Systematic Review on the Risk and Benefit of Different Cholesterol-Lowering Interventions
Abstract
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.
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.12 In contrast to previous trials, both of these studies showed no increase in risk of death from noncardiovascular causes.3456 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,78 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,510 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.
Methods
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 trials1112131415 ; pravastatin, 6 trials21617181920 ; and simvastatin, 2 trials121 ); fibrates, 12 trials (clofibrate, 9 trials222324252627282930 ; gemfibrozil, 2 trials3132 ; and bezafibrate, 1 trial33 ); resins, 8 trials (cholestyramine, 3 trials343536 ; colestipol, 5 trials3738394041 ); hormones, 8 trials (estrogen, 7 trials42434445464748 ; thyroxine, 1 trial49 ); n-3 fatty acids and their precursors, 3 trials505152 ; and niacin, 2 trials.2944 Sixteen trials were dietary interventions and were grouped into 1 category.34535455565758596061626364656667 Two trials were single interventions with probucol68 and partial ileal bypass grafting69 and were therefore not grouped.
We excluded 6 trials with multiple drug interventions707172737475 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.
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-up×[number alive at the end of the trial+0.5 (number dying during the study)]}×1000. 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
Results
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.
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).
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).
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.
Discussion
Recent guidelines on cholesterol screening in asymptomatic adults have stressed 3 important concepts.7882 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 guidelines78 rely on meta-analyses that were published before publication of the large HMG-CoA reductase inhibitor trials. These meta-analyses3456 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.8285 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.
Reprint requests to Heiner C. Bucher, MD, MPH, Medizinsche Universitäts-Poliklinik, Kantonsspital Basel, CH-4031 Basel, Switzerland.
Figure 1. Risk ratio for coronary heart disease mortality in 59 randomized, controlled trials of cholesterol-lowering interventions.
Figure 2. Risk ratio for overall mortality in 59 randomized, controlled trials of cholesterol-lowering interventions.
Figure 3. Risk ratio for mortality other than from coronary heart disease in 59 randomized, controlled trials of cholesterol-lowering interventions.
| Study (Year of Publication) Reference No. | Type of Intervention | Type of Study | Duration, y | Baseline Cholesterol, mmol/L (Percent Reduction) | No. of Individuals Intervention/Control | Fatal Coronary Heart Disease | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. Intervention/Control | Risk Ratio (95% CI) | |||||||||||||
| Statins | ||||||||||||||
| Sahni (1991)11 | Lovastastin/placebo | S,U | 2.0 | 5.4 (12.8) | 79 /78 | 2 /4 | 0.55 (0.12–2.50) | |||||||
| EXCEL (1991)12 | Lovastatin/placebo | P,U | 0.9 | 6.7 (24.0) | 6582 /1663 | 28 /3 | 2.06 (0.68–6.24) | |||||||
| MARS (1993)13 | Lovastatin/placebo | S,U | 2.0 | 6.0 (32.0) | 123 /124 | 0 /1 | 0.34 (0.01–8.17) | |||||||
| PMSG (1993)16 | Pravastatin/placebo | S,U | 0.5 | 6.8 (18.4) | 530 /532 | 0 /1 | 0.33 (0.01–8.20) | |||||||
| Weintraub (1994)14 | Lovastatin/placebo | S,U | 0.5 | 5.3 (34.0) | 203 /201 | 3 /1 | 2.31 (0.34–15.50) | |||||||
| SSSS (1994)1 | Simvastatin/placebo | S,U | 5.4 | 6.75 (26.0) | 2221 /2223 | 111 /189 | 0.59 (0.47–0.74) | |||||||
| MAAS (1994)21 | Simvastatin/placebo | S,U | 4.0 | 6.4 (22.7) | 193 /188 | 4 /5 | 0.80 (0.23–2.73) | |||||||
| Waters (1994)15 | Lovastatin/placebo | S,U | 2.0 | 6.5 (19.6) | 165 /166 | 2 /1 | 1.68 (0.22–12.55) | |||||||
| Furberg (1994)17 | Pravastatin/placebo | S,U | 3.0 | 4.3 (29.0) | 75 /76 | 2 /2 | 1.01 (0.18–5.68) | |||||||
| REGRESS (1995)18 | Pravastatin/placebo | S,U | 2.0 | 6.0 (18.7) | 450 /434 | 1 /1 | 0.96 (0.10–9.24) | |||||||
| WOSCOPS (1995)2 | Pravastatin/placebo | S,U | 4.9 | 7.1 (20.0) | 3302 /3293 | 38 /52 | 0.73 (0.48–1.11) | |||||||
| KAPS (1995)19 | Pravastatin/placebo | S,U | 3.0 | 6.7 (20.1) | 224 /223 | 0 /2 | 0.20 (0.01–4.12) | |||||||
| CARE (1996)20 | Pravastatin/placebo | S,U | 5.0 | 5.4 (20.0) | 2081 /2078 | 96 /116 | 0.81 (0.62–1.05) | |||||||
| n-3 Long-chain fatty acids and precursors | ||||||||||||||
| DART (1989)50 | Fish/low fat | S,U | 2.0 | 6.5 (4.0) | 1015 /1018 | 78 /116 | 0.67 (0.51–0.89) | |||||||
| de Lorgeril (1994)51 | α-Linoleic acid/usual diet | S,U | 2.3 | 6.5 (5.1) | 302 /303 | 3 /16 | 0.21 (0.07–0.67) | |||||||
| Sacks (1995)52 | Fish oil/olive oil | S,U | 2.4 | 4.9 (0.12) | 31 /28 | 0 /1 | 0.30 (0.01–7.13) | |||||||
| Fibrates | ||||||||||||||
| Harrold (1969)22 | Clofibrate/placebo | S,U | 1.0 | NA | 30 /33 | 0 /2 | 0.22 (0.01–4.39) | |||||||
| Newcastle (1971)23 | Clofibrate/placebo | S,U | 5.0 | 6.5 (9.8) | 244 /253 | 25 /44 | 0.59 (0.38–0.94) | |||||||
| Scottish (1971)24 | Clofibrate/placebo | S,U | 6.0 | 7.0 (16.0) | 350 /367 | 34 /35 | 1.02 (0.65–1.50) | |||||||
| Begg (1971)25 | Clofibrate/placebo | S,U | 3.5 | 6.5 (10.8) | 76 /79 | 4 /9 | 0.49 (0.17–1.45) | |||||||
| Acheson (1972)26 | Clofibrate/placebo | S,U | 6.0 | 7.5 (8.5) | 47 /48 | 13 /5 | 2.51 (1.01–6.21) | |||||||
| VA Neurology Section (1974)27 | Clofibrate/placebo | S,U | 1.8 | 6.3 (3.0) | 268 /264 | 11 /12 | 0.91 (0.41–1.98) | |||||||
| Cullen (1974)28 | Clofibrate/placebo | P,U | 2.0 | NA | 20 /20 | 0 /1 | ||||||||
| CDP (1975)29 | Clofibrate/placebo | S,U | 6.2 | 6.5 (6.8) | 1103 /2789 | 195 /583 | 0.85 (0.73–0.98) | |||||||
| WHO (1978)30 | Clofibrate/olive oil | P,U | 5.3 | 6.8 (9.0) | 5331 /5296 | 91 /77 | 1.17 (0.87–1.58) | |||||||
| Frick (1987)32 | Gemfibrozil/placebo | P,U | 5.0 | 6.9 (10.1) | 2051 /2030 | 14 /19 | 0.74 (0.37–1.45) | |||||||
| Frick (1993)31 | Gemfibrozil/placebo | S,U | 5.0 | 6.9 (8.5) | 311 /317 | 17 /8 | 2.10 (0.94–4.69) | |||||||
| Ericsson (1996)33 | Bezafibrate/placebo | S,U | 5.0 | 6.9 (8.4) | 42 /39 | 2 /0 | ||||||||
| Resins | ||||||||||||||
| Gross (1973)38 | Colestipol/placebo | S,U | 1.0 | 8.0 (19.5) | 23 /29 | 1 /0 | 3.75 (0.16–87.98) | |||||||
| Ryan (1974)39 | Colestipol/placebo | P,U | 3.0 | 7.6 (16.0) | 44 /48 | 1 /1 | 1.09 (0.12–10.09) | |||||||
| Gundersen (1976)41 | Colestipol/placebo | P,U | 0.8 | 6.0 (15.1) | 36 /30 | 36 /29 | 0.28 (0.01–6.62) | |||||||
| Dorr (1978)37 | Colestipol/placebo | P,U | 1.9 | 7.9 (9.4) | 1149 /1129 | 19 /31 | 0.61 (0.35–1.06) | |||||||
| Ruoff (1978)40 | Colestipol/placebo | P,U | 3.2 | 7.8 (22.4) | 21 /19 | 21 /18 | 0.30 (0.01–7.02) | |||||||
| NHLBI (1984)36 | Cholestyramine/placebo | S,U | 5.0 | 8.4 (11.5) | 71 /72 | 5 /6 | 0.86 (0.29–2.55) | |||||||
| LCCPPT (1984)36 | Cholestyramine/placebo | P,U | 7.4 | 7.2 (8.5) | 1906 /1900 | 30 /38 | 0.79 (0.49–1.26) | |||||||
| STARS (1992)34 | Cholestyramine/usual diet | S,U | 3.0 | 7.2 (23.8) | 30 /30 | 0 /3 | 0.14 (0.01–2.65) | |||||||
| Niacin | ||||||||||||||
| VA drug (1968)44 | Niacin/placebo | S,U | 3.2 | 6.2 (13.2) | 77 /143 | 71 /23 | 1.02 (0.67–1.57) | |||||||
| CDP (1975)29 | Niacin/placebo | S,U | 6.2 | 6.5 (8.2) | 1119 /2789 | 203 /583 | ||||||||
| Hormones | ||||||||||||||
| Oliver (1961)46 | Estrogen/lactose | S,U | 5.0 | 6.1 (12.4) | 50 /50 | 13 /10 | 1.29 (0.63–2.61) | |||||||
| Marmorstein (1962)42 | Estrogen/placebo | S,U | 5.0 | NA | 285 /147 | 63 /29 | 1.11 (0.75–1.64) | |||||||
| Stamler (1963)43 | Estrogen/placebo | S,U | 5.0 | 6.4 (3.0) | 156 /119 | 34 /39 | 0.67 (0.45–0.99) | |||||||
| VA Neurology Section (1966)48 | Estrogen/placebo | S,U | 1.4 | NA | 295 /287 | 11 /11 | 0.97 (0.44–2.17) | |||||||
| All Deaths | Non–Coronary Heart Disease Deaths | ||||
|---|---|---|---|---|---|
| No. Intervention/Control | Risk Ratio (95% CI) | No. Intervention/Control | Risk Ratio (95% CI) | ||
| 4 /5 | 0.81 (0.24–2.70) | 2 /1 | 1.65 (0.22–12.16) | ||
| 33 /3 | 2.42 (0.81–7.27) | 5 /0 | 2.78 (0.15–50.26) | ||
| 1 /0 | 1.01 (0.11–9.56) | 1 /0 | 3.02 (0.12–73.53) | ||
| 0 /1 | 0.33 (0.01–8.20) | 0 /0 | |||
| 3 /1 | 2.31 (0.34–15.50) | 0 /0 | |||
| 182 /256 | 0.71 (0.60–0.85) | 71 /67 | 1.06 (0.76–1.47) | ||
| 4 /11 | 0.38 (0.13–1.11) | 0 /6 | 0.07 (0.0–1.32) | ||
| 2 /2 | 1.01 (0.18–5.73) | 0 /1 | 0.34 (0.01–8.17) | ||
| 3 /5 | 0.64 (0.18–2.37) | 1 /3 | 0.43 (0.07–2.86) | ||
| 3 /3 | 0.96 (0.22–4.22) | 2 /2 | 0.96 (0.17–5.54) | ||
| 106 /136 | 0.78 (0.61–1.01) | 68 /83 | 0.82 (0.60–1.12) | ||
| 3 /4 | 0.77 (0.19–3.09) | 1 /2 | 0.60 (0.08–4.48) | ||
| 180 /196 | 0.92 (0.75–1.11) | 84 /77 | 1.08 (0.80–1.47) | ||
| 94 /130 | 0.72 (0.56–0.93) | 16 /14 | 1.14 (0.56–2.30) | ||
| 8 /20 | 0.42 (0.19–0.91) | 5 /4 | 1.23 (0.36–4.22) | ||
| 0 /1 | 0.30 (0.01–7.13) | 0 /0 | |||
| 0 /3 | 0.16 (0.01–2.91) | 0 /1 | 0.37 (0.02–8.65) | ||
| 31 /51 | 0.63 (0.42–0.95) | 6 /7 | 0.90 (0.32–2.53) | ||
| 42 /45 | 0.98 (0.66–1.45) | 8 /10 | 0.85 (0.35–2.07) | ||
| 4 /10 | 0.45 (0.15–1.28) | 0 /1 | 0.35 (0.01–8.37) | ||
| 23 /20 | 1.17 (0.75–1.81) | 10 /15 | 0.69 (0.35–1.36) | ||
| 22 /30 | 0.73 (0.43–1.22) | 11 /18 | 0.61 (0.30–1.25) | ||
| 1 /2 | 0.60 (0.09–4.14) | 1 /1 | |||
| 281 /723 | 0.98 (0.87–1.11) | 86 /140 | 1.56 (1.20–2.01) | ||
| 236 /91 | 2.57 (2.02–3.26) | 145 /14 | 9.97 (5.82–17.08) | ||
| 44 /43 | 1.01 (0.67–1.53) | 30 /24 | 1.23 (0.73–2.09) | ||
| 19 /12 | 1.59 (0.80–3.18) | 2 /4 | 0.57 (0.12–2.64) | ||
| 2 /0 | 0 /0 | ||||
| 1 /2 | 0.75 (0.11–5.28) | 0 /2 | 0.25 (0.01–4.96) | ||
| 1 /1 | 1.09 (0.12–10.09) | 0 /0 | |||
| 0 /1 | 0.28 (0.01–6.62) | 0 /0 | |||
| 37 /48 | 0.76 (0.50–1.15) | 18 /17 | 1.04 (0.54–1.99) | ||
| 0 /1 | 0.30 (0.01–7.02) | 0 /0 | 0.91 (0.02–43.71) | ||
| 5 /7 | 0.74 (0.26–2.13) | 0 /1 | 0.34 (0.01–8.16) | ||
| 68 /71 | 0.96 (0.69–1.32) | 38 /33 | 1.15 (0.72–1.81) | ||
| 0 /3 | 0.14 (0.01–2.65) | 0 /0 | |||
| 81 /27 | 1.0 (0.68–1.47) | 10 /4 | 0.79 (0.26–2.33) | ||
| 273 /723 | 70 /140 | ||||
| 17 /12 | 1.40 (0.76–2.59) | 4 /2 | 1.80 (0.40–8.04) | ||
| 71 /32 | 1.14 (0.79–1.64) | 8 /3 | 1.26 (0.37–4.29) | ||
| 37 /40 | 0.71 (0.49–1.03) | 3 /1 | 1.78 (0.27–11.90) | ||
| 34 /29 | 1.14 (0.72–1.81) | 23 /18 | 1.24 (0.69–2.22) | ||
| Study (Year of Publication) Reference No. | Type of Intervention | Type of Study | Duration, y | Baseline Cholesterol, mmol/L (Percent Reduction) | No. of Individuals Intervention/Control | Fatal Coronary Heart Disease | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. Intervention/Control | Risk Ratio (95% CI) | |||||||||||||
| VA drug (1968)44 | Estrogen/thyroxine/placebo | S,U | 3.2 | 6.2 (6.3) | 427 /143 | 11 /11 | 1.06 (0.58–1.95) | |||||||
| CDP (1975)49 | Thyroxine/placebo | S,U | 3.0 | 6.5 (11.0) | 1083 /2715 | 119 /274 | 1.09 (0.89–1.34) | |||||||
| CDP (1975)47 | Estrogen 5.0 mg/placebo | S,U | 1.5 | 6.5 (n.a.) | 1119 /2788 | 67 /133 | 1.26 (0.95–1.67) | |||||||
| CDP (1975)46 | Estrogen 2.5 mg/placebo | S,U | 4.7 | 6.5 (NA) | 1101 /2789 | 162 /410 | 1.00 (0.85–1.19) | |||||||
| Dietary interventions | ||||||||||||||
| Low fat (1965)53 | Low fat/usual diet | S,U | 3.0 | 6.8 (6.6) | 123 /129 | 17 /20 | 0.89 (0.50–1.61) | |||||||
| Rose (1965)54 | Olive oil/usual diet | S,U | 2.0 | 6.7 (3.6) | 54 /26 | 8 /1 | 2.78 (0.52–14.83) | |||||||
| Dayton (1969)55 | Diet/usual diet | P,U | 8.0 | 6.1 (12.7) | 424 /422 | 41 /50 | 0.82 (0.55–1.21) | |||||||
| Soya bean (1968)56 | Soya bean oil/usual diet | S,U | 3.2 | 7.0 (14.3) | 199 /194 | 25 /25 | 0.98 (0.58–1.63) | |||||||
| Oslo diet (1970)57 | Diet/usual diet | S,U | 5.0 | 7.7 (14.4) | 206 /206 | 37 /50 | 0.74 (0.51–1.08) | |||||||
| Woodhill (1978)58 | Diet/usual diet | S,U | 5.0 | 7.3 (4.0) | 221 /237 | 35 /26 | 1.44 (0.90–2.30) | |||||||
| Kallio (1979)59 | Diet/usual diet | S,M | 3.0 | 6.0 (12.0) | 188 /187 | 35 /55 | 0.64 (0.44–0.92) | |||||||
| Hjermann (1981)60 | Diet/usual diet | P,M | 6.5 | 8.4 (10.0) | 604 /628 | 6 /14 | 0.47 (0.19–1.17) | |||||||
| MRFIT (1982)61 | Diet/usual diet | P,M | 6.5 | 6.5 (2.0) | 6428 /6438 | 115 /124 | 0.93 (0.72–1.19) | |||||||
| Miettinen (1985)62 | Diet, drugs/usual diet | P,M | 5.0 | 7.1 (6.0) | 612 /610 | 4 /1 | 2.99 (0.47–18.91) | |||||||
| WHO collaborative (1986)63 | Diet/usual diet | P,M | 5.5 | 5.5 (1.0) | 24 615 /25 169 | 428 /398 | 0.95 (0.83–1.09) | |||||||
| Gothenburg (1986)64 | Diet drugs/no intervention | P,M | 10.0 | 6.5 (0) | 10 004 /20 028 | 462 /923 | 1.00 (0.90–1.12) | |||||||
| Minnesota (1989)65 | Diet/usual diet | P,U | 1.0 | 5.4 (13.8) | 4541 /4516 | 61 /54 | 1.12 (0.78–1.61) | |||||||
| Ornish (1990)66 | Diet/usual diet | S,M | 1.0 | 6.1 (25.8) | 28 /20 | 1 /0 | 2.17 (0.09–50.75) | |||||||
| STARS (1992)34 | Diet/usual diet | S,U | 3.0 | 7.2 (11.1) | 30 /30 | 1 /3 | 0.43 (0.07–2.72) | |||||||
| Singh (1992)67 | Strict diet/usual diet | S,U | 2.0 | 5.9 (9.0) | 204 /202 | 25 /45 | 0.55 (0.36–0.87) | |||||||
| Nongrouped interventions | ||||||||||||||
| McCaughan (1981)68 | Probucol/placebo | S,U | 1.0 | 7.9 (8.0) | 88 /30 | 2 /2 | 0.35 (0.06–1.92) | |||||||
| POSCH (1990)69 | Partial ileum bypass surgery/control | S,U | 6.5 | 6.5 (22.5) | 421 /417 | 32 /44 | 0.72 (0.47–1.11) | |||||||
| Trials using different combination therapies that reported mortality data were excluded from the analysis. | ||||||||||||||
| CLAS (1987)70 | Colestipol, niacin/placebo | S,U | 2.0 | 6.3 (22.0) | 94 /94 | 0 /1 | 0.33 (0.01–8.08) | |||||||
| Stockholm (1988)71 | Clofibrate, niacin/placebo | S,U | 5.0 | 6.4 (13.0) | 279 /276 | 47 /73 | 0.64 (0.46–0.88) | |||||||
| SCOR (1990)72 | Various drugs/diet | P,U | 2.0 | 9.6 (24.5) | 48 /49 | 0 /0 | ||||||||
| FATS (1990)73 | Various drugs/diet | S,U | 2.5 | 7.0 (24.9) | 94 /52 | 1 /0 | 1.67 (0.07–40.37) | |||||||
| SCRIP (1994)74 | Various drugs/usual care | S,M | 4.0 | 5.9 (15.1) | 145 /155 | 2 /3 | 0.76 (0.15–3.81) | |||||||
| HARP (1994)75 | Various drugs/placebo | S,U | 2.5 | 5.4 (28.0) | 40 /39 | 1 /1 | 0.98 (0.11–8.99) | |||||||
| All Deaths | Non–Coronary Heart Disease Deaths | ||||
|---|---|---|---|---|---|
| No. Intervention/Control | Risk Ratio (95% CI) | No. Intervention/Control | Risk Ratio (95% CI) | ||
| 34 /29 | 1.04 (0.60–1.82) | 23 /18 | 1.03 (0.22–4.70) | ||
| 160 /339 | 1.18 (1.00–1.41) | 41 /65 | 1.59 (1.08–2.33) | ||
| 91 /193 | 1.18 (0.93–1.50) | 24 /60 | 1.01 (0.63–1.60) | ||
| 219 /525 | 1.06 (0.92–1.22) | 57 /115 | 1.26 (0.93–1.72) | ||
| 20 /24 | 0.88 (0.52–1.49) | 3 /4 | 0.82 (0.21–3.23) | ||
| 8 /1 | 2.78 (0.52–14.83) | 0 /0 | |||
| 174 /178 | 0.97 (0.83–1.14) | 133 /128 | 1.03 (0.85–1.26) | ||
| 28 /31 | 0.88 (0.55–1.41) | 3 /6 | 0.53 (0.15–1.90) | ||
| 41 /55 | 0.75 (0.53–1.06) | 4 /5 | 0.82 (0.24–2.80) | ||
| 39 /28 | 1.49 (0.95–2.32) | 4 /2 | 1.93 (0.42–8.96) | ||
| 41 /56 | 0.73 (0.52–1.03) | 6 /1 | 4.31 (0.74–25.15) | ||
| 16 /24 | 0.70 (0.38–1.29) | 10 /10 | 1.04 (0.45–2.43) | ||
| 265 /260 | 1.02 (0.86–1.21) | 150 /136 | 1.10 (0.88–1.39) | ||
| 10 /5 | 1.90 (0.68–5.31) | 6 /4 | 1.44 (0.44–4.76) | ||
| 1325 /1186 | 0.99 (0.92–1.07) | 897 /788 | 1.01 (0.92–1.11) | ||
| 1293 /1636 | 1.58 (1.48–1.70) | 831 /1713 | 0.97 (0.90–1.05) | ||
| 269 /248 | 1.08 (0.91–1.28) | 208 /194 | 1.07 (0.88–1.29) | ||
| 1 /0 | 2.17 (0.09–50.75) | 0 /0 | |||
| 1 /3 | 0.43 (0.07–2.72) | 0 /0 | |||
| 28 /51 | 0.55 (0.36–0.83) | 3 /6 | 0.53 (0.15–1.93) | ||
| 2 /3 | 0.25 (0.05–1.20) | 0 /1 | 0.12 (0–2.78) | ||
| 49 /62 | 0.78 (0.55–1.11) | 17 /18 | 0.94 (0.49–1.77) | ||
| 0 /1 | 0.33 (0.01–8.08) | 0 /0 | |||
| 61 /82 | 0.74 (0.55–0.98) | 14 /9 | 1.51 (0.68–3.36) | ||
| 0 /1 | 0.34 (0.01–8.15) | 0 /1 | 0.34 (0.01–8.15) | ||
| 1 /0 | 1.67 (0.07–40.37) | 0 /0 | |||
| 3 /3 | 1.07 (0.25–4.62) | 1 /0 | 3.21 (0.13–78.07) | ||
| 1 /1 | 0.98 (0.11–8.99) | 0 /0 | |||
| Type of Cholesterol-Lowering Intervention (Reference No.) | Number of Trials | Intervention, n | Control, n | Cholesterol Reduction, Mean % (Range) | Follow-up Mean y (Range) | Mortality From Coronary Heart Disease in Control Groups,1 % | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Statins1,2,11–21 | 13 | 16 228 | 11 279 | 22.86 (12.8–32.0) | 2.67 (0.9–5.0) | 2 | |||||||
| n-3 Long-chain fatty acids and precursors50–52 | 3 | 1348 | 1349 | 3.07 (0.1–5.1) | 2.23 (2.0–2.4) | 9 | |||||||
| Fibrates22–27,29–33,68 | 122 | 9873 | 11 496 | 9.09 (3.0–16.0)3 | 4.06 (1.00–6.20) | 5 | |||||||
| Resins22,34,36–42 | 84 | 3280 | 3257 | 15.78 (8.5–23.8) | 2.81 (0.8–7.4) | 2 | |||||||
| Hormones42–46,48,49,53 | 82 | 4516 | 9039 | 8.18 (3.0–12.4)3 | 3.6 (1.4–5.0) | 8 | |||||||
| Niacin acids29,44 | 22 | 1196 | 2932 | 10.70 (8.2–13.2) | 4.70 (3.2–6.2) | 21 | |||||||
| Probucol68 | 1 | 88 | 30 | 8.00 | 1.0 | 8 | |||||||
| Partial ileum bypass surgery69 | 1 | 421 | 417 | 22.50 | 6.5 | 1.2 | |||||||
| Diet34,53–67 | 164 | 48 481 | 59 042 | 9.14 (0–25.8) | 4.48 (1.0–10.0) | 2 | |||||||
| Risk Ratio (95% CI) [P Value for Test of Heterogeneity] | ||
|---|---|---|
| Coronary Heart Disease Mortality | Total Mortality | Non–Coronary Heart Disease Mortality |
| 0.69 (0.59–0.80) | 0.79 (0.71–0.89) | 0.97 (0.81–1.16) |
| [P>0.10] | [P>0.10] | [P>0.10] |
| 0.44 (0.18–1.07) | 0.68 (0.53–0.88) | 1.15 (0.63–2.11) |
| [P>0.10] | [P>0.10] | [P>0.10] |
| 0.98 (0.78–1.24) | 1.06 (0.78–1.46) | 1.16 (0.63–2.12) |
| [P<0.001] | [P<0.001] | [P<0.001] |
| 0.71 (0.51–0.99) | 0.85 (0.66–1.08) | 1.07 (0.74–1.56) |
| [P=0.03] | [P>0.10] | [P>0.10] |
| 1.04 (0.93–1.17) | 1.09 (1.00–1.20) | 1.29 (1.06–1.57) |
| [P>0.10] | [P>0.10] | [P>0.10] |
| 0.95 (0.83–1.10) | 0.96 (0.86–1.08) | 0.99 (0.76–1.29) |
| [P>0.10] | [P>0.10] | [P>0.10] |
| 0.34 (0.06–1.91) | 0.24 (0.05–1.20) | 0.12 (0.0–2.78) |
| 0.72 (0.46–1.13) | 0.78 (0.55–1.11) | 0.93 (0.49–1.77) |
| 0.91 (0.82–1.01) | 0.97 (0.81–1.15) | 1.00 (0.95–1.05) |
| [P<0.001] | [P=0.10] | [P>0.10] |
This study was supported by grant 32-38793.93 from the Swiss National research foundation to H.C.B.
References
- 1 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.1994; 344:1383–1389.MedlineGoogle Scholar
- 2 Shepard J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlaine PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med.1995; 333:1301–1307.CrossrefMedlineGoogle Scholar
- 3 Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentration and mortality: a quantitative review of primary prevention trials. BMJ.1990; 301:309–314.CrossrefMedlineGoogle Scholar
- 4 Ravnskov U. Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome. BMJ.1992; 305:15–19.CrossrefMedlineGoogle Scholar
- 5 Smith GD, Song F, Sheldon TA. Cholesterol lowering and mortality: the importance of considering initial level of risk. BMJ.1993; 306:1367–1373.CrossrefMedlineGoogle Scholar
- 6 Silberberg JS, Henry DA. The benefits of reducing cholesterol levels; the need to distinguish primary from secondary prevention. Med J Aust.1991; 155:665–674.MedlineGoogle Scholar
- 7 American College of Physicians. Guidelines for using serum cholesterol, high-density lipoprotein cholesterol, and triglyceride levels as screening tests for preventing coronary heart disease in adults. Ann Intern Med.1996; 124:515–517.CrossrefMedlineGoogle Scholar
- 8 Garber AM, Browner WS, Hulley SB. Cholesterol screening in asymptomatic adults, revisited. Ann Intern Med.1996; 124:518–531.CrossrefMedlineGoogle Scholar
- 9 Gould LA, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit: a new look at old data. Circulation.1995; 91:2274–2282.CrossrefMedlineGoogle Scholar
- 10 Holme I. Relation of coronary heart disease incidence and total mortality to plasma cholesterol reduction in randomized trials: use of meta-analysis. Br Heart J.1993; 69:S42–S50.CrossrefMedlineGoogle Scholar
- 11 Sahni R, Mantiet AR, Voci G, Banka VS. Prevention of restenosis by lovastatin after successful coronary angioplasty. Am Heart J.1991; 121:1600–1608.CrossrefMedlineGoogle Scholar
- 12 Bradford RH, Shear CL, Chremos AN, Dujovne C, Downton M, Franklin FA, Gould L, Hesney M, Higgins J, Hurley DP, Langendorfer A, Nash DT, Pool JL, Schnaper H. Expanded clinical evaluation of lovastatin (EXCEL) study results. Arch Intern Med.1991; 151:43–49.CrossrefMedlineGoogle Scholar
- 13 Blankenhorn DH, Azen SP, Kramsch DM, Mack WJ, Cashin-Hemphill L, Hodis HN, DeBoer LWV, Mahrer PR, Masteller MJ, Vailas LI, Alaupovic P, Hirsch LJ. Coronary angiographic changes with lovastatin therapy. Ann Intern Med.1993; 119:969–976.CrossrefMedlineGoogle Scholar
- 14 Weintraub WS, Boccuzzi SJ, Klein JL, Kosinski AS, King SB, Ivanhoe R, Cedarholm JC, Stillabower ME, Talley JD, DeMaio SJ, O’Neill WW, Frazier JE, Cohen-Bernstein CL, Robbins DC, Brown CL, Alexander RW. Lack of effect of lovastatin on restenosis after coronary angioplasty. N Engl J Med.1994; 331:1331–1337.CrossrefMedlineGoogle Scholar
- 15 Waters D, Higginson L, Gladstone P, Kimball B, Le May M, Boccuzzi SJ, Lespérance J. Effects of monotherapy with HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography: the Canadian Coronary Atherosclerosis Trial. Circulation.1994; 89:959–968.CrossrefMedlineGoogle Scholar
- 16 The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol.1993; 72:1031–1037.CrossrefMedlineGoogle Scholar
- 17 Furberg CD, Byington RP, Crouse JR, Espeland MA. Pravastatin, lipids and major coronary events. Am J Cardiol.1994; 73:1133–1134.CrossrefMedlineGoogle Scholar
- 18 Jukema JW, Bruschke AVG, Van Boven AJ, Reiber JHC, Bal ET, Zwinderman AH, Jansen H, Boerma JM, van Rappard FM, Lie KI. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderate elevated serum cholesterol levels: the Regression Growth Evaluation Statin Study (REGRESS). Circulation.1995; 91:2528–2540.CrossrefMedlineGoogle Scholar
- 19 Salonen R, Nyyssönen K, Porkkola E, Rummakainen J, Belder R, Park JS, Salonen JT. Kuopio Atherosclerosis Prevention Study (KAPS): a population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation.1995; 92:1758–1764.CrossrefMedlineGoogle Scholar
- 20 Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med.1996; 335:1001–1009.CrossrefMedlineGoogle Scholar
- 21 MAAS Investigators. Effect of simvastatin on coronary atheroma: the Multicenter Anti-Atheroma Study (MAAS). Lancet.1994; 344:633–638.CrossrefMedlineGoogle Scholar
- 22 Harrold BP, Marmion VJ, Gough KR. A double-blind controlled trial of clofibrate in the treatment of diabetic retinopathy. Diabetes.1969; 18:285–291.CrossrefMedlineGoogle Scholar
- 23 Group of the Newcastle upon Tyne Region. Trial of clofibrate in the treatment of ischaemic heart disease: five year study. BMJ.1971; 4:767–775.CrossrefMedlineGoogle Scholar
- 24 Research Committee of the Scottish Society of Physicians. Ischaemic heart disease: a secondary prevention trial using clofibrate. BMJ.1971; 4:775–784.CrossrefMedlineGoogle Scholar
- 25 Begg TB, Rifkind BM. Valutazione della terapia con clofibrate nelle arteriopatie periferiche. Minerva Med.1971; 62:3469–3475.MedlineGoogle Scholar
- 26 Acheson J, Hutchinson EC. Controlled trial of clofibrate in cerebral vascular disease. Atherosclerosis.1972; 15:177–183.CrossrefMedlineGoogle Scholar
- 27 Veterans Administration Cooperative Study Group. The treatment of cerebrovascular disease with clofibrate. Stroke.1973; 4:684–693.CrossrefMedlineGoogle Scholar
- 28 Cullen JF, Town SM, Campbell CJ. Double-blind trial of atromid-S in exudative diabetic retinopathy. Trans Ophthalmol Soc.1974; 94:554–562.Google Scholar
- 29 Coronary Drug Project. Clofibrate and niacine in coronary heart disease. JAMA.1975; 231:360–380.CrossrefMedlineGoogle Scholar
- 30 Committee of Principal Investigation. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J.1978; 40:1069–1118.CrossrefMedlineGoogle Scholar
- 31 Frick MH, Heinonen OP, Huttunen JK, Koskinen P, Mänttäri M, Manninen V. Efficacy of gemfibrozil in dyslipidemic subjects with suspected heart disease: an ancillary study in the Helsinki heart study frame population. Ann Med.1993; 25:41–45.CrossrefMedlineGoogle Scholar
- 32 Frick MH, Elo O, Haapa K, Heinonen AP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA. Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med.1987; 317:1237–1245.CrossrefMedlineGoogle Scholar
- 33 Ericsson CG, Hamsten A, Nilsson J, Grip L, Svande B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet.1996; 347:849–853.CrossrefMedlineGoogle Scholar
- 34 Watts GF, Lewis B, Brunt JNH, Lewis ES, Coltrart DJ, Smith LDR, Mann JI, Svan AV. Effects on coronary heart disease of lipid-lowering diet, or diet plus cholestyramin, in the St Thomas’ Atherosclerosis Regression Study (STARS). Lancet.1992; 339:563–569.CrossrefMedlineGoogle Scholar
- 35 Brensike JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM, Loh IK, Stone NJ, Aldrich RF, Battaglini JW, Moriarty DJ, Fisher MR, Friedman L, Friedewald W, Detre KM, Epstein SE. Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI type II coronary intervention study. Circulation.1984; 69:313–324.CrossrefMedlineGoogle Scholar
- 36 Lipid Research Clinics Program. The lipid research clinics coronary primary prevention trial results, I: reduction in incidence of coronary heart disease. JAMA.1984; 251:351–364.CrossrefMedlineGoogle Scholar
- 37 Dorr AE, Gundersen K, Schneider JC, Spencer TW, Martin WB. Colestipol hydrochloride in hypercholesterolemic patients: effect on serum cholesterol and mortality. J Chronic Dis.1978; 31:5–14.CrossrefMedlineGoogle Scholar
- 38 Gross L, Figueredo R. Long-term cholesterol-lowering effect of colestipol resin in humans. J Am Geriatr Soc.1973; 21:552–556.CrossrefMedlineGoogle Scholar
- 39 Ryan JR, Jain AK, McMahon FG. Long-term treatment of hypercholesterolemia with colestipol hydrochloride. Clin Pharmacol Ther.1974; 17:83–87.Google Scholar
- 40 Ruoff G. Colestipol hydrochloride for treatment of hypercholesterolemia in a family practice: five-year study. J Am Geriatr Soc.1978; 26:121–126.CrossrefMedlineGoogle Scholar
- 41 Gundersen K, Cooper EE, Ruoff G, Nikolai T, Assenzo JR. Cholesterol-lowering effect of colestipol hydrochloride given twice daily in hypercholesterolemic patients. Atherosclerosis.1976; 25:303–310.CrossrefMedlineGoogle Scholar
- 42 Marmorstein J, Moore FJ, Hopkins CE, Kuzma OT, Weiner J. Clinical studies of long-term estrogen therapy in men with myocardial infarction. Proc Soc Exp Biol Med.1962; 110:400–408.CrossrefMedlineGoogle Scholar
- 43 Stamler J, Pick R, Katz LN, Pick A, Kaplan BM, Berkson DM, Century D. Effectiveness of estrogens for therapy of myocardial infarction in middle-age men. JAMA.1963; 183:106–112.Google Scholar
- 44 Schoch HK. The US Veterans Administration cardiology drug-lipid study: an interim report. Adv Exp Med Biol.1996; 4:405–420.Google Scholar
- 45 Oliver MF, Boyd GS. Influence of reduction of serum lipids on prognosis of coronary heart-disease: a five-year study using oestrogen. Lancet.1961; 2:499–505.CrossrefMedlineGoogle Scholar
- 46 The Coronary Drug Project Research Group. Findings leading to discontinuation of the 2.5 mg/day estrogen group. JAMA.1973; 226:652–657.CrossrefMedlineGoogle Scholar
- 47 The Coronary Drug Project Research Group. The coronary drug project: initial findings leading to modifications of its research protocol. JAMA.1970; 214:1303–1313.CrossrefMedlineGoogle Scholar
- 48 Veterans Administration Cooperative Study of Atherosclerosis NS. An evaluation of estrogenic substances in the treatment of cerebral vascular disease. Circulation. 1966;(suppl 2)23; 24:II-3–II-9.Google Scholar
- 49 The Coronary Drug Project Research Group. The Coronary Drug Project. Findings leading to further modifications of its protocol with respect to dextrothyroxine. JAMA.1972; 220:996–1008.CrossrefMedlineGoogle Scholar
- 50 Burr ML, Gilbert JF, Holliday RM, Elwood PC, Fehily AM, Rogers S, Sweetnam PM, Deadman NM. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet.1989; 2:757–761.CrossrefMedlineGoogle Scholar
- 51 de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, Guidollet J, Touboul P, Delaye J. Mediterranean α-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet.1994; 343:1454–1459.CrossrefMedlineGoogle Scholar
- 52 Sacks FM, Stone PH, Gibson CM, Silverman DI, Rosner B, Pasternak RC. Controlled trial of fish oil for regression of human coronary atherosclerosis. J Am Coll Cardiol.1995; 25:1492–1498.CrossrefMedlineGoogle Scholar
- 53 Research Committee. Low-fat diet in myocardial infarction: a controlled trial. Lancet.1965; 2:501–504.CrossrefMedlineGoogle Scholar
- 54 Rose GA, Thomson WB, Williams RT. Corn oil treatment of ischaemic heart disease. BMJ.1965; 1:1531–1533.CrossrefMedlineGoogle Scholar
- 55 Dayton S, Pearce ML, Hashimoto S, Dixon WJ, Tomiyasu U. A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation. 1969;40(suppl II):1–63.Google Scholar
- 56 Research Committee. Controlled trial of soya-bean oil in myocardial infarction. Lancet.1968; 2:693–700.MedlineGoogle Scholar
- 57 Leren P. The effect of plasma cholesterol lowering diet in male survivors of myocardial infarction. Acta Med Scand. 1966;(suppl 466):1–92.Google Scholar
- 58 Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist C, Blacket RB. Low fat, low cholesterol diet in secondary prevention of coronary heart disease. Adv Exp Med Biol.1978; 109:317–330.CrossrefMedlineGoogle Scholar
- 59 Kallio V, Hakkila J, Hämäläinen H, Luurila O. Reduction in sudden deaths by a multifactorial intervention programme after acute myocardial infarction. Lancet.1979; 2:1091–1094.CrossrefMedlineGoogle Scholar
- 60 Hjermann I, Velve Byre K, Holme I, Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease: report from the Oslo Study Group of a randomised trial in healthy men. Lancet.1981; 2:1303–1310.CrossrefMedlineGoogle Scholar
- 61 Multiple Risk Factor Intervention Trial. Risk factor changes and mortality results: Multiple Risk Factor Intervention Trial Research Group. JAMA.1982; 248:1465–1477.CrossrefMedlineGoogle Scholar
- 62 Miettinen TA, Huttunen JK, Naukkarinen V, Strandberg T, Mattila S, Kumlin T, Sarna S. Multifactorial primary prevention of cardiovascular disease in middle-aged men: risk factor changes, incidence, and mortality. JAMA.1985; 254:2097–2102.CrossrefMedlineGoogle Scholar
- 63 World Health Organisation European Collaborative Group. European collaborative trial of multifactorial prevention of coronary heart disease: final report on the 6-year results. Lancet.1986; 1:869–872.MedlineGoogle Scholar
- 64 Wilhelmsen L, Berglund G, Elmfeldt G, Tibblin G, Wedel H, Pennert K, Vedin A, Wilhelmsson C, Werkö L. The multifactor primary prevention trial in Goteborg, Sweden. Eur Heart J.1986; 7:279–288.CrossrefMedlineGoogle Scholar
- 65 Frantz ID, Dawson EA, Ashman PL, Gatewood LC, Bartsch GE, Kuba K, Brewer ER. Test of effect of lipid lowering by diet in cardiovascular risk: the Minnesota Coronary Survey. Atherosclerosis.1989; 9:129–135.Google Scholar
- 66 Ornish D, Brown SE, Scherwitz LW, Billings JH, Armstrong WT, Ports TA, McLanahan SM, Kirkeeide RL, Brand RJ, Gould KL. Can lifestyle changes reverse coronary heart disease? the lifestyle heart trial. Lancet.1990; 336:129–133.CrossrefMedlineGoogle Scholar
- 67 Singh RB, Rastogi SS, Verma R, Laxmi B, Singh R, Ghosh S, Niaz MA. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. BMJ.1992; 304:1015–1019.CrossrefMedlineGoogle Scholar
- 68 McCaughan D. The long-term effects of probucol on serum lipid levels. Arch Intern Med.1981; 141:1428–1432.CrossrefMedlineGoogle Scholar
- 69 Buchwald H, Vargo RL, Matts JP, Long JM, Fitch LL, Campell GS, Pearce MB, Yellin AE, Edmiston WA, Smink RD, Sawin HS, Campos CT, Hansen BJ, Tuna N, Karnegis JN, Sanmarco ME, Amplatz K, Castaneda-Zuniga WR, Hunter DW, Bissett JK, Weber FJ, Stevenson JW, Leon AS, Chalmers TC. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. N Engl J Med.1990; 323:946–955.CrossrefMedlineGoogle Scholar
- 70 Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA.1987; 257:3233–3240.CrossrefMedlineGoogle Scholar
- 71 Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study with clofibrate and nicotinic acid. Acta Med Scand.1988; 223:405–418.CrossrefMedlineGoogle Scholar
- 72 Kane JP, Malloy MJ, Ports TA, Philips NR, Diehl JC, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA.1990; 264:3007–3012.CrossrefMedlineGoogle Scholar
- 73 Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med.1990; 323:1289–1298.CrossrefMedlineGoogle Scholar
- 74 Haskell WL, Alderman EL, Fair JM, Maron DJ, Mackey SF, Superko HR, Williams PT, Johnstone IM, Champagne MA, Krauss RM, Farquhar JW. Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease: the Stanford Coronary Risk Intervention Project (SCRIP). Circulation.1994; 89:975–990.CrossrefMedlineGoogle Scholar
- 75 Sacks FM, Pasternak RC, Gibson CM, Rosner B, Stone PH. Effect on coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolaemic patients. Lancet.1994; 344:1182–1186.CrossrefMedlineGoogle Scholar
- 76 Suurküla M, Agewall S, Fagerberg B, Wendelhag I, Wikstrand J. Multiple risk intervention in high-risk hypertensive patients: a 3-year ultrasound study of intima-media thickness and plaques in the carotid artery. Arterioscler Thromb Vasc Biol.1996; 16:462–470.CrossrefMedlineGoogle Scholar
- 77 Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA, Trosian K, Hamilton MA, Moriguchi JD, Kawata N, Hage A, Dringwater DC, Stevenson LW. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med.1995; 333:621–627.CrossrefMedlineGoogle Scholar
- 78 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials.1986; 7:177–188.CrossrefMedlineGoogle Scholar
- 79 Fleiss JL. The statistical basis of meta-analysis. Stat Methods Med Res.1993; 2:121–145.CrossrefMedlineGoogle Scholar
- 80 Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev.1987; 9:1–30.CrossrefMedlineGoogle Scholar
- 81 SAS Institute Inc. sas: Version 6.03. Cary, NC: SAS Institute Inc; 1988.Google Scholar
- 82 Haq IU, Jackson PR, Yeo WW, Ramsay LE. Sheffield risk and treatment table for cholesterol lowering for primary prevention of coronary heart disease. Lancet.1995; 346:1467–1471.CrossrefMedlineGoogle Scholar
- 83 Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. BMJ.1993; 308:373–379.Google Scholar
- 84 Oxman AD, Guyatt GH. A consumer’s guide to subgroup analyses. Ann Intern Med.1992; 116:78–84.CrossrefMedlineGoogle Scholar
- 85 Dyslipidemia Advisory Group on behalf of the scientific committee of the National Heart Foundation of New Zealand. 1996 National Heart Foundation clinical guidelines for the assessment and management of dyslipidemia. N Z Med J.1996; 109:224–231.MedlineGoogle Scholar
- 86 Pharoah PD, Hollingworth W. Cost effectiveness of lowering cholesterol concentration with statins in patients with and without pre-existing coronary heart disease: life table method applied to health authority population. BMJ.1996; 312:1443–1448.CrossrefMedlineGoogle Scholar
