Laurie L. Fitch

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)

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 less than 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 less than 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 greater than or equal to 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 less than 0.001). During follow-up, 137 control-group and 52 surgery-group patients underwent coronary-artery bypass grafting (P less than 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 less than 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.

Program on surgical control of the hyperlipidemias (POSCH): Recruitment experience

The Program on Surgical Control of the Hyperlipidemias (POSCH) is an investigator-initiated NHLBI grant-funded secondary coronary heart disease intervention trial using partial ileal bypass (PIB) for lipid reduction. Randomization started in September 1975 and ended in July 1983 with enrollment of 838 participants (421 surgery, 417 controls). The trial is scheduled to reveal the atherosclerosis impact of the lipid changes in 1990, at which time the average individual in the program will have been followed for 9.6 years. Initially, the magnitude of the recruitment task was greatly underestimated. An area containing 500,000 people was judged to be sufficient to randomize one patient per month. Actually, a population of 2.4-10.5 million, depending upon proximity to a clinic, was needed to achieve this goal. The study design was changed in 1981, due to recruitment costs, with reduction of the number of individuals to be randomized from 1000 to 838 and with extension of the duration of minimum follow-up from 5 to 7 years. Only with the development of a uniform model clinic concept, with specified levels of performance calculated from actual recruitment data, did accrual of patients into the trial become predictable and achievable. Some of the recruitment delays in POSCH were related to problems, in part generic to the existent grant funding mechanism and associated with decisions made by NHLBI and its Advisory Council. These delays were manifested by denial of reallocation of approved funds to initiate replacement clinics for discontinued ones, an 18-month delay in implementation of a protocol change in lipid criteria suggested by the Data Monitoring Committee, and a 2-year delay in the starting date for the fourth active clinic.

Women in the POSCH Trial Effects of Aggressive Cholesterol Modification in Women With Coronary Heart Disease

The Program on the Surgical Control of the Hyperlipidemias (POSCH) provided the clearest and the most convincing evidence supporting the beneficial effects of cholesterol lowering in hypercholesterolemic survivors of a myocardial infarction. In POSCH, 78 of the 838 patients (9.3%) were women, with 32 randomized to the diet-control group and 46 to the diet plus partial ileal bypass surgery-intervention group. At 5 years, the mean per cent change from baseline was -23.9% for total plasma cholesterol (p < 0.0001), -36.1% for low-density lipoprotein cholesterol (p < 0.0001), and +8.5% for high-density lipoprotein cholesterol (p = not significant). Because of the small number of women, no statistically significant changes in clinical event rates were observed between the control and the surgery groups. A comparison of 162 coronary arteriography film pairs in the POSCH women, between baseline and 3, 5, 7, and 10 years, consistently showed less disease progression in the surgery group (p = 0.013 for combined assessments of the baseline to the longest follow-up film). Because the lipid and coronary arteriography findings in the POSCH women paralleled these findings in the total POSCH population and in the POSCH men, and because the arteriography changes in POSCH have previously been demonstrated to be statistically significant surrogate end points for certain clinical events and predictors of overall and atherosclerotic coronary heart disease mortality rates, we conclude that the lipid modification achieved in the POSCH women by partial ileal bypass reduced their atherosclerosis progression. The POSCH findings in women support the aggressive treatment of hyperlipidemia in the general management of atherosclerosis in women.

Overview of randomized clinical trials of lipid intervention for atherosclerotic cardiovascular disease.

This paper is a review of the scientific and economic (when possible) impact of 15 randomized clinical trials of lipid intervention for atherosclerotic cardiovascular disease. No effort has been made to be all-inclusive and certain smaller and first generation studies have been omitted. No effort has been made to offer detailed analyses of protocols; we have limited discussion to summaries of the salient features of each study presented. After stating the data, we introduce certain reflections and raise some of the more obvious questions that emerge.

Subgroup analyses of the major clinical endpoints in the program on the surgical control of the hyperlipidemias (POSCH): Overall mortality, atherosclerotic coronary heart disease (ACHD) mortality, and ACHD mortality or myocardial infarction

The Program on the Surgical Control of the Hyperlipidemias (POSCH) was a secondary atherosclerosis intervention trial employing partial ileal bypass surgery as the intervention modality. For this report, we analyzed 105 subgroups in 35 variables in POSCH, chosen predominantly for their potential relationship to the risk of atherosclerotic coronary heart disease (ACHD). We defined potential differential effects as those with: (1) an absolute z-value > or = 2.0 for the subgroup, if the absolute z-value for the overall effect was < 2.0; and (2) an absolute z-value > or = 3.0 for the subgroup and a relative risk < or = 0.5, if the absolute z-value for the overall effect was > or = 2.0. For each of three major POSCH endpoints of overall mortality, ACHD mortality and ACHD mortality or confirmed nonfatal myocardial infarction, we found seven subgroups with a differential risk reduction in the surgery group as compared to the control group. Allowing for identical subgroups for more than one endpoint, there were 13 individual subgroups with differential effects. Of these, seven demonstrated internal consistency across endpoints, and five of these seven displaced external consistency with known ACHD risk factors and for biological plausibility: triglyceride concentration > or = 200 mg/dl; cigarette smoking; overt or borderline diabetes mellitus; a Minnesota ECG Q-QS code of 1-1; and obesity. A greater risk reduction, in comparison to the overall treatment effect, by the reduction of a single risk factor, hypercholesterolemia, in patients with at least two major ACHD risk factors was a provocative and an hypothesis-generating outcome of this analysis. The clinical implications of this finding may lead to more aggressive cholesterol intervention in patients with multiple ACHD risk factors.

Program on the surgical control of the hyperlipidemias (POSCH): Patient entry characteristics

The entry characteristics of patients in the Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized, controlled, clinical trial, are described in this article. The primary objective addressed by POSCH was whether lowering total plasma cholesterol by partial ileal bypass surgery results in a reduction in mortality and morbidity in post-myocardial infarction patients. Between 1975 and 1983, 838 patients between the ages of 30 and 64 years were randomized into POSCH. The mean age at entry was 51 years, and 91% of the patients were men. The mean time between myocardial infarction and entry was 2.2 years. The mean baseline total plasma cholesterol was 251 mg/dl, with a mean LDL-cholesterol of 179 mg/dl and a mean HDL-cholesterol of 40 mg/dl. Significant disease (greater than or equal to 50% occlusion) of one or more major coronary arteries was found in 91% of the patients. In addition to a description of the POSCH patient population at entry, comparisons of the POSCH patient population to populations of participants in other lipid-lowering trials are presented to provide a perspective on how POSCH relates to these trials.

Predictors of total and low-density lipoprotein cholesterol change after partial ileal bypass.

POSCH is a prospective, randomized secondary intervention trial examining the effect of maximal lipoprotein modification achieved by partial ileal bypass on overall mortality and the course of coronary heart disease. In the initial 189 surgical patients, total cholesterol levels decreased from 256.7 +/- 2.6 mg/dl to 166.6 +/- 2 mg/dl, and low-density lipoprotein cholesterol levels decreased from 181.5 +/- 2.7 mg/dl to 94.1 +/- 1.7 mg/dl 3 months after operation. These significant decreases were sustained through 5 years of follow-up (p less than 0.001). The total cholesterol level was 29.2 +/- 0.9 percent lower and the low-density lipoprotein cholesterol level was 43.2 +/- 1 percent lower at 5 years compared with the baseline level. Decreases of similar magnitude were seen in each of the common WHO lipoprotein phenotypes. The baseline total cholesterol level was the only significant independent preoperative predictor of the 5 year total cholesterol level (correlation coefficient 0.547; p less than 0.001), and the baseline low-density lipoprotein cholesterol level was the only significant independent preoperative determinant of the 5 year low-density lipoprotein cholesterol level (correlation coefficient 0.599; p less than 0.001). These relationships are expressed by the following equations: 5 year total cholesterol = 0.54 X baseline total cholesterol + 42.3, and 5 year low-density lipoprotein cholesterol = 0.455 X baseline low-density lipoprotein cholesterol + 19.2. The decrease in total and low-density lipoprotein cholesterol levels after partial ileal bypass are greater than reported by any trial of drug or diet intervention, including the Lipid Research Clinics Coronary Primary Prevention Trial which examined cholestyramine. Estimation of the change in total and low-density lipoprotein cholesterol levels after partial ileal bypass can be made based on preoperative lipid analysis and is essential in comparing different therapeutic modalities and assessing the role of partial ileal bypass among strategies aimed at lowering coronary heart disease risk.

Effect of aspirin use on death and recurrent myocardial infarction in current and former cigarette smokers

The purpose of this study was to examine the effects of aspirin use on mortality and morbidity rates in a subset of the control group of the Program on the Surgical Control of the Hyperlipidemias (POSCH) that was stratified by cigarette smoking status at the time of randomization. The clinical impact of aspirin intake in cigarette smokers and former cigarette smokers has not been well studied. POSCH was a randomized, controlled, clinical trial designed to ascertain the effects of lipid modification by the partial ileal bypass operation on clinical end-points and arteriographic changes in postmyocardial infarction subjects with hypercholesterolemia. Cohorts of cigarette smokers in the diet-control group were evaluated for overall and atherosclerotic coronary heart disease (ACHD) mortality rates and recurrent confirmed nonfatal myocardial infarction rates. In current cigarette smokers at baseline (n = 90) with a mean follow-up of 8.3 years, the overall mortality rate was 45.2% in patients with no aspirin use and 10.4% in patients who reported even infrequent aspirin use (relative risk = 4.3, 95% confidence interval (CI) = 2.4 to 10.6, p < 0.001). For ACHD mortality in this cohort, the relative risk was 17.1 (35.7% vs 2.1%, 95% CI = 1.4 to 125.0, p < 0.001); for the combined end-point of ACHD mortality and nonfatal myocardial infarction, the relative risk was 2.4 (40.5% vs 16.7%, 95% CI = 1.2 to 5.1, p = 0.018).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of cigarette smoking on survivors of a single myocardial infarction

The effect of smoking on arteriographically documented atheroscleroctic coronary heart disease (A-CHD), total mortality (TN), atherosekratic coronary heart disease mortality (CHD-H), and HI was examined in 334 control group patients from the Frogram on the Surgical Control of the Hyperlipidemias. The male and female patients were between the ages of 30 to 64 years, had elevated cholesterol levels, had suffered a single MI and included 128 current smokers (CS) and 206 former smokers (FS) at entry into the study. At 3,5,7, and 10 years of tollow.up, there were no differences in A-CHD progression from baseline for CS vs FS as assessed by visual readings of the paired coronary arteriograma by two cardiologists blinded to the temporal order of the films and to the patient’s smoking status. Below is shown the relative risk (CS va PS) at up to 10 years of follow-up, without and with adjustment for age, HDLend LDL-cholesterol, LV ejection fraction, quetelet index, and amount of coronary atherosclerosis at baseline, using Cox regression. TM CHD-M CHD-H+HI CS vs FS 2.4* 2 I 7* 2.0* CS vs FS adjusted 2.6* 3.3* 2.4* *mp<.oo3 : Post-MI patientr who continue to smoke, compared to post-HI patients who stop snok:ng, are at increased risk of death and recurrent MI. The lack of a difference in arteriographically documented coronary atherosclerosis progression between tht ;;o groups may indicate that other factors such as vasospasm or clotting mechanisms are involved.

Interactive systems to assume informed patient consent

A plan for an interactive computer-based expert-type system that would more fully inform the patient and provide legal documentation of the medical process is proposed. When combined with videodisc technology, this scheme is believed to provide a very comprehensive tool. Background information on the issue of patient consent and a brief literature review are included.<<ETX>>