Simon Ogston

Effect of Metformin on Mortality in Patients With Heart Failure and Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (DM) plus chronic heart failure (CHF) is a common but lethal combination and therapeutic options are limited. Metformin is perceived as being relatively contraindicated in this context, although mounting evidence indicates that it may be beneficial. This study was carried out to investigate the use of metformin therapy for treating patients with DM and CHF in a large population-based cohort study. The Health Informatics Centre-dispensed prescribing database for the population of Tayside, Scotland (population ∼400,000) was linked to the Diabetes Audit and Research in Tayside Scotland (DARTS) information system. Patients with DM and incident CHF from 1994 to 2003 receiving oral hypoglycemic agents but not insulin were identified. Cox regression was used to assess differences in all-cause mortality rates between patients prescribed metformin and patients prescribed sulfonylureas with adjustment for co-morbidities and other therapies. Four hundred twenty-two study subjects (mean ± SD 75.4 ± 0.5 years of age, 46.2% women) were identified: metformin monotherapy (n = 68, mean age 75.5 ± 1.1 years, 48.5% women), sulfonylurea monotherapy (n = 217, mean age 76.7 ± 0.7 years, 45.2% women), and combination (n = 137, mean age, 73.4 ± 0.7 years, 46.7% women). Fewer deaths occurred in metformin users, alone or in combination with sulfonylureas, compared to the sulfonylurea monotherapy cohort at 1 year (0.59, 95% confidence interval 0.36 to 0.96) and over long-term follow up (0.67, 95% confidence interval 0.51 to 0.88). In conclusion, this large observational data suggest that metformin may be beneficial in patients with CHF and DM. These findings need to be verified by a prospective clinical trial.

Protective effect of breast feeding against infection.

OBJECTIVE--To assess the relations between breast feeding and infant illness in the first two years of life with particular reference to gastrointestinal disease. DESIGN--Prospective observational study of mothers and babies followed up for 24 months after birth. SETTING--Community setting in Dundee. PATIENTS--750 pairs of mothers and infants, 76 of whom were excluded because the babies were preterm (less than 38 weeks), low birth weight (less than 2500 g), or treated in special care for more than 48 hours. Of the remaining cohort of 674, 618 were followed up for two years. INTERVENTIONS--Detailed observations of infant feeding and illness were made at two weeks, and one, two, three, four, five, six, nine, 12, 15, 18, 21, and 24 months by health visitors. MAIN OUTCOME MEASURE--The prevalence of gastrointestinal disease in infants during follow up. RESULTS--After confounding variables were corrected for babies who were breast fed for 13 weeks or more (227) had significantly less gastrointestinal illness than those who were bottle fed from birth (267) at ages 0-13 weeks (p less than 0.01; 95% confidence interval for reduction in incidence 6.6% to 16.8%), 14-26 weeks (p less than 0.01), 27-39 weeks (p less than 0.05), and 40-52 weeks (p less than 0.05). This reduction in illness was found whether or not supplements were introduced before 13 weeks, was maintained beyond the period of breast feeding itself, and was accompanied by a reduction in the rate of hospital admission. By contrast, babies who were breast fed for less than 13 weeks (180) had rates of gastrointestinal illness similar to those observed in bottle fed babies. Smaller reductions in the rates of respiratory illness were observed at ages 0-13 and 40-52 weeks (p less than 0.05) in babies who were breast fed for more than 13 weeks. There was no consistent protective effect of breast feeding against ear, eye, mouth, or skin infections, infantile colic, eczema, or nappy rash. CONCLUSION--Breast feeding during the first 13 weeks of life confers protection against gastrointestinal illness that persists beyond the period of breast feeding itself.

Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial

Summary Background Experimental evidence suggests that xanthine oxidase inhibitors can reduce myocardial oxygen consumption for a particular stroke volume. If such an effect also occurs in man, this class of inhibitors could become a new treatment for ischaemia in patients with angina pectoris. We ascertained whether high-dose allopurinol prolongs exercise capability in patients with chronic stable angina. Methods 65 patients (aged 18–85 years) with angiographically documented coronary artery disease, a positive exercise tolerance test, and stable chronic angina pectoris (for at least 2 months) were recruited into a double-blind, randomised, placebo-controlled, crossover study in a hospital and two infirmaries in the UK. We used computer-generated randomisation to assign patients to allopurinol (600 mg per day) or placebo for 6 weeks before crossover. Our primary endpoint was the time to ST depression, and the secondary endpoints were total exercise time and time to chest pain. We did a completed case analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 82040078. Findings In the first treatment period, 31 patients were allocated to allopurinol and 28 were analysed, and 34 were allocated to placebo and 32 were analysed. In the second period, all 60 patients were analysed. Allopurinol increased the median time to ST depression to 298 s (IQR 211–408) from a baseline of 232 s (182–380), and placebo increased it to 249 s (200–375; p=0·0002). The point estimate (absolute difference between allopurinol and placebo) was 43 s (95% CI 31–58). Allopurinol increased median total exercise time to 393 s (IQR 280–519) from a baseline of 301 s (251–447), and placebo increased it to 307 s (232–430; p=0·0003); the point estimate was 58 s (95% CI 45–77). Allopurinol increased the time to chest pain from a baseline of 234 s (IQR 189–382) to 304 s (222–421), and placebo increased it to 272 s (200–380; p=0·001); the point estimate was 38 s (95% CI 17–55). No adverse effects of treatment were reported. Interpretation Allopurinol seems to be a useful, inexpensive, well tolerated, and safe anti-ischaemic drug for patients with angina. Funding British Heart Foundation.

Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis.

PURPOSE Depression is common in primary care. There are no systematic reviews of depression treatment comparing antidepressants with placebo; hence, we do not know whether these medications are effective in primary care. METHODS We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Group register of controlled trials, MEDLINE, International Pharmaceutical abstracts, PsycINFO, and EMBASE. Abstracts of potential studies were reviewed independently by 2 authors. Studies needed to include randomized controlled trials of either a tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor (SSRI), or both, and placebo in a primary care setting. The data and quality of the studies were extracted and assessed by 2 authors blind to the other’s choice. Disagreements were resolved by discussion. The main outcome measures were the standardized mean difference and weighted mean difference of the final mean depression scores, the relative risk of improvement, and the number withdrawing because of side effects. Pooling of results was done using Review Manager 4.2.2. RESULTS There were 10 studies in which TCAs were compared with placebo, 3 in which SSRIs were compared with placebo, and 2 with both compared with placebo. One half of the studies were of low methodological quality, and nearly all studies were of short duration, typically 6 to 8 weeks. Pooled estimates of efficacy data showed a relative risk of 1.26 (95% CI, 1.12–1.42) for improvement with TCAs compared with placebo; For SSRIs, relative risk was 1.37 (95% CI, 1.21–1.55). Most patients, 56% to 60%, responded well to active treatment compared with 42% to 47% for placebo. The number needed to treat for TCAs was about 4, and for SSRIs it was 6. The numbers needed to harm (for withdrawal caused by side effects) ranged from 5 to 11 for TCAs and 21 to 94 for SSRIs. Low-dose (100 mg or 75 mg) as well as high-dose TCAs were effective. CONCLUSION This systematic review is the first comparing antidepressants with placebo for treatment of depression in primary care. Both TCAs and SSRIs are effective. This review is also the first to show that low-dose TCAs are effective in primary care. Prescribing antidepressants in primary care is a more effective clinical activity than prescribing placebo.

Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis

Abstract Objective: To compare the efficacy and tolerability of tricyclic antidepressants with selective serotonin reuptake inhibitors in depression in primary care. Design: Systematic review and meta-analysis of randomised controlled trials. Data sources: Register of the Cochrane Collaborations depression, anxiety, and neurosis group. Reference lists of initial studies and other relevant review papers. Selected authors and experts. Selection of studies: Studies had to meet minimum requirements on: adequacy of sample size, adequate allocation concealment, clear description of treatment, representative source of subjects, use of diagnostic criteria or clear specification of inclusion criteria, details regarding number and reasons for withdrawal by group, and outcome measures described clearly or use of validated instruments. Main outcome measures: Standardised mean difference of final mean depression scores and relative risk of response when using the clinical global impression score. Relative risk of withdrawing from treatment at any time, and the number withdrawing due to side effects. Results: 11 studies (2951 participants) compared a selective serotonin reuptake inhibitor with a tricyclic antidepressant. Efficacy between selective serotonin reuptake inhibitors and tricyclics did not differ significantly (standardised weighted mean difference, fixed effects 0.07, 95% confidence interval −0.02 to 0.15; z=1.59, P<0.11). Significantly more patients receiving a tricyclic withdrew from treatment (relative risk 0.78, 95% confidence interval 0.68 to 0.90; z=3.37, P<0.0007) and withdrew specifically because of side effects (0.73, 0.60 to 0.88; z=3.24, P<0.001). Most studies included were small and supported by commercial funding. Many studies were of low methodological quality or did not present adequate data for analysis, or both, and were of short duration, typically six to eight weeks. Conclusion: The evidence on the relative efficacy of selective serotonin reuptake inhibitors and tricyclic antidepressants in primary care is sparse and of variable quality. The study setting is likely to be an important factor in assessing the efficacy and tolerability of treatment with antidepressant drugs. What is already known on this topic Previous meta-analyses have included comparatively large numbers of secondary care based studies that indicate no significant differences in efficacy between selective serotonin reuptake inhibitors and tricyclics Previous meta-analyses are conflicting regarding the relative tolerability between selective serotonin reuptake inhibitors and tricyclics, but do suggest a small but significant difference in favour of selective serotonin reuptake inhibitors Such meta-analyses show notable heterogeneity What this study adds Selective serotonin reuptake inhibitors are better tolerated than tricyclics by primary care patients and may be better tolerated by primary care patients than secondary care patients Study setting seems to be important and should be considered before licences are given to specific antidepressants Although there are limited high quality data, available evidence shows that the most commonly prescribed classes of antidepressants in primary care (selective serotonin reuptake inhibitors and tricyclics) are equally effective in the short term for primary care patients, but the literature has many gaps

QT and QTc dispersion are accurate predictors of cardiac death in newly diagnosed non-insulin dependent diabetes: cohort study

Patients with non-insulin dependent diabetes mellitus have an excess risk of dying from cardiovascular disease. One small study suggested that a prolonged QT interval could predict cardiac death in patients with diabetic nephropathy who have received insulin treatment. The question now is whether the same is true in newly diagnosed diabetes in patients who have no apparent complications. In addition, QT dispersion, a new but related electrocardiographic variable, predicts cardiac death in patients who have chronic heart failure, peripheral vascular disease, or essential hypertension.1–3 We investigated whether it also predicted cardiac death in diabetic patients. The study group of 182 patients with non-insulin dependent diabetes mellitus (103 men; mean age 52.8 (SD 8.5) years) represented the Dundee cohort of the United Kingdom prospective diabetes study, which was recruited between 1982 and 1988. Patients were followed up for a mean of 10.3 (1.7) years. …

A cohort study of the risk of cancer associated with type 2 diabetes

Background:There is evidence to suggest that diabetes may increase the risk of incidence and mortality from cancer.Methods:In a cohort study using record-linkage health-care datasets for Tayside, Scotland in 1993–2004, we followed up 9577 newly diagnosed patients with type 2 diabetes, and two matched non-diabetic comparators, in the national cancer register.Results and conclusions:The risk ratio for any cancer, adjusted for deprivation, was 0.99 (95%CI 0.90–1.09). Significantly increased risks were observed for pancreatic, liver and colon cancer.

Standards for ultrasound fetal growth velocity

Objective An ultrasound study to establish the nature and limits of fetal growth in a low risk population from 22 weeks of gestation until term.

The value of procalcitonin at predicting the severity of acute pancreatitis and development of infected pancreatic necrosis: Systematic review

BACKGROUND Many studies have evaluated serum levels of procalcitonin (PCT) as a predictor in the development of severe acute pancreatitis (SAP) and infected pancreatic necrosis (IPN). This study assesses the value of PCT as a marker of development of SAP and IPN. METHODS Medline, Web of Science, the Cochrane clinical trials register, and international conference proceedings were searched systematically for prospective studies, which evaluated the usefulness of PCT as a marker of SAP and IPN. The sensitivity, specificity, and diagnostic odds ratios (DORs) were calculated for each study, and the study quality and heterogeneity among the studies were evaluated. RESULTS Twenty-four of 59 studies identified were included in data extraction. The sensitivity and specificity of PCT for development of SAP were 0.72 and 0.86, respectively (area under the curve [AUC] = 0.87; DOR = 14.9; 95% confidence interval [CI] = 5.6-39.8), albeit with a significant degree of heterogeneity (Q = 28.56, P < .01). The sensitivity and specificity of PCT for prediction of infected pancreatic necrosis were 0.80 and 0.91 (AUC = 0.91; DOR = 28.3; 95% CI = 13.8-58.3) with no significant heterogeneity (Q = 7.83, P = .18). No significant heterogeneity was observed among the studies when only higher quality studies (AUC = 0.91; DOR = 30.7; 95% CI = 10.7-87.8) or studies that used a cutoff PCT level >0.5 ng/mL (AUC = 0.88, 32.8; 95% CI = 10.1-106.6) were included. CONCLUSION Serum measurements of PCT may be valuable in predicting the severity of acute pancreatitis and the risk of developing infected pancreatic necrosis.

Cross sectional study of contribution of clinical assessment and simple cardiac investigations to diagnosis of left ventricular systolic dysfunction in patients admitted with acute dyspnoea

Abstract Objective: To assess the comparative contribution of clinical assessment, electrocardiography, and chest radiography to the diagnosis of left ventricular systolic dysfunction in patients admitted to a general medical ward with acute dyspnoea. Design: Prospective cross sectional study. Setting: Acute medical admissions ward of a teaching hospital. Subjects: 71 randomly selected patients admitted with acute dyspnoea. Main outcome measures: Sensitivity and specificity of each investigation and logistic regression analysis of each variable in identifying left ventricular systolic dysfunction. Results: Clinical assessment in this cohort of patients with severe dyspnoea was generally sensitive (sensitivity 81%). Patients were divided into three groups on the basis of clinical assessment. In the first group (37 patients) the diagnosis of systolic dysfunction was clear, in the second (22) it was in doubt, and in the third (12) it was unlikely. The sensitivity of clinical assessment in identifying left ventricular systolic dysfunction was 81% and the specificity was 47%. The specificity of diagnosis was improved by electrocardiography (69%) and chest radiography (92%). Logistic regression analysis showed that isolated pulmonary crepitations were a comparatively poor predictor of left ventricular systolic dysfunction (2=10.215, P=0.0014) but that a full clinical examination had reasonable predictive value (2=24.82, P<0.00001). The combination of clinical assessment and chest radiography improved the accuracy of diagnosis (2=28.08, P<0.00001), as did the combination of clinical assessment and electrocardiography (2=32.41, P<0.00001). Conclusion: Clinical assessment in patients admitted with acute dyspnoea is comparatively accurate. Patients with abnormal results on chest radiography, electrocardiography, and clinical examination have a high likelihood of having left ventricular systolic dysfunction. Echocardiography contributes little more to the diagnosis in these patients and may be more efficiently directed towards patients in whom the diagnosis is still in doubt after clinical assessment, chest radiography, and electrocardiography. Key messages The availability of echocardiography is limited for patients admitted to hospital with acute dyspnoea The presence of isolated lung crepitations is a poor predictor of left ventricular systolic dysfunction Full clinical assessment is sensitive in detecting left ventricular systolic dysfunction, with specificity being added by either chest radiography or electrocardiography Echocardiography should be reserved for cases with the most diagnostic doubt