Stanley E. Williams

The earlier detection of colorectal cancers. A preliminary report of the results of the occult blood study

A long‐term clinical study is underway to evaluate the merit of occult stool blood testing in the earlier detection of colorectal cancers; 48,000 participants have been enrolled. Thus far, 873 patients with occult stool blood have been examined, and 77 gastrointestinal cancers have been found in 74 patients. Although data from the control group are not yet available for comparison, most of the cancers found appear to be relatively early in their development. Conventional barium‐enema examinations were noted to have “missed” one third of the colon cancers and two‐thirds of the colon polyps which were found on colonoscopy. Preliminary results of the study appear encouraging. Definitive analysis will await the availability of additional pertinent data.

Sensitivity, specificity, and positive predictivity of the Hemoccult test in screening for colorectal cancers. The University of Minnesota's Colon Cancer Control Study.

Data are presented on the sensitivity, specificity, and positive predictivity of the Hemoccult test based on the experience of the Minnesota Colon Cancer Control Study, a randomized clinical trial to determine whether the use of the Hemoccult test can reduce mortality from colorectal cancer. Rehydrating the slides with a drop of water before processing resulted in an increase in positivity (2.4% to 9.8%), and sensitivity (80.8% to 92.2%) but a decrease in specificity (97.7% to 90.4%) and positive predictivity (5.6% to 2.2%). The effects of age and sex were also evaluated. The test was less specific for men than women (p = 0.03). Specificity was highest for those less than 60 yr of age and decreased with increasing age (p = 0.05). The positive predictivity increased with age from 1.6% for those under 60 yr to 3.6% for those over 70 yr (p = 0.0004).

Disease-free intervals after partial ileal bypass in patients with coronary heart disease and hypercholesterolemia: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH)☆

OBJECTIVES We sought to analyze the disease-free intervals and calculate the freedom from atherosclerosis events in the Program on the Surgical Control of the Hyperlipidemias (POSCH). BACKGROUND The POSCH study was a randomized, secondary lipid/atherosclerosis intervention trial that provided strong evidence for reduction in atherosclerosis progression as demonstrated by clinical and arteriographic end points. The 417 control group patients received American Heart Association phase II diet instruction, and the 421 intervention group patients received identical dietary instruction and underwent a partial ileal bypass operation. METHODS Four outcome measures were determined: 1) overall mortality, 2) coronary heart disease mortality, 3) coronary heart disease mortality and confirmed nonfatal myocardial infarction, and 4) coronary/cardiac interventions. RESULTS An overall mortality rate of 10% occurred at 6.7 years in the control group and 9.4 years in the intervention group, for a gain in disease-free interval of 2.7 years in the intervention group (p = 0.032). A coronary heart disease mortality rate of 8% occurred at 7.2 years in the control group and 11 years in the intervention group, for a gain of 3.8 years (p = 0.046). Twenty percent of patients demonstrated the combined end point of coronary heart disease mortality and confirmed nonfatal myocardial infarction at 5.9 years in the control group and 11.4 years in the intervention group, for a gain of 5.5 years (p < 0.001). Twenty-five percent of patients underwent either coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty or heart transplantation at 5.4 years in the control group and 12.4 years in the intervention group, for a gain of 7 years (p < 0.001). CONCLUSIONS The marked lipid modification achieved by partial ileal bypass in the POSCH trial led to demonstrable increases in the disease-free intervals for overall mortality, coronary heart disease mortality, coronary heart disease mortality and confirmed nonfatal myocardial infarction, and coronary intervention procedures. For the clinician and the patient, estimation of disease-free intervals may be more relevant than assessment of differences in incidence rates and risk ratios.

The design of a study to assess occult-blood screening for colon cancer.

Abstract It is our experience to date that large numbers of high risk individuals can be induced to use the self-administered Hemoccult test on a periodic basis. The study will determine not only whether a significant reduction in mortality can be effected by such periodic screening for colorectal cancer, but will also attempt to arrive at such parameters as the optimal period for rescreening by estimating mean lead time gained at different rescreening intervals using the methodology of Zelen and Feinleib [10] and Prorok [11, 12]. In addition, screening at two different intervals (Groups I and II) will yield empirical data about the effect of screening frequency on mortality and survivorship. Combining these methodologies may yield new information on optimal screening frequency. Such information could then be used to set up screening programs which would significantly reduce mortality from colorectal cancer on a nation-wide basis.

Overall mortality, incremental life expectancy, and cause of death at 25 years in the program on the surgical control of the hyperlipidemias.

Objective:To present the longest follow-up report of any lipid-atherosclerosis intervention trial. Summary of Background Data:The Program on the Surgical Control of the Hyperlipidemias (POSCH), a secondary, clinical/arteriographic, randomized controlled trial, was the first lipid-atherosclerosis trial to demonstrate unequivocally that low density lipoprotein cholesterol reduction reduced the incidence of coronary heart disease death and myocardial infarction. Methods:We report POSCH 25 years follow-up for overall mortality, specific cause of death, and certain subgroup analyses, as well as a prediction for increase in life expectancy derived from the POSCH database, supplemented by the 2006 National Death Index, 1989–2006. Results:There were 838 patients randomized in POSCH (421 surgery, 417 control). At 25 years follow-up, the difference in the restricted mean survival and the logrank (Mantel-Haenszel) statistic was statistically significant, with survival probabilities of 0.57 (surgery) and 0.51 (controls). Cause of death data indicated a significant increase in cardiovascular deaths in the control group; cancer deaths were also greater in the control group but this was not significant. The most compelling subgroup analysis was a significant increase in survival, starting at 5 years after randomization, in the surgery group for patients with an ejection fraction ≥50%, with relative probabilities of 0.61 (surgery) and 0.51 (control). The estimated incremental increase in life expectancy over more than 25 years of follow-up was 1.0 year overall and 1.7 years in the cohort with an ejection fraction ≥50%. Conclusions:A 25-year mortality follow-up in POSCH shows statistically significant gains in overall survival, cardiovascular disease-free survival, and life expectancy in the surgery group compared with the control group.

Impact of cholesterol reduction on peripheral arterial disease in the Program on the Surgical Control of the Hyperlipidemias (POSCH).

BACKGROUND Few lipid/atherosclerosis intervention trials have assessed the impact of cholesterol reduction on peripheral arterial disease. The 838 patients evaluated in the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial represent more than the total number of patients in the seven previously reported studies. METHODS Peripheral arterial disease in POSCH was assessed by progression of clinical disease, serial changes in the systolic blood pressure ankle/brachial index (ABI), and changes on sequential peripheral arteriograms. RESULTS At the time of formal closure of the POSCH trial on July 19, 1990, claudication or limb-threatening ischemia was exhibited in 72 of 417 control group (CG) patients and in 54 of 421 intervention group (IG) patients (IG relative risk [RR] 0.702, 95% confidence interval [CI] 0.169 to 1.000, p = 0.049). With additional follow-up evaluation to September 30, 1994, clinical peripheral arterial disease was evident in 91 CG patients and 64 IG patients (RR 0.656, 95% CI 0.200 to 0.903, p = 0.009). At the 5-year follow-up evaluation, an ABI of less than 0.95 was present in 41 of 120 CG patients and in 24 of 126 IG patients, all of whom had an ABI of 0.95 or greater at baseline (RR in the IG of 0.557, 95% CI 0.360 to 0.863, p < 0.01). No appreciable differences were noted in the progression or regression of arteriographic peripheral arterial disease between the two groups. CONCLUSIONS Effective cholesterol reduction in POSCH led to statistically significant differences between the control and the intervention groups in the development of clinically evident peripheral arterial disease and in the ABI values, but not in the peripheral arteriograms. Additional studies need to assess the correlation between peripheral arterial changes and coronary arterial changes and clinical atherosclerosis events. Intervention trials that study peripheral arterial disease have intrinsic value in the evaluation of the impact of risk factor modification on progression of atherosclerotic peripheral arterial disease.

Overall mortality in the program on the surgical control of the hyperlipidemias.

BACKGROUND The Program on the Surgical Control of the Hyperlipidemias (POSCH), a secondary intervention trial, was the only lipid/atherosclerosis randomized clinical trial that used a surgical modality--partial ileal bypass. POSCH provided solid evidence for the clinical and arteriographic benefits of lipid profile normalization. Few longterm followup reports have been published in this field. This report concerns overall mortality, the primary endpoint of POSCH, with a mean followup of 18 years (range 15.5 to 23.0 years). STUDY DESIGN Overall mortality data were compiled from reports to the POSCH clinics, followup telephone calls, death certificates, and the US National Death Index. RESULTS There were 144 deaths in the control group (n = 417) and 120 deaths in the intervention group (n = 421), using intent-to-treat analysis. The risk reduction in the intervention group was 0.201 (20%); the risk ratio was 0.799, or 0.8 (95% confidence intervals, 0.628 to 1.018, p = 0.07). The proportion of patients alive was 65.7% in the control group and 72.0% in the intervention group, for a difference of 6.3% in the intervention group (p = 0.05). Kaplan-Meier survival analysis (p = 0.046) and disease-free intervals analysis at 70% survival (p < 0.001) were confirmatory. The gain in life expectancy in the intervention group was 2.7 years. CONCLUSIONS Longterm followup POSCH data demonstrate that lipid profile normalization will decrease overall mortality and will maintain a persistent and constant increase in life expectancy.

Plasma lipids and cardiovascular risk: a POSCH report

Quantifying the relationship between changes in lipid variables and clinical endpoints has been difficult. We studied the predictive value of various lipid variables on three endpoints in the Program on the Surgical Control of the Hyperlipidemias (POSCH): overall mortality, coronary heart disease (CHD) mortality, and CHD mortality and confirmed nonfatal myocardial infarction (MI) combined. We measured lipid variables for the annual visits from baseline to 5 years for actual follow-up values, actual and percentage differences between baseline and follow-up values, as well as the parameters comparing baseline only to 5 years for actual differences, percentage differences, and the ratio of baseline to 5 years. The lipid variables included were total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, triglycerides, and the LDL cholesterol/HDL cholesterol ratio. The analytic method used was that of Cox regression, with age and sex as secondary covariates, and each lipid or ratio of lipids as the primary (univariate) covariate. As a result, 108 univariate Cox regressions were conducted. The combined findings for the control and the intervention groups are presented. The number of events for the combined group were: overall mortality, 190; CHD mortality, 119; and CHD mortality and confirmed nonfatal MI, 262. The highest hazard ratios were found for the lipid variable of the LDL cholesterol/HDL cholesterol ratio (e.g. 1.196 for a 1-unit increase). Only for the combined endpoint of CHD mortality and confirmed nonfatal MI was there a substantial number of statistically significant relationships (P<0.01) of lipid variables and parameters of assessment.

Gender-based mortality follow-up from the Program on the Surgical Control of the Hyperlipidemias (POSCH) and meta-analysis of lipid intervention trials. Women in POSCH and other lipid trials.

OBJECTIVE The authors assessed the clinical results of lipid-lowering therapy in women. SUMMARY BACKGROUND DATA The Program on the Surgical Control of the Hyperlipidemias (POSCH) has demonstrated that effective lowering of total cholesterol and low-density lipoprotein cholesterol in a postmyocardial infarction population significantly reduces atherosclerotic coronary heart disease (ACHD) mortality, ACHD mortality combined with a new confirmed nonfatal myocardial infarction, and the number of coronary artery bypass grafting and angioplasty procedures performed. METHODS A review and meta-analysis were performed of the seven primary or secondary lipid/ atherosclerosis intervention trials-including POSCH-published in the English-language literature that included women and published results in women separate from the results in men or in the entire trial population. The main outcome measure analyzed was overall mortality. RESULTS The Scottish Physicians Clofibrate Study, the Newcastle upon Tyne Clofibrate Study, and the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) Trial may have demonstrated a possible benefit in ACHD prognosis from effective lipid intervention in women. The other four available trials did not. The Minnesota Coronary Survey reported a 15.6% increase in overall mortality rate and a 30.6% increase in a combined cardiovascular endpoint rate in the lipid-intervention group. The Upjohn Colestipol Study demonstrated statistically significant reductions in overall and ACHD mortality in the men, but not in the women. The Scandinavian.

Myocardial infarction and percent arteriographic stenosis of culprit lesion: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH).

The objective of this study was to assess the percent stenosis of the culprit lesion responsible for subsequent myocardial infarction in the Program on the Surgical Control of the Hyperlipidemias (POSCH). It is unknown if the susceptible coronary artery culprit lesion responsible for an acute myocardial infarction is relatively large ( > or = 50% arteriographic stenosis) and hemodynamically significant ( > or = 70% stenosis), or small ( < 50%, stenosis) and asymptomatic. Certain necropsy and arteriography studies support the large progenitor lesion concept, and other arteriography studies support the small lesion hypothesis. We analyzed the coronary arteriogram immediately preceding a Q wave (transmural) myocardial infarction for the degree of stenosis of the suspected culprit lesion, which was selected by visual inspection of the coronary circulation supplying the electrocardiogram-defined area of myocardial infarction. There was no perceptible difference with respect to vessel segment distribution of culprit lesions or time to infarction between the 52 control-group patients and the 27 intervention-group patients. For the two groups combined (n=79), the predominantly involved segments were the middle right coronary artery and the proximal left anterior descending coronary artery. The time interval from the preceding coronary arteriogram closest to the index myocardial infarction ranged from 0 days to 10 years; however, 64.6% of the arteriograms were performed 2 years or less prior to the myocardial infarction. Only 5.1% of the patients in both groups combined had a culprit lesion stenosis < 50%, while 88.6% of the patients in both groups combined had a culprit lesion stenosis > or = 70%. The results strongly favor the large lesion hypothesis of causation for myocardial infarction. It is premature, however, to state that the relative size of the culprit lesion has been indisputably determined. The resolution of this problem has exceedingly important practical implications for the management of patients with known atherosclerotic coronary heart disease and for those asymptomatic individuals with silent atherosclerotic coronary heart disease.