHD% was explained by
TC%. A similar relationship appeared when all 16 trials were
included in the regression analysis
(R2=0.39, P=.010), and the two
regression curves were almost superimposable (Fig 1). The curves
predicted a decrease in CHD by 38% from an unrealistic 90% reduction
in TC. However, most of this benefit was recovered already at a TC%
of 15. Indeed, the cumulative standardized benefit (CHD%:TC%)
was 4.9 for TC reductions up to 3%, 3.7 up to 5%, and only 1.2 up to
25% (Table 3). The additional
standardized benefit from 1% further reduction in TC was 2 at a
TC% of 3 and only 0.27 at a TC% of 25 (Table 3). These results
indicate that less and less additional clinical benefit should be
expected from average TC reductions >15%. Indeed, if studies with TC
reductions 
10%6 7 8 18 are considered, there is
no definite trend between studies in actually observed CHD reductions
(Fig 1). Recently, posthoc stratifications of CARE data showed that
TC% >10 provided no further clinical
benefit.27
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Before the WOSCOPS6 and CARE8 studies were reported, Holme11 arrived at a similar conclusion regarding major CHD events and Gould et al12 did also for mortality from CHD from meta-analyses using linear regression of log-transformed weighted-odds ratios.
The dose-effect relationship for statins is also exponential. Each doubling of dose provides about 6% additional decrease in LDL cholesterol.28 29 This indicates that very large reductions in TC may be achieved by progressively increasing doses and costs with less and less further clinical benefit. The clinical and health-economic dilemma is obvious.
Achieved Levels of Total Cholesterol and CHD
Incidence
The above conclusions were based on mean reductions in different
study cohorts and say little about the need in the individual patient.
Severely hypercholesterolemic subjects may benefit from
larger relative reductions in cholesterol and vice versa.
This possibility was supported by the fact that the incidence of CHD
events increased with increasing levels of achieved TC (Fig 2). When control and intervention groups
of all secondary prevention trials were included, the regression
analysis (R2=0.44,
P=.003; cf, legend to Fig 2) indicated that the risk
increased progressively and that the achieved TC explained about 44%
of the observed CHD incidence. A 10% reduction from a TC of 300 mg/dL
(7.8 mmol/L) predicted a reduction in major CHD events from 86 to
68 per 1000 PYE (ie, about 21%), whereas the same percent reduction
from 200 mg/dL (5.2 mmol/L) suggested a reduction from 39 to 34
per 1000 PYE (ie, about 14%).
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) groups of all 16 trials. The control and
intervention groups in each trial have been joined with lines. Primary
(A) (dashed lines) and secondary (B) (solid lines) trials were treated
separately. (Note the different ranges on the y-axes in
A and B.) The regression curves were derived from the log-transformed
regression equations for primary (log incidence=0.333+0.0023x
[achieved TC (mg/dL)], R2=0.24,
P=.078) and secondary (log
incidence=0.915+0.0034x[achieved TC (mg/dL)],
R2=0.44, P=.003)
trials.
There was a similar trend in the seven primary prevention trials
(R2=0.24, P=.078; cf legend to
Fig 2). As expected, the risk was lower, the curve was flatter, and TC
explained only 24% of the CHD incidence. The curve suggested that a
decrease in TC of 10% from 300 mg/dL (7.8 mmol/L) predicted a
risk reduction from 10.5 to 9.0 CHD events per 1000 PYE (ie, 18%),
whereas the same reduction from 200 mg/dL (5.2 mmol/L) suggested a
reduction from 6.2 to 5.6 events per 1000 PYE (ie, 10%). Clearly, TC
reductions determine CHD reduction in relative as well as absolute
terms.
Although there was a considerable variation between studies, the lines
connecting control and intervention groups in the individual trials
were roughly parallel to the fitted curves in primary as well as
secondary prevention trials (Fig 2). They were steep in the high end
and flat in the low end of the TC distribution. Obviously, TC reduction
is more cost-effective among severely
hypercholesterolemic than among
normocholesterolemic subjects with or without previous
infarction, and there is a lower limit below which further reduction is
not cost-effective.
Posthoc stratifications of data in the CARE trial8 in myocardial infarction patients with rather normal TC levels support these conclusions directly. The results showed that patients having TC above the study average (209 mg/dL [5.4 mmol/L]) experienced a greater reduction in major CHD events from pravastatin treatment than those below average. These analyses also showed that subjects with initial LDL cholesterol levels of 150 to 175 mg/dL (3.9 to 4.5 mmol/L) showed a 35% reduction and those with 125 to 150 mg/dL (3.2 to 3.9 mmol/L) showed a 26% reduction, whereas those with <125 mg/dL (3.2 mmol/L) experienced no clinical benefit (3% increase) from treatment. Based on CARE data, an LDL cholesterol level of 125 mg/dL would correspond to a TC of about 150 mg/dL (3.9 mmol/L).
In the secondary prevention 4S trial with simvastatin among
CHD patients with moderately elevated TC (mean 6.75, range 5.5 to
8 mmol/L or mean 260, range 210 to 310 mg/dL), posthoc
stratification according to baseline LDL cholesterol have
been published.30 The results showed a similar
relative risk reduction of about 35% across the quartiles of baseline
LDL cholesterol. No patients in the 4S trial
represented the very low levels of LDL
cholesterol <125 mg/dL shown in the CARE trial to
experience no clinical benefit from cholesterol reduction.
The LDL cholesterol levels in the 4S cohort were more
comparable with the levels of the upper stratum in the CARE trial, with
which it shared a closely similar CHD reduction. This was positioned in
the flat part of the curve in Fig 1. Therefore, much variation may not
be expected in this region. Consequently, the 4S trial does not
invalidate the conclusion from the CARE study and the present
analysis that CHD patients with low TC levels experience low
clinical and cost benefits from cholesterol-lowering
therapy.
Clinical Benefit in Strata of Total Cholesterol
Holme9 showed a significant
(P=.001) relationship between TC and the percent CHD
reduction per percent TC reduction in a weighted analysis on
log-transformed data. He concluded that the clinical benefit from every
percent TC reduction is about twice higher in the upper than in the
lower range of distribution of baseline TC levels.
Here, the standardized benefit (CHD%:TC%) showed an overall
mean of 1.8. This suggested close to 2% return in CHD reduction per
percent TC reduction. The difference between strata of reference
(control) TC was not significant in the unweighted analysis
performed here (P=.152) but tended to increase from 1.3 in
the lowest to 2.6 in the highest quartile of mean TC. The simplistic
approach may have blunted the current statistics and, certainly, they
do not invalidate the conclusion of Holme. Consequently, the same
degree of cholesterol-lowering provides less clinical
benefit among subjects with low than with high TC levels.
Estimation of Recoverable Benefits From Cholesterol
Reduction
The conclusions in the present analysis were based on
the cumulative number of clinical endpoints and included the first
year(s) when little/no difference occurred between the two groups. It
is likely that the differences were most pronounced between the groups
beyond the 5th year as suggested by Law et al,5
but neither study was sized to provide reliable data for parts of the
projected study period. A separate analysis was undertaken
to test to what extent an achieved TC value reflected the recoverable
clinical benefit during the duration of the trials.
Pooled data from the three prospective epidemiological
studies2 3 4 showed the expected progressive
increase in CHD incidence with increasing TC levels. The relationship
was highly significant (R2=0.67,
P=.0002; Fig 3 and legend).
This suggested that baseline TC predicted about 65% of future CHD
events. When achieved TC from the primary prevention trials were
introduced into the regression equation, estimated incidences were
obtained (Table 4). These estimates
represented predictions from the unintervened populations.
Clearly, observed (mean 10.0) and estimated (mean 9.8) incidences per
1000 PYE were closely similar in the control groups
(P=.917), and this supported the validity of the approach.
However, this was true also for the treated groups (means 7.6 versus7.5
events per 1000 PYE, P=.950). The mean ratio between
observed and estimated incidences was 1.07 (0.77 to 1.37) in the
control groups and 1.06 (0.70 to 1.43) in the intervention groups. This
was not significantly different from 1. Consequently, these results
suggested that most clinical benefit had been recovered within the
duration (mean 6 years) of the primary preventive trials.
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For secondary prevention, results from the control groups were used to
obtain the regression equation for untreated cohorts ([log
incidence]=0.7514+0.0042x [achieved TC (mg/dL)],
R2=0.50, P=.032). Assuming that
baseline and achieved TC were roughly the same, they also predict about
50% of future CHD after a major CHD event. This equation was
subsequently used to calculate estimated incidences in the secondary
intervention groups (Table 5). There was
no significant difference between observed (mean 46.9) and estimated
(mean 41.7) incidences per 1000 PYE (P=.187). The mean ratio
was 1.13 and the 95% confidence interval (0.91 to 1.35) included 1,
suggesting that most clinical benefit had been recovered also within
the duration (mean 4 years) of the secondary prevention trials.
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Concluding Remarks
The clinical benefit from cholesterol-lowering therapy
is well established. The current results strongly support this
conclusion and show that type of therapy is less important than degree
of cholesterol reduction. They also show that most of the
TC-attributable CHD incidence is reduced in proportion to relative as
well as absolute cholesterol reductions and that this
clinical benefit is recovered within about 4 to 6 years. The clinical
benefit is 6 times better in secondary than in primary prevention and
double in cohorts with severe compared with mild
hypercholesterolemia. This means that 6 times
as many need to be treated to avoid one clinical event in primary as in
secondary prevention and twice as many in mild compared with severe
hypercholesterolemia.
Mean relative reductions in TC >15 (LDL
cholesterol >20)% are not meaningful since they require
large doses and costs of drugs and provide little extra clinical
benefit. In contrast, a TC reduction of 3%, which is possible to
achieve by changes in eating habits, provides a 15% reduction in CHD.
Applied to the large population without obvious
hypercholesterolemia or CHD, dietary changes
may mean a lot in reducing the incidence of CHD in the community. Fewer
and fewer major CHD events are avoided by reducing TC much below an
absolute level of about 150 mg/dL (3.9 mmol/L) (LDL
cholesterol110 mg/dL2.8 mmol/L), and the large
numbers of subjects in these strata make drug costs per prevented event
very high. In contrast, the clinical benefit is high among the rather
few subjects, who have very high levels of TC and need very large
absolute and relative reductions in TC. Ideally, efficient
cholesterol-lowering drugs should provide absolute and
relative TC reductions, which increase progressively with increasing
baseline TC levels, but the mean reduction does not have to be
extreme.
This leaves us with a difficult choice; should we try to maintain full health by preventing a first attack among great numbers at a high cost of drugs or try to prevent a second attack among few, who already suffer sequelae from a previous attack, at a lower cost?
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This analysis was supported by grants from the Swedish Medical Research Council (4531) and the Swedish Heart-Lung Foundation (51044); this support is gratefully acknowledged.
Received June 18, 1997; accepted August 6, 1997.
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F. A. McAlister, A. Laupacis, G. A. Wells, D. L. Sackett, and for the Evidence-Based Medicine Working Group Users' Guides to the Medical Literature: XIX. Applying Clinical Trial Results; B. Guidelines for Determining Whether a Drug Is Exerting (More Than) a Class Effect JAMA, October 13, 1999; 282(14): 1371 - 1377. [Full Text] [PDF]
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