Program On The Surgical Control Of The Hyperlipidemias Research Articles

Partial ileal bypass affords protection from onset of type 2 diabetes

BackgroundPartial ileal bypass (PIB) in the National Institutes of Health–sponsored Program on the Surgical Control of the Hyperlipidemias (POSCH) randomized controlled trial was found to reduce plasma cholesterol, in particular low density lipoprotein cholesterol, with concomitant retardation of atherosclerotic cardiovascular disease and increased life expectancy. Glucagon-like peptide-1, related to amelioration of type 2 diabetes, is increased over 5-fold after PIB. We hypothesized that PIB, in addition to its action on cholesterol metabolism, may also prevent type 2 diabetes. MethodsWe surveyed by telephone inquiry of former POSCH patients the 30+year posttrial incidence of type 2 diabetes or prediabetes, the presence of which was a trial exclusion criteria. We were able to contact 17.4% (n = 838) of the original POSCH population. ResultsOf 66 control responders, 17 contracted type 2 diabetes (25.8%); of 80 PIB responders, 8 contracted type 2 diabetes (10%). The difference between groups was significant (P = .015 by Fisher exact test) with an odds ratio of .320 for the PIB group and an over 2-fold (2.6) increase in the incidence of type 2 diabetes in the controls. Including borderline type 2 diabetes (prediabetic) patients, these values were 22 of 66 controls (33.3%) and 10 of 80 PIB patients (12.5%), with an odds ratio of .286 and a P<.004, and again an over 2-fold (2.7) increase in the incidence of type 2 diabetes in the control patients. ConclusionPIB appears to afford partial protection from the onset of type 2 diabetes for over 30 years.

The Program on the Surgical Control of the Hyperlipidemias (POSCH) and the Lipid Regulatory Hypothesis

Background: The Lipid Regulatory Hypothesis (LRH) states that the best way to regress atherosclerotic plaque is to simultaneously decrease the cholesterol being transported into the arterial wall by low-density lipoprotein (LDL) and increase the cholesterol being removed from the arterial wall, via reverse cholesterol transport, by high-density lipoprotein (HDL). The cholesterol retention fraction (CRF) is defined as (LDL cholesterol minus HDL cholesterol) divided by LDL cholesterol. The Program on the Surgical Control of the Hyperlipidemias (POSCH), which employed partial ileal bypass as the intervention modality, was selected for verification of the LRH and the validity of the CRF. Methods: POSCH coronary arteriographic plaque progression or non-progression (stabilisation/regression) from baseline to 3 years was stratified on a five-by-five factorial grid with 25 cohort cells combining LDL cholesterol and HDL cholesterol changes from baseline to 1 year following intervention. Predictive capacity for arteriography changes of LDL cholesterol and CRF were compared. Statistics used were logistic regressions. Results: There were 731 paired arteriographic assessments of individual POSCH patients: 163 progression (22%) and 568 non-progression (stabilisation/regression) (78%). A reciprocal LDL cholesterol and HDL cholesterol relationship represented as a five-by-five factorial showed non-progression above and progression below the dividing diagonal. 100% (163/163) of patients with plaque progression had a rise in their CRF; and 100% (568/568) of patients with plaque non-progression had a fall in their CRF. LDL cholesterol, HDL cholesterol, and CRF were all highly significant predictors of plaque progression and non-progression (p&lt;0.0001). Conclusion: In POSCH, the partial ileal bypass-induced changes in the LDL cholesterol, HDL cholesterol, and the CRF are highly correlated with the sequential coronary arteriography changes of plaque progression and non-progression. This study affirms that individual patient prognosis can be predicted by the magnitude of response to lipid intervention.

Interview: Metabolic/bariatric surgery

Attended Columbia College (Valedictorian, 1954) and the College of Physicians and Surgeons of Columbia University. He studied under Drs Wangensteen and Varco at the University of Minnesota (USA). He is Professor of Surgery and Biomedical Engineering at the University of Minnesota, and was the first Owen H and Sarah Davidson Wangensteen Chair in Experimental Surgery at the University of Minnesota. Dr Buchwald served as President of the International Federation for the Surgery of Obesity (IFSO), American Society for Metabolic/Bariatric Surgery (ASMBS), Central Surgical Association, International Study Group for Implantable Insulin Delivery Devices and the Owen H Wangensteen Society. He was principal investigator of the Program on the Surgical Control of the Hyperlipidemias (POSCH), the first randomized clinical trial to demonstrate, in 1990, that cholesterol lowering via the partial ileal bypass resulted in reductions in myocardial infarctions, angina pectoris and peripheral vascular disease; arteriographic...

Overall Mortality, Incremental Life Expectancy, and Cause of Death at 25 Years in the Program on the Surgical Control of the Hyperlipidemias

To present the longest follow-up report of any lipid-atherosclerosis intervention trial. 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. 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. 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 > or = 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 > or = 50%. 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.

Abstract: 98 METABOLIC SURGERY FOR THE METABOLIC SYNDROME

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 nofatal 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 = 1.25 to 5.1, p = 0.018). In former cigarette smokers with no aspirin use at baseline (n = 92) with a mean follow-up of 8.8 years, the relative risk of overall mortality was 3.1 (20.0% vs 6.5%, 95% CI = 1.0 to 10.2, p = 0.07), ACHD mortality, 3.4 (167.% vs 4.8%, 95% CI = 0.9 to 13.5, p = 0.11); and combined ACHD mortality and confirmed nonfatal myocardial infarction, 1.1 (23.3% vs 21.0%, 95% CI = 0.5 to 2.5, p = 0.79). After adjustment for age, gender, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, Quetelet index, ejection fraction, extent of coronary disease at baseline, and length of follow-up, none of these relative risks changed appreciably. The risk of overall mortality, aCHD mortality, and combined ACHD mortality and recurrent confirmed nonfatal myocardial infarction may be significantly reduced by aspirin use in post-myocardial infarction cigarette smokers. However, the subjects included in this analysis were highly selected and may not be totally representative of postmyocardial infarction patients. Nonetheless, when extensive counseling regarding the negative consequences of continued cigarette smoking fails to cause smoking cessation in postmyocardial infarction patients, it may be exceedingly prudent to recommended aspirin usage.

Surgical Intervention For The Treatment Of Morbid Obesity And The Dyslipidemias

To meet the expanding epidemic of worldwide morbid obesity, giving rise to significant dyslipidemia, knowledge of the surgical history of the development of the partial ileal bypass operation, the contribution of the Program on the Surgical Control of the Hyperlipidemias (POSCH), and the efficacious outcomes of bariatric surgery procedures is essential to the armamentarium of the researcher and the practitioner. This review provides a brief summary of metabolic surgery as applied to the normalization of circulating lipid concentrations, the impact of this modification on body lipid mechanisms and the practical use of bariatric surgery procedures today.

Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy, part IV: The 1984 Coronary Primary Prevention Trial ends it—almost

As of the early 1980s, despite the wealth of evidence from experimental animal models, the extensive epidemiologic evidence, the powerful genetic evidence, and the strongly suggestive clinical intervention trial results, most clinicians still remained unpersuaded regarding the relevance of the lipid hypothesis. What was needed was a well-designed, large-scale, long-term, double-blind study demonstrating a statistically significant impact of treatment on coronary heart disease events. The National Institutes of Health (NIH) had laid the groundwork for such a study as early as 1970, but the study was not completed and the results published until 1984. This study, the Coronary Primary Prevention Trial, showed that treatment with a bile acid binding resin reduced major coronary events in hypercholesterolemic men by 19%, with a P value of 0.05. The NIH followed this up with a national Consensus Development Conference on Lowering Blood Cholesterol to Prevent Heart Disease. For the first time, the NIH now went on record advocating screening for hypercholesterolemia and urging aggressive treatment for those at high risk. The Institute initiated a national cooperative program to that end, the National Cholesterol Education Program. For the first time, preventing coronary heart disease became a national public health goal.

Exploiting the Vascular Protective Effects of High-Density Lipoprotein and Its Apolipoproteins

“ An invasion of armies can be resisted but not an idea whose time has come.” —Victor Hugo. Vaso-occlusive disease resulting from atherosclerosis and thrombosis is the leading cause of death and morbidity in the United States and other industrialized nations. Although the precise cause of atherosclerosis is unclear, an emerging paradigm suggests that atherosclerosis involves multiple pathways in which lipoprotein entry and retention, injury to the vessel wall from diverse stimuli, and an associated long-term inflammatory and immune response seem to play a key role.1–4 Dyslipidemia characterized predominantly by elevated levels of one or more circulating non-HDL cholesterol lipoproteins [LDL, VLDL, lipoprotein(a), triglycerides] and/or reduced HDL cholesterol is one of the key risk factors for atherosclerosis and cardiovascular disease.5–16 Over the past several years, a number of large, prospective, randomized, controlled clinical trials have demonstrated both angiographic and clinical benefits of lipid-lowering therapy, with a significant reduction in fatal and nonfatal cardiovascular events.17–23 These studies have primarily targeted LDL cholesterol through pharmacotherapy (mostly statins), with or without dietary counseling, lifestyle modification, or surgery (intestinal bypass in Program on the Surgical Control of the Hyperlipidemias [POSCH] trial). Overall, a significant and clinically worthwhile relative risk reduction ranging from 20% to 40% in major cardiovascular events has been achieved with these strategies, without significant adverse effects or increased noncardiovascular mortality. These remarkable results prompted Brown and Goldstein24 to predict that heart attacks will be gone with the century. This clearly reflects an overoptimistic point of view, because 60% to 70% of adverse cardiovascular events continue to occur despite LDL-lowering therapy. Potential reasons why cardiovascular events may continue to occur despite low LDL levels or despite LDL-lowering therapy include the following: (1) we may not be lowering LDL cholesterol to optimal levels, because optimal levels are not clearly …

Surgical Management of Dyslipidemia: Clinical and Experimental Evidence

Coronary artery disease (CAD) is still a major cause of mortality in developed countries, and dyslipidemia is one of its major causes. In an attempt to reduce both mortality and morbidity from CAD, several dietary, pharmacological, and surgical approaches have been used to reduce plasma cholesterol levels. In this brief review, we summarize the evidence for cholesterol-lowering effects and safety of partial ileal bypass (PIB) procedure in both human and animal studies. The results of the Program on the Surgical Control of the Hyperlipidemias (POSCH), which involved a total of 838 subjects with myocardial infarction, are promising. A 5-year follow-up of this study revealed significant reductions of up to 27% in total cholesterol (TC) and up to 42% in low-density lipoprotein (LDL) cholesterol levels along with an increase of up to 8% in high-density lipoprotein (HDL) cholesterol levels as compared to controls. These changes were associated with other benefits such as increased HDL/TC and HDL/LDL ratios, and a significant decrease in apolipoprotein (apo) B100 and increase in apo AI levels. Similar results were also demonstrated by other studies. PIB surgery is one of the most effective methods for reduction of plasma cholesterol levels, particularly in patients with heterozygous familial hypercholesterolemia. This procedure is also applicable to treatment of sitosterolemia, a rare genetic disorder in which the absorption of plant sterols is abnormally high. Although no major complications of this method have been reported, more extensive studies are required to evaluate its long-term effects on renal and hepatic function. Similarly, long-term impact of this procedure on progression/regression of atherosclerotic lesions must be documented. Finally, indications for this procedure should be carefully considered, particularly in view of availability of other treatments of dyslipidemia.

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.

Role of the surgeon in managing hypercholesterolemia

In 1962 the partial ileal bypass (PIB) was introduced as the first operation specifically designed to treat hypercholesterolemia. 1 Buchwald H. Surgical operation to lower circulating cholesterol. Circulation. 1963; 28: II649 Google Scholar Ten years later the Program on the Surgical Control of the Hyperlipidemias (POSCH) was launched, with PIB used as the intervention modality. POSCH (1972 to 1997) has been the only surgical randomized clinical trial to test the efficacy of cholesterol lowering in the management of atherosclerosis and its clinical manifestations. 2 Buchwald H Varco RL Matts JP Long JM Fitch LL Campbell GS et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. N Engl J Med. 1990; 323: 946-955 Crossref PubMed Scopus (853) Google Scholar , 3 Buchwald H Matts JP Fitch LL Campos CT Sanmarco ME Amplatz K et al. Changes in sequential coronary arteriograms and subsequent coronary events. JAMA. 1992; 268: 1429-1433 Crossref PubMed Scopus (163) Google Scholar , 4 Buchwald H Campos CT Varco RL Boen JR Williams SE Hansen BJ et al. Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Arch Intern Med. 1998; 158: 1253-1261 Crossref PubMed Scopus (115) Google Scholar PIB and POSCH are the subjects of this short review of the role of the surgeon in managing hypercholesterolemia.

Role of the surgeon in managing hypercholesterolemia

In 1962 the partial ileal bypass (PIB) was introduced as the first operation specifically designed to treat hypercholesterolemia.1 Ten years later the Program on the Surgical Control of the Hyperlipidemias (POSCH) was launched, with PIB used as the intervention modality. POSCH (1972 to 1997) has been the only surgical randomized clinical trial to test the efficacy of cholesterol lowering in the management of atherosclerosis and its clinical manifestations.2-4 PIB and POSCH are the subjects of this short review of the role of the surgeon in managing hypercholesterolemia.

EVIDENCE-BASED MEDICINE CRITERIA APPLIED TO HYPOLIPIDEMIC AND ANTIHYPERTENSIVE DRUG TRIALS: IS DRUG EFFICACY ALWAYS THE SAME?

Changes in cardiovascular risk after lipid lowering medications are generally expressed as relative risk reduction (RRR). Comparison of the eight major studies published in this last decade indicates that the RRRs ranged from a minimum (19%) for the LRC Study with cholestyramine, to maximal values of 34–37% for studies such as the HHS, 4S and AFCAPS/TexCAPS. These RRRs were barely related to the drugs’ effects on major lipid parameters, e.g. LDL cholesterol. Instead, by using the absolute risk reduction (ARRs), easily calculated by subtracting the percentage end points for the drug treated from these values of the placebo group in all studies, a wide range of values was found, also adding to the series a non pharmacological study such as the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial. Calculated ARRs were directly correlated to the baseline cardiovascular (CV) risk in all studies, thus allowing an easy prediction of a drug's effect in the selected population. Drugs with different mechanisms (statins, fibrates and resins) all fitted into this correlation nomogram. These findings clearly indicate that the CV effects of lipid changes, such as LDL cholesterol and triglyceride reduction or HDL rises, are in the same direction, and can be well predicted. The similar, almost identical behavior of drugs affecting LDL cholesterolemia to a different degree or not at all, indicates that novel approaches should be sought to improve risk reduction and that individual therapy should be ideally pursued, rather than a ‘one drug’ approach.

Effects of Lipid Lowering on Coronary Plaques and Coronary Events

C linical trials evaluating the efficacy of interventions to lower serum total and LDL-cholesterol levels often use angiographic induction of regression and slowing of progression of coronary narrowing as endpoints.1,2 In the Program on the Surgical Control of the Hyperlipidemias (POSCH), Buchwald et al3 used partial ileal bypass and dietary management to lower total and LDL-cholesterol levels in men and women with healed myocardial infarction. At 5 years, there was a 35% reduction in combined CAD-related death and confirmed nonfatal myocardial infarction in the surgery group compared to the control group (dietary counseling alone; 125 vs 82, p 5 0.001). Mean serum total cholesterol levels were decreased by 23% (p ,0.0001) and LDL-cholesterol levels decreased by 38% (p ,0.0001). Follow-up of coronary arteriograms at 3, 5, 7, and 10 years demonstrated significantly less progression (p ,0.001) in the surgery group. The POSCH trial also reported a decrease in new coronary narrowing and some reversal of previously existing narrowing.3 Several angiographic trials have evaluated the ability of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and other lipid-lowering drugs to promote regression and slow progression of coronary atherosclerotic plaques in CAD patients. Overall, these trials have demonstrated a reduction in coronary events. Some major trials included the Multicentre Anti-Atheroma Study (MAAS), the Stanford Coronary Risk Intervention Project (SCRIP), and the Familial Atherosclerosis Treatment Study (FATS).4–6 In MAAS, patients treated with simvastatin 20 mg/day over 4 years had significantly less progression and more regression of their atherosclerotic disease combined when compared to placebo (p 5 0.02). Reductions in total and LDL-cholesterol levels were 23% and 31%, respectively, when compared to placebo. Although the study was not designed to look at clinical outcomes, fewer patients in the simvastatintreated group had coronary angioplasty or bypass procedures.4 In SCRIP, intensive risk reduction including diet, exercise, weight loss, smoking cessation, and lipid-lowering therapy was evaluated in patients with atherosclerosis. The study disclosed a reduced rate of progression of narrowing in coronary arteries (p ,0.02), fewer new narrowings per patient (p 5 0.06), and fewer segments with new narrowings (p 5 0.05).5 Mortality rates were similar, and hospitalization for cardiac causes were reduced. In the FATS trial, the efficacy of cholesterol-lowering drug therapy was evaluated in men with existing CAD.6 At 2.5 years, patients treated with lovastatin plus colestipol had a 33% reduction in serum total cholesterol, with reductions of 23% and 3% found in the colestipol plus niacin and placebo groups, respectively. Plaque regression, as measured by angiography, was more common in the treatment groups. The frequency of combined fatal and nonfatal myocardial infarction was lower in the drug treatment groups compared to placebo (lovastatin/colestipol 5 4%, niacin/colestipol 5 6%, placebo 5 19%). Clinical trial data indicate that the slowing of progression or regression of coronary atherosclerosis results in a decrease in coronary events. Although many of these trials were not designed to show the effect on clinical outcome, the results provide information consistent with cholesterol lowering trials such as the Scandinavian Simvastatin Survival Study (4S) and the Coronary and Recurrent Events (CARE) trials that evaluated clinical events as a primary outcome.7,8

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

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. 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. 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. 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.

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.

The authors assessed the clinical results of lipid-lowering therapy in women. 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. 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. 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.

Reversal of Atherosclerosis with Therapy: Update of Coronary Angiographic Trials

Publisher Summary There is now serial angiographic evidence for atherosclerotic lesion improvement induced by diverse modes of intervention. The weight of evidence indicates that atherosclerotic lesions as well as clinical coronary events are reduced by intervention. The Cholesterol-Lowering Atherosclerosis Study (CLAS) gave the first clear indication of the importance of triglyceride-rich lipoproteins in lesion progression-an effect manifested after LDL-C was removed as a risk factor. Although clinical events were not significantly different between drug and placebo groups during the 2 years of intervention, 10 year follow-up indicates a significantly lower clinical coronary event rate in the drug group. This chapter concentrates on familial atherosclerosis treatment study (FATS), NHLBl type II coronary intervention study, cholesterol-lowering atherosclerosis study (CLAS), research intervention trials, monitored atherosclerosis regression study (MARS), multicentre anti-atheroma study (MAAS), Heidelberg exercise-diet study, and the program on the surgical control of the hyperlipidemias (POSCH). Many interesting and important findings have resulted from coronary angiographic trials that need further attention if it is to increase our success with secondary preventive measures. The majority of the coronary angiographic trials, NHLBI Type II, CLAS, FATS, STARS, MARS, CCAIT, MAAS, Leiden Intervention Trial, and Lifestyle Heart Trial indicate that LDL-C reduction preferentially regresses lesions 250%S and typically retards coronary artery lesion progression in only 50 to 80% of subjects. Improved therapeutic regimens to alter progression of coronary atherosclerosis may require adjunctive therapy in concert with LDL-C reduction to prevent new lesion formation or to induce early lesion regression, such as for lesions

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.

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 nofatal 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 = 1.25 to 5.1, p = 0.018). In former cigarette smokers with no aspirin use at baseline ( n = 92) with a mean follow-up of 8.8 years, the relative risk of overall mortality was 3.1 (20.0% vs 6.5%, 95% CI = 1.0 to 10.2, p = 0.07), ACHD mortality, 3.4 (167.% vs 4.8%, 95% CI = 0.9 to 13.5, p = 0.11); and combined ACHD mortality and confirmed nonfatal myocardial infarction, 1.1 (23.3% vs 21.0%, 95% CI = 0.5 to 2.5, p = 0.79). After adjustment for age, gender, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, Quetelet index, ejection fraction, extent of coronary disease at baseline, and length of follow-up, none of these relative risks changed appreciably. The risk of overall mortality, aCHD mortality, and combined ACHD mortality and recurrent confirmed nonfatal myocardial infarction may be significantly reduced by aspirin use in post-myocardial infarction cigarette smokers. However, the subjects included in this analysis were highly selected and may not be totally representative of postmyocardial infarction patients. Nonetheless, when extensive counseling regarding the negative consequences of continued cigarette smoking fails to cause smoking cessation in postmyocardial infarction patients, it may be exceedingly prudent to recommended aspirin usage.

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 ⩾2.0 for the subgroup, if the absolute z-value for the overall effect was <2.0; and (2) an absolute z-value ⩾3.0 for the subgroup and a relative risk ⩽0.5, if the absolute z-value for the overall effect was ⩾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 displayed external consistency with known ACHD risk factors and for biological plausibility: triglyceride concentration ⩾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.