Showing papers by "Clinical Trial Service Unit published in 2006"

Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials

Abstract: Objective To assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events. Design Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs. Data sources Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck. Review methods Eligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks9 duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group. Results In placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year9s duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9%/year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac. Conclusions Selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.

Residential radon and lung cancer – detailed results of a collaborative analysis of individual data on 7148 persons with lung cancer and 14 208 persons without lung cancer from 13 epidemiologic studies in Europe

Abstract: Objectives: Studies seeking direct estimates of the lung cancer risk associated with residential radon exposure lasting several decades have been conducted in many European countries. Individually these studies have not been large enough to assess moderate risks reliably. Therefore data from all 13 European studies of residential radon and lung cancer satisfying certain prespecified criteria have been brought together and analyzed. Methods: Data were available for 7148 persons with lung cancer and 14 208 controls, all with individual smoking histories and residential radon histories determined by long-term radon gas measurements. Results: The excess relative risk of lung cancer per 100 Bq/m3 increase in the observed radon concentration was 0.08 [95% confidence interval (95% CI) 0.03-0.16; P=0.0007] after control for confounding. The dose-response relationship was linear with no evidence of a threshold, and it remained significant when only persons with observed radon concentrations of <200 Bq/m3 were included. There was no evidence that the excess relative risk varied with age, sex, or smoking history. Removing the bias induced by random uncertainties related to radon exposure assessment increased the excess relative risk of lung cancer to 0.16 (95% CI 0.05-0.31) per 100 Bq/m3. With this correction, estimated risks at 0, 100, and 400 Bq/m3, relative to lifelong nonsmokers with no radon exposure, were 1.0, 1.2, and 1.6 for lifelong nonsmokers and 25.8, 29.9, and 42.3 for continuing smokers of 15-24 cigarettes/day. Conclusions: These data provide firm evidence that residential radon acts as a cause of lung cancer in the general population. They provide a solid basis for the formulation of policies with which to manage risk from radon and reduce deaths from the most common fatal cancer in Europe.

Fibrinogen and coronary heart disease: test of causality by 'Mendelian randomization'

Abstract: BACKGROUND: Blood concentrations of fibrinogen have been associated with coronary heart disease risk in epidemiological studies, but it is uncertain whether this association is causal or reflects residual confounding by other risk factors. We investigated the relationship between the single nucleotide polymorphism at position -148 in the beta-fibrinogen gene promoter (beta - 148C/T), blood fibrinogen levels, and risk of myocardial infarction (MI) in sufficiently large numbers of coronary disease cases to reliably address this question. METHODS: Genotyping and measurement of blood fibrinogen concentration were carried out in 4,685 cases of confirmed MI and 3,460 controls with no history of coronary disease. A meta-analysis of ISIS and 19 other studies of beta-fibrinogen genotypes involving a total of 12,220 coronary disease cases and 18,716 controls was conducted. RESULTS: Among the ISIS controls, mean plasma fibrinogen concentrations with the C/C, C/T and T/T genotypes were 3.34 (SE 0.015), 3.48 (0.022), and 3.60 (0.064) g/l, respectively, corresponding to an increase of 0.14 (0.024) g/l per T allele (trend P < 0.0001). In the case-control comparison, 0.14 g/l higher usual plasma fibrinogen concentration was associated with an age-adjusted and sex-adjusted risk ratio for MI of 1.17 [95% confidence interval (95% CI) 1.14-1.19; P < 0.0001]. But, after further adjustment for smoking, body mass index, and plasma apolipoprotein B/A(1) ratio, this risk ratio fell to 1.03 (95% CI 1.00-1.05; P = 0.05). Moreover, fibrinogen genotype was not significantly associated with MI incidence: risk ratio of 1.06 (95% CI 0.96-1.16) per higher-fibrinogen allele in ISIS alone and of 1.00 (95% CI 0.95-1.04) per allele in the meta-analysis. CONCLUSIONS: Genotypes that produce lifelong differences in fibrinogen concentrations do not materially influence coronary disease incidence. As these genotype-dependent differences in fibrinogen were allocated randomly at conception (Mendelian randomization), this association is not likely to be confounded by other factors. Consequently, these genetic results provide strong evidence that long-term differences in fibrinogen concentrations are not a major determinant of coronary disease risk.

Estimates of the cancer burden in Europe from radioactive fallout from the Chernobyl accident.

Abstract: The Chernobyl accident, which occurred April 26, 1986, resulted in a large release of radionuclides, which were deposited over a very wide area, particularly in Europe. Although an increased risk of thyroid cancer in exposed children has been clearly demonstrated in the most contaminated regions, the impact of the accident on the risk of other cancers as well as elsewhere in Europe is less clear. The objective of the present study was to evaluate the human cancer burden in Europe as a whole from radioactive fallout from the accident. Average country- and region-specific whole-body and thyroid doses from Chernobyl were estimated using new dosimetric models and radiological data. Numbers of cancer cases and deaths possibly attributable to radiation from Chernobyl were estimated, applying state-of-the-art risk models derived from studies of other irradiated populations. Simultaneously, trends in cancer incidence and mortality were examined over time and by dose level. The risk projections suggest that by now Chernobyl may have caused about 1,000 cases of thyroid cancer and 4,000 cases of other cancers in Europe, representing about 0.01% of all incident cancers since the accident. Models predict that by 2065 about 16,000 (95% UI 3,400-72,000) cases of thyroid cancer and 25,000 (95% UI 11,000-59,000) cases of other cancers may be expected due to radiation from the accident, whereas several hundred million cancer cases are expected from other causes. Although these estimates are subject to considerable uncertainty, they provide an indication of the order of magnitude of the possible impact of the Chernobyl accident. It is unlikely that the cancer burden from the largest radiological accident to date could be detected by monitoring national cancer statistics. Indeed, results of analyses of time trends in cancer incidence and mortality in Europe do not, at present, indicate any increase in cancer rates -- other than of thyroid cancer in the most contaminated regions -- that can be clearly attributed to radiation from the Chernobyl accident.

Adolescents with acute lymphoblastic leukaemia: Emerging from the shadow of paediatric and adult treatment protocols

Abstract: Adolescents and young adults (AYA) with acute lymphoblastic leukaemia (ALL) constitute a distinct population from children and older adults Based on patterns of referral, they may be treated by either paediatric or adult oncologists As a group, AYA with ALL have a worse survival and event-free survival (EFS) compared to that achieved by younger children A systematic review of all published clinical trials, which provide data on treatment and outcome of adolescents with ALL, has been summarised in an effort to determine whether they should be treated on paediatric or adult type protocols Adolescents appear to have a consistent survival advantage when treated on paediatric regimens

Effect of alcohol on risk of coronary heart disease and stroke: causality, bias, or a bit of both?

Abstract: Epidemiological studies of middle-aged populations generally find the relationship between alcohol intake and the risk of coronary heart disease (CHD) and stroke to be either U- or J-shaped This review describes the extent that these relationships are likely to be causal, and the extent that they may be due to specific methodological weaknesses in epidemiological studies The consistency in the vascular benefit associated with moderate drinking (compared with non-drinking) observed across different studies, together with the existence of credible biological pathways, strongly suggests that at least some of this benefit is real However, because of biases introduced by: choice of reference categories; reverse causality bias; variations in alcohol intake over time; and confounding, some of it is likely to be an artefact For heavy drinking, different study biases have the potential to act in opposing directions, and as such, the true effects of heavy drinking on vascular risk are uncertain However, because of the known harmful effects of heavy drinking on non-vascular mortality, the problem is an academic one Studies of the effects of alcohol consumption on health outcomes should recognise the methodological biases they are likely to face, and design, analyse and interpret their studies accordingly While regular moderate alcohol consumption during middle-age probably does reduce vascular risk, care should be taken when making general recommendations about safe levels of alcohol intake In particular, it is likely that any promotion of alcohol for health reasons would do substantially more harm than good

Cancer and the immortal strand hypothesis.

Abstract: THE main causes of mortality in the Western world are largely a matter of somatic genetics. As we age, our cells accumulate more and more mutations. Eventually one of them acquires a set of changes in phenotype that allows it to generate an expanding clone of descendants, causing an atheromatous plaque in an artery or an invasive cancer. These changes are the result of a cumulative process extending throughout our life, as is demonstrated in the relation between smoking and lung cancer and between pregnancy and breast cancer. Someone who started smoking at the age of 15 will, when 65, have a higher risk of lung cancer than someone who started at 20, showing that lungs can store for half a century the damage acquired in your teenage years (Doll and Peto 1981). Conversely, because pregnancy protects somewhat against the subsequent risk of breast cancer, a woman who first became pregnant when 13 will, when 70, have a lower risk of breast cancer than a woman whose first pregnancy was in her 20s, showing that the latter was accumulating risk as a teenager (MacMahon et al. 1973). Long-lived animals protect themselves from the physical and chemical dangers of their environment by continuous replacement of the cells on their external surfaces and it is in these sites of continuous cell division that most human cancers arise. An adult human contains ∼1012 rapidly multiplying cells. During a life span of ∼30,000 days, each of us makes and discards from skin, gut, and certain internal organs such as lymph glands and bone marrow about one-third of these cells each day (Potten and Morris 1988). If all these 1012 cells divide every third day, the cells remaining after 80 years would each have had ∼10,000 successive divisions in their ancestry. So by the age of 80, given a mutation rate of ∼10−6/gene/replication (Drake 1999), 1 in 100 of the copies of each gene would be mutant. In a collection of 1012 cells, 1010 would have a mutant copy of any particular gene, 108 would have mutations in any pair of genes, and a million would have mutations in any trio of genes. Nevertheless, despite there being many combinations of mutant genes that can trigger cancer (Hahn and Weinberg 2002), most people never develop cancer. So there must be some feature of multicellular systems that slows the rate of accumulation of replication errors.

Lymphotoxin-α Gene and Risk of Myocardial Infarction in 6,928 Cases and 2,712 Controls in the ISIS Case-Control Study

Abstract: Lymphotoxin-α (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-α (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case-control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p = 0.004) and lower concentrations of albumin (p = 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease.

Body mass index and mortality from ischaemic heart disease in a lean population: 10 year prospective study of 220 000 adult men

Abstract: Conclusions Lower BMI is associated with lower IHD risk among people in the so-called normal range of BMI values (20–25 kg/m 2 ), but below that range the association may well

Balancing potential risks and benefits of using confidential data

Abstract: Public health benefits arising from advances in medical research often rely on the use of personal data. How can we ensure that protecting patients9 interests does not unduly hamper scientific study?

Statins: are any questions unanswered?

Abstract: Purpose of review To summarize recent and ongoing randomized trials of statin therapy for the prevention of major vascular events. Recent findings Four large-scale randomized trials have compared high-dose vs. standard doses of statin therapy among patients with coronary heart disease, and their results suggest that higher doses are more effective for preventing major vascular events, albeit with evidence of increased toxicity. There is now clear evidence that statin therapy is effective among most patients with type 2 diabetes, although uncertainty remains about the benefits in those with advanced nephropathy. Ongoing trials will assess whether statin therapy is beneficial among patients with noncoronary vascular disease (such as congestive heart failure, cerebrovascular disease, or aortic stenosis), and among people with comorbid conditions or risk factors that increase the risk of vascular disease (including chronic kidney disease and raised C-reactive protein with below average low-density lipoprotein cholesterol). Summary Statin therapy safely reduces the risk of vascular events in a wide range of patients. Uncertainties persist about the effects of higher statin doses and the role of statins among patients with specific conditions or risk factors.

The Citizenship Safety Project: a pilot study

Abstract: The Government White Paper Saving Lives: Our Healthier Nation (1999) provides a clear indication that accidents are a serious public health problem and have been targeted by the Department of Health as a key area for prevention over the next 10 years. School-based injury prevention programmes have been identified as one of the key settings for the implementation of the White Paper’s heath promotion strategies. The Citizen Safety Project (CSP) is a peer-delivered injury prevention programme for Year 10 students (14‐15 years) and Year 2 pupils (6‐7 years). This paper summarizes the findings of a pilot study that assessed the feasibility of implementing the CSP in schools and of conducting a larger study. Working as part of their Personal Social Health Education lessons, 11 pairs (n 5 22) of Year 10 students developed a project to take one accident prevention theme of their choice into a primary school to teach small groups of five or six Year 2 pupils (n 5 55). A formative evaluation was conducted, based on interviews with Year 2 and Year 10 teachers (n 5 2), and the diaries of Year 10 students. Knowledge of accident prevention and risk awareness was measured in Year 2 pupils using the Draw and Write technique, and impact on Year 10 students was measured using self-esteem and locus of control inventories. Using both statistical and thematic analysis the study concludes that the CSP is well accepted, improves knowledge in Year 2 pupils and boosts confidence in Year 10 students, while concurrently achieving key stage attainment targets. Implications of the study are discussed in terms of future research, as are recommendations with regard to modifications to the project.