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Lipid research clinics coronary primary prevention trial: Results and implications
Lipid Research Clinics Coronary Primary Prevention Trial: Results and Implications BASIL M. RIFKIND, MD, FRCP
The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) tested the efficacy of lowering cholesterol levels in reducing the risk of coronary heart disease (CHD) in 3,808 asymptomatic, middle-aged men with primary hypercholesterolemia. The group treated with cholestyramine” had 8.5% and 12.8% greater reductions in total and low-density lipoprotein levels, respectively, than those achieved In the placebo group. The cholestyramine group had a 19 % reduction in risk (p <0.05) of the primary endpoint of definite CHD, death or definite nonfatal myocardial infarction. Corresponding and significant reductions were also seen for angina, development of a positive exercise test, and coronary bypass surgery. All-cause mortality was only slightly, and not significantly, reduced in the cholestyramine group, reflecting more violent and accidental deaths in the cholestyramine subjects.
When the cholestyramine group was analyzed separately, a 19% reduction in CHD risk was also associated with each decrement of 8 % in the total cholesterol level. Moreover, CHD incidence in men in whom a decrease of 25% in total cholesterol was sustained, a typical response to the prescribed dosage (24 g/day) of cholestyramine resin, was half that of men who remained at the pretreatment level. The LRC-CPPT findings show that reducing the total cholesterol level by lowering the LDL cholesterol level can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of increased LDL cholesterol levels. These results have considerable importance for the prevention of CHD through cholesterol lowering, at both the clinical and public health levels.
It is well established that plasma cholesterol level is a major risk factor for coronary heart disease (CHD), that is, the higher the level of cholesterol, the greater the risk of a subsequent heart attack. Evidence relating cholesterol to atherosclerotic disease comes from many sources, including (1) pathologic studies of the atherosclerotic plaque; (2) studies in animal species, especially the nonhuman primate; (3) observations of various familial hypercholesterolemic states in which severe hypercholesterolemia is accompanied by the early onset of atherosclerotic CHD; (4) metabolic studies that are clarifying how lipid is deposited in the atherosclerotic plaque; and (5) different types of epidemiologic studies.r It also has been shown that the level of plasma cholesterol can be lowered by diets: Several large-scale clinical trials have demonstrated that dietary inter-
vention can produce a 10 to 15% decrease in plasma or serum cholesterol levels among large numbers of subjects over a considerable time. Moreover, addition of appropriate drugs may further decrease cholesterol level. If one could assume that cholesterol level reduction will prevent CHD, these findings would have farreaching impact. However, although there have been many clinical trials of decreasing cholesterol level to prevent CHD, several encouraging, none has yielded conclusive results. Many of the studies are limited by problems in design, implementation or both, including the absence of randomization or of a double-blind procedure, insufficient numbers of study participants, inadequate periods of follow-up or problems with compliance to the study regimen. The ideal trial of cholesterol lowering would involve diet adjustment, inasmuch as it is held that higher than optimum cholesterol levels in our population result from a diet rich in saturated fat and cholesterol. The 1971 Arteriosclerosis Task Force of the then National Heart and Lung Institute considered the possibility of conducting a clinical trial with dietary intervention but recommended against such a study. Important considerations in this decision were the virtual inability to
From the Lipid Metabolism-Atherogenesis Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Address for reprints: Basil M. Fiifkind, MD, Lipid Metabolism-Atherogenesis Branch, NHLBI, Federal Building 401, Bethesda, MD 20205. Questran@ Mead Johnson & Company, Evansville, Indiana. l
(Am J Cardiol
1984;54:3OC-34C)
August
TABLE
I
Baseline Characteristics (LRC CPPT)
HDL
CPPT
ml)
II
JOURNAL
Study Endpoints
OF CARDIOLOGY
291.5 218.8 44.0 38.6 120178 47.6
LRC CPPT Trial.
= Lipid
Research
Volume
54
31c
(LRC CPPT)
Primary endpoint Definite coronary heart disease infarction, or both Other endpoints All-cause mortality Angina Positive exercise electrocardiogram Coronary bypass surgery
Cholestyramine (II = 1906)
291.8 218.9 43.9 36.8 120178 47.9
THE AMERICAN
TABLE
of Study Subjects Placebo (n = 1900)
Total blood cholesterol (mg/lOO LDL cholesterol (mg/ 100 ml) HDL cholesterol (mg/lOO ml) Current cigarette smokers (%) Blood pressure (mmHg) Age (years)
27, 1984
death,
Clinics
nonfatal
Coronary
myocardial
Primary
Prevention
= highdensity lipoprotein; LDL = lowdensity lipoprotein; LRC = Lipid Research Clinics Coronary Primary Prevention Trial.
sorbed, but remains in the gastrointestinal tract; this accounts for its freedom from systemic toxicity. It was prescribed at a dosage of 24 g/day (6 packets), taken 2 to 4 times daily. Placebo packets were prescribed on the same schedule. The randomization process resulted in 2 similar treatment groups, especially with respect to total plasma and lipoprotein cholesterol levels, and the other major coronary risk factors such as cigarette smoking and blood pressure (Table Il. The average age of the group at onset was approximately 48 years. The trial was monitored by a Safety and Data Monitoring Board. Study participants were followed for a minimum of 7 years, and often for up to 10 years. Criteria for comparison: The primary endpoint of the study was a combination of definite CHD death or definite nonfatal myocardial infarction (MI) or both (Table II). Other important endpoints included all-cause mortality, the development of Rose Questionnaire angina, the development of a positive exercise electrocardiogram (ECG) or selection for coronary bypass surgery.
devise a double-blind study of diet, and the study cost, which could have exceeded 1 billion dollars. Lipid Research Clinics Trial An alternative approach, taken in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC CPPT), involved use of a cholesterol-lowering drug for which a suitable placebo was available. Because the study participants were at high risk for CHD due to hypercholesterolemia, the sample size requirements were reduced, thus making the study feasible. Methods The LRC CPPT was a multicenter, randomized, doubleblind clinical trial on the efficacy of cholesterol lowering in middle-aged men with primary hypercholesterolemia (Type II hyperlipoproteinemia). The study participants consisted of 3,896 men, aged 35 to 59 years, studied at 12 Lipid Research Clinics. The principal entry criteria into the study were a plasma cholesterol level >265 mg/106 ml and the absence of clinical CHD. Men with high blood pressure or other major illnesses were excluded. The clinics screened 436,679 men to obtain the 3,866 men who were ultimately randomized. During the prerandomization phase, a diet designed to lower plasma cholesterol by 3 to 5% was prescribed. Participants whose LDL cholesterol levels decrea,sed below 175 mg/dl while following the diet were excluded. The participants were randomized into 2 treatment groups. Both continued to receive the cholesterol-lowering diet. One group received the bile acid sequestrant and powerful cholesterol-lowering agent cholestyramine, whereas the other group received a suitable placebo. Cholestyramine is not ab-
Results When the trial dietary regimen was introduced, both groups experienced a 3.4% decrease in total plasma cholesterol levels. This decrease was more or less maintained thereafter in the placebo group. In the cholestyramine group, the introduction of the drug was associated with an additional decrease of 13.4% in total cholesterol level during the first year of follow-up (Fig. 1). The total cholesterol level increased slowly in the cholestyramine group in succeeding years due to decreasing compliance, so that, at the end of the trial, the average cholesterol decrease was 8.5% more than that obtained in the placebo group.
LDL Cholesterol
Total Cholesterol 0
Placebo
al f
FffiURE 1. Cholesterol lowering in study populations. From the Lipid Research Clinics Coronary Primary Prevention Trial. LDL = low.density lipoprotein.
5 $
+ Diet
-\
\
-10
\ \
\
_----
e-----
c-
Chzestyramine
-20
+ Diet
i
Base- 0
1 1
2
3
4
line
Year of Follow-Up
5
6
7
y-z-
Cholestyramine
0
1
2
3
+ Diet
4
Year of Follow-Up
5
6
(
7
32C
DECLINE
IN CORONARY
HEART
DISEASE
MORTALITY
SYMPOSIUM
Endpoints: The placebo group experienced 187 definite CHD deaths or definite nonfatal MIS or both, whereas the cholestyramine group had 155 such events. With appropriate statistical adjustment, this corresponds to a 19% lower incidence of CHD in the cholestyramine group than in the placebo group (p <0.05, Fig. 2). There was a 24% decrease in definite CHD death and a 19% decrease in definite nonfatal MIS. When so-called suspect CHD events were added to the definite events categories, results were similar: there was a 15% decrease in risk of the combined endpoints, with a 30% decrease in fatal and a 15% decrease in nonfatal MIS in the cholestyramine group. When the cumulative incidence of primary endpoints was examined as plotted in Figure 3, it was observed that, early in the follow-up period, the number of CHD events was slightly higher in the cholestyramine group. However, by the second year the rates were identical, and thereafter the rate in the placebo group diverged from the cholestyramine group. By year seven, the CHD rate was 8.6% in the placebo group and 7% in the cholestyramine group, again a decrease of 19%. The incidence of other CHD endpoints in which a large number of events occurred showed reductions Number 200
of
similar to the 19% decrease observed for the primary endpoint. The cholestyramine group showed reductions of 20% in the incidence of angina (p
Events
150 FIGURE 2. Primary-endpoint (definite coronary heart disease death or nonfatal myocardial infarction or both). C = cholestyramine; P = placebo. Data from the Lipid Research Clinics Coronary Primary Prevention Trial.
100
50
I
Cholestyramine
0
Life
Table
Cumulative
Incidence(%)
11 10 9 8 7 6 1
5 4 3 2 1 0 0
1
2
3
4 Years
5 of Follow-Up
6
7
a
FIGURE 3. Primary endpoint Research Clinics Coronary
life table. Data from Primary Prevention
the Lipid Trial.
August
TABLE
III
Mean
Dose-Response Relation Levels (LRC CPPT)
Daily
Packet
Count
o-1
=
in Total
Cholesterol
Cholestyramine
. liooorotein: . .
CPPT
= Lipid
established explanation could connect cholestyramine treatment, per se, with the accidental and violent deaths. It was thought likely that the differences reflected a chance occurrence. Other risk factors: To assess the possibility that changes other than those in cholesterol levels were responsible for the observed benefit, dietary intake, levels of the major CHD risk factors and other measurements were carefully monitored throughout the course of the study. These levels were similar in both groups over the duration of the trial; thus, they do not explain the observed benefit. Side effects and toxicity: Adverse gastrointestinal (GI) effects: There were no noteworthy differences between the groups in the number or types of adverse non-G1 effects. Initially, adverse GI effects occurred frequently in the cholestyramine group, with 68% of the men having at least 1 adverse GI effect in the first year; the corresponding rate in the placebo group was 43%. By the seventh year, side effects diminished in frequency and the rates were similar in both groups (29 versus 26%). The main adverse effects were constipation and heartburn, abdominal pain, belching or bloating, gas and nausea. They were usually treated effectively with standard clinical approaches. Adverse effects requiring hospitalization: Hospitalizations and procedures were also carefully monitored. The only differences found in the many categories were that an increased number of participants in the cholestyramine group had a primary diagnosis of deviated nasal septum, or had operations or procedures involving the nervous’ system. It was difficult to attribute these events to cholestyramine treatment and they too were regarded as a chance occurrence, given the large number of procedures monitored. Because the use of certain lipid level-lowering drugs has been associated with an increase in the incidence of gallstones, all diagnoses and procedures involving the gallbladder were monitored, but no significant differences were observed. Neoplusms: The inc:idence of fatal cases of malignant neoplasms was similar in both groups. The cholestyramine-treated group had more malignant neoplasms than the placebo group in some categories (the buccal cavity and pharynx), and fewer in others (the respiratory system, prostate and melanomas), but the numbers were small. When all of the GI cancers were considered, there were 21 incident (8 fatal) cases in the cholestyra-
OF CARDIOLOGY
TABLE
Clinics
IV
33c
54
in LDL Cholesterol Placebo
-6.6 -8.7 -13.1 -16.5 -20.9 -28.3 Research
Volume
in Plasma Cholesterol
Cholestyramine
-3.2 -1.7 -4.0 -3.5 -4.1 -5.4 LRC
JOURNAL
% Change
Placebo
-5.4 -8.2 -11.1 -14.0 -19.0 lowdensitv
THE AMERICAN
of Study Drugs and Change
-3.9
l-2 2-3 3-4 4-5 >5 LDL Trial.
% Change
27, 1984
Coronary
-4.8 -3.6 -6.9 -6.3 -6.0 -a.4 Primary
Prevention
Relation of Decrease in Cholesterol Level to Decrease in Coronary Heart Disease Risk (LRC CPPT)
Packet Count
Patients (NJ
o-2 2-5 5-6
439 496 965
CHD = coronary Coronary Primary
Total Cholesterol Lowering (%I 4.4 11.5 19.0
heart disease; LRC CPPT Prevention Trial.
Decrease in CHD Risk W) 10.9 26.1 39.3 = Lipid Research
Clinics
mine group, and II incident (1 fatal) cases in the placebo group. There were 6 incident colon cancers in each treatment group. No conclusions can be drawn in view of these small numbers. However, inasmuch as cholestyramine resin is confined to the GI tract and not absorbed, and because it has been found to be a promoter of colon cancer in animal experiments when a cancerinducing agent was also administered, further follow-up study of the participants is planned. Dose-response relationship: Having demonstrated the efficacy of cholestyramine treatment in preventing CHD, the LRC CPPT results were considered critically with respect to the quantitative impact of cholesterollowering on CHD incidence. Thus, the relation between cholesterol level decrease and medication intake was explored. In the cholestyramine group, a clear doseresponse relation was seen between the dose of the medication and the reduction in total plasma and low density lipoprotein (LDL) cholesterol levels (Table III). Such a relation was not observed in the placebo group. In the cholestyramine group, both the decrease in cholesterol levels and the decrease in CHD risk were related to the dose of the drug. All patients were prescribed 24 g/day, but often did not take it; actual intake was assessed for this part of the study. Thus, among participants who averaged 0 to 2 packets/day, cholesterol levels decreased by only 4.4% and the decrease in risk was about 11.0%. In contrast, participants who reported taking 5 to 6 packets/day had a 19% decrease in cholesterol levels and a decrease in coronary risk of nearly 40% (Table IV). The relation among the dose of the drug, cholesterol-lowering, and decrease in CHD risk was further
34c
DECLINE
TABLE V
IN CORONARY
HEART
DISEASE
MORTALITY
SYMPOSIUM
Relation of Decrease in LDL Cholesterol Level to Decrease in Coronary Heart Disease Risk (LRC CPPT) Cholesterol Total WI
CHD = coronary Coronary Primary
Reduction LDL
(%I
Reduction in CHD Risk (%)
TABLE VI
Summary
of Results (LRC CPPT)
19 % decrease in total and nonfatal heart attacks Decreases in other coronary heart disease endpoints (angina, positive exercise electrocardiogram, coronary bypass surgery) The greater the degree of cholesterol-lowering, the greater the decrease in coronary heart disease risk (risk cut in half by a 25 % decrease in blood cholesterol level) LRC CPPT Trial.
= Lipid Research
Clinics
Coronary
Primary
Prevention
heart disease; LRC CPPT = Lipid Research Clinics Prevention Trial; LDL = low-density lipoprotein.
Conclusions explored, using the Cox Proportional Hazards Model. This analysis showed that adherence to cholestyramine, but not to placebo (as measured by the mean packet count), was significantly related to the decreased risk of CHD. In the cholestyramine-treated study participants, the relation between reduction in total plasma or LDL cholesterol and the reduction in CHD risk was highly significant (p
A limited interpretation of the LRC CPPT study would apply its results only to the use of bile acid sequestrants in middle-aged men with cholesterol levels >265 mg/lOO ml. However, serious consideration should be given to extending the results to other groups. It seems justified to recommend treatment to younger persons with hypercholesterolemia, because the earlier intervention is commenced, the more likely it is to hinder the development of atherosclerosis and its consequences. CHD is also the major cause of death in women, although at a later age than in men. Cholesterol level is a major risk factor; cholesterol-lowering in hypercholesterolemic women should be applied to prevent CHD. Furthermore, cholesterol levels in the LRC CPPT men were in the upper 5% of the cholesterol distribution of the general population. Persons with more moderate degrees of hypercholesterolemia are also at increased risk for CHD. It is suggested, therefore, that some of these less severely hypercholesterolemic patients-at least those in the top quintile (20%) of the cholesterol distribution, that is, with cholesterol levels >240 mg/lOO ml-should take steps to reduce their cholesterol levels. Finally, although the LRC CPPT did not directly assess the impact of dietary-induced cholesterol-lowering in the prevention of CHD, its findings, taken in conjunction with the large amount of evidence relating diet to plasma cholesterol levels and CHD, would suggest that cholesterol level reduction through diet is desirable. Certainly in hypercholesterolemic patients, dietary treatment should be offered before drug therapy is considered. References WB, Ceetelll WP, Gordon T, et al. Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham Study. Ann Intern Med 1971;74:1-12. 2. Rlfklnd BY, Goor R, Schucker 8. Compliance and cholesterol-lowering in clinical trials: efficacy of diet. In Schettler, Gotto, Middlehoff, Habenicht and of the Sixth International Jwutka, eds. Atherosclerosis VI. Rocwdi Symposium. New York: Springer-Verlag 198?? :306-310. 1. Kannel
The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) tested the efficacy of lowering cholesterol levels in reducing the risk of coronary heart disease (CHD) in 3,808 asymptomatic, middle-aged men with primary hypercholesterolemia. The group treated with cholestyramine” had 8.5% and 12.8% greater reductions in total and low-density lipoprotein levels, respectively, than those achieved In the placebo group. The cholestyramine group had a 19 % reduction in risk (p <0.05) of the primary endpoint of definite CHD, death or definite nonfatal myocardial infarction. Corresponding and significant reductions were also seen for angina, development of a positive exercise test, and coronary bypass surgery. All-cause mortality was only slightly, and not significantly, reduced in the cholestyramine group, reflecting more violent and accidental deaths in the cholestyramine subjects.
When the cholestyramine group was analyzed separately, a 19% reduction in CHD risk was also associated with each decrement of 8 % in the total cholesterol level. Moreover, CHD incidence in men in whom a decrease of 25% in total cholesterol was sustained, a typical response to the prescribed dosage (24 g/day) of cholestyramine resin, was half that of men who remained at the pretreatment level. The LRC-CPPT findings show that reducing the total cholesterol level by lowering the LDL cholesterol level can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of increased LDL cholesterol levels. These results have considerable importance for the prevention of CHD through cholesterol lowering, at both the clinical and public health levels.
It is well established that plasma cholesterol level is a major risk factor for coronary heart disease (CHD), that is, the higher the level of cholesterol, the greater the risk of a subsequent heart attack. Evidence relating cholesterol to atherosclerotic disease comes from many sources, including (1) pathologic studies of the atherosclerotic plaque; (2) studies in animal species, especially the nonhuman primate; (3) observations of various familial hypercholesterolemic states in which severe hypercholesterolemia is accompanied by the early onset of atherosclerotic CHD; (4) metabolic studies that are clarifying how lipid is deposited in the atherosclerotic plaque; and (5) different types of epidemiologic studies.r It also has been shown that the level of plasma cholesterol can be lowered by diets: Several large-scale clinical trials have demonstrated that dietary inter-
vention can produce a 10 to 15% decrease in plasma or serum cholesterol levels among large numbers of subjects over a considerable time. Moreover, addition of appropriate drugs may further decrease cholesterol level. If one could assume that cholesterol level reduction will prevent CHD, these findings would have farreaching impact. However, although there have been many clinical trials of decreasing cholesterol level to prevent CHD, several encouraging, none has yielded conclusive results. Many of the studies are limited by problems in design, implementation or both, including the absence of randomization or of a double-blind procedure, insufficient numbers of study participants, inadequate periods of follow-up or problems with compliance to the study regimen. The ideal trial of cholesterol lowering would involve diet adjustment, inasmuch as it is held that higher than optimum cholesterol levels in our population result from a diet rich in saturated fat and cholesterol. The 1971 Arteriosclerosis Task Force of the then National Heart and Lung Institute considered the possibility of conducting a clinical trial with dietary intervention but recommended against such a study. Important considerations in this decision were the virtual inability to
From the Lipid Metabolism-Atherogenesis Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Address for reprints: Basil M. Fiifkind, MD, Lipid Metabolism-Atherogenesis Branch, NHLBI, Federal Building 401, Bethesda, MD 20205. Questran@ Mead Johnson & Company, Evansville, Indiana. l
(Am J Cardiol
1984;54:3OC-34C)
August
TABLE
I
Baseline Characteristics (LRC CPPT)
HDL
CPPT
ml)
II
JOURNAL
Study Endpoints
OF CARDIOLOGY
291.5 218.8 44.0 38.6 120178 47.6
LRC CPPT Trial.
= Lipid
Research
Volume
54
31c
(LRC CPPT)
Primary endpoint Definite coronary heart disease infarction, or both Other endpoints All-cause mortality Angina Positive exercise electrocardiogram Coronary bypass surgery
Cholestyramine (II = 1906)
291.8 218.9 43.9 36.8 120178 47.9
THE AMERICAN
TABLE
of Study Subjects Placebo (n = 1900)
Total blood cholesterol (mg/lOO LDL cholesterol (mg/ 100 ml) HDL cholesterol (mg/lOO ml) Current cigarette smokers (%) Blood pressure (mmHg) Age (years)
27, 1984
death,
Clinics
nonfatal
Coronary
myocardial
Primary
Prevention
= highdensity lipoprotein; LDL = lowdensity lipoprotein; LRC = Lipid Research Clinics Coronary Primary Prevention Trial.
sorbed, but remains in the gastrointestinal tract; this accounts for its freedom from systemic toxicity. It was prescribed at a dosage of 24 g/day (6 packets), taken 2 to 4 times daily. Placebo packets were prescribed on the same schedule. The randomization process resulted in 2 similar treatment groups, especially with respect to total plasma and lipoprotein cholesterol levels, and the other major coronary risk factors such as cigarette smoking and blood pressure (Table Il. The average age of the group at onset was approximately 48 years. The trial was monitored by a Safety and Data Monitoring Board. Study participants were followed for a minimum of 7 years, and often for up to 10 years. Criteria for comparison: The primary endpoint of the study was a combination of definite CHD death or definite nonfatal myocardial infarction (MI) or both (Table II). Other important endpoints included all-cause mortality, the development of Rose Questionnaire angina, the development of a positive exercise electrocardiogram (ECG) or selection for coronary bypass surgery.
devise a double-blind study of diet, and the study cost, which could have exceeded 1 billion dollars. Lipid Research Clinics Trial An alternative approach, taken in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC CPPT), involved use of a cholesterol-lowering drug for which a suitable placebo was available. Because the study participants were at high risk for CHD due to hypercholesterolemia, the sample size requirements were reduced, thus making the study feasible. Methods The LRC CPPT was a multicenter, randomized, doubleblind clinical trial on the efficacy of cholesterol lowering in middle-aged men with primary hypercholesterolemia (Type II hyperlipoproteinemia). The study participants consisted of 3,896 men, aged 35 to 59 years, studied at 12 Lipid Research Clinics. The principal entry criteria into the study were a plasma cholesterol level >265 mg/106 ml and the absence of clinical CHD. Men with high blood pressure or other major illnesses were excluded. The clinics screened 436,679 men to obtain the 3,866 men who were ultimately randomized. During the prerandomization phase, a diet designed to lower plasma cholesterol by 3 to 5% was prescribed. Participants whose LDL cholesterol levels decrea,sed below 175 mg/dl while following the diet were excluded. The participants were randomized into 2 treatment groups. Both continued to receive the cholesterol-lowering diet. One group received the bile acid sequestrant and powerful cholesterol-lowering agent cholestyramine, whereas the other group received a suitable placebo. Cholestyramine is not ab-
Results When the trial dietary regimen was introduced, both groups experienced a 3.4% decrease in total plasma cholesterol levels. This decrease was more or less maintained thereafter in the placebo group. In the cholestyramine group, the introduction of the drug was associated with an additional decrease of 13.4% in total cholesterol level during the first year of follow-up (Fig. 1). The total cholesterol level increased slowly in the cholestyramine group in succeeding years due to decreasing compliance, so that, at the end of the trial, the average cholesterol decrease was 8.5% more than that obtained in the placebo group.
LDL Cholesterol
Total Cholesterol 0
Placebo
al f
FffiURE 1. Cholesterol lowering in study populations. From the Lipid Research Clinics Coronary Primary Prevention Trial. LDL = low.density lipoprotein.
5 $
+ Diet
-\
\
-10
\ \
\
_----
e-----
c-
Chzestyramine
-20
+ Diet
i
Base- 0
1 1
2
3
4
line
Year of Follow-Up
5
6
7
y-z-
Cholestyramine
0
1
2
3
+ Diet
4
Year of Follow-Up
5
6
(
7
32C
DECLINE
IN CORONARY
HEART
DISEASE
MORTALITY
SYMPOSIUM
Endpoints: The placebo group experienced 187 definite CHD deaths or definite nonfatal MIS or both, whereas the cholestyramine group had 155 such events. With appropriate statistical adjustment, this corresponds to a 19% lower incidence of CHD in the cholestyramine group than in the placebo group (p <0.05, Fig. 2). There was a 24% decrease in definite CHD death and a 19% decrease in definite nonfatal MIS. When so-called suspect CHD events were added to the definite events categories, results were similar: there was a 15% decrease in risk of the combined endpoints, with a 30% decrease in fatal and a 15% decrease in nonfatal MIS in the cholestyramine group. When the cumulative incidence of primary endpoints was examined as plotted in Figure 3, it was observed that, early in the follow-up period, the number of CHD events was slightly higher in the cholestyramine group. However, by the second year the rates were identical, and thereafter the rate in the placebo group diverged from the cholestyramine group. By year seven, the CHD rate was 8.6% in the placebo group and 7% in the cholestyramine group, again a decrease of 19%. The incidence of other CHD endpoints in which a large number of events occurred showed reductions Number 200
of
similar to the 19% decrease observed for the primary endpoint. The cholestyramine group showed reductions of 20% in the incidence of angina (p
Events
150 FIGURE 2. Primary-endpoint (definite coronary heart disease death or nonfatal myocardial infarction or both). C = cholestyramine; P = placebo. Data from the Lipid Research Clinics Coronary Primary Prevention Trial.
100
50
I
Cholestyramine
0
Life
Table
Cumulative
Incidence(%)
11 10 9 8 7 6 1
5 4 3 2 1 0 0
1
2
3
4 Years
5 of Follow-Up
6
7
a
FIGURE 3. Primary endpoint Research Clinics Coronary
life table. Data from Primary Prevention
the Lipid Trial.
August
TABLE
III
Mean
Dose-Response Relation Levels (LRC CPPT)
Daily
Packet
Count
o-1
=
in Total
Cholesterol
Cholestyramine
. liooorotein: . .
CPPT
= Lipid
established explanation could connect cholestyramine treatment, per se, with the accidental and violent deaths. It was thought likely that the differences reflected a chance occurrence. Other risk factors: To assess the possibility that changes other than those in cholesterol levels were responsible for the observed benefit, dietary intake, levels of the major CHD risk factors and other measurements were carefully monitored throughout the course of the study. These levels were similar in both groups over the duration of the trial; thus, they do not explain the observed benefit. Side effects and toxicity: Adverse gastrointestinal (GI) effects: There were no noteworthy differences between the groups in the number or types of adverse non-G1 effects. Initially, adverse GI effects occurred frequently in the cholestyramine group, with 68% of the men having at least 1 adverse GI effect in the first year; the corresponding rate in the placebo group was 43%. By the seventh year, side effects diminished in frequency and the rates were similar in both groups (29 versus 26%). The main adverse effects were constipation and heartburn, abdominal pain, belching or bloating, gas and nausea. They were usually treated effectively with standard clinical approaches. Adverse effects requiring hospitalization: Hospitalizations and procedures were also carefully monitored. The only differences found in the many categories were that an increased number of participants in the cholestyramine group had a primary diagnosis of deviated nasal septum, or had operations or procedures involving the nervous’ system. It was difficult to attribute these events to cholestyramine treatment and they too were regarded as a chance occurrence, given the large number of procedures monitored. Because the use of certain lipid level-lowering drugs has been associated with an increase in the incidence of gallstones, all diagnoses and procedures involving the gallbladder were monitored, but no significant differences were observed. Neoplusms: The inc:idence of fatal cases of malignant neoplasms was similar in both groups. The cholestyramine-treated group had more malignant neoplasms than the placebo group in some categories (the buccal cavity and pharynx), and fewer in others (the respiratory system, prostate and melanomas), but the numbers were small. When all of the GI cancers were considered, there were 21 incident (8 fatal) cases in the cholestyra-
OF CARDIOLOGY
TABLE
Clinics
IV
33c
54
in LDL Cholesterol Placebo
-6.6 -8.7 -13.1 -16.5 -20.9 -28.3 Research
Volume
in Plasma Cholesterol
Cholestyramine
-3.2 -1.7 -4.0 -3.5 -4.1 -5.4 LRC
JOURNAL
% Change
Placebo
-5.4 -8.2 -11.1 -14.0 -19.0 lowdensitv
THE AMERICAN
of Study Drugs and Change
-3.9
l-2 2-3 3-4 4-5 >5 LDL Trial.
% Change
27, 1984
Coronary
-4.8 -3.6 -6.9 -6.3 -6.0 -a.4 Primary
Prevention
Relation of Decrease in Cholesterol Level to Decrease in Coronary Heart Disease Risk (LRC CPPT)
Packet Count
Patients (NJ
o-2 2-5 5-6
439 496 965
CHD = coronary Coronary Primary
Total Cholesterol Lowering (%I 4.4 11.5 19.0
heart disease; LRC CPPT Prevention Trial.
Decrease in CHD Risk W) 10.9 26.1 39.3 = Lipid Research
Clinics
mine group, and II incident (1 fatal) cases in the placebo group. There were 6 incident colon cancers in each treatment group. No conclusions can be drawn in view of these small numbers. However, inasmuch as cholestyramine resin is confined to the GI tract and not absorbed, and because it has been found to be a promoter of colon cancer in animal experiments when a cancerinducing agent was also administered, further follow-up study of the participants is planned. Dose-response relationship: Having demonstrated the efficacy of cholestyramine treatment in preventing CHD, the LRC CPPT results were considered critically with respect to the quantitative impact of cholesterollowering on CHD incidence. Thus, the relation between cholesterol level decrease and medication intake was explored. In the cholestyramine group, a clear doseresponse relation was seen between the dose of the medication and the reduction in total plasma and low density lipoprotein (LDL) cholesterol levels (Table III). Such a relation was not observed in the placebo group. In the cholestyramine group, both the decrease in cholesterol levels and the decrease in CHD risk were related to the dose of the drug. All patients were prescribed 24 g/day, but often did not take it; actual intake was assessed for this part of the study. Thus, among participants who averaged 0 to 2 packets/day, cholesterol levels decreased by only 4.4% and the decrease in risk was about 11.0%. In contrast, participants who reported taking 5 to 6 packets/day had a 19% decrease in cholesterol levels and a decrease in coronary risk of nearly 40% (Table IV). The relation among the dose of the drug, cholesterol-lowering, and decrease in CHD risk was further
34c
DECLINE
TABLE V
IN CORONARY
HEART
DISEASE
MORTALITY
SYMPOSIUM
Relation of Decrease in LDL Cholesterol Level to Decrease in Coronary Heart Disease Risk (LRC CPPT) Cholesterol Total WI
CHD = coronary Coronary Primary
Reduction LDL
(%I
Reduction in CHD Risk (%)
TABLE VI
Summary
of Results (LRC CPPT)
19 % decrease in total and nonfatal heart attacks Decreases in other coronary heart disease endpoints (angina, positive exercise electrocardiogram, coronary bypass surgery) The greater the degree of cholesterol-lowering, the greater the decrease in coronary heart disease risk (risk cut in half by a 25 % decrease in blood cholesterol level) LRC CPPT Trial.
= Lipid Research
Clinics
Coronary
Primary
Prevention
heart disease; LRC CPPT = Lipid Research Clinics Prevention Trial; LDL = low-density lipoprotein.
Conclusions explored, using the Cox Proportional Hazards Model. This analysis showed that adherence to cholestyramine, but not to placebo (as measured by the mean packet count), was significantly related to the decreased risk of CHD. In the cholestyramine-treated study participants, the relation between reduction in total plasma or LDL cholesterol and the reduction in CHD risk was highly significant (p
A limited interpretation of the LRC CPPT study would apply its results only to the use of bile acid sequestrants in middle-aged men with cholesterol levels >265 mg/lOO ml. However, serious consideration should be given to extending the results to other groups. It seems justified to recommend treatment to younger persons with hypercholesterolemia, because the earlier intervention is commenced, the more likely it is to hinder the development of atherosclerosis and its consequences. CHD is also the major cause of death in women, although at a later age than in men. Cholesterol level is a major risk factor; cholesterol-lowering in hypercholesterolemic women should be applied to prevent CHD. Furthermore, cholesterol levels in the LRC CPPT men were in the upper 5% of the cholesterol distribution of the general population. Persons with more moderate degrees of hypercholesterolemia are also at increased risk for CHD. It is suggested, therefore, that some of these less severely hypercholesterolemic patients-at least those in the top quintile (20%) of the cholesterol distribution, that is, with cholesterol levels >240 mg/lOO ml-should take steps to reduce their cholesterol levels. Finally, although the LRC CPPT did not directly assess the impact of dietary-induced cholesterol-lowering in the prevention of CHD, its findings, taken in conjunction with the large amount of evidence relating diet to plasma cholesterol levels and CHD, would suggest that cholesterol level reduction through diet is desirable. Certainly in hypercholesterolemic patients, dietary treatment should be offered before drug therapy is considered. References WB, Ceetelll WP, Gordon T, et al. Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham Study. Ann Intern Med 1971;74:1-12. 2. Rlfklnd BY, Goor R, Schucker 8. Compliance and cholesterol-lowering in clinical trials: efficacy of diet. In Schettler, Gotto, Middlehoff, Habenicht and of the Sixth International Jwutka, eds. Atherosclerosis VI. Rocwdi Symposium. New York: Springer-Verlag 198?? :306-310. 1. Kannel