Original Article
Effect of Partial Ileal Bypass Surgery on Mortality and Morbidity from Coronary Heart Disease in Patients with Hypercholesterolemia — Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH)
N Engl J Med 1990; 323:946-955October 4, 1990
- Abstract
- Abstract
Background and Methods
The Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized clinical trial, was designed to test whether cholesterol lowering induced by the partial ileal bypass operation would favorably affect overall mortality or mortality due to coronary heart disease. The study population consisted of 838 patients (417 in the control group and 421 in the surgery group), both men (90.7 percent) and women, with an average age of 51 years, who had survived a first myocardial infarction. The mean follow-up period was 9.7 years.
Results
When compared with the control group at five years, the surgery group had a total plasma cholesterol level 23.3 percent lower (4.71±0.91 vs. 6.14±0.89 mmol per liter [mean ±SD]; P<0.0001), a low-density lipoprotein cholesterol level 37.7 percent lower (2.68±0.78 vs. 4.30±0.89 mmol per liter; P<0.0001), and a high-density lipoprotein cholesterol level 4.3 percent higher (1.08±0.26 vs. 1.04±0.25 mmol per liter; P = 0.02). Overall mortality and mortality due to coronary heart disease were reduced, but not significantly so (deaths overall [control vs. surgery], 62 vs. 49, P = 0.164; deaths due to coronary disease, 44 vs. 32, P = 0.113). The overall mortality in the surgery subgroup with an ejection fraction ≥50 percent was 36 percent lower (control vs. surgery, 39 vs. 24; P = 0.021). The value for two end points combined — death due to coronary heart disease and confirmed nonfatal myocardial infarction — was 35 percent lower in the surgery group (125 vs. 82 events; P<0.001). During follow-up, 137 control-group and 52 surgery-group patients underwent coronary-artery bypass grafting (P<0.0001). A comparison of base-line coronary arteriograms with those obtained at 3, 5, 7, and 10 years consistently showed less disease progression in the surgery group (P<0.001). The most common side effect of partial ileal bypass was diarrhea; others included occasional kidney stones, gallstones, and intestinal obstruction.
Conclusions
Partial ileal bypass produces sustained improvement in the blood lipid patterns of patients who have had a myocardial infarction and reduces their subsequent morbidity due to coronary heart disease. The role of this procedure in the management of hypercholesterolemia remains to be determined. These results provide strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression. (N Engl J Med 1990; 323:946–55.)
Media in This Article
Figure 1
Total Plasma Cholesterol Levels in the Control and Surgery Groups.Figure 2
Confirmed Myocardial Infarction and Death Due to Atherosclerotic Coronary Heart Disease as a Combined End Point ("Event") in the Study Groups.Article Activity
- Article
THE Program on the Surgical Control of the Hyperlipidemias (POSCH) was a multi-clinic, randomized, prospective, secondary atherosclerosis-intervention trial designed to ascertain whether the reduction in plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol and the increase in the plasma level of high-density lipoprotein (HDL) cholesterol induced by the partial ileal bypass operation would favorably affect overall mortality and mortality and morbidity due to coronary heart disease. A specific objective of the program was to assess the validity of the use of changes observed on coronary arteriograms as surrogate end points for clinical atherosclerotic events. Between 1975 and 1983, 838 survivors of a single myocardial infarction documented by electrocardiograms and changes in enzyme values were entered into this study: 417 patients were randomly assigned to treatment with diet instruction only (control group), and 421 to diet instruction plus partial ileal bypass (surgery group). We report here the trial results as of July 1990 with follow-up between 7 and 14.8 years (mean, 9.7).
The trial was designed to assess whether lowering the total plasma cholesterol level would lead to a reduction in the progression of atherosclerosis. Over the past 25 years, the validity of this hypothesis has been supported by extensive epidemiologic data.1 2 3 4 5 6 However, it has been difficult to prove the hypothesis by means of rigorous, randomized, controlled clinical trials.7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Methods
Management of the Trial
Detailed descriptions of the design and methods of the POSCH trial,24 as well as the enrollment of patients,25 have been presented elsewhere. During the screening visit, eligibility was determined and most of the base-line values for the study variables were obtained. Before randomization, all patients received instruction in the American Heart Association Phase II diet, according to which less than 25 percent of total daily calories is consumed as fat (one third as saturated, one third as monounsaturated, and one third as polyunsaturated fat) and no more than 200 to 250 mg of cholesterol is consumed daily. All patients taking hypocholesterolemic drugs were asked to discontinue this treatment at least six weeks before base-line plasma lipid measurement, and all patients were encouraged not to resume or start taking hypocholesterolemic medications during their participation in the trial.
Immediately after the base-line coronary arteriogram was obtained and while the patient remained in the hospital, randomization was performed by the Coordinating Center. At each clinic, patients underwent randomization within 18 strata based on the total plasma cholesterol level, the lipoprotein phenotype, and the extent of coronary artery disease determined arteriographically.24 Control-group patients were discharged from the hospital. Surgery-group patients remained in the hospital and underwent partial ileal bypass. Three hundred seventy-eight patients were entered into the study at the University of Minnesota (Minneapolis), 135 at the University of Arkansas (Little Rock), 141 at the University of Southern California (Los Angeles), and 184 at the Lankenau Hospital and Research Center (Philadelphia). The first patient was enrolled in September 1975, and the last in July 1983. On the basis of calculations of the study's power made in 1982 — one year before the end of recruitment — termination of the formal trial was scheduled for July 1990.
All patients were followed by means of clinic visits and telephone calls, according to a uniform protocol.24 Lipid analyses were performed at base line, 3 months after randomization, and at every clinic visit (annual visits during the first 5 years and one visit at 7 or 10 years). Follow-up coronary and peripheral arteriograms were obtained at 3 and 5 years and at either 7 years (in patients enrolled on or after June 1, 1980) or 10 years (in patients enrolled before June 1, 1980).
Partial Ileal Bypass
The partial ileal bypass procedure has been previously described in detail.24 , 26 27 28 29 30 31 The operation involves the bypass of either the distal 200 cm or the distal third of the small intestine, whichever is greater, with restoration of bowel continuity by an end-to-side ileocecostomy. One surgeon at each clinic performed all the surgical procedures.
Criteria for Eligibility and Exclusion
Patients were eligible for study if they were between the ages of 30 and 64 years and had survived one myocardial infarction, documented by electrocardiographic and enzymatic changes, that had occurred between 6 and 60 months before the date of randomization. They were required to have a total plasma cholesterol level of at least 5.69 mmol per liter (220 mg per deciliter) or an LDL cholesterol level of at least 3.62 mmol per liter (140 mg per deciliter) if their total plasma cholesterol level was between 5.17 and 5.66 mmol per liter (200 and 219 mg per deciliter), after they had followed the Phase II diet for a minimum of six weeks.
Most of the potentially confounding major risk factors for atherosclerosis were criteria for exclusion: hypertension (systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥105 mm Hg), a body weight 40 percent above the ideal weight according to the Metropolitan Life Insurance Company weight tables,32 and the presence of diabetes as described by the University Group Diabetes Program.33 Patients with the risk factor of cigarette smoking and other potential risk factors for atherosclerosis were distributed during the randomization process. In addition, patients with certain impairments of the cardiovascular system or other major organ systems (e.g., cancer occurring within five years of randomization) that could potentially influence the study outcome were excluded. Patients who had undergone cardiac surgery or the implantation of a permanent cardiac pacemaker were ineligible, as were patients with a stenosis of the left main coronary artery that was more than 75 percent or with no measurable coronary-artery stenosis on the arteriogram obtained before randomization.
End Points
The primary end point of the trial was death due to any cause. A secondary end point was cause-specific death, a determination based on blinded review of all available records by the POSCH Mortality Review Committee. Other secondary end points were recurrent myocardial infarctions, whether confirmed or suspected; episodes of unstable angina; and the documentation of other atherosclerotic events (e.g., de novo angina, atherosclerotic cerebrovascular accident or intermittent cerebral ischemia, aortic-aneurysm formation, clinical occurrence or progression of peripheral vascular disease, and progressive cardiomegaly). A detailed description of the criteria for these manifestations of atherosclerosis is available from the authors on request. The diagnosis of a nonfatal myocardial infarction required a combination of electrocardiographic and cardiac-enzyme changes, as well as ischemic cardiac pain. Myocardial infarctions were assessed by a cardiologist blinded to the patient's assigned treatment. Coronary-artery bypass surgery, percutaneous transluminal coronary angioplasty, cardiac transplantation, and peripheral vascular surgery were considered secondary end points. Assessments of other health-related events were recorded, as were all adverse effects of partial ileal bypass, including the occurrence of bowel obstruction, diarrhea, gallstones, and kidney stones.
Certain data-derived subgroup analyses were performed, including analysis of overall mortality as a function of the left ventricular ejection fraction (<50 percent vs. ≥50 percent) according to the method of Sandler and Dodge.34
Sequential Arteriography
The assessments of the sequential coronary arteriography were made by two-member teams from the POSCH Arteriography Review Panel; no team member was from the clinic at which the arteriograms were obtained. The films were interpreted in pairs, with the readers blinded to the patient's assigned treatment and the sequence of the films. With use of an evaluation protocol identical to that employed in the Cholesterol Lowering Atherosclerosis Study,35 a global evaluation of the severity of the coronary artery disease was derived by consensus.24 An eight-point scale was used to grade the change between two films (-3, -2, -1, -0, +0, +1, +2, and +3; -3 = much worse, and +3 = much better).
Peripheral vascular disease was defined arteriographically as a reduction of 20 percent or more in the luminal diameter of any of seven arterial segments visualized (the distal 4 cm of the abdominal aorta, the right and left common and external iliac arteries, and the right and left common femoral arteries). The base-line and follow-up pelvic arteriograms were interpreted unpaired and independently in blinded fashion by a single reader. No radiopaque markers were used during partial ileal bypass, to prevent unblinding of treatment assignment when the pelvic arteriograms were evaluated.
Other Sequential Assessments
Electrocardiography
Resting and exercise electrocardiograms were obtained at each follow-up visit. Exercise electrocardiography was performed according to a modified Bruce protocol, with the addition of a three-minute stage zero at 1.7 mph and a grade of 0 percent.36 The electrocardiograms were evaluated in blinded manner by the POSCH Electrocardiography Laboratory.
Doppler Ultrasonography
After March 1981, the peripheral pulse pressures were determined by Doppler ultrasonography at each clinic visit, and the ankle—arm index was calculated — i.e., the ratio of the systolic blood pressure in the ankle (posterior tibial or dorsalis pedis) to that in the arm (brachial). An index ratio of 0.95 or more indicated the absence of peripheral vascular disease.
Lipid Measurement
Sequential lipid profiles consisted of measurement of the total plasma cholesterol, total plasma triglycerides, LDL cholesterol, very-low-density lipoprotein (VLDL) cholesterol, HDL cholesterol, and lipoprotein phenotyping.37 38 39 In 1985 and afterward, the levels of the HDL2 and HDL3 subfractions and apolipoprotein A-I and B-100 were determined as well.40 , 41 All lipid samples were obtained after a fast of at least 14 hours. The lipid analyses were performed in the POSCH Lipid Laboratory, whose procedures had been standardized and certified by the Lipid Standardization Laboratory of the Centers for Disease Control (Atlanta).
Statistical Analysis
All analyses are based on randomization assignment (intention-to-treat), whether or not the treatment was actually carried out. Confidence intervals and risk reductions were based on the proportion of events per group, without adjustment for the length of follow-up. In the life-table analyses, the date of randomization was used as the starting point. The MantelHaenszel statistic42 and the Gehan statistic43 were used in comparisons of survival and events, to account for differences in the length of follow-up. To adjust for base-line covariates, other analyses of survival employed Cox regression.44 In interim data analyses, a 3 SE rule was employed to allow for early termination of the trial. This convention adequately protected the P value, so that the nominal P value could be used in the assessment of the final results.45 To evaluate data from sequential coronary arteriography, the patients were divided into three groups: those worse (-3, -2, or -1), those unchanged (-0 or +0), and those better (+1, +2, or +3). Analyses were then performed with a three-by-two chi-square test and a chi-square test for linear trend.46 A two-sided Fisher's exact test was employed to assess the sequential peripheral arteriograms.47 Other data analyses were performed with standard chi-square tests, paired and unpaired Student's t-tests, and Spearman correlation coefficients (for measures of agreement). A two-sided P value less than 0.05 was considered to indicate statistical significance.
Results
Population Characteristics and Compliance
The average age of the patients at randomization was 51 years. Of the 838 patients, 90.7 percent were men and 97.9 percent were white. The base-line mean total plasma cholesterol level was 6.49 mmol per liter (251 mg per deciliter), with an average LDL cholesterol level of 4.62 mmol per liter (179 mg per deciliter) and an average HDL cholesterol level of 1.04 mmol per liter (40 mg per deciliter). The mean interval between the qualifying myocardial infarction and entry into the trial was 2.2 years. Of the total study population, 83.8 percent had smoked cigarettes and 35.0 percent were cigarette smokers at base line. The characteristics of the population at base line are presented in detail elsewhere.48
Of the 421 patients assigned to surgery, 22 refused to undergo the operation but were nonetheless included in the surgery group for purposes of statistical assessment. Twenty-three patients underwent reversal of the bypass surgery between 2 and 11 years postoperatively, because of diarrhea (n = 17), intractable nephrolithiasis (n = 3), carcinoma of the cecum (n = 1), lymphoma of the small bowel (n = 1), and excessive weight loss (n = 1). No control-group patient underwent a partial ileal bypass. At 1, 5, 7, and 10 years of follow-up, 5.3, 16.4, 25.1, and 31.5 percent of the control-group patients were taking at least one cholesterol-lowering medication. In the surgery group, the corresponding figures were 0.5, 3.0, 6.2, and 3.7 percent. No patient was lost to follow-up, and the vital status of all 838 patients was known as of July 20, 1990. A total of 7694 follow-up visits were completed by the patients; 187 follow-up visits (4.8 percent) were missed by patients in the control group and 79 visits (2.0 percent) by those in the surgery group.
During the follow-up clinic visits, complete lipid analyses were obtained in 99.2 percent of the control-group patients and in 99.3 percent of the surgery-group patients. The completion rates for laboratory chemical evaluations, hemograms, and urinalyses were 97.1 percent in the control group and 96.9 percent in the surgery group. Exercise electrocardiography was performed in 90.1 percent of the control group and in 91.0 percent of the surgery group during the follow-up clinic visits. Follow-up coronary arteriograms were obtained in 80.7 percent of the control-group patients and 84.7 percent of the surgery-group patients, either at the appropriate clinic visits or within one year before or after these visits. Any incompleteness of data was due to loss of films or nonperformance of procedures.
Lipid Profiles
Some of the changes in the lipid and lipoprotein levels of the patients have been previously described,49 50 51 as well as an analysis of the predictors of the changes in total plasma cholesterol and LDL cholesterol levels after partial ileal bypass.52 The levels observed at base line and at 1,5,7, and 10 years are shown in Table 1Table 1
Plasma Lipid Values in the Control and Surgery Groups at Base Line and during Follow-up.. Up to five years after randomization, nearly all surviving patients underwent annual measurement of lipids and lipoproteins. At five years, the surgery group, as compared with the control group, had a 23.3±1.0 (mean ±SE) percent lower total plasma cholesterol level (P<0.0001) (Fig. 1Figure 1Total Plasma Cholesterol Levels in the Control and Surgery Groups.), a 37.7±1.2 percent lower LDL cholesterol level (P<0.0001), a 4.3±1.8 percent higher HDL cholesterol level (P = 0.02), an 18.3±7.5 percent higher VLDL cholesterol level (P = 0.02), a 19.8±6.5 percent higher triglyceride level (P = 0.003), a 37.8±2.8 percent higher ratio of HDL cholesterol to total plasma cholesterol (P<0.0001), and a 71.8±4.3 percent higher ratio of HDL cholesterol to LDL cholesterol (P<0.0001). The measurement of apolipoprotein and HDL subfractions was added to the protocol for lipid determinations in June 1985. At five years, the surgery group had a significantly higher level of the HDL2 subfraction (P<0.0001) and apolipoprotein A-I (P<0.0001), and a significantly lower level of apolipoprotein B-100 (P<0.0001), than the control group.Overall and Cause-Specific Mortality
There were 62 deaths in the control group, as compared with 49 in the surgery group (149 per 1000 vs. 116 per 1000). The 21.7 percent risk reduction in overall mortality in the surgery group was not statistically significant (95 percent confidence interval, -17.0 to 47.6; P = 0.164). Adjustments for the base-line covariates did not significantly alter the results for overall mortality or for any of the other end points. The distribution of deaths according to cause is shown in Table 2Table 2
Distribution of Deaths in the Study Groups, According to Cause.. The mortality due to atherosclerotic coronary heart disease was reduced 28.0 percent (95 percent confidence interval, -16.1 to 55.3; P = 0.113). The number of deaths due to this cause-specific end point was 44 (106 per 1000) in the control group and 32 (76 per 1000) in the surgery group.In a data-derived, subgroup analysis, the study population was divided into two groups according to left ventricular ejection fraction: patients with an ejection fraction of ≥50 percent and patients with a lower ejection fraction. In the subgroup with an ejection fraction ≥50 percent, 39 of 292 control-group patients died and 24 of 281 surgery-group patients died. The reduction in overall mortality in this subgroup was 36.1 percent (95 percent confidence interval, -9.4 to 62.9; 134 per 1000 in the control group and 85 per 1000 in the surgery group; P = 0.052 by MantelHaenszel test, and P = 0.021 by Gehan test). There was no significant difference in overall mortality in the subgroup with an ejection fraction of less than 50 percent.
End Points Combined with Mortality
Analysis of the combined end point of death due to coronary heart disease and confirmed nonfatal myocardial infarction showed that 125 of such events occurred in the control group (29 deaths from coronary heart disease) and 82 occurred in the surgery group (23 deaths from coronary heart disease) (Fig. 2Figure 2
Confirmed Myocardial Infarction and Death Due to Atherosclerotic Coronary Heart Disease as a Combined End Point ("Event") in the Study Groups.). The surgery group had a 35.0 percent risk reduction (95 percent confidence interval, 9.1 to 52.8) for this end point (300 per 1000 in the control group and 195 per 1000 in the surgery group; P<0.001).When suspected nonfatal myocardial infarctions were combined with deaths due to coronary heart disease and confirmed nonfatal myocardial infarctions, 138 events were observed in the control group and 91 events in the surgery group (P<0.001). When deaths due to atherosclerotic coronary heart disease, all myocardial infarctions, and episodes of unstable angina were combined, 222 events were observed in the control group and 160 events in the surgery group (P<0.0001). At least one episode of unstable angina was reported by 143 control-group patients and 99 surgery-group patients (P<0.001).
When overall mortality was combined with nonfatal clinical events, 141 deaths or confirmed myocardial infarctions were observed in the control group and 97 in the surgery group (P<0.001); 153 deaths or confirmed or suspected myocardial infarctions were observed in the control group and 104 in the surgery group (P<0.001); and 234 deaths, myocardial infarctions, or episodes of unstable angina were observed in the control group and 173 in the surgery group (P<0.0001).
Peripheral Vascular Disease or Intermittent Claudication
In the control group, 71 occurrences of peripheral vascular disease or intermittent claudication were reported, as compared with 52 events in the surgery group (170 per 1000 in the control group and 124 per 1000 in the surgery group; P = 0.038). On measurement of peripheral pulses by Doppler ultrasonography, the development of peripheral vascular disease was demonstrated in more patients in the control group than in the surgery group, at each successive follow-up visit: at five years, this disorder had been detected in 33.6 percent of the 119 control-group patients and 19.0 percent of the 126 surgery-group patients (P<0.01).
Cerebrovascular Events
A cerebrovascular accident was confirmed in 15 control-group and 14 surgery-group patients and suspected in 3 control-group and 4 surgery-group patients. Intermittent cerebral ischemia was recorded in 7 control-group patients and 10 surgery-group patients. A suspected transient ischemic attack was observed in 20 control-group and 25 surgery-group patients. When all cerebrovascular events were analyzed together, there was at least one event in 44 control-group and 49 surgery-group patients (P = 0.69).
Coronary-Artery Bypass Grafting, Angioplasty, and Heart Transplantation
Coronary-artery bypass grafting was performed in 137 control-group patients and 52 surgery-group patients (329 per 1000 in the control group and 124 per 1000 in the surgery group; P<0.0001). Repeat operations were required in nine control-group patients and two surgery-group patients. In addition, 33 control-group patients and 15 surgery-group patients underwent percutaneous transluminal coronary angioplasty with or without coronary-artery bypass grafting (79 per 1000 in the control group and 36 per 1000 in the surgery group; P = 0.005). Three control-group patients and two surgery-group patients underwent cardiac transplantation. The total number of cardiac procedures performed in the control group was 2.6 times greater than the total number in the surgery group.
Sequential Arteriograms and Electrocardiograms
The changes observed on coronary arteriography from base line to follow-up at 3, 5, 7, and 10 years are summarized in Table 3Table 3
Changes on Coronary Arteriography in the Study Groups during Follow-up.. The percentage of patients with disease progression increased in both study groups as follow-up progressed, but was consistently higher in the control group. At each follow-up interval, the difference between the control and surgery groups in the percentage of patients with definite disease progression (a score of -1, -2, or -3) was significant (P<0.001; control vs. surgery, 41.4 percent vs. 28.1 percent at 3 years, 65.4 percent vs. 37.5 percent at 5 years, 77.0 percent vs. 48.1 percent at 7 years, and 85.0 percent vs. 54.7 percent at 10 years). The precision of the interpretation of the films was assessed by 109 blinded repeat readings (Spearman r = 0.84).When peripheral arteriography was performed, it was undertaken in conjunction with coronary arteriography. At 5, 7, and 10 years, the proportion of patients free of peripheral vascular disease on arteriographic assessment was higher in the surgery group; this difference approached statistical significance at 10 years (P = 0.09). The difference between the study groups in the proportion of patients with positive exercise electrocardiograms was not statistically significant at any follow-up visit.
Side Effects of Partial Ileal Bypass
There were no immediate, in-hospital deaths after partial ileal bypass. The 30-day mortality after surgery was limited to two deaths, at day 23 and day 29. One death was due to an event related to atherosclerotic coronary heart disease and was so attributed; the other was secondary to complications of a bowel obstruction. The second death attributed to partial ileal bypass occurred shortly after reversal of the procedure and was due to sepsis.
The principal side effect of partial ileal bypass was diarrhea. At each of the follow-up visits, the surgery-group patients reported having an average of more than 3.0 bowel movements per day, whereas the control-group patients had fewer than 1.5 movements per day (P<0.0001). In addition to more frequent bowel movements, the surgery-group patients had looser stools. During the first five years of follow-up, 6 to 8 percent of the surgery group had watery or frothy stools, as compared with 0 to 1 percent of the control group (P<0.0001).
During the course of the trial, a higher incidence of kidney stones and gallstones was observed among the patients who had undergone partial ileal bypass. The incidence rate of kidney stones was approximately 4 percent per year in the surgery group, as compared with approximately 0.7 percent in the control group (P<0.0001). Of the 286 control-group patients and 320 surgery-group patients whose gallbladder was found to be free of gallstones at base line or immediately after partial ileal bypass surgery, 4 control-group patients and 14 surgery-group patients underwent cholecystectomy during the first five years of follow-up and an additional 10 control-group patients and 40 surgery-group patients had gallstones that were detected by oral cholecystography or ultrasonography. The difference between the groups in the five-year rate of gallstone formation was significant (P<0.0001).
The incidence of symptoms of bowel obstruction (at least one episode) was increased in the surgery group: 57 patients (13.5 percent) had symptoms, 15 (3.6 percent) of whom required operative intervention. The majority of patients who had symptoms of bowel obstruction (n = 39) had them within the first year after operation. The surgery group had a mean weight loss of 5.3 kg (P<0.0001).
Cancer Incidence
Twenty-eight neoplasms were detected after randomization in the control group and 32 in the surgery group. Two cancers of the small bowel were identified in the surgery group; both were carcinoids detected incidentally at the time of partial ileal bypass. There were four colon or rectal cancers in the control group, and three in the surgery group.
Discussion
The basis for the theory of a link between lipid levels and atherosclerosis is found in certain clinical observations of the 19th century,53 , 54 classic experiments in rabbits during the early 20th century,55 56 57 and epidemiologic studies performed since World War II.1 2 3 4 5 6 , 58 Randomized; controlled clinical trials have failed to offer conclusive proof that a reduction of total plasma cholesterol levels is associated with a significant reduction in the clinical incidence and the mortality of atherosclerosis. The specific effects of 13 of these trials have been reviewed.59
The recent cholesterol-lowering trials have suggested that patients benefit from favorable alterations in their plasma lipid profile. The findings of the National Heart, Lung, and Blood Institute Type II Coronary Intervention Study implied that a reduction in the total plasma cholesterol level by cholestyramine slowed the progression of atherosclerotic coronary heart disease as assessed by serial coronary arteriograms.20 This finding, however, lacked statistical significance, and no differences were observed between the intervention group and the control group in the rate of atherosclerotic events. A more definite conclusion was reached in the Cholesterol-Lowering Atherosclerosis Study.22 There was significantly less progression of coronary atherosclerosis in the native circulation and the coronary-artery bypass grafts on the arteriograms of patients treated with colestipol and nicotinic acid (P<0.001). That trial22 was not designed to measure overall or cardiovascular mortality or to evaluate the validity of the use of sequential changes on coronary arteriograms as surrogate end points of clinical atherosclerotic events. In the Helsinki Heart Study,23 the rate for the combined end point of three clinical events — fatal myocardial infarction, confirmed nonfatal myocardial infarction, and sudden cardiac death — was significantly lower in patients treated with gemfibrozil (P = 0.02). However, no statistically significant difference in overall mortality was noted. The cholesterol-lowering trial that has been most widely cited is the Lipid Research Clinics—Coronary Primary Prevention Trial (LRC-CPPT), in which patients were treated with cholestyramine or placebo.21 The difference between the study groups in overall mortality was negligible; there was evidence of benefit with respect to the combined end points of death due to atherosclerotic coronary heart disease and confirmed nonfatal myocardial infarction, but only by a one-sided test of significance.
With the failure of individual trials to validate conclusively the benefit of cholesterol lowering, the pooling of results from independent trials, conducted in vastly different populations, has been suggested.45 , 60 Meta-analysis, when applied to trials of diet and drug therapy for the reduction of plasma cholesterol, has demonstrated a decrease in deaths due to atherosclerotic coronary heart disease and an increase in deaths due to noncardiovascular diseases, with no net effect on overall mortality.61
The recent reports of observations made after the period of a clinical trial must be viewed with circumspection. The 15-year follow-up results in the placebo and nicotinic acid groups of the Coronary Drug Project were assessed 10 years after the end of the formal trial, and the maintenance of nicotinic acid therapy during the interval is unknown.62 The post-trial report of the Multiple Risk Factor Intervention Trial63 needs to be examined with similar caution.
Our findings offer good evidence that lowering lipid levels is beneficial, even though overall mortality as a single end point was not significantly reduced. The data-derived, subgroup analysis based on values for the left ventricular ejection fraction provides some evidence of an overall survival benefit from interventions to change lipid levels in patients with hypercholesterolemia whose ejection fraction is normal after a myocardial infarction. For the combined end point of death due to atherosclerotic coronary heart disease or confirmed myocardial infarction — the primary end point chosen in the LRC-CPPT21 — the surgery group in our study had a 35.0 percent lower incidence (125 events in the control group vs. 82 events in the surgery group; P<0.001). The consistency and strength of the finding of significance (all P values <0.01) in all the evaluations of combined end points serve as additional evidence that lipid modification is associated with significant reductions in the risk of clinical atherosclerosis. Unlike many of the previous trials, ours found no noticeable increase in nonatherosclerotic deaths in the intervention (surgery) group.
The beneficial effect of lipid modification in limiting the progression of coronary atherosclerosis is also evident in the differential rates of cardiac procedures in the control and surgery groups. The surgery group had 62.4 percent fewer operations for coronary-artery bypass grafting (P<0.0001), 78.0 percent fewer repeat operations for coronary bypass, and 55.0 percent fewer operations for percutaneous transluminal coronary angioplasty (P = 0.005). The increased rate of operations for coronary-artery bypass grafting and percutaneous transluminal angioplasty among the patients in the control group may have improved their survival64 65 66 and may have blunted the observed trend toward a reduction in overall mortality in the surgery group.
The findings on sequential coronary arteriography in our trial extend the findings on arteriographic evaluations reported in the Type II Coronary Intervention Study20 (116 film pairs) and the Cholesterol Lowering Atherosclerosis Study (162 film pairs).22 Virtually all patients in our study (1866 film pairs) underwent arteriography at base line, and an average of 82.7 percent of all surviving patients had sequential arteriograms at 3, 5, and either 7 or 10 years. Each follow-up evaluation revealed greater progression of coronary artery disease in the control group (P<0.001). If the frequency of scores of +1, +2, and +3, which indicate improvement in the global assessment of atherosclerotic coronary heart disease, is compared between groups, the rate of regression in the surgery group exceeded that observed in the control group. This apparent regression, however, may represent random variation in the arteriographic evaluation. In assessing the trends of the clinical coronary events and the findings on coronary arteriography, our trial would seem to validate the use of change on coronary arteriography as a surrogate end point for clinical atherosclerotic events. No intervention trial before the POSCH trial has documented a significant reduction in clinical end points in conjunction with a reduction in atherosclerosis progression on sequential coronary arteriography. This finding may help to justify the design of shorter studies of lipid modification for atherosclerosis, involving relatively small patient cohorts followed exclusively by means of arteriographic assessment.
Partial ileal bypass was chosen as the intervention in this study because of its powerful capability in lowering lipid levels and its acceptable morbidity, but the precise role of this intervention in the treatment of hypercholesterolemia remains uncertain. The mechanism of action of partial ileal bypass has been well described.67 68 69 70 71 This procedure was introduced clinically for the management of hypercholesterolemia at the University of Minnesota in 1963.72 Radioisotope studies in volunteers who had undergone the operation confirmed the mechanism by which it led to a reduction in the total plasma cholesterol level.27 , 73 In these studies, the absorption of cholesterol by the intestine was reduced by 60 percent. There was a 5.8-fold increase in total fecal steroid excretion. A compensatory 5.7-fold increase in the cholesterol synthesis rate occurred; after one year a 33 percent reduction was noted in the total-exchangeable-cholesterol pool, reflecting decreases not only in the pool of freely miscible cholesterol (from plasma, red cells, liver, and intestinal mucosa) but also in the pool of less freely miscible cholesterol (from fat stores, muscle, solid organs, and vessel walls).
Our analysis of the results of partial ileal bypass, extending to nearly 15 years, is the most rigorous evaluation of any means of lipid modification available. It establishes the efficacy of partial ileal bypass in favorably altering plasma lipid levels, as well as the lasting nature of its effects. In addition to these findings, the durability of the effects on lipid levels has been confirmed in a recent follow-up evaluation of the first 57 patients who underwent partial ileal bypass at the University of Minnesota (1963 through 1969).74 These patients, who served as their own controls, had reductions of 34, 28, 35, 35, and 30 percent in total plasma cholesterol levels 1, 2 to 5, 6 to 10, 11 to 15, and more than 20 years after operation.
Partial ileal bypass therapy is obligatory, as long as the operation is not reversed. In the POSCH study, 94 percent of patients undergoing the operation had operative integrity over an average of 9.7 years. By contrast, the long-term compliance of participants in the LRC-CPPT21 was limited; only 73 percent of the patients were taking their prescribed medication after 7 years.
The side effects and complications of partial ileal bypass have been well documented in our study, and include diarrhea, kidney stones, and gallstones. In addition, as expected with an intervention requiring a celiotomy, bowel obstructions requiring operative intervention developed in 15 of the 399 patients undergoing the operation. There were no immediate in-hospital postoperative deaths.
What is the applicability of our results beyond the population represented in this study? Since the eligibility criteria excluded patients with confounding risk factors for atherosclerosis — hypertension, diabetes, and obesity — are the findings relevant to patients with these risk factors? The evidence is undeniable that hypertension,3 diabetes,75 and obesity76 are independent risk factors for atherosclerosis and, furthermore, that lipid modification in patients with multiple risk factors is warranted. Our results do not address recommendations for lipid modification in persons at the extremes of age — i.e., those who are over 65 years old or children. The mortality among the 78 women in the trial was similar to that in the men. Although our study included women, most large studies of lipid modification have excluded them by protocol.21 22 23
In conclusion, partial ileal bypass induced sustained and obligatory decreases in the plasma levels of total cholesterol and LDL cholesterol and led to an increase in the HDL cholesterol level. The operation was safe, and its long-term side effects and complications could be tolerated by most of the patients. The changes in lipid levels resulting from this procedure were associated with a significant decrease in the number of operations for coronary-artery bypass grafting and percutaneous transluminal coronary angioplasty and in the incidence of all combined clinical end points. The combined end point of death due to atherosclerotic coronary heart disease or confirmed myocardial infarction was significantly reduced. The reduction in overall mortality was not statistically significant. However, a trend toward a decrease in overall mortality in the subgroup with an ejection fraction ≥50 percent was observed, suggesting that aggressive lipid modification may be of benefit to patients with hypercholesterolemia in whom left ventricular function is preserved after a myocardial infarction. The results of coronary arteriography provided evidence of less progression of atherosclerosis in the surgery group than in the control group. The changes observed on coronary arteriography paralleled the clinical atherosclerotic events, thus supporting the use of arteriographic change as a surrogate end point in trials of intervention for lipid modification and atherosclerosis. The ultimate role of this procedure in the management of hypercholesterolemia still remains to be determined, but the POSCH results provide new, strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression.
Supported by a grant (RO1-HL-15265) from the National Heart, Lung, and Blood Institute and by a Minnesota State Special Legislative Appropriation.
To be presented at the annual meeting of the American College of Surgeons, October 8, 1990, in San Francisco.
*The following were members of the POSCH (Program on the Surgical Control of the Hyperlipidemias) Group. Principal Investigators: H. Buchwald, M.D., Ph.D.; and R.L. Varco, M.D., Ph.D. University of Minnesota Clinic: H. Buchwald, M.D., Ph.D.; A.S. Leon, M.D.; J Rindal, R.N., M.A.; and R.A. Hagen, R.N., M.S.; University of Arkansas Clinic: G.S. Campbell, M.D., Ph.D.; M.B. Pearce, M.D.; J.K. Bissett, M.D.; and M.R. Stuenkel, B.S.N.; University of Southern California Clinic: A.E. Yellin, M.D.; W.A. Edmiston, M.D.; D.C. Fujii; and J.A. Hatch, B.S.N., R.N.; Lankenau Hospital and Research Center Clinic: R.D. Smink, Jr., M.D.; H.S. Sawin, Jr., M.D.; F.J. Weber, M.D., Ph.D.; H.B. Brooks, B.S.; R.F. Cairns, M.S.N.; and M.E. Trobovic, R.N. Electrocardiography Laboratory: N. Tuna, M.D., Ph.D.; J.N. Karnegis, M.D., Ph.D.; J.E. Stevenson, M.D.; R.A. Brykovsky; and M.A. Linssen; Lipid Laboratory: J.C. Speech, M.S.; Arteriography/Radiology Laboratory: K. Amplatz, M.D.; M.E. Sanmarco, M.D.; W.R. Castaneda-Zuniga, M.D.; and D.W. Hunter, M.D. Coordinating Center: J.M. Long, Ed.D.; J.P. Matts, Ph.D.; L.L. Fitch, M.P.H.; J.W. Johnson, M.S.; R.K. LaBounty, M.S.; C.T. Campos, M.D.; and L.L. Christie, M.S.; Administration: B.A. Ley, B.S.; and B.J. Hansen, R.N.; Data Monitoring Committee: T.C. Chalmers, M.D. (chairman); J.E. Bearman, Ph.D.; G.R. Cooper, M.D., Ph.D.; S.W. Greenhouse, Ph.D.; J.W. Kennedy, M.D.; P. Meier, Ph.D.; C.L. Meinert, Ph.D.; J. Stamler, M.D.; D.E. Strandness, M.D.; and former member C.R. Conti, M.D. Mortality Review Committee: J.E. Edwards, M.D. (chairman); L.S.C Griffith, M.D.; A.J. Moss, M.D.; D.M. Spain, M.D.; and J.L. Titus, M.D., Ph.D.; Electrocardiography Review Panel: N. Tuna, M.D., Ph.D. (chairman); J.K. Bissett, M.D.; W.A. Edmiston, M.D.; J.N. Karnegis, M.D., Ph.D.; A.S. Leon, M.D.; M.B. Pearce, M.D.; H.S. Sawin, Jr., M.D.; and J.E. Stevenson, M.D.; Arteriography Review Panel: M.E. Sanmarco, M.D. (chairman); K. Amplatz, M.D.; J.K. Bissett, M.D.; W.R. Castaneda-Zuniga, M.D.; W.A. Edmiston, M.D.; D.W. Hunter, M.D.; M.B. Pearce, M.D.; H.S. Sawin, Jr., M.D.; and F.J. Weber, M.D., Ph.D. Consultants: D.H. Blankenhorn, M.D.; L. Cashin-Hemphill, M.D.; J. Cornfield, B.A. (deceased); W.L. Holmes, Ph.D. (deceased); R.B. Moore, M.D.; and M.D. Morris, Ph.D.; Policy and Data Monitoring Board: A.M. Gotto, Jr., M.D., D.Phil. (chairman); C.M. Hawkins, Sc.D.; J.J. Leonard, M.D.; F.D. Loop, M.D.; E. Rapaport, M.D.; D.L. Sylwester, Ph.D.; D. Tulcin, B.A.; former member D. Steinberg, M.D. and former member R. Zeppa, M.D.; Initial Policy Advisory Board: J. Cornfield, B.A. (chairman, deceased); H.R. Casdorph, M.D.; A. V. Chobanian, M.D.; H.W. Scott, M.D.; J.W. Hurst, M.D.; and R.C. Schlant, M.D. National Heart, Lung, and Blood Institute Project Officers: T.P. Blaszkowski, Ph.D.; L.M. Friedman, M.D.; C.D. Furberg, M.D.; and J.L. Probstfield, M.D.
We are indebted to the patients and their referring physicians for their unwavering participation in and support of this study.
Source Information
From the Departments of Surgery, Medicine, and Radiology of the University of Minnesota, Minneapolis (H.B., R.L.V., J.P.M., J.M.L., L.L.F., C.T.C., B.J.H., N.T., K.A., W.R.C.-Z., D.W.H., J.W.S., A.S.L.); the University of Arkansas, Little Rock (G.S.C., M.B.P., J.K.B.); the University of Southern California, Los Angeles (A.E.Y., W.A.E., M.E.S.); Lankenau Hospital and Research Center, Philadelphia (R.D.S., H.S.S., F.J.W.); the University of Nebraska, Omaha (J.N.K.); and Harvard University, Boston (T.C.C.). Address reprint requests to Dr. Buchwald at Box 290 UMHC, University of Minnesota, Minneapolis, MN 55455.
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William S. Weintraub. (2002) Is atherosclerotic vascular disease related to a high-fat diet?. Journal of Clinical Epidemiology 55:11, 1064-1072
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Henry Buchwald, Stanley E Williams, John P Matts, Phuong A Nguyen, James R Boen. (2002) Overall mortality in the program on the surgical control of the hyperlipidemias1 1No competing interests declared.. Journal of the American College of Surgeons 195:3, 327-331
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Philip J Barter. (2002) Coronary plaque regression: role of low density lipoprotein-apheresis. Journal of the American College of Cardiology 40:2, 228-230
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Henry Buchwald, Stanley Williams, John Matts, James Boen, for the POSCH Group. (2002) Journal of Cardiovascular Risk 9:2, 83-87
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Roberto Aquilani, Stefano Boni, Sandro Verdirosi, Ornella Pastoris, Jole Assandri, Angelo Rossi, Vincenzo Paganini, Roberto Riccardi, Alberto Cajelli, Marcello Pernice, Manuela Verri, Maurizia Dossena, Franco Cobelli. (2002) An Organizational Model to Translate Nutritional Recommendations into Routine Clinical Practice in Secondary Prevention of Coronary Artery Disease. Preventive Medicine 34:2, 138-143
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Rolf Bambauer, Ralf Schiel, Reinhard Latza. (2001) Current Topics on Low-Density Lipoprotein Apheresis. Therapeutic Apheresis and Dialysis 5:4, 293-300
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Fernando González-Fernández, Ana Jiménez, Almudena López-Blaya, Sandra Velasco, Marı́a M. Arriero, Ángel Celdrán, Luis Rico, Jerónimo Farré, Santos Casado, Antonio López-Farré. (2001) Cerivastatin prevents tumor necrosis factor-α-induced downregulation of endothelial nitric oxide synthase: role of endothelial cytosolic proteins. Atherosclerosis 155:1, 61-70
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Kazuyuki Ozaki, Tadashi Yamamoto, Takaharu Ishibashi, Taku Matsubara, Matomo Nishio, Yoshifusa Aizawa. (2001) Regulation of Endothelial Nitric Oxide Synthase and Endothelin-1 Expression by Fluvastatin in Human Vascular Endothelial Cells.. The Japanese Journal of Pharmacology 85:2, 147-154
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Henry Buchwald, Thomas J O'Dea, Hector J Menchaca, Van N Michalek, Thomas D Rohde. (2000) Effect Of Plasma Cholesterol On Red Blood Cell Oxygen Transport. Clinical and Experimental Pharmacology and Physiology 27:12, 951-955
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Henry Buchwald, Hector J Menchaca, Van N Michalek, Thomas D Rohde, Donald B Hunninghake, Thomas J O’Dea. (2000) Plasma cholesterol: an influencing factor in red blood cell oxygen release and cellular oxygen availability11No competing interests declared.. Journal of the American College of Surgeons 191:5, 490-497
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Henry Buchwald. (1999) Role of the surgeon in managing hypercholesterolemia. Surgery 125:5, 465-467
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