Special Article
The Value of Lowering Cholesterol after Myocardial Infarction
N Engl J Med 1990; 323:1112-1119October 18, 1990
- Article
CURRENT recommendations for lowering the cholesterol level to prevent coronary heart disease have focused largely on primary prevention and have paid less attention to the issue of lowering cholesterol in patients who already have coronary disease.1 2 3 4 5 6 It remains a common conception that in survivors of infarction the extent of myocardial damage is the prime determinant of outcome and serum cholesterol is not a major risk factor.7 The opposing view is that the modifiable risk factors after a myocardial infarction are the same as those before and merit treatment.8 , 9 In current practice, it appears that most patients with coronary disease do not receive cholesterol-lowering treatment.10 11 12 We review the relevant data from observational and clinical trials and conclude that cholesterol lowering should be pursued actively in most patients with coronary disease.
Risk of Reinfarction
In patients with manifestations of coronary disease, the relative risk of myocardial infarction is five to seven times higher than in persons without overt coronary disease.13 14 15 However, the decision to carry out measures to prevent a disease is influenced more by the absolute risk of contracting that disease than by the relative risk. Some older follow-up studies of untreated patients with myocardial infarction show the high absolute risk of reinfarction and death in patients with coronary disease. In the Framingham Study, men 35 to 64 years of age with previous myocardial infarction had reinfarctions at a cumulative rate of 22 percent over a six-year period, and in women the rate was 24 percent, as compared with first-infarction rates of 7 percent in men and 3 percent in women who had been free of coronary disease.16 In the British Regional Heart Study, 14 percent of 242 men with electrocardiographic signs of definite infarction had reinfarctions over a 4.2-year follow-up, as compared with only 2 percent of those with a normal electrocardiogram.13 In the control groups of the secondary prevention trials, the reinfarction rates ranged from 20 to 39 percent over periods of three to six years (or about 6 percent annually),17 18 19 20 21 22 23 whereas in primary prevention trials the first-infarction rate was 3 to 17 percent over periods of five to eight years (or 1 to 2 percent annually), even though these trials selected high-risk participants.24 25 26 27 For example, the Coronary Drug Project recruited into its placebo group 2789 men 30 to 64 years of age who had had a previous myocardial infarction; over the next five years, 26.2 percent had a recurrent infarction, 16.2 percent died of infarction, and 20.9 percent died from all causes.28
Currently, many patients with myocardial infarction are treated with beta-blocking agents or aspirin, and their rates of reinfarction are likely to be lower than those described above. Even allowing for the reduction of 22 to 25 percent that can be expected with the use of these agents,29 , 30 however, reinfarction rates will remain several times higher than the rate of first events. The placebo group of the recently reported Multicenter Diltiazem Postinfarction Trial had a reinfarction rate of 13 percent in the first year and 5 percent in the second year, even though 56 percent of the patients were taking beta-blocking agents and 33 percent were taking aspirin.31
The view that the serum cholesterol level has little to do with the reinfarction rate can be traced to the finding in the Coronary Drug Project that several indicators of myocardial damage rank higher than serum cholesterol as predictors of reinfarction.7 , 32 There is no dispute that the extent of myocardial damage and the severity of coronary artery disease are important predictors of risk, particularly during the first few months after an infarction.33 Over the longer term, however, serum cholesterol does continue to influence the outcome. This was the case in the Coronary Drug Project28 and nine other longitudinal studies.13 , 15 , 34 35 36 37 38 39 40 The relation held after adjustment for indicators of myocardial impairment.28 , 39 Similarly, high-density lipoprotein cholesterol retains its predictive power after a myocardial infarction.13 , 34 , 40 Smoking35 , 37 , 41 and high blood pressure13 , 35 , 36 , 42 also continue to be adverse characteristics.
Although statistically significant, the relative risk of infarction associated with elevations of the serum cholesterol level in prospective studies of men with existing coronary disease has frequently been lower than that found in men free of coronary disease at base line. In the placebo group in the Coronary Drug Project, the largest study of men with coronary disease, the relative risk associated with the highest as compared with the lowest quintile of serum cholesterol was 1.5,28 whereas in the subjects screened for the Multiple Risk Factor Intervention Trial who were free of coronary disease at base line the relative risk was 3.4.34 However, in studies following men with and men without antecedent coronary disease separately, the relative risks in the two groups have been similar,13 , 15 and in the Lipid Research Clinics Follow-up Study the relative risk was higher in men with antecedent disease (10.4) than in men without (4.2).40
The critical observation is that men with cardiac ischemia have a higher absolute risk of future coronary death, whatever their level of cholesterol, than men free of ischemia (Fig. 1Figure 1
Mortality from Coronary Heart Disease, According to Plasma Cholesterol Level, in Men with Cardiovascular Disease (Squares), Men without Cardiovascular Disease (Diamonds), and All Men in the Lipid Research Clinics Follow-up Study (Crosses).40 ).40 To a large degree, this high absolute risk is a function of the underlying disease, which constitutes a relatively irreversible component of the overall risk. However, the persistence of a relation between coronary mortality and serum cholesterol across the range of cholesterol levels does create considerable potential for reduction in the excess risk attributable to cholesterol. This excess risk represents the number of morbid events or deaths that could be avoided by cholesterol management in this subgroup of men with coronary disease. The potential is large because the increase in relative risk attributable to higher cholesterol levels is superimposed on the already high absolute rate of events in persons who have had a myocardial infarction or have other evidence of cardiovascular disease.Even when the relative risk is moderate, the absolute risk attributable to serum cholesterol remains high. In the control group of the Coronary Drug Project, for example, the five-year rate of death from coronary disease among men in the highest quintile of serum cholesterol was 196 per 1000, as compared with 129 per 1000 for men in the lowest quintile.28 The difference in rates (196 minus 129, or 67 per 1000) represents the excess risk — the deaths that were potentially avoidable had the cholesterol levels of the men in the upper quintile been reduced to those of the men in the lower quintile. However, the excess risk related to cholesterol was not confined to the men in the highest quintile but was also present in the men in each of the three intermediate quintiles. By comparison, over a six-year period the subjects screened for the Multiple Risk Factor Intervention Trial who were free of coronary disease at base line and who were in the upper quintile of cholesterol had an excess risk of 11 minus 3 or 8 per 1000 — i.e., only 8 coronary deaths per 1000 men treated were potentially avoidable by cholesterol reduction.43 In the Lipid Research Clinics Follow-up Study, the excess risk of coronary death over a 10-year period for men with preexisting cardiovascular disease who had cholesterol levels above 6.2 mmol per liter, as compared with those who had levels below 5.2 mmol per liter, was 170 minus 16, or 154 per 1000, whereas men free of disease at base line had an excess risk of only 27 minus 6, or 21 per 1000.40 When experience in the Coronary Drug Project is used to obtain the most conservative estimate, at least one third of the coronary deaths in the men with the highest levels of cholesterol were potentially avoidable, if one assumes that lowering the cholesterol level will reduce the rate of coronary events, as the trial data reviewed below indicate.
This potential may not be fully attainable, however, because reduction in the plasma cholesterol level may be inadequate and because a full reduction of the risk may not be possible. The secondary prevention trials provide an indication of the risk reduction attainable in practice. Because most of the controlled cholesterol-lowering clinical trials have involved patients with existing coronary disease, extensive information is available.
Reducing Rates of Reinfarction by Lowering Cholesterol Levels
Secondary prevention trials have used diet or drugs, alone or in combination, to lower cholesterol levels. They have a statistical advantage over primary prevention trials in that they yield more end points. Even so, many published studies had inadequate power in themselves because of small numbers, but they are informative when studied in aggregate. The eight secondary prevention trials listed in Table 1Table 1
Rates of Myocardial Infarction in Secondary Prevention Trials of Cholesterol Lowering.* allow such an overall judgment.17 18 19 20 21 22 23 They have been selected as the most informative in terms of size and design, according to the following uniform criteria: at least 100 participants in each group, at least three years' duration, randomized assignment to treatment or control group, and the absence of potentially confounding interventions addressing other risk factors. All trials meeting these criteria were included, regardless of outcome, except that trials using hormones now known to be toxic (e.g., thyroxine and estrogens) were excluded. Unlike those in the primary prevention trials,24 25 26 27 participants in the secondary prevention trials were unselected with regard to serum cholesterol level; the mean base-line levels ranged from 6.33 to 7.67 mmol per liter. The secondary prevention trials generally required that participants have survived at least the first postinfarction month, making many patients with more severe myocardial damage ineligible.The results of these trials are persuasive in showing that reductions in elevated serum cholesterol levels are attended by decreases in the number of both nonfatal and fatal myocardial infarctions. In four of eight secondary prevention trials, the incidence of nonfatal and fatal myocardial infarctions combined was reduced significantly.17 , 19 , 20 , 23 Although the numbers became small when nonfatal and fatal infarctions were considered separately in individual trials, significant reductions in nonfatal infarctions were obtained in one trial21 and in fatal infarctions in two.17 , 20 A meta-analysis29 , 44 of the combined data for 7837 participants in these eight secondary prevention trials indicates that the reductions in observed nonfatal (odds ratio, 0.75; P<0.001), fatal (odds ratio, 0.84; P<0.01), and total (odds ratio, 0.78; P<0.001) myocardial infarctions were significant (Table 1). The risk reductions calculated from the odds ratios are higher than those obtained directly from the difference in event rates in the treated and control groups, because of the high event rates in secondary prevention trials. For purposes of comparison with the primary prevention trials, the mean reductions in risk (weighted according to number of infarctions — i.e., for study size) were recalculated from the event rates. A 10 percent mean reduction in the serum cholesterol level in the the secondary prevention trials led to reductions of 19, 12, and 15 percent in the number of nonfatal, fatal, and all myocardial infarctions, respectively; in the primary prevention trials, a 10 percent reduction in the cholesterol level led to corresponding reductions of 25, 12, and 22 percent.24 25 26 27 Overall, the results of the secondary prevention trials were similar to those of four primary prevention trials selected according to the same criteria.
These conclusions about the efficacy of cholesterol reduction in patients with or without existing coronary disease do not seem to be biased by a focus on the studies selected. Yusuf et al. reached the same conclusions by a meta-analysis of a wider range of 22 primary and secondary randomized intervention trials.29 These included the studies we have considered, as well as smaller and shorter ones. The reductions in the rate of infarction are the more impressive in view of the apparent two-year interval between cholesterol lowering and a decline in the incidence of coronary events,24 , 25 the relative brevity of the trials in relation to the evolution of atherosclerosis, and the limited reductions achieved in the serum cholesterol level. The participants in the secondary prevention trials were selected on the basis of rigorous criteria for previous myocardial infarction; they would have tended, therefore, to have advanced coronary disease. Persons with less advanced coronary heart disease, identified by less rigorous criteria, may have potential for increased risk reduction.15
Can secondary prevention, usually seen as falling into the clinical domain, affect the burden of coronary disease in the population? An appreciable proportion of the population has some manifestation of coronary disease; there are an estimated 7.2 million cases of prevalent coronary disease in the United States.45 By the age of 50 to 59, 5 percent of American men have signs of infarction or ischemia on resting electrocardiography, 8 percent have abnormalities on stress electrocardiography, and 4 percent have angina; these proportions increase with age.46 Nearly one in three British men have symptoms or electrocardiographic evidence of coronary disease at the age of 50 to 59.47 If cholesterol reduction in this large group is beneficial, then substantial further morbidity and mortality might be avoided.
Men with preexisting coronary disease add substantially to the burden of coronary deaths in the population, as has been shown by the Lipid Research Clinics Follow-up Study (Fig. 1).40 Although men with ischemia constituted only one sixth of that population, their absolute risk was so high that it raised the cholesterol-related coronary death curve of the total population substantially above that of the healthy men. Infarction in men with some indication of preexisting coronary disease accounts for 50 percent of all cases of myocardial infarction,13 , 15 , 40 and approximately 20 percent have had a myocardial infarct.31 Treating this easily identifiable group of patients could prevent a large number of infarctions — a situation unlike that seen in primary prevention, in which treating the same number would prevent relatively fewer infarctions. For example, our meta-analysis of the eight secondary prevention trials shows that the 3623 treated patients had 98 fewer infarctions than expected, or 27 fewer per 1000 patients treated. On the other hand, in a similar analysis (data not shown) of four primary prevention trials,24 25 26 27 the difference between observed and expected infarctions was only 6 per 1000. It should be noted that in the case of both primary and secondary prevention, this calculation underestimates the actual difference between the control and the treated groups by about half (see the footnote to Table 1). Over a longer period than was typical of the trials, and with more effective cholesterol lowering, the number of events prevented would be much larger, since the effect of elevated cholesterol levels over a period of 25 years, for example, would be considerable.48
Angiographic Studies
The overall positive findings of trials using clinical end points are complemented by evidence from coronary angiographic studies indicating that the course of coronary atherosclerosis can be modified favorably by cholesterol reduction. Recent trials involving marked changes in lipid risk factors have confirmed the findings of earlier studies showing that the natural history of lesions can be influenced.49 50 51 52 53 In the Cholesterol-Lowering Atherosclerosis Study, a combination of diet, colestipol, and niacin over two years reduced serum cholesterol levels by 22 percent and low-density lipoprotein cholesterol levels by 39 percent, and increased high-density lipoprotein cholesterol levels by 37 percent.52 In the treated group, progression of coronary lesions was less frequent (39 percent, vs. 61 percent in controls) and stabilization of lesions more frequent (45 vs. 37 percent), and there was regression in 16 percent (as compared with 2 percent of controls, P = 0.002). The benefit was not confined to patients with high initial cholesterol levels; patients with levels in the range of 4.78 to 6.20 mmol per liter also responded to treatment.
In the Familial Atherosclerosis Treatment Study, a combination of lovastatin and colestipol led to a reduction of 48 percent in the level of low-density lipoprotein cholesterol and an increase of 14 percent in the level of high-density lipoprotein cholesterol; after 2 1/2 years, 38 percent of the treated patients had regression, as compared with 10 percent of the controls (P<0.05).53 In a second group treated with niacin plus colestipol, reductions of 34 percent in the level of lowdensity lipoprotein cholesterol and increases of 41 percent in the level of high-density lipoprotein cholesterol were achieved. Regression was seen in 47 percent of the treated patients (P<0.01).
These studies suggest that not only can progression be slowed, but also regression can be induced by lipid management. Trials that successfully demonstrated regression lowered serum cholesterol levels to well below 5.17 mmol per liter in most of the treated patients.52 , 53
Mortality
Concern has been voiced that the clinical trials of cholesterol lowering have not reduced overall mortality.7 One possible explanation is that individual trials have lacked sufficient statistical power. Because total mortality reflects all causes of death and some substitution of death from noncardiac causes can be expected when the number of cardiac deaths is reduced,54 trials of measures designed to reduce the number of coronary deaths would be expected to produce smaller percentage reductions in total mortality than in coronary deaths; hence, the detection of changes in total mortality requires a far larger sample, a longer study period, or both, than the detection of changes in coronary events. In addition, in some trials deaths from causes other than myocardial infarction were unreported, so that the power of even meta-analysis to detect effects on total mortality is decreased.30 For these reasons, lipid-lowering therapy should not be dismissed on the grounds that total mortality has not decreased consistently. Nonetheless, the significant excess of noncardiovascular mortality noted in previous meta-analyses of the combined primary and secondary cholesterol-lowering trials cannot be ignored.30 A distinction needs to be made, however, between the two types of trials in regard to noncardiovascular and total mortality.
In the setting of secondary prevention, our metaanalysis of eight trials indicated that there are more grounds for optimism in regard to both total mortality and noncardiovascular mortality than was apparent in the primary prevention trials (Table 2Table 2
Mortality in Secondary Prevention Trials of Cholesterol Lowering.*). The secondary prevention trials differed quantitatively from the primary prevention trials in that a higher proportion of deaths were cardiovascular (82 percent). Perhaps as a result, the decrease for this end point (odds ratio, 0.88; P<0.05) was not quite counterbalanced by the numerically small increase in noncardiovascular deaths (odds ratio, 1.30; P not significant); hence, the trend for the total death rate remained favorable (odds ratio, 0.91; P not significant). Among the noncardiovascular deaths, there was a small decrease in the number of deaths from cancer (odds ratio, 0.75; P not significant) and an increase in the number of noncancer deaths (odds ratio, 2.10; P<0.001). In the four primary prevention trials, there were consistent increases in the small numbers of deaths due to accidents and violence; unfortunately, the secondary prevention trials contain little published information about the exact causes of death in the noncardiovascular, noncancer category. Because the numbers of deaths in this category are small and heavily influenced by one study (the Coronary Drug Project), their analysis needs to be performed with caution.Longer follow-up in both primary and secondary intervention trials may yield a clearer answer with regard to total mortality. The niacin arm of the Coronary Drug Project had a small (4 percent) reduction in total mortality within the 6-year trial period,19 but within 2 years of further follow-up the mortality rates began to diverge, and after 9 years (a total follow-up of 15 years) there was a significant reduction (11 percent) in total deaths.55 The 11-year follow-up of the Oslo Diet-Heart Study showed a small (9 percent, P not significant) decrease in total mortality in the treated group56; however, the recent results of an 8 1/2-year follow-up in the Oslo Diet and Antismoking Trial (a primary prevention study) did show a much larger reduction (40 percent) in total mortality.57 The investigators in the Multiple Risk Factor Intervention Trial, who found no difference in total mortality during the 6.9 years of the trial, found a 16 percent reduction (one-sided P = 0.02) in the first 3.8 years after the trial, giving an overall difference of 8 percent after a total follow-up of 10.7 years (P not significant).58 It appears that the follow-up of 3 to 8 years usual in intervention studies is insufficient to show reductions in total mortality, but that a longer follow-up (on the order of 8 1/2 to 15 years) may do so.
Morbidity
Even if overall mortality were not significantly reduced, reductions in cardiac morbidity remain as a net gain. This would be a sufficient goal. Fries et al.59 argue that substantial further gains in life expectancy are unlikely in developed societies and that as a result the primary purpose of risk reduction becomes to compress morbidity into the last few years of life and improve the quality and vigor of life. The magnitude of the burden of coronary morbidity has perhaps not received the attention it deserves. The estimated 7.2 million Americans with prevalent coronary disease account for more than 27 million office visits and more than 2 million hospitalizations annually, and nationally the direct costs amounted to an estimated $15.3 billion in 1987.45 Apart from the evident health benefits, reducing morbidity should substantially reduce medical expenditures. The average direct costs of a nonfatal myocardial infarction over a five-year period have been estimated at $51,211, those of angina pectoris at $24,890, and those of unstable angina at $40,581.60 These costs are considerably higher than those of sudden death ($9,078) or nonsudden cardiac death ($19,697). Angioplasty and coronary-artery bypass surgery are expensive components of the cost of coronary disease as compared with medical therapy. The costs of medical therapy are increased if angina or reinfarction follows the initial infarction. If the number of patients who have angina, have a reinfarction, or need surgical procedures could be reduced through greater use of relatively inexpensive medical therapy, it can be anticipated that the direct cost of coronary disease would decrease. In view of the evidence, such medical therapy should include the aggressive management of high serum levels of cholesterol (and other risk factors), in addition to the use of medications such as aspirin and beta-blocking agents.
Conclusions
The causal role of cholesterol in reinfarction has been demonstrated by the higher relative risk in men with coronary disease who have elevated serum cholesterol levels and the positive outcomes of the trials discussed. The need for preventive action in patients who have had a myocardial infarction is predicated on their high absolute risk of reinfarction; this already high risk is aggravated by an elevated serum cholesterol level. The secondary prevention trials have demonstrated that a 10 percent reduction in cholesterol can be expected to reduce the rate of nonfatal reinfarction by 19 percent and of fatal infarction by 12 percent. With vigorous dietary treatment and the use as indicated of effective drugs, singly or in combination, substantial lowering of lipid levels is feasible61 and should result in a larger reduction in reinfarction rates than those achieved in the clinical trials. Since half the patients admitted with a myocardial infarction will have had a previous infarction or other evidence of coronary disease, the identification of this group and the reduction of its reinfarction rate should reduce the total burden of myocardial infarction substantially.
Assessment of the risk attached to elevated cholesterol levels has largely been based on estimates of relative rather than absolute risk and has been derived from prospective studies of healthy persons or from general populations comprising both healthy persons and persons with coronary disease. The men screened in the Multiple Risk Factor Intervention Trial who had serum cholesterol levels above 6.2 mmol per liter were at high relative risk but had an overall six-year coronary death rate of less than 1 percent.43 Although the absolute risk to the general population from exposure to high cholesterol levels over a longer period is considerable, the absolute risk to patients with coronary disease is substantially higher and more immediate. Patients with coronary disease are at high absolute risk whatever their level of serum cholesterol, and no low point has been established at which the serum cholesterol level ceases to influence the outcome. The relative risks associated with various serum cholesterol levels may be similar to those of healthy persons, but the effect of even slight elevations of the serum cholesterol level on the absolute risk in such patients is greater than that of higher elevations in persons without coronary disease.
The treatment of patients with existing coronary disease is a particularly attractive area for clinicians. Since cardiovascular deaths predominate (82 percent of all deaths), there is less concern about a possible excess of noncardiac deaths related to treatment. Treatment is targeted to a group that stands to gain most in terms of a reduction in absolute risk. Furthermore, it is triggered by the cardiac event and is thus likely to begin at a later age and last a shorter time than in primary prevention, with attendant savings in direct costs. It represents a practical approach to coronary disease that can be implemented easily by the clinician. At the same time, it should be acknowledged that secondary prevention cannot replace primary prevention, because it cannot reach half the patients who will have coronary events in the future and because, once coronary disease has manifested itself, it is unlikely that the risk can be reduced to that of persons free of disease.
Two thirds of patients with coronary disease have serum cholesterol levels above 5.17 mmol per liter and would thus be subjected to lipoprotein analysis under current guidelines; the great majority of these would have low-density lipoprotein cholesterol levels above 3.36 mmol per liter and would thus be considered for treatment.2 A considerable proportion (about one third) of those with serum cholesterol levels below 5.17 mmol per liter may also have low-density lipoprotein cholesterol levels above 3.36 mmol per liter (and two thirds may have high-density lipoprotein cholesterol levels below 0.90 mmol per liter).62 For these reasons, we recommend that all patients with coronary disease have a fasting lipoprotein analysis rather than a screening test of the serum cholesterol level. Current recommendations are that in patients with coronary disease the minimal goal of treatment should be to reduce low-density lipoprotein cholesterol to below 3.36 mmol per liter and serum cholesterol to below 5.17 mmol per liter.2 However, the Adult Treatment Panel of the National Cholesterol Education Program recognized that a level of low-density lipoprotein cholesterol as low as 2.58 mmol per liter may be considered by some to be an ideal goal in patients with definite coronary disease or other major risk factors.2 We believe that this more stringent goal may indeed be justified in most patients with coronary disease, in view of their high absolute risk even with commonly occurring levels of serum cholesterol and in view of the evidence emerging from angiographic studies that regression can be obtained by reducing cholesterol to very low levels.
Furthermore, although we acknowledge that it would be helpful to have direct evidence (in the form of clinical trials) of benefit from the treatment of patients who already have levels of low-density lipoprotein cholesterol below the "desirable" level of 3.36 mmol per liter, we are inclined to recommend that such treatment be considered in patients with coronary disease and that the goal should again be to lower the level of low-density lipoprotein cholesterol toward 2.58 mmol per liter. Clearly, other considerations would influence the decision to treat an individual patient, among them the patient's age, cardiac and overall health status, and the presence of other risk factors. Other risk factors need to be treated in their own right, and cholesterol reduction is most likely to be successful in the context of a comprehensive program of risk management63 , 64 that includes smoking cessation and the judicious treatment of hypertension.
Source Information
From the Lipid Metabolism—Atherogenesis Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. (J.E.R., B.M.R.), and the Rayne Institute, St. Thomas' Hospital, London (B.L.). Address reprint requests to Dr. Rifkind at the Lipid Metabolism—Atherogenesis Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Federal Bldg., Rm. 401, Bethesda, MD 20892.
- References
References
1
Lowering blood cholesterol to prevent heart disease . JAMA 1985; 253:2080–6.
CrossRef | Web of Science2
Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults . Arch Intern Med 1988; 148:36–69.
CrossRef | Web of Science | Medline3
Study Group, European Atherosclerosis Society
Web of Science4
Study Group, European Atherosclerosis Society
Web of Science | Medline5
The British Cardiac Society Working Group on Coronary Prevention: conclusions and recommendations . Br Heart J 1987; 57:188–9.
CrossRef | Web of Science | Medline6
Committee on Diet and Health, Food and Nutrition Board, Commission on Life Sciences, National Research Council. Diet and health: implications for reducing chronic disease risk. Washington, D.C.: National Academy Press, 1989.
7
Secondary prevention of coronary disease with lipid-lowering drugs . Lancet 1989; 1:473–4.
Web of Science | Medline8
Siegel
Web of Science | Medline9
Evans
CrossRef | Web of Science | Medline10
Crouse
Web of Science | Medline11
Watt
Web of Science | Medline12
Hoad
CrossRef | Web of Science | Medline13
Shaper
CrossRef | Web of Science | Medline14
Gordon
CrossRef | Web of Science | Medline15
Rose
CrossRef | Web of Science | Medline16
Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham Study: an epidemiologic investigation of cardiovascular disease. Section 35. Survival following initial cardiovascular events: thirty year follow-up. Washington, D.C.: Government Printing Office, 1988. (NIH publication no. 88–2969.)
17
Trial of clofibrate in the treatment of ischaemic heart disease: five-year study by a group of physicians of the Newcastle upon Tyne region . BMJ 1971; 14:767–75.
18
Ischaemic heart disease: a secondary prevention trial using clofibrate: report by a research committee of the Scottish Society of Physicians . BMJ 1971; 4:775–84.
CrossRef | Web of Science19
The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease . JAMA 1975; 231:360–81.
CrossRef | Web of Science20
Carlson
CrossRef | Web of Science | Medline21
A Research Committee
CrossRef | Web of Science | Medline22
Controlled trial of soya-bean oil in myocardial infarction: report of research committee to the Medical Research Council . Lancet 1968; 2:693–700.
Web of Science | Medline23
Leren
Medline24
Lipid Research Clinics Program
CrossRef | Web of Science25
Frick
Full Text | Web of Science | Medline26
A Cooperative trial in the primary prevention of ischaemic heart disease using clofibrate: report from the Committee of Principal Investigators . Br Heart J 1978; 40:1069–118.
CrossRef | Web of Science | Medline27
Dayton 28
Coronary Drug Project Research Group
CrossRef | Web of Science | Medline29
Yusuf
CrossRef | Web of Science30
Yusuf
CrossRef | Web of Science | Medline31
The Multicenter Diltiazem Postinfarction Trial research Group
Full Text | Web of Science | Medline32
Schlant
CrossRef | Web of Science | Medline33
Moss
Full Text | Web of Science | Medline34
Goldbourt
CrossRef | Web of Science | Medline35
Heliövaara
CrossRef | Web of Science | Medline36
Wong
Web of Science | Medline37
Jenkins
Web of Science | Medline38
Frost
CrossRef | Web of Science | Medline39
Ulvenstam
CrossRef | Web of Science | Medline40
Pekkanen
Full Text | Web of Science | Medline41
Jafri
CrossRef | Web of Science | Medline42
Khaw
CrossRef43
Stamler
CrossRef | Web of Science | Medline44
Mantel
Web of Science | Medline45
National Heart, Lung, and Blood Institute. Data fact sheet: morbidity from coronary heart disease in the United States. Bethesda. Md.: NHLBI Education Program Information Center, June 1990.
46
Abernathy
CrossRef | Web of Science | Medline47
Shaper
CrossRef | Web of Science | Medline48
Pekkanen
CrossRef | Web of Science | Medline49
Brensike
CrossRef | Web of Science | Medline50
Arntzenius
Full Text | Web of Science | Medline51
Nikkila
CrossRef | Web of Science | Medline52
Blankenhorn
CrossRef | Web of Science | Medline53
Brown 54
Rose
CrossRef | Web of Science | Medline55
Canner
CrossRef | Web of Science | Medline56
Leren
Web of Science | Medline57
Hjermann
CrossRef | Web of Science | Medline58
The Multiple Risk Factor Trial Research Group
CrossRef | Web of Science59
Fries
CrossRef | Web of Science | Medline60
Wittels
CrossRef | Web of Science | Medline61
Grundy
Full Text | Web of Science | Medline62
Miller
CrossRef | Web of Science | Medline63
Kallio
CrossRef | Web of Science | Medline64
Ornish
CrossRef | Web of Science | Medline
- Citing Articles (80)
Citing Articles
1
J. P. Miller. (2011) Comment on 'The great cholesterol myth: unfortunate consequences of Brown and Goldstein's mistake'. QJM
CrossRef2
John Ikechukwu Ihedioha, Onyinyechukwu Ada Noel-Uneke, Thelma Ebele Ihedioha. (2011) Reference values for the serum lipid profile of albino rats (Rattus norvegicus) of varied ages and sexes. Comparative Clinical Pathology
CrossRef3
Michael H. Davidson, Joanne M. Donovan, Soamnauth Misir, Michael R. Jones. (2010) A 50-Week Extension Study on the Safety and Efficacy of Colesevelam in Adults with Primary Hypercholesterolemia. American Journal Cardiovascular Drugs 10:5, 305-314
CrossRef4
Sankar D Navaneethan, Sagar U Nigwekar, Vlado Perkovic, David W Johnson, Jonathan C Craig, Giovanni FM Strippoli, Sankar D Navaneethan. 2009. HMG CoA reductase inhibitors (statins) for dialysis patients. .
CrossRef5
Sankar D Navaneethan, Sagar U Nigwekar, Ashwini R Sehgal, Giovanni FM Strippoli, Sankar D Navaneethan. 2009. Aldosterone antagonists for preventing the progression of chronic kidney disease. .
CrossRef6
Theodoros I. Kassimatis, Panagiotis A. Konstantinopoulos. (2009) The role of statins in chronic kidney disease (CKD): Friend or foe?. Pharmacology & Therapeutics 122:3, 312-323
CrossRef7
Harlan M. Krumholz, Jeffrey L. Anderson, Brian L. Bachelder, Francis M. Fesmire, Stephan D. Fihn, JoAnne M. Foody, P. Michael Ho, Mikhail N. Kosiborod, Frederick A. Masoudi, Brahmajee K. Nallamothu. (2008) ACC/AHA 2008 Performance Measures for Adults With ST-Elevation and Non–ST-Elevation Myocardial Infarction. Journal of the American College of Cardiology 52:24, 2046-2099
CrossRef8
P A Ades, P D Savage, M J Toth, D J Schneider, M C Audelin, J Y Bunn, M Ludlow. (2008) The influence of obesity and consequent insulin resistance on coronary risk factors in medically treated patients with coronary disease. International Journal of Obesity 32:6, 967-974
CrossRef9
Victor H. H. Goh, Terry Y. Y. Tong, Helen P. P. Mok, Baharudin Said. (2007) Differential impact of aging and gender on lipid and lipoprotein profiles in a cohort of healthy Chinese Singaporeans. Asian Journal of Andrology 9:6, 787-794
CrossRef10
Richard A. Bernstein. (2007) Statin therapy to prevent stroke in the elderly. Current Cardiovascular Risk Reports 1:4, 324-329
CrossRef11
Eric J. Stanek, Chaitanya Sarawate, Vincent J. Willey, Scott L. Charland, Mark J. Cziraky. (2007) Risk of cardiovascular events in patients at optimal values for combined lipid parameters. Current Medical Research and Opinion 23:3, 553-563
CrossRef12
Richard A. Bernstein. (2006) Cholesterol lowering to prevent stroke: Who, when, and how?. Current Treatment Options in Neurology 8:6, 496-502
CrossRef13
I. Scott, P. Greenberg, P. Poole, D. Campbell. (2006) Cautionary tales in the interpretation of systematic reviews of therapy trials. Internal Medicine Journal 36:9, 587-599
CrossRef14
Patricia M Kearney, Colin Baigent. (2006) Statins: are any questions unanswered?. Current Opinion in Lipidology 17:4, 418-425
CrossRef15
Michel R. Hoenig, Barbara E. Rolfe, Julie H. Campbell. (2006) Cholestanol: A serum marker to guide LDL cholesterol-lowering therapy. Atherosclerosis 184:2, 247-254
CrossRef16
(2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. The Lancet 366:9493, 1267-1278
CrossRef17
Lluı́s Masana, Jesús Villoria, Mariano Sust, Emilio Ros, Nuria Plana, Francisco Pérez-Jiménez, Miguel Franco, Josefina J Oliván, Xavier Pintó, Sebastián Videla. (2004) Treatment of type IIb familial combined hyperlipidemia with the combination pravastatin-piperazine sultosilate. European Journal of Pharmacology 496:1-3, 205-212
CrossRef18
T.G.W Speel, H van Langen, E.J.H Meuleman. (2003) The Risk of Coronary Heart Disease in Men with Erectile Dysfunction. European Urology 44:3, 366-371
CrossRef19
Gregg C. Fonarow. (2003) In-hospital initiation of statin therapy in patients with acute coronary events. Current Atherosclerosis Reports 5:5, 394-402
CrossRef20
David E. Harris, N. Burgess Record, Jane Gilbert-Arcari, Sheena Bunnell, Sandra S. Record, Katherine Norton. (2003) Cardiac Rehabilitation With Nurse Care Management and Telephonic Interactions at a Community Hospital. Lippincott's Case Management 8:4, 141-157
CrossRef21
John C. Corbelli, David M. Janicke, Jennifer A. Corbelli, Sheryl Chow, Mary Pruski. (2003) Acute Coronary Syndrome Emergency Treatment Strategies. Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine 2:2, 71-87
CrossRef22
SETH KELLER, WILLIAM H. FRISHMAN. (2003) Neuropsychiatric Effects of Cardiovascular Drug Therapy. Cardiology in Review 11:2, 73-93
CrossRef23
Philip A Ades, Thomas E Kottke, Nancy Houston Miller, John C McGrath, N.Burgess Record, Sandra S Record. (2002) Task Force #3—getting results: who, where, and how?. Journal of the American College of Cardiology 40:4, 615-630
CrossRef24
Gregg C. Fonarow. (2002) Statin therapy after acute myocardial infarction: Are we adequately treating high-risk patients?. Current Atherosclerosis Reports 4:2, 99-106
CrossRef25
Ades, Philip A., . (2001) Cardiac Rehabilitation and Secondary Prevention of Coronary Heart Disease. New England Journal of Medicine 345:12, 892-902
Full Text26
Diego Vanuzzo, Lorenza Pilotto, Giovanni B. Ambrosio, Kalevi Pyörälä, Seppo Lehto, Dirk De Bacquer, Guy De Backer, David Wood. (2000) Potential for cholesterol lowering in secondary prevention of coronary heart disease in Europe: findings from EUROASPIRE study. Atherosclerosis 153:2, 505-517
CrossRef27
Martin Brochu, Eric T. Poehlman, Philip A. Ades. (2000) Obesity, Body Fat Distribution, and Coronary Artery Disease. Journal of Cardiopulmonary Rehabilitation 20:2, 96-108
CrossRef28
Noralou P. Roos, Charlyn Black, Leslie L. Roos, Norman Frohlich, Carolyn DeCoster, Cameron Mustard, Marni D. Brownell, Marian Shanahan, Patricia Fergusson, Fred Toll, Keumhee Chough Carriere, Charles Burchill, Randy Fransoo, Leonard MacWilliam, Bogdan Bogdanovic, David Friesen. (1999) Managing Health Services. Medical Care 37:SUPPLEMENT, JS27-JS41
CrossRef29
Antonio M Gotto. (1999) Lipid-lowering therapy for the primary prevention of coronary heart disease. Journal of the American College of Cardiology 33:7, 2078-2082
CrossRef30
William Stanford, Brad H. Thompson. (1999) IMAGING OF CORONARY ARTERY CALCIFICATION. Radiologic Clinics of North America 37:2, 257-272
CrossRef31
Daniel E. Hilleman, Jeffrey O. Phillips, Syed M. Mohiuddin, Kay L. Ryschon, Craig A. Pedersen. (1999) A population-based treat-to-target pharmacoeconomic analysis of HMG-CoA reductase inhibitors in hypercholesterolemia. Clinical Therapeutics 21:3, 536-562
CrossRef32
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. (1998) Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels. New England Journal of Medicine 339:19, 1349-1357
Full Text33
Scott M. Grundy. (1998) THE ROLE OF CHOLESTEROL MANAGEMENT IN CORONARY DISEASE RISK REDUCTION IN ELDERLY PATIENTS. Endocrinology & Metabolism Clinics of North America 27:3, 655-675
CrossRef34
A.Maziar Zafari, Nanette K. Wenger. (1998) Secondary prevention of coronary heart disease. Archives of Physical Medicine and Rehabilitation 79:8, 1006-1017
CrossRef35
Ronald C. Plotnikoff, Nick Higginbotham. (1998) Protection motivation theory and the prediction of exercise and low-fat diet behaviours among Australian cardiac patients. Psychology & Health 13:3, 411-429
CrossRef36
Mona From Attebring, Marianne Hartf. (1998) Risk Indicators for Recurrence Among Patients with Coronary Artery Disease: Problems Associated with their Modification. Scandinavian Cardiovascular Journal 32:1, 9-16
CrossRef37
Roland Carlsson. (1998) Serum Cholesterol, Lifestyle, Working Capacity and Quality of Life in Patients with Coronary Artery Disease. Experiences from a Hospital-based Secondary Prevention Programme. Scandinavian Cardiovascular Journal 32:50, 1-20
CrossRef38
LeLorier, Jacques, Grégoire, Geneviève, Benhaddad, Abdeltif, Lapierre, Julie, Derderian, François, . (1997) Discrepancies between Meta-Analyses and Subsequent Large Randomized, Controlled Trials. New England Journal of Medicine 337:8, 536-542
Full Text39
PA Sáiz, J Bobes, MP Gonzalez, I Cocaña, P González-Quiros, M Bousoño. (1997) Searching for a predictive peripherical biological model in parasuicidal behaviour. European Psychiatry 12:2, 75-81
CrossRef40
H.J.C Swan, Bernard J. Gersh, Thomas B. Graboys, Daniel J. Ullyot. (1996) Task force 7. Evaluation and management of risk factors for the individual patient (case management). Journal of the American College of Cardiology 27:5, 1030-1039
CrossRef41
Harald Herholz, David C. Goff, David J. Ramsey, Frances A. Chan, Carmen Ortiz, Darwin R. Labarthe, Milton Z. Nichaman. (1996) Women and mexican Americans receive fewer cardiovascular drugs following myocardial infarction than men and non-hispanic whites: The Corpus Christi Heart Project, 1988–1990. Journal of Clinical Epidemiology 49:3, 279-287
CrossRef42
Kalevi Pyörälä, George Steiner. (1996) Will Correction of Dyslipoproteinaemia Reduce Coronary Heart Disease Risk in Patients with Non-insulin-dependent Diabetes? Need for Trial Evidence. Annals of Medicine 28:4, 357-362
CrossRef43
Claudio Borghi, Ettore Ambrosioni. (1996) Primary and Secondary Prevention of Myocardial Infarction. Clinical and Experimental Hypertension 18:3-4, 547-558
CrossRef44
The PPP Project Investigators. (1995) Design, rationale, and baseline characteristics of the Prospective Pravastatin Pooling (PPP) project—A combined analysis of three large-scale randomized trials: Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID), Cholesterol and Recurrent Events (CARE), and West of Scotland Coronary Prevention Study (WOSCOPS). The American Journal of Cardiology 76:12, 899-905
CrossRef45
Paul E. Cundey, Martin J. Frank. (1995) Cardiac rehabilitation and secondary prevention after a myocardial event. Clinical Cardiology 18:10, 547-553
CrossRef46
I Todd, S Donald, B Pentland. (1995) Cardiac rehabilitation for older people. Reviews in Clinical Gerontology 5:03, 321
CrossRef47
Hanna Bloomfield Rubins. (1995) Cholesterol in patients with coronary heart disease. Journal of General Internal Medicine 10:8, 464-471
CrossRef48
Helen Elliott. (1995) Community nutrition education for people with coronary heart disease-who attends?. Australian Journal of Public Health 19:2, 205-210
CrossRef49
Harvey D White, John K French, Andrew W Hamer, Michael A Brown, Barbara F Williams, John A Ormiston, David B Cross. (1995) Frequent reocclusion of patent infarct-related arteries between 4 weeks and 1 year: Effects of antiplatelet therapy. Journal of the American College of Cardiology 25:1, 218-223
CrossRef50
J. S. Silberberg. (1994) After the meta-analyses: a commentary on treatment of dyslipidaemia in the primary prevention of coronary heart disease*. Australian and New Zealand Journal of Medicine 24:6, 717-721
CrossRef51
W. C. TAYLOR, G. T. MOORE. (1994) Health promotion and disease prevention: integration into a medical school curriculum. Medical Education 28:6, 481-487
CrossRef52
Peter T.KUO. (1994) Dyslipidemia and coronary artery disease. Clinical Cardiology 17:10, 519-527
CrossRef53
John C. LaRosa. (1994) Cholesterol and public policy. Atherosclerosis 108, S137-S141
CrossRef54
Lewis H. Kuller. (1994) Future in lipid and lipoprotein research: from preventing clinical disease to preventing elevated risk factors. Atherosclerosis 108, S143-S156
CrossRef55
B.Fendley Stewart, B.Greg Brown, Xue-Qiao Zhao, Lynn A. Hillger, Alan D. Sniderman, Alice Dowdy, Lloyd D. Fisher, John J. Albers. (1994) Benefits of lipid-lowering therapy in men with elevated apolipoprotein B are not confined to those with very high low density lipoprotein cholesterol. Journal of the American College of Cardiology 23:4, 899-906
CrossRef56
Kam S. Woo, M.D, Harvey D. White, M.B. (1994) FACTORS AFFECTING OUTCOME AFTER RECOVERY FROM MYOCARDIAL INFARCTION. Annual Review of Medicine 45:1, 325-339
CrossRef57
A. Stewart Truswell. (1994) Review of dietary intervention studies: effect on coronary events and on total mortality. Australian and New Zealand Journal of Medicine 24:1, 98-106
CrossRef58
Millicent Higgins, Claude Lenfant. (1993) Dissent “Consider what a long way you've come” —The white queen to Alice. Journal of Clinical Epidemiology 46:12, 1347-1350
CrossRef59
A.D. Mbewu, P.N. Durrington, S. Bulleid, M.I. Mackness. (1993) The immediate effect of streptokinase on serum lipoprotein(a) concentration and the effect of myocardial infarction on serum lipoprotein(a), apolipoproteins A1 and B, lipids and C-reactive protein. Atherosclerosis 103:1, 65-71
CrossRef60
Matthew F. Muldoon, Jacques E. Rossouw, Stephen B. Manuck, Charles J. Glueck, Jay R. Kaplan, Peter G. Kaufmann. (1993) Low or lowered cholesterol and risk of death from suicide and trauma. Metabolism 42:9, 45-56
CrossRef61
Robert S. Rosenson. (1993) Myocardial injury: The acute phase response and lipoprotein metabolism. Journal of the American College of Cardiology 22:3, 933-940
CrossRef62
Russell, Louise B., . (1993) The Role of Prevention in Health Reform. New England Journal of Medicine 329:5, 352-354
Full Text63
Gilbert R. Thompson. (1993) Treatment of hyperlipidaemia. Clinical Endocrinology 38:4, 337-342
CrossRef64
(1993) Possibly Disappointing Results of Treatment with Gemfibrozil. New England Journal of Medicine 328:2, 139-140
Full Text65
M. H. Frick, O. P. Heinonen, J. K. Huttunen, P. Koskinen, M. Mänttäri, V. Manninen. (1993) Efficacy of Gemfibrozil in Dyslipidaemic Subjects with Suspected Heart Disease. An Ancillary Study in the Helsinki Heart Study Frame Population. Annals of Medicine 25:1, 41-45
CrossRef66
W. Virgil Brown. (1992) When do we treat hypercholesterolemia?. Clinical Cardiology 15:S3, 10-14
CrossRef67
Antonio M. Gotto. (1992) Therapeutic intervention for hypercholesterolemia. Clinical Cardiology 15:S3, 18-21
CrossRef68
Lau, Joseph, Antman, Elliott M., Jimenez-Silva, Jeanette, Kupelnick, Bruce, Mosteller, Frederick, Chalmers, Thomas C., . (1992) Cumulative Meta-Analysis of Therapeutic Trials for Myocardial Infarction. New England Journal of Medicine 327:4, 248-254
Full Text69
(1992) More on SI Units. New England Journal of Medicine 327:1, 50-52
Full Text70
M. F. OLIVER. (1992) Is cholesterol reduction always safe?. European Journal of Clinical Investigation 22:7, 441-442
CrossRef71
Manson, JoAnn E., Tosteson, Heather, Ridker, Paul M., Satterfield, Suzanne, Hebert, Patricia, O'Connor, Gerald T., Buring, Julie E., Hennekens, Charles H., . (1992) The Primary Prevention of Myocardial Infarction. New England Journal of Medicine 326:21, 1406-1416
Full Text72
M. J. Gibney. (1992) Are there conflicts in dietary advice for prevention of different diseases?. Proceedings of the Nutrition Society 51:01, 35-45
CrossRef73
John W. Frank, Dwayne M. Reed, John S. Grove, Richard Benfante. (1992) Will lowering population levels of serum cholesterol affect total mortality? Expectations from the honolulu heart program. Journal of Clinical Epidemiology 45:4, 333-346
CrossRef74
G.F Watts, B Lewis, E.S Lewis, D.J Coltart, L.D.R Smith, A.V Swan, J.N.H Brunt, J.I Mann. (1992) Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS). The Lancet 339:8793, 563-569
CrossRef75
(1991) Deaths from Injury, Violence, and Suicide in Secondary Prevention Trials of Cholesterol Lowering. New England Journal of Medicine 325:25, 1813-1813
Full Text76
B. LEWIS. (1991) On lowering lipids in the post-infarction patient. Journal of Internal Medicine 229:6, 483-488
CrossRef77
M.F. Oliver. (1991) Might treatment of hypercholesterolaemia increase non-cardiac mortality?. The Lancet 337:8756, 1529-1531
CrossRef78
(1991) Mortality Experience in Cholesterol-Reduction Trials. New England Journal of Medicine 324:13, 922-923
Full Text79
(1991) Effect of Partial Ileal Bypass Surgery on Coronary Heart Disease. New England Journal of Medicine 324:8, 562-564
Full Text80
David Strachan, Geoffrey Rose. (1991) Strategies of prevention revisited: Effects of imprecise measurement of risk factors on the evaluation of “high-risk” and “population-based” approaches to prevention of cardiovascular disease. Journal of Clinical Epidemiology 44:11, 1187-1196
CrossRef
- Letters
