© 1999 American Heart Association, Inc.
Brief Review |
Systematic Review on the Risk and Benefit of Different Cholesterol-Lowering Interventions
From Medizinsche Universitäts-Poliklinik, Kantonsspital Basel, Basel, Switzerland (H.C.B.), and the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada (L.E.G., G.H.G.).
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Abstract |
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Abstract—Meta-analyses have investigated the efficacy of cholesterol-lowering interventions in relation to the underlying risk of coronary heart disease and the extent and duration of cholesterol reduction. We systematically reviewed the efficacy of antilipidemic interventions on major mortality outcomes in relation to drug classes. We searched MEDLINE and EMBASE from 1966 through October 1996 for randomized, controlled trials of any cholesterol-lowering interventions reporting mortality data. We included 59 trials involving 85 431 participants in the intervention and 87 729 participants in the control groups. We pooled these trials into 7 pharmacological categories of cholesterol-lowering interventions: statins (13 trials), fibrates (12 trials), resins (8 trials), hormones (8 trials), niacin acid (2 trials), n-3 fatty acids (3 trials), and dietary interventions (16 trials). Of the cholesterol-lowering interventions, only statins showed a large and statistically significant reduction in mortality from coronary heart disease (risk ratio, 0.66; 95% confidence interval [CI], 0.54 to 0.79) and from all causes (risk ratio, 0.75; 95% CI, 0.65 to 0.86). For both all-cause and cardiovascular mortality, the difference between statins and the combined estimate of the other classes of agents was unlikely to be due to chance (P<0.02 for both comparisons). Meta-regression analysis demonstrated that variability in results across trials could be largely explained on the basis of differences in the magnitude of cholesterol reduction. Statins have the largest effect on the reduction of cardiovascular and all-cause mortality, and this result recommends their use in preference to other antilipidemic agents. The greater effect of statins is likely due to the larger reduction in cholesterol.
Key Words: coronary disease • hypercholesterolemia • meta-analysis • myocardial infarction • mortality
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Introduction |
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Recently, 2 large clinical trials in the primary and secondary prevention of coronary heart disease have shown that cholesterol-lowering interventions with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce coronary heart disease and overall mortality.1 2 In contrast to previous trials, both of these studies showed no increase in risk of death from noncardiovascular causes.3 4 5 6 These findings suggest that the net benefit and adverse effects of cholesterol-lowering interventions may depend on drug class. Recent guidelines, including those of the American College of Physicians,7 8 have therefore emphasized the need to base treatment decisions on the separate evaluation of each type of cholesterol-lowering intervention.
However, information from systematic reviews of the efficacy of cholesterol-lowering interventions according to drug classes is limited.9 The focus of previous systematic reviews was primarily on the underlying risk of coronary heart disease5 or the extent and duration of cholesterol reduction in relation to the expected benefit,5 10 and all were based on data before publication of the large HMG-CoA reductase inhibitor trials. We present a comprehensive, systematic review that specifically examines the effects of different types of cholesterol-lowering interventions on mortality outcomes.
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Methods |
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Selection Criteria
We systematically searched the literature by using MEDLINE, EMBASE, and previously published meta-analyses to identify randomized, controlled trials of any cholesterol-lowering intervention published from 1966 through October 1996. We included all trials that reported mortality outcomes irrespective of the duration, the type of cholesterol-lowering intervention (multifactorial or unifactorial cholesterol-lowering intervention), or setting (primary or secondary prevention trials of coronary heart disease). Angiographic studies that fulfilled the selection criteria were also included. For trials with missing mortality data, we contacted the authors of the original publications or the authors of previously published meta-analyses and requested the missing information. We evaluated the impact of treatment on total mortality, mortality from coronary heart disease, and mortality from causes other than coronary heart disease.
We identified 66 randomized, controlled trials reporting mortality data. We classified trials based on similar pharmacological characteristics to lower cholesterol into the following categories: HMG-CoA reductase inhibitors, 13 trials (lovastatin, 5 trials11 12 13 14 15 ; pravastatin, 6 trials2 16 17 18 19 20 ; and simvastatin, 2 trials1 21 ); fibrates, 12 trials (clofibrate, 9 trials22 23 24 25 26 27 28 29 30 ; gemfibrozil, 2 trials31 32 ; and bezafibrate, 1 trial33 ); resins, 8 trials (cholestyramine, 3 trials34 35 36 ; colestipol, 5 trials37 38 39 40 41 ); hormones, 8 trials (estrogen, 7 trials42 43 44 45 46 47 48 ; thyroxine, 1 trial49 ); n-3 fatty acids and their precursors, 3 trials50 51 52 ; and niacin, 2 trials.29 44 Sixteen trials were dietary interventions and were grouped into 1 category.34 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 Two trials were single interventions with probucol68 and partial ileal bypass grafting69 and were therefore not grouped.
We excluded 6 trials with multiple drug
interventions70 71 72 73 74 75 because these studies did not allow us
to assign them to a specific type of cholesterol-lowering
intervention. We additionally excluded 1 study because no
cause-specific mortality data were reported76 and 1 trial
that was conducted in patients with cardiac
transplantation.77 Thus, we included 59 trials involving
85 431 subjects in the intervention and 87 729 subjects in the
control groups. Table 1
provides detailed information about relevant data from the included
trials.
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Statistical Analysis
We computed summary estimates with 95% confidence intervals
(CIs) for each cholesterol-lowering category and calculated
a weighted-average risk ratio of all outcomes by using a random-effect
model.78 We report 2-tailed P values for all
analyses. We tested for heterogeneity by using
the Breslow-Day test.79 When we found a relevant
treatment effect for a specific drug category, we tested whether this
difference was statistically significant when compared with the total
of all other cholesterol-lowering interventions. We used
the z score from such drug categories and from the remaining
studies and divided the difference of the summary log relative risk
from both groups by the standard error of the difference.
For the control group of each trial, we calculated the death rate from coronary heart disease per 1000 person-years. This rate reflects the degree of risk of death from coronary heart disease for participants enrolled in a trial and randomly allocated to the no-treatment group. The rate was calculated by dividing the number of deaths from coronary heart disease occurring in the control group by an approximation of the person-years at risk in the study by using the following formula5 : {coronary heart disease deaths/year of follow-upx[number alive at the end of the trial+0.5 (number dying during the study)]}x1000. Coronary heart disease death rates were then combined for each intervention category. Each trial was weighted by the inverse of the variance. Data on average cholesterol reduction by intervention category represent the unweighted mean percent reduction.
To further explore the relationship of the type of cholesterol-lowering intervention with coronary heart disease and overall mortality, we conducted a meta-regression by using a weighted least-squares linear regression model. The dependent variable in the model was the natural logarithm of the relative risk (ln RR) for each study, and the weights were the reciprocals of the variances for the ln RR.80 The independent variables we considered for analysis were the type of intervention (HMG-CoA reductase inhibitors versus all other interventions), trial setting (primary versus secondary prevention), trial design (unifactorial versus multifactorial intervention), baseline risk for coronary heart disease, and absolute and relative reductions of cholesterol. All analyses were conducted using the Statistical Analysis System.81
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Results |
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Coronary Heart Disease Mortality
Trials with HMG-CoA reductase inhibitors achieved the highest mean cholesterol reduction (22.9%; range, 12.8% to 32.0%) compared with the other intervention categories. The baseline risk of death from coronary heart disease in trials with HMG-CoA reductase inhibitors was 2% and lower when compared with other drug or dietary interventions. Of all cholesterol-lowering interventions, only HMG-CoA reductase inhibitors showed a statistically significant reduction of coronary heart disease mortality (Table 2
and Figure 1). The risk ratio of death from
coronary heart disease was 0.69 (95% CI, 0.59 to 0.80). This
estimate was statistically significantly different from the combined
estimates of all other interventions (risk ratio of coronary
heart disease mortality from all trials with the exception of HMG-CoA
reductase inhibitors, 1.03; 95% CI, 0.86 to 1.24;
P value for difference of summary estimates=0.02). For
resins, we found a risk ratio of borderline significance (0.71; 95%
CI, 0.51 to 0.99), but there was also significant
heterogeneity. For all other interventions, summary
estimates did not reach conventional levels of significance.
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Overall Mortality
HMG-CoA reductase inhibitors and n-3 fatty acids
and their precursors were the intervention categories that showed a
statistically significant reduction in overall mortality (Table 2
and Figure 2). For
HMG-CoA reductase inhibitors, the risk ratio of death from
all causes was 0.79 (95% CI, 0.71 to 0.89). The summary risk ratio for
HMG-CoA reductase inhibitors was statistically
significantly different when compared with the combined estimates of
all other interventions (risk ratio of overall mortality from all
trials with the exception of HMG-CoA reductase inhibitors,
1.03; 95% CI, 0.86 to 1.25; P value for difference=0.02).
For n-3 fatty acids, the risk ratio of death from all causes was 0.68
(95% CI, 0.53 to 0.88), which was statistically significantly
different when compared with all other cholesterol-lowering
interventions (risk ratio, 1.00; 95% CI, 0.88 to 1.13; P
value for difference=0.007).
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Mortality From Causes Other Than Coronary Heart
Disease
For HMG-CoA reductase inhibitors, the risk ratio of
death from causes other than coronary heart disease was 0.97
(95% CI, 0.81 to 1.16; Table 2 and Figure 3). This estimate was also
statistically significantly different when compared with all other
cholesterol-lowering interventions (risk ratio, 1.51; 95%
CI, 1.07 to 2.13). The summary estimate for hormones indicated harm,
with increased mortality from non–coronary heart disease
causes (risk ratio, 1.29; 95% CI, 1.06 to 1.57) and mortality from all
causes (risk ratio, 1.09; 95% CI, 1.00 to 1.20).
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Exploring Additional Reasons for Variability in Results
In a meta-regression analysis, we further explored the
relationship of the type of cholesterol-lowering
intervention and coronary heart disease and overall mortality.
In univariate analysis, the type of intervention
(HMG-CoA reductase inhibitors compared with other
interventions) was highly significantly related to both
coronary heart disease and overall mortality
(P=0.006 for each end point). Additional factors that were
statistically significantly related to overall mortality were trial
setting (lower mortality reduction in primary versus secondary
prevention trials; P=0.0001), trial design (higher mortality
reduction in unifactorial versus multifactorial intervention trials;
P=0.0001), baseline risk for coronary heart disease
(higher mortality reduction in trials in which patients were at higher
risk; P=0.0006), and the absolute and relative reductions of
cholesterol (higher mortality reduction when
cholesterol reduction was greater; P=0.0001 in
both cases). The factors that were additionally related to
coronary heart disease mortality were the absolute and relative
reductions of cholesterol (higher mortality reduction when
cholesterol reduction was greater; P=0.001 and
P=0.002, respectively).
Multivariable analysis showed that after entering the trial setting (primary versus secondary prevention), trial design (unifactorial versus multifactorial intervention), and baseline risk for coronary heart disease into the model, the type of intervention still explained a statistically significant degree of variability for both cardiovascular and all-cause mortality (P=0.004 for overall mortality and P=0.0001 for coronary heart disease mortality). However, when we entered the degree of cholesterol reduction into the model, no other variable explained a statistically significant degree of the remaining variability in analysis of either end point.
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Discussion |
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Recent guidelines on cholesterol screening in asymptomatic adults have stressed 3 important concepts.7 8 82 First, patients with a higher risk of coronary heart disease receive greater benefit from lowering their cholesterol. Second, clinicians should make treatment recommendations based on the patient's overall risk for coronary heart disease and not simply on the their cholesterol level. Finally, the benefits of cholesterol-lowering agents should be assessed separately for each drug treatment category.
Available guidelines7 8 rely on meta-analyses that were published before publication of the large HMG-CoA reductase inhibitor trials. These meta-analyses3 4 5 6 have led to much controversy because they suggested that antilipidemic treatment increased mortality from causes other than coronary heart disease. Some authors therefore excluded trials with negative results from their analysis and concluded that cholesterol lowering may reduce mortality in primary prevention.83 The post hoc exclusion of trials with negative results, however, may be biased toward finding a favorable effect, even if there is none.
The present systematic review differs from previous reviews because it examines to what extent the type of cholesterol-lowering regimen has on coronary heart disease and overall mortality. We considered only mortality data as end points because mortality data are more reliably and consistently reported. There are a number of reasons that our finding that HMG-CoA reductase inhibitors preferentially lower cardiac and overall mortality is robust.84 First, the cardiovascular and total mortality difference between HMG-CoA reductase inhibitors and other agents was both clinically important and statistically significant. Second, participants in the HMG-CoA reductase inhibitor trials had a similar or lower risk of death than in other trials. Third, trials with statins achieved the highest reduction of cholesterol, providing a biological rationale for higher efficacy. Indeed, our multivariable meta-regression analyses showed that the extent of cholesterol reduction was the most powerful factor in explaining the difference in mortality reduction across trials. This finding provides support for the suggestion that the greater benefit of HMG-CoA reductase inhibitors is related to their increased ability to lower serum cholesterol. Finally, we restricted our analysis to 1 subgroup comparison, the type of intervention, which reduces the possibility of a false-positive finding from multiple-hypothesis testing.
Not only are HMG-CoA reductase inhibitors the most effective cholesterol-lowering drugs, but they also show a favorable risk profile. We found no suggestion of an increase in non–coronary heart disease mortality with HMG-CoA reductase inhibitors. Mortality from non–coronary heart disease was statistically significantly lower in HMG-CoA reductase inhibitor trials when compared with all other interventions.
We also found a statistically significant reduction in overall but not in cardiovascular mortality with n-3 fatty acids and their precursors. Given the small number of trials and the large CIs, a lack of statistical power is the most likely explanation for our failure to show a reduction in coronary heart disease mortality with this intervention. n-3 Fatty acids and their precursors reduce triglycerides and have antithrombotic effects on platelets and thus may have additional mechanisms of cardioprotective effects. Our results suggest that n-3 fatty acids and precursors may warrant investigation in a larger trial.
Fibrates, resins, and hormones all showed a trend toward an increased mortality from causes other than coronary heart disease and smaller effects on coronary artery disease mortality than did HMG-CoA reductase inhibitors. There seems little reason to use these drugs, with the possible exception of patients at high risk of coronary heart disease who have large elevations in serum triglycerides. Whether newer fibrates like bezafibrate or fenofibrate have a more favorable risk profile must be investigated in clinical trials examining mortality end points. Estrogens may be beneficial for the primary prevention of coronary heart disease in females, and a large-scale, randomized, controlled trial to address this issue is underway.
In conclusion, HMG-CoA reductase inhibitors are currently the only cholesterol-lowering drugs that should be used in primary and secondary prevention of coronary heart disease. Because of limited data on the long-term safety of HMG-CoA reductase inhibitors, their use in hypercholesterolemic patients at very low risk of coronary events remains questionable.82 85 In addition, treatment of patients with hyperlipidemia and a low risk of coronary heart disease would compete with other uses for societal resources, potentially both within and outside the healthcare system.86 In higher-risk patients, however, the arguments for HMG-CoA reductase inhibitor administration are strong.
Note Added in Proof
At completion of this meta-analysis, the full results of 2 large randomized trials with HMG-CoA reductase inhibitors, the AFCAPS/TexCAPS trial and the LIPID trial, were not yet available but have since been published.
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Acknowledgments |
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This study was supported by grant 32-38793.93 from the Swiss National research foundation to H.C.B.
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Footnotes |
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Reprint requests to Heiner C. Bucher, MD, MPH, Medizinsche Universitäts-Poliklinik, Kantonsspital Basel, CH-4031 Basel, Switzerland.
Received December 30, 1997; accepted May 25, 1998.
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