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We report the results of a randomized single-centre study designed to assess the effects of simvastatin on blood lipids, blood biochemistry, haematology and other measures of safety and tolerability in preparation for a large-scale multicentre mortality study. Six hundred and twenty-one individuals considered to be at increased risk of coronary heart disease were randomized, following a 2-month placebo ‘run-in’ period, to receive 40 mg daily simvastatin, 20 mg daily simvastatin or matching placebo. Their mean age was 63 years, 85% were male, 62% had a history of prior myocardial infarction (MI), and the mean baseline total cholesterol was 7·0 mmol. 1. Median follow-up in the present report is 3·4 years. Eight weeks after randomization, 40 mg daily simvastatin had reduced non-fasting total cholesterol by 29·2% ± 1·1 (2·03 ± 0·08 mmol. 1)and 20 mg daily simvastatin had reduced it by 26·8% ± 1·0 (1·87 ± 0·07 mmol. 1). Almost all of tile difference in total cholesterol at 8 weeks was due to the reduction in LDL cholesterol (40·8±1·6 and 38·2%±1·4 among patients allocated 40mg and 20mg of simvastatin daily respectively), but simvastatin also reduced triglycerides substantially (19·0% and 17·3%) and produced a small increase in HDL cholesterol (6·4% and 4·8%). These effects were largely sustained over the next 3 years, with 40 mg daily simvastatin producing a slightly greater reduction in total cholesterol at 3 years (25·7%±1·9 reduction) than did 20 mg daily simvastatin (22·2%±1·8). There were no differences between the treatment groups in the numbers of reports of ‘possible adverse effects’ of treatment or of a range of different symptoms or conditions (including those related to sleep or mood) recorded at regular clinic follow-up. Mean levels of alanine aminotransferase, aspartate aminotransferase and creatine kinase were slightly increased by treatment, but there were no significant difference between the treatment groups in the numbers of patients with significantly elevated levels. A slightly lower platelet count in the simvasatin group was the only haematological difference from placebo, with no difference in the numbers of patients with low platelet counts. In summary, the simvastatin regimens studied produced large sustained reductions in total cholesterol, LDL cholesterol and triglyceride and small increases in HDL cholesterol. They were well tolerated, with no evidence of serious side-effects during the first 3 years of this study. Consequently, simvastatin provides an opportunity to conduct large randomized studies that assess the effects of cholesterol lowering on total mortality and on cause-spec mortality. Even with such an effective cholesterol lowering treatment, however such mortality studies will still need to be prolonged and to involve some tens of thousands of patients at substantial risk of coronary heart disease if clear evidence is to emerge. [ABSTRACT FROM PUBLISHER]

The cumulative occlusion rates of aorto-coronary artery venous bypass grafts average from 16 to 26% per distal anastomosis within 12 months and about 2% per following year. The potential benefit of oral anticoagulants and platelet inhibitor drugs has been tested to prevent graft occlusion and to retard the atherosclerotic process. Oral anticoagulants started on the third postoperative day do not significantly reduce graft occlusion after 6 months. Among the platelet inhibitor drugs, dipyridamole started before surgery, followed by dipyridamole and aspirin soon after surgery, was the drug regimen with the best results. More randomised double-blind clinical trials are highly desirable to confirm these findings and to resolve the question of relative efficacy and safety for the various drugs reported to have shown benefit when used in combination. [ABSTRACT FROM PUBLISHER]

475 patients with suspected uncomplicated myocardial infarction (MI) were divided into 3 groups based on their entry ECG: group 1 — significant ST elevation; group 2a — ST depression or T inversion, group 2b — normal ECG. Infarction was confirmed in 99.7% of group 1, 68.5% of group 2a and 39.7% of group 2b patients. Despite similar clinical, haemodynamic and historical variables at presentation, group 1 patients had significantly larger MI, more in-hospital complications and a higher short-term and longterm mortality (P<0.005) than group 2 patients. The entry ECG of patients with suspected MI is an excellent and simple predictor of those who are most likely to have an MI confirmed and identifies a group of patients at high risk of death or developing complications. [ABSTRACT FROM PUBLISHER]

Heterotopic cardiac transplantation where the recipient heart remains in tandem with the donor heart has a one-year survival of approximately 80%. Rhythm disturbances after heterotopic cardiac transplantation have rarely been described and their potential influence on the patients symptoms and prognosis is unclear. We report a case of supraventricular tachycardia of the recipient heart in a patient following heterotopic heart transplantation recorded during ambulatory electrocardiographic monitoring. [ABSTRACT FROM PUBLISHER]

Aims: Plasma levels of apolipoprotein B (apoB), the main surface protein on LDL particles, and LDL-C, the amount of cholesterol in those particles, are closely correlated and, considered separately, are positive risk factors. Plasma levels of apolipoprotein A(1), the main surface protein on HDL particles, and HDL-C, the amount of cholesterol in those particles, are also closely correlated with each other and, considered separately, are negative risk factors. The interdependence of these four risk factors is unclear., Methods and Results: Case-control study among 3510 acute myocardial infarction patients (without prior vascular disease, diabetes, or statin use) in UK hospitals and 9805 controls. Relative risks (age, sex, smoking, and obesity-adjusted) were more strongly related to apoB than to LDL-C and, given apoB, more strongly negatively related to apoA(1) than to HDL-C. The ratio apoB/apoA(1) was uncorrelated with time since symptom onset in cases, was reproducible in samples collected a few years apart in controls (correlation 0.81), and encapsulated almost all the predictive power of these four measurements. Its effect was continuous, substantial throughout the UK normal range [relative risk, top vs. bottom decile of this ratio, 7.3 (95% CI 5.8-9.2)] and varied little with age. The ratio apoB/apoA(1) was substantially more informative about risk (chi(1)(2) = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol (chi(1)(2) = 407, 334, 204, and 105, respectively). Given apoB and apoA(1), the relationship with risk of LDL-C was reversed, and this reversal was strengthened by appropriate allowance for random measurement errors in two correlated variables. Given usual apoB, lower LDL-C (consistent with smaller LDL particles) was associated with higher risk (P < 0.0001). During the first 8 h after symptom onset HDL-C increased by about 10%, precluding reliable assessment of the joint relationship of apoA(1) and pre-onset HDL-C with risk in such retrospective case-control studies., Conclusion: Apolipoprotein ratios are more informative about risk than lipid fractions are. This suggests that, among lipoprotein particles of a particular type (LDL or HDL), some smaller and larger subtypes differ in their effects on risk. Direct measurements of even more specific subtypes of lipoprotein particles may be even more informative about risk.

Randomized clinical trials (RCTs) are the definitive contributors to evidence-based medicine. RCTs assessing serious outcomes in cardiovascular disease have grown, with 'megatrials' becoming more common with the realization that wrong conclusions resulted from random error in inadequately sized trials. Simple design and a heterogeneous patient population were early features, but multinational trials have increased in scientific, logistical, bureaucratic, regulatory, and legal complexity. These studies now exceed the financial means of academia or medical charities. Governments have left the bill with the pharmaceutical industry, encouraging a symbiosis with academics, who contribute medical and scientific expertise, and access to patients. Industry provides pharmacological, pharmaceutical, technical and regulatory know-how, good clinical practice expertise, and legal assistance during the trial. Study supervision is then in the hands of an independent steering committee and associated subcommittees, until appropriate dissemination of results. Prospectively defined interaction with the sponsor facilitates unbiased design and conduct, but arrangements need careful implementation to avoid conflicts of interest. The patient is protected by a strong data safety monitoring board that is wholly independent. Megatrials are under threat from over-regulation, increasing costs, and difficulties in execution. These issues merit urgent public and political education and debate.