Vladimir Bezlyak

Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled trial

BACKGROUND There are few therapeutic options for the prevention of gastrointestinal mucosal damage caused by low-dose aspirin. We therefore investigated the efficacy of famotidine, a well-tolerated histamine H(2)-receptor antagonist, in the prevention of peptic ulcers and erosive oesophagitis in patients receiving low-dose aspirin for vascular protection. METHODS Adult patients (aged >/=18 years) from the cardiovascular, cerebrovascular, and diabetes clinics at Crosshouse Hospital, Kilmarnock, UK, were eligible for enrolment in this phase III, randomised, double-blind, placebo-controlled trial if they were taking aspirin 75-325 mg per day with or without other cardioprotective drugs. Patients without ulcers or erosive oesophagitis on endoscopy at baseline were randomly assigned by computer-generated randomisation sequence to receive famotidine 20 mg twice daily (n=204) or placebo twice daily (n=200). Patients had a final endoscopic examination at 12 weeks. The primary endpoint was the development of new ulcers in the stomach or duodenum or erosive oesophagitis at 12 weeks after randomisation. Analysis was by intention to treat, including all randomised patients who received at least one dose of study drug (famotidine or placebo). This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN96975557. FINDINGS All randomised patients received at least one dose and were included in the ITT population. 82 patients (famotidine, n=33; placebo, n=49) did not have the final endoscopic examination and were assumed to have had normal findings; the main reason for participant withdrawal was refusal to continue. At 12 weeks, comparing patients assigned to famotidine with patients assigned to placebo, gastric ulcers had developed in seven (3.4%) of 204 patients compared with 30 (15.0%) of 200 patients (odds ratio [OR] 0.20, 95% CI 0.09-0.47; p=0.0002); duodenal ulcers had developed in one (0.5%) patient compared with 17 (8.5%; OR 0.05, 0.01-0.40; p=0.0045); and erosive oesophagitis in nine (4.4%) compared with 38 (19.0%; OR 0.20, 0.09-0.42; p<0.0001), respectively. There were fewer adverse events in the famotidine group than in the placebo group (nine vs 15); four patients in the placebo group were admitted to hospital with upper gastrointestinal haemorrhage. The other most common adverse event was angina (famotidine, n=2; placebo, n=4). INTERPRETATION Famotidine is effective in the prevention of gastric and duodenal ulcers, and erosive oesophagitis in patients taking low-dose aspirin. These findings widen the therapeutic options for the prevention of gastrointestinal damage in patients needing vascular protection. FUNDING Merck Laboratories and Astellas Pharma.

Validation of Magnetic Resonance Myocardial Perfusion Imaging With Fractional Flow Reserve for the Detection of Significant Coronary Heart Disease

Background— Magnetic resonance myocardial perfusion imaging (MRMPI) has a number of advantages over the other noninvasive tests used to detect reversible myocardial ischemia. The majority of previous studies have generally used quantitative coronary angiography as the gold standard to assess the accuracy of MRMPI; however, only an approximate relationship exists between stenosis severity and functional significance. Pressure wire–derived fractional flow reserve (FFR) values <0.75 correlate closely with objective evidence of reversible ischemia. Accordingly, we have compared MRMPI with FFR. Methods and Results— One hundred three patients referred for investigation of suspected angina underwent MRMPI with a 1.5-T scanner. The stress agent was intravenous adenosine (140 &mgr;g · kg−1 · min−1), and the first-pass bolus contained 0.1 mmol/kg gadolinium. In the following week, coronary angiography with pressure wire studies was performed. FFR was recorded in all patent major epicardial coronary arteries, with a value <0.75 denoting significant stenosis. MRMPI scans, analyzed by 2 blinded observers, identified perfusion defects in 121 of 300 coronary artery segments (40%), of which 110 had an FFR <0.75. We also found that 168 of 179 normally perfused segments had an FFR ≥0.75. The sensitivity and specificity of MRMPI for the detection of functionally significant coronary heart disease were 91% and 94%, respectively, with positive and negative predictive values of 91% and 94%. Conclusion— MRMPI can detect functionally significant coronary heart disease with excellent sensitivity, specificity, and positive and negative predictive values compared with FFR.

Cognitive behaviour therapy for violent men with antisocial personality disorder in the community: an exploratory randomized controlled trial

BACKGROUND Little information exists on treatment effectiveness in antisocial personality disorder (ASPD). We investigated the feasibility and effectiveness of carrying out a randomized controlled trial of cognitive behaviour therapy (CBT) in men with ASPD who were aggressive. METHOD This was an exploratory two-centre, randomized controlled trial in a community setting. Fifty-two adult men with a diagnosis of ASPD, with acts of aggression in the 6 months prior to the study, were randomized to either treatment as usual (TAU) plus CBT, or usual treatment alone. Change over 12 months of follow-up was assessed in the occurrence of any act of aggression and also in terms of alcohol misuse, mental state, beliefs and social functioning. RESULTS The follow-up rate was 79%. At 12 months, both groups reported a decrease in the occurrence of any acts of verbal or physical aggression. Trends in the data, in favour of CBT, were noted for problematic drinking, social functioning and beliefs about others. CONCLUSIONS CBT did not improve outcomes more than usual treatment for men with ASPD who are aggressive and living in the community in this exploratory study. However, the data suggest that a larger study is required to fully assess the effectiveness of CBT in reducing aggression, alcohol misuse and improving social functioning and view of others. It is feasible to carry out a rigorous randomized controlled trial in this group.

Differences in atherosclerosis according to area level socioeconomic deprivation: cross sectional, population based study

Objectives To examine the relation between area level social deprivation and ultrasound markers of atherosclerosis (common carotid intima-media thickness and plaque score), and to determine whether any differences can be explained by “classic” (currently recognised) or “emerging” (novel) cardiovascular risk factors. Design Cross sectional, population based study. Setting NHS Greater Glasgow Health Board area. Participants 666 participants were selected on the basis of how their area ranked in the Scottish Index of Multiple Deprivation 2004. Approximately equal numbers of participants from the most deprived areas and the least deprived areas were included, as well as equal numbers of men and women and equal numbers of participants from each age group studied (35-44, 45-54, and 55-64 years). Main outcome measures Carotid intima-media thickness and plaque score, as detected by ultrasound. Results The mean age and sex adjusted intima-media thickness was significantly higher in participants from the most deprived areas than in those from the least deprived areas (0.70 mm (standard deviation (SD) 0.16 mm) v 0.68 mm (SD 0.12 mm); P=0.015). On subgroup analysis, however, this difference was only apparent in the highest age tertile in men (56.3-66.5 years). The difference in unadjusted mean plaque score between participants from the most deprived and those from the least deprived areas was more striking than the difference in intima-media thickness (least deprived 1.0 (SD 1.5) v most deprived 1.7 (SD 2.0); P<0.0001). In addition, a significant difference in plaque score was apparent in the two highest age tertiles in men (46.8-56.2 years and 56.3-66.5 years; P=0.0073 and P<0.001) and the highest age tertile in women (56.3-66.5 years; P<0.001). The difference in intima-media thickness between most deprived and least deprived males remained significant after adjustment for classic risk factors, emerging risk factors, and individual level markers of socioeconomic status (P=0.010). Adjustment for classic risk factors and emerging cardiovascular risk factors, either alone or in combination, did not abolish the deprivation based difference in plaque presence (as a binary measure; adjusted odds ratio of 1.73, 95% confidence interval 1.07 to 2.82). However, adjustment for classic risk factors and individual level markers of early life socioeconomic status abolished the difference in plaque presence between the most deprived and the least deprived individuals (adjusted odds ratio 0.94, 95% CI 0.54 to 1.65; P=0.84). Conclusions Deprivation is associated with increased carotid plaque score and intima-media thickness. The association of deprivation with atherosclerosis is multifactorial and not adequately explained by classic or emerging risk factors.

Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis

Background Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Methods and Findings Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs. Conclusions We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.

Psychological, social and biological determinants of ill health (pSoBid): Study Protocol of a population-based study

BackgroundDisadvantaged communities suffer higher levels of physical and mental ill health than more advantaged communities. The purpose of the present study was to examine the psychosocial, behavioural and biological determinants of ill health within population groups in Glasgow that differed in socioeconomic status and in their propensity to develop chronic disease especially coronary heart disease and Type 2 diabetes mellitus.MethodsParticipants were selected at random from areas known to be at the extremes of the socioeconomic continuum in Glasgow. Within the categories of least deprived and most deprived, recruitment was stratified by sex and age to achieve an overall sample containing approximately equal numbers of males and females and an even distribution across the age categories 35–44, 45–54 and 55–64 years. Individuals were invited by letter to attend for assessment of their medical history, risk factor status, cognitive function and psychological profile, morbidity, and carotid intima-media thickness and plaque count as indices of atherosclerosis. Anonymised data on study subjects were collected from the General Practice Administration System for Scotland to analyse characteristics of participants and non-participants.Results700 subjects were recruited. The response (active participants per 100 invitation letters) in the least deprived group was 35.1% and in the most deprived group was 20.3%. Lowest response was seen in young males (least deprived 22.4% and most deprived 14.1%).ConclusionThis cross-sectional study recruited the planned sample of subjects from least deprived and most deprived areas within Glasgow. As evident in other studies response differed between the most and least deprived areas. This study brought together researchers/academics from diverse disciplines to build a more sophisticated understanding of the determinants of health inequalities than can be achieved through unidisciplinary approaches. Future analyses will enable an understanding of the relationships between the different types of measure, and of the pathways that link poverty, biology, behaviour and psychology and lead to health inequalities.

Profile of microvolt T-wave alternans testing in 1003 patients hospitalized with heart failure.

Observational studies in selected populations have suggested that microvolt T‐wave alternans (MTWA) testing may identify patients with heart failure (HF) at risk of sudden cardiac death. The aims of this study were to investigate the utility of MTWA testing in an unselected population of patients with HF and to evaluate the clinical characteristics associated with the MTWA results.