Richard Peto

Beta blockade during and after myocardial infarction: An overview of the randomized trials

Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value, and for many such patients mortality reductions of about 25% can be achieved. No important differences are clearly apparent among the benefits of different beta blockers, although some are more convenient than others (or have slightly fewer side effects), and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit. If monitored, the side effects of long-term therapy are not a major problem, as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment. By contrast, although very early IV short-term beta blockade can definitely limit infarct size, more reliable information about the effects of such treatment on mortality will not be available until a large trial (ISIS) reports later this year, with data on some thousands of patients entered within less than 4 hours of the onset of pain. Our aim has been not only to review the 65-odd randomized beta blocker trials but also to demonstrate that when many randomized trials have all applied one general approach to treatment, it is often not appropriate to base inference on individual trial results. Although there will usually be important differences from one trial to another (in eligibility, treatment, end-point assessment, and so on), physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related randomized trials and not just a few particular trial results. Although most trials are too small to be individually reliable, this defect of size may be rectified by an overview of many trials, as long as appropriate statistical methods are used. Fortunately, robust statistical methods exist--based on direct, unweighted summation of one O-E value from each trial--that are simple for physicians to use and understand yet provide full statistical sensitivity. These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another. (Moreover, they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust.) Their robustness, sensitivity, and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews.

Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.

PURPOSEnTo examine long-term cause-specific mortality in patients irradiated for breast cancer as part of a randomized clinical trial.nnnPATIENTS AND METHODSnWe studied all available information from randomized trials initiated before 1975 in which radiotherapy was the randomized option and surgery was the same for both treatment arms. Eight such trials were identified.nnnRESULTSnThe increased all-cause mortality rate in 10-year survivors previously reported is no longer significant, although a numerical difference in favor of non-irradiated patients remains. This result was strongly influenced by the earliest trials, and more recent trials have found a nonsignificant net benefit in overall mortality associated with radiation therapy. An excess of cardiac deaths was apparent in both early and more recent trials (P < .001), but this was offset by a reduced number of deaths due to breast cancer, especially in more recent trials.nnnCONCLUSIONnThe reduction of breast cancer deaths suggests that radiation therapy may have a value beyond the clearly established improvements obtainable for local control. Use of techniques that minimize cardiac dose is important in reducing the risks of adjuvant radiotherapy, especially in good-prognosis patients.

Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease.

Antiplatelet therapy, particularly with aspirin, has become the focus of much research in the treatment and prevention of cardiovascular disease. In this paper, we review the evidence of efficacy; first, for patients who have a history of myocardial infarction (M1), stroke, transient cerebral ischemia (TCI), or unstable angina; second, for those actually undergoing acute myocardial infarction (AMI); and, finally, for apparently healthy individuals.

China Kadoorie Biobank of 0.5 million people: survey methods, baseline characteristics and long-term follow-up

BACKGROUNDnLarge blood-based prospective studies can provide reliable assessment of the complex interplay of lifestyle, environmental and genetic factors as determinants of chronic disease.nnnMETHODSnThe baseline survey of the China Kadoorie Biobank took place during 2004-08 in 10 geographically defined regions, with collection of questionnaire data, physical measurements and blood samples. Subsequently, a re-survey of 25,000 randomly selected participants was done (80% responded) using the same methods as in the baseline. All participants are being followed for cause-specific mortality and morbidity, and for any hospital admission through linkages with registries and health insurance (HI) databases.nnnRESULTSnOverall, 512,891 adults aged 30-79 years were recruited, including 41% men, 56% from rural areas and mean age was 52 years. The prevalence of ever-regular smoking was 74% in men and 3% in women. The mean blood pressure was 132/79 mmHg in men and 130/77 mmHg in women. The mean body mass index (BMI) was 23.4 kg/m(2) in men and 23.8 kg/m(2) in women, with only 4% being obese (>30 kg/m(2)), and 3.2% being diabetic. Blood collection was successful in 99.98% and the mean delay from sample collection to processing was 10.6 h. For each of the main baseline variables, there is good reproducibility but large heterogeneity by age, sex and study area. By 1 January 2011, over 10,000 deaths had been recorded, with 91% of surviving participants already linked to HI databases.nnnCONCLUSIONnThis established large biobank will be a rich and powerful resource for investigating genetic and non-genetic causes of many common chronic diseases in the Chinese population.

Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease.

Physical activity and sedentary leisure time and their associations with BMI, waist circumference, and percentage body fat in 0.5 million adults: the China Kadoorie Biobank study

BACKGROUNDnFew large studies in China have investigated total physical activity and sedentary leisure time and their associations with adiposity.nnnOBJECTIVEnWe investigated determinants of physical activity and sedentary leisure time and their associations with adiposity in China.nnnDESIGNnA total of 466,605 generally healthy participants (age: 30-79 y, 60% female) in the China Kadoorie Biobank were included in this cross-sectional analysis. Self-reported information on a range of activities was collected by interviewer-administered questionnaire. Physical activity was calculated as metabolic equivalent task hours per day (MET-h/d) spent on work, transportation, housework, and nonsedentary recreation. Sedentary leisure time was quantified as hours per day. Adiposity measures included BMI, waist circumference, and percentage body fat (by bioimpedance analysis). Associations were estimated by linear and logistic regression.nnnRESULTSnThe mean physical activity was 22 MET-h/d, and the mean sedentary leisure time was 3.0 h/d. For each sex, physical activity was about one-third lower among professionals/administrators than among factory workers, with intermediate levels for other occupational categories. A 1-SD (14 MET-h/d) greater physical activity was associated with a 0.15-unit (95% CI: 0.14, 0.16) lower BMI (in kg/m(2)), a 0.58-cm (95% CI: 0.55, 0.61) smaller waist circumference, and 0.48 (95% CI: 0.45, 0.50) percentage points less body fat. In contrast, a 1-SD (1.5 h/d) greater sedentary leisure time was associated with a 0.19-unit higher BMI (95% CI: 0.18, 0.20), a 0.57-cm larger waist circumference (95% CI: 0.54, 0.59), and 0.44 (95% CI: 0.42, 0.46) percentage points more body fat. For any given physical activity level, greater sedentary leisure time was associated with a greater prevalence of increased BMI, as was lower physical activity for any given sedentary leisure time.nnnCONCLUSIONSnIn adult Chinese, physical activity varies substantially by occupation, and lack of physical activity and excess sedentary leisure time are independently and jointly associated with greater adiposity.

Calculation of carcinogenic potency from long-term animal carcinogenesis experiments.

An index of carcinogenic potency for chemicals tested in chronic animal experiments is described. By analogy with the well-known lethal dose 50 (LD50) of quantal bioassay, a tumorigenic dose 50 (TD50) may be defined (in the absence both of tumors in the control group and of intercurrent deaths) as that (daily) dose of chemical which gives 50% of the test animals tumors by some fixed age. Tumors in the control (zero-dose) group are handled exactly as for the LD50, and intercurrent deaths are handled by life-table methods. Nonparametric procedures are developed for estimating the TD50 and for constructing confidence intervals. These are based on likelihoods which assume that the tumor hazard is linear in dose.

The exon 1-8C/G SNP in the PSMA6 gene contributes only a small amount to the burden of myocardial infarction in 6946 cases and 2720 controls from a United Kingdom population

The proteasome system is a proteolytic pathway that regulates the expression of genes involved in inflammation. Polymorphisms in the gene encoding subunit α type 6 (PSMA6) – in particular the rs1048990 exon 1–8C/G SNP – have been implicated with susceptibility to myocardial infarction (MI) in a Japanese study. We examined whether several polymorphisms in the PSMA6 gene were related to MI risk in 6946 nonfatal MI cases and 2720 unrelated controls in a UK population. The homozygous GG genotype for rs1048990 was much less frequent in this UK population than in the Japanese population (2.1 vs 8.9%), and was associated with an odds ratio (OR) for MI of 1.09 (95% confidence interval (CI): 0.98–1.21) per G allele in a co-dominant genetic model and 1.32 (95% CI: 0.90–1.93) in a recessive genetic model. Although not statistically significant, these results for this variant are still consistent with the Japanese hypothesis-generating study. Our findings, when taken together with four other studies (including the hypothesis-generating one), yielded a combined OR for MI of 1.15 (95% CI: 1.08–1.21) per G allele in a co-dominant model and 1.38 (95% CI: 1.22–1.57) for the GG genotype in a recessive model. Larger studies involving more than 10u2009000 disease cases would be required to further elucidate the role of this variant for susceptibility to MI. However, given the rarity of this variant in Caucasians, the attributable risk of rs1048990 for MI is unlikely to be great in western populations.

Epidemiology and the control of disease in China, with emphasis on the Chinese Biobank Study.

Similar to many other developing countries, China is facing a double burden of disease as a result of epidemiological transition. Non-communicable diseases (NCDs) represent a major challenge, having an adverse effect on the health of the Chinese population and increasing the economic burden of health care. In todays era of evidence-based medicine and decision making, China, as a developing country, has a lack of local scientific evidence which will affect the effectiveness of NCD prevention and control. As such, and on the basis of decades of cooperation and trust with the University of Oxford, the Chinese Biobank Study [Kadoorie Study of Chronic Disease in China (KSCDC)] was commenced in 2004. KSCDC, an international prospective project, aims to establish the basis of a blood-based health database, using genetic, environmental and lifestyle aspects to investigate and understand the causes, risk factors, pathogenesis, prevalence patterns and trends of major chronic diseases in China (such as stroke, coronary heart disease, cancer, diabetes, hypertension, chronic obstructive pulmonary disease etc.). This study has a duration of 15-20 years, and will provide scientific evidence for strategic planning of NCD prevention and control, and development of new treatment and intervention approaches. In total, approximately 510,000 adults aged 30-79 years have been recruited from the general population in 10 geographically defined regions (five rural and five urban) of China, with differing disease profiles and differing risk exposures. Extensive data collection has been undertaken with questionnaires, physical measurements, and collection and storage of blood samples. KSCDC is a multi-factor, multi-disease, multi-disciplinary large-scale chronic disease epidemiological study, and is also one of the largest long-term blood-based population cohort studies ever conducted in the world. It is worth mentioning that all gene specimens are kept in China, and all associated intellectual property rights are owned by international cooperation groups; this breaks new ground for Chinese and foreign international cooperation. This article describes the study design, baseline description and main results to date.

Comparative Carcinogenicity for Mouse-Skin of Smoke Condensates Prepared from Cigarettes Made from the Same Tobacco Cured by Two Processes

Bright tobacco grown in Mexico was either flue-cured and redried (FC) or air-cured and bulk-fermented (AC). Both FC and AC were made into cigarettes standardized for draw resistance. FC and AC cigarettes were smoked under similar conditions in a smoking machine (one 2-second 25 ml. puff per minute down to a 20 mm. butt length). Condensates were kept at 0-4° C. until applied to the skin of mice.Three groups of 400 female Swiss mice were treated as follows: Group 1— thrice weekly application of 60 mg. FC in 0.25 ml. acetone to the clipped dorsal skin: Group 2— similar treatment with AC; Group 3—thrice weekly application of 0.25 ml. acetone only.Chemical analysis of the 2 tobaccos and 2 condensates revealed only small differences in composition and it is noteworthy that the concentration of reducing sugars was almost as high as in the AC tobacco as in the FC tobacco.The risk of development of skin tumours, particularly malignant skin tumours, was higher in FC-treated mice than in AC-treated mice (p < 0.01), but the difference may have been due to the use of equal weights of condensates rather than the use of extracts from equal numbers of cigarettes, since the AC cigarettes produced more condensate. The rates of detection of pulmonary tumours also varied between groups (p < 0.01) but this does not necessarily imply that the incidence rates of pulmonary tumours varied. There was no evidence that the detection or incidence rates of any other neoplasms, including malignant lymphoma, were affected by treatment with either of the condensates.