Based on a presentation from the Millennium Festival of Medicine The idea that a single hospital can provide all the facilities necessary for its catchment area is no longer tenable. In 1998 the Scottish acute services review recognised this and proposed the development of managed clinical networks as an innovative way of providing acute services in the NHS in Scotland.1 We describe here the characteristics of these networks. Managed clinical networks are linked groups of health professionals and organisations from primary, secondary, and tertiary care, working in a coordinated manner that is not constrained by existing organisational or professional boundaries to ensure equitable provision of high quality, clinically effective care. Networks can be of several types—for example, they can cover a specific disease, such as peripheral vascular disease; a specific specialty, such as neurology; or a specific function, such as medical receiving. The term network might suggest diffused responsibility, but these networks are not casual or informal: the point is that they are managed. The core principles of a managed clinical network were set out by the Scottish Office department of health management executive in 1999.2 They include:

OBJECTIVES The purpose of the study was to assess the effect of lipid reduction with pravastatin on hospital admissions in middle-aged men with hypercholesterolemia in the West of Scotland Coronary Prevention Study.BACKGROUND A prospective, randomized controlled trial was undertaken in primary care centers in the West of Scotland.METHODS A total of 6,595 participants randomized to receive pravastatin 40 mg or placebo daily were followed up for a mean of 4.9 years (range 3.5 to 6.1 years). Analysis of hospital admissions was undertaken according to the "intention to treat" principle both for cardiovascular diseases and noncardiovascular diseases (including malignant neoplasms, psychiatric diagnoses, trauma and other causes). A secondary analysis of hospitalization in patients who were greater than or equal to 75% compliant was performed.RESULTS During the trial, 2,198 (33%) of the 6,595 men were admitted to hospital on 4,333 occasions, of which 1,234 (28%) were for cardiovascular causes. Pravastatin reduced the number of subjects requiring hospital admission for cardiovascular causes by 21% (95% CI [confidence interval] 9 to 31, p = 0.0008) overall, and by 27% (95% CI 15 to 38) in compliant participants. The number of admissions per 1,000 subject-years for cardiovascular disease was reduced by 10.8 (95% CI 4 to 17.4, p = 0.0013) in all subjects, and by 15.6 (95% CI 8.3 to 23, p < 0.0001) in compliant participants. Pravastatin had no significant influence on hospital admission for any noncardiovascular diagnostic category. There were 13.4 fewer admissions per 1,000 subject years for all causes in the pravastatin-treated group (95% CI -0.4 to 27.3, p = 0.076). No significant difference in duration of hospital stay was found between the pravastatin and placebo patients in any diagnostic group.CONCLUSIONS Pravastatin therapy reduced the burden of hospital admissions for cardiovascular disease, without any adverse effect on noncardiovascular hospitalization. (J Am Coll Cardiol 1999;33:909-15) (C) 1999 by the American College of Cardiology.

The article by Kluijtmans and colleagues 1 (Circulation, October 21, 1997) adds to the growing literature on the relationship between the common thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) and risk of vascular disease.In an angiographically assessed cohort of subjects with coronary artery disease (CAD) participating in a statin regression trial (RE-GRESS), significantly increased homocysteine concentrations were found in subjects homozygous (ϩ/ϩ) or heterozygous (ϩ/Ϫ) for the thermolabile variant compared with those carrying only the normal variant (Ϫ/Ϫ).Median levels were 2.8 and 0.8 mol/L higher in the ϩ/ϩ and ϩ/Ϫ subjects, respectively.Compared with population-based controls, there was trend toward higher risk of CAD in subjects carrying the thermolabile variant, but this did not reach significance (OR for ϩ/ϩ versus Ϫ/Ϫ: 1.21 [0.87 to 1.68]; ϩ/Ϫ versus Ϫ/Ϫ: 1.14 [0.94 to 1.38]).However, when the results were combined with those of 6 other studies, including our own, 2 in a meta-analysis, there was a significant increase in relative risk in subjects with the ϩ/ϩ genotype (OR, 1.22; 95% CI, 1.10 to 1.47).The data of Kluijtmans et al in a large cohort of wellcharacterized CAD patients are welcome.However, I am concerned by their meta-analysis.They have pooled together data from studies that have examined different phenotypes.For example, in our study, 2 we recruited subjects with myocardial infarction.Although there is, of course, a relationship between angiographic CAD and myocardial infarction, the 2 are not synonymous, and each has distinct determinants.This is likely to extend to genetic causes.Indeed, analysis of different phenotypes may explain at least some of the discrepancies that have been reported not only in relation to the thermolabile MTHFR mutation but also to other genetic factors.Meta-analysis, even when restricted to a single phenotype, has several well-recognized limitations. 3 When added to by heterogeneity in the phenotype, its validity is highly questionable.The meta-analysis carried out by Kluijtmans et al adds little to their primary data.Although positive, it should not be interpreted as strong evidence in support of a role for the MTHFR thermolabile mutation as a determinant of coronary risk.

The West of Scotland Coronary Prevention Study recently demonstrated the benefits of pravastatin therapy in the prevention of coronary heart disease events in middle-aged hypercholesterolemic men without prior myocardial infarction. We present an analysis of the influence of baseline risk factors on coronary events and total mortality in the trial, and their interaction with therapy, using the Cox proportional hazards model. The multivariate predictors of fatal or nonfatal coronary events were treatment allocation (pravastatin or placebo), current smoking, diabetes mellitus, nitrate consumption, minor electrocardiographic abnormalities, angina pectoris, family history of premature coronary death, widowhood, blood pressure, and total cholesterol/high density lipoprotein cholesterol ratio. Independent of other risk factors, pravastatin reduced the risk of definite coronary heart disease death or nonfatal myocardial infarction by 32% (95% confidence interval 17 to 44, p = 0.0001), definite or suspected coronary heart disease death by 35% (3 to 56, p = 0.035), cardiovascular death by 33% (4 to 53, p = 0.027), coronary revascularization procedures by 38% (11 to 56, p = 0.009), and all-cause mortality by 24% (2 to 41, p = 0.037). The 5-year risk of fatal or nonfatal myocardial infarction, calculated using the predictors identified in the Cox analysis, ranged from <4.4% in the lowest quartile of risk to >9.6% in the highest quartile. The proportional benefit achieved by pravastatin was independent of other risk factors; hence, the absolute benefit of therapy was greatest in subjects with the highest baseline risk. Such subjects can be identified easily in the population and deserve high priority for treatment. (C) 1997 by Excerpta Medica, Inc.

Aims To assess the additional benefit gained from high compliance in the West of Scotland Coronary Prevention Study and to examine cases where withdrawal from trial medication was due to an adverse event.Methods The incidence of definite coronary heart disease or non-fatal myocardial infarction, cardiovascular mortality, definite or suspect coronary heart disease death or non-fatal myocardial infarction, the need for coronary revascularization procedures, all-cause mortality and incident cancers were measured in the entire cohort and compared with the high compliance group. The adverse events associated with withdrawal were coded by body system.Results In subjects with compliance greater than or equal to 75%, treatment with pravastatin resulted in a 38% risk reduction for definite coronary heart disease death or non-fatal myocardial infarction and for cardiovascular mortality, a 46% reduction in risk or coronary revascularization and a 32% risk reduction (P = 0.015) for all-cause mortality.Conclusions The analysis of the effect of pravastatin in the subgroup of high compliers to randomized medication demonstrated a substantial increase in the estimated risk reductions in comparison with that achieved in the intention-to-treat analysis. This result has significant implications for the motivation of high compliance among patients and for the assessment of the cost-effectiveness of treatment.

The effects of colestipol therapy alone (20 g/d) or combined with simvastatin (20 mg/d) were examined in a group of eight male patients with primary moderate hypercholesterolemia (total cholesterol > or = 6.5 mmol/L [> or = 250 mg/dL]) who had undergone coronary artery bypass grafting more than 3 months previously. Colestipol therapy decreased total cholesterol by 14% (P < .001) and LDL cholesterol (LDL-C) by 23% (P < .001), while dual therapy decreased total cholesterol by 38% and LDL-C by 52% (both P < .001 versus baseline). No significant changes were observed in plasma triglyceride, VLDL cholesterol, or HDL cholesterol levels. VLDL subfraction turnovers were conducted at baseline and again on each regimen. ApoB kinetic parameters derived from a multicompartmental model suggested that colestipol therapy resulted in an expansion of the total VLDL apoB pool (36%, P < .05) that was largely due to a fall in the clearance rate of VLDL1 apoB (49%), while the LDL apoB pool decreased 23% as a result of diminished direct LDL input. The model used also revealed that addition of simvastatin to the resin therapy caused increases in the fractional transfer rates of VLDL2 to IDL and IDL to LDL together with a 37% increment in the LDL apoB fractional catabolic rate. Compared with baseline, combined therapy generated falls in both IDL (35%, P = .01) and LDL (37%, P < .04) apoB pools due to enhanced clearance of IDL (214%, P < .03) and reduced total input of LDL (39%, P < .003).

Background We assessed the potential benefit of treatment for low-risk and high-risk groups in the West of Scotland Coronary Prevention Study (WOSCOPS) population, and compared the benefits of primary and secondary prevention of coronary heart disease (CHD) by lipid lowering with the benefits of blood pressure reduction in the primary prevention of stroke.Methods We did a subgroup analysis of placebo-treated men in the WOSCOPS population by age, vascular disease at trial entry, and other established risk factors. We also compared WOSCOPS findings with those of the Scandinavian Simvastatin Survival Study (4S) and the Medical Research Council (MRC) trial of treatment for mild to moderate hypertension in middle-aged men. The WOSCOPS population comprised 6595 men aged 45-64 years with no history of myocardial infarction (MI) and plasma total cholesterol concentrations of 6 . 5-8 . 0 mmol/L at initial screening. Participants were randomly allocated pravastatin (40 mg daily) or placebo, and followed up for an average of 4 . 9 years.Findings Coronary event rates at 5 years in the WOSCOPS placebo group were higher than 10% (the recommended treatment threshold) in men with pre-existing vascular disease and in those 55 years or older without symptoms least one other low in men with hypercholesterolaemia but no other risk factor: 3 . 5% (95% CI 1 . 3-5 . 7) for men aged 45-54 years and 5 . 3% (2 . 7-8 . 0) for men aged 55-64 years. Three times more men had to be treated for 5 years to prevent one endpoint in WOSCOPS than in 4S, By contrast, two to four times fewer men with hyperlipidaemia were treated to save one coronary event in WOSCOPS than hypertensives to save one stroke in the MRC trial. These differences persisted after adjustment for the low-risk status of many of the patients with hypertension who took part in the MRC trial.Interpretation There were a substantial number of men whose risk of a coronary event was more than 10% at 5 years in the WOSCOPS cohort, The absolute benefit of pravastatin treatment of hyperlipidaemia is less in the primary prevention of CHD than in secondary prevention, but is similar to that for primary prevention of stroke by treatment of mild to moderate hypertension in middle-aged men.

The effects of combined therapy with acipimox (1250 mg/day) and cholestyramine (20 g/day) were examined in a group of 7 subjects with primary moderate hypercholesterolaemia (total cholesterol >=7 mmol/L). Radiolabeled VLDL subfraction turnovers were performed at baseline, during acipimox therapy and during combined therapy. Acipimox and combined therapies lowered plasma low density lipoprotein (LDL)-cholesterol by 20% (P<0.001) and 27% (P<0.001) respectively. The marked fall in LDL-cholesterol associated with acipimox therapy, was due to a reduced production rate of LDL (apolipoprotein) apoB. This is shown to be a result of reduced direct LDL apoB production, reduced IDL to LDL transfer consistent with inhibition of hepatic triglyceride lipase, and with a reduction in the overall throughput of VLDL1 apoB. With combined therapy both reduced production and increased catabolism of apoB containing LDL precursors and of LDL itself have to be invoked to explain the fall in plasma LDL-cholesterol.

BACKGROUND:Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease.METHODS:We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points.RESULTS:Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051).CONCLUSIONS:Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.

The West of Scotland Coronary Prevention Study (WOSCOPS) is a randomized, double-blind, placebo-controlled trial of pravastatin in a primary prevention context. The primary end point of the trial is definite coronary artery disease (CAD) death and/or nonfatal acute myocardial infarction, This study describes the baseline characteristics of the trial recruits and of the subjects who were screened during the recruitment process; 6,595 men, aged 45 to 64 years, with raised cholesterol levels, were randomized in equal numbers to placebo or pravastatin after initial screening of approximately 81,000 subjects in the West of Scotland, With the exception of cholesterol levels and history of CAD, the recruits had a similar risk factor profile and demographic distribution to the group of screenees from which they were selected. Compared with previous primary prevention studies of cholesterol-lowering drugs, the WOSCOPS recruits are, on average, 7 to 9 years older than subjects in other trials and have average total cholesterol levels 0.5 mmol/L (19.4 mg/dl) lower than those in the Helsinki Heart Study and the Lipid Research Clinics-Coronary Primary Prevention Trial, The study has achieved its initial goal of accumulating >30,000 patient-years of randomized follow-up, Recruits had their final trial visits in the first half of 1995 and the main results will be available in the fourth quarter of 1995.

An analysis of apolipoprotein (apo) B turnovers conducted in subjects with moderate hypercholesterolemia was performed to discover relationships that may exist between apoB kinetic parameters and plasma lipid and lipoprotein levels. A group of 21 subjects with plasma cholesterol in the range 250-300 mg/dl and triglyceride < 265 mg/dl were injected with tracers of 131I-labeled very low density lipoprotein 1 (VLDL1, Sf 60-400) and 125I-labeled VLDL2 (Sf 20-60) prepared by cumulative flotation ultracentrifugation. The metabolism of apoB in these fractions was followed through intermediate density (IDL, Sf 12-20) to low density (LDL, Sf 0-12) lipoprotein. The most consistent feature giving rise to the higher apoB levels that occurred in VLDL2, IDL, and LDL in the hypercholesterolemic group was increased input of VLDL2 (787 +/- 607 (SD) mg/day vs. 349 +/- 213 in normals, P < 0.01). VLDL1 apoB input was variably affected and not significantly different from normal. However, the plasma residence time of this subfraction was increased (0.15 +/- 0.07 days vs. 0.08 +/- 0.03 days in normals, (P < 0.001) due to a decreased fractional rate of direct catabolism. Fractional transfer rates (FTR) down the delipidation cascade and other fractional rates of direct catabolism were, overall, not significantly different from normal. The plasma residence time of VLDL2 apoB and LDL apoB was similar in hypercholesterolemic and normal subjects, while that of IDL apoB was slightly increased. Variation in LDL apoB mass within the hypercholesterolemic group correlated with VLDL1 apoB input (r = 0.58, P = 0.006), the fractional rate of transfer from IDL to LDL (r = 0.61, P = 0.003), and direct LDL input (r = 0.64, P = 0.002). The proportion of LDL apoB mass derived by direct, i.e., VLDL-independent input, varied from 5 to 50% and was inversely correlated with plasma triglyceride (r = -0.53, P = 0.014) and positively with HDL2 (r = 0.66, P = 0.002). In addition, the amount of direct LDL input was related to the amount of VLDL1 removed by direct catabolism (r = 0.53, P = 0.013). The analysis indicated that moderate hypercholesterolemia arose principally from overproduction of small VLDL, while variation in VLDL1 input and the IDL to LDL conversion rate (presumably hepatic lipase-mediated) modulated the extent of the elevation in LDL apoB.