Dapagliflozin therapy for type 2 diabetes in primary care: Changes in HbA1c, weight and blood pressure over 2 years follow-up.

AIMS: To investigate prescribing patterns and effect of dapagliflozin among individuals with T2DM using UK primary care data. METHODS: Adult patients with T2DM initiating dapagliflozin treatment were identified from the Clinical Practice Research Datalink. Changes in HbA1c, body weight and systolic blood pressure were assessed in subgroups defined by glucose lowering treatment at baseline and compliance with the Summary of Product Characteristics. Logistic regression examined the association of baseline characteristics with achievement of target HbA1c (≤53mmol/mol) and weight reduction (by ≥3.0%). RESULTS: Among 5828 eligible individuals, HbA1c was reduced from a baseline mean of 80.0mmol/mol (SD 17.6) by -12.8 (95% CI -13.8, -11.8)mmol/mol at >12-24 months. The corresponding value for weight reduction (baseline mean 101.7kg) was -5.0 (-5.4, -4.5)kg, and for systolic blood pressure reduction (baseline mean 134.1mmHg) was -3.1 (-4.0, -2.2) mmHg. Lower baseline HbA1c values (<69; 69-85 versus ≥86mmol/mol) were positively associated with achievement of target HbA1c <53mmol/mol. CONCLUSIONS: Treatment with dapagliflozin in T2DM was associated with reductions in HbA1c, weight and systolic blood pressure over time periods up to 2 years. Changes in these parameters were consistent with those reported in RCTs.

Prolonged dual antiplatelet therapy in stable coronary disease: comparative observational study of benefits and harms in unselected versus trial populations.

OBJECTIVE:  To estimate the potential magnitude in unselected patients of the benefits and harms of prolonged dual antiplatelet therapy after acute myocardial infarction seen in selected patients with high risk characteristics in trials. DESIGN:  Observational population based cohort study. SETTING:  PEGASUS-TIMI-54 trial population and CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records). PARTICIPANTS:  7238 patients who survived a year or more after acute myocardial infarction. INTERVENTIONS:  Prolonged dual antiplatelet therapy after acute myocardial infarction. MAIN OUTCOME MEASURES:  Recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease. Fatal, severe, or intracranial bleeding. RESULTS:  1676/7238 (23.1%) patients met trial inclusion and exclusion criteria ("target" population). Compared with the placebo arm in the trial population, in the target population the median age was 12 years higher, there were more women (48.6% v 24.3%), and there was a substantially higher cumulative three year risk of both the primary (benefit) trial endpoint of recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease (18.8% (95% confidence interval 16.3% to 21.8%) v 9.04%) and the primary (harm) endpoint of fatal, severe, or intracranial bleeding (3.0% (2.0% to 4.4%) v 1.26% (TIMI major bleeding)). Application of intention to treat relative risks from the trial (ticagrelor 60 mg daily arm) to CALIBER's target population showed an estimated 101 (95% confidence interval 87 to 117) ischaemic events prevented per 10 000 treated per year and an estimated 75 (50 to 110) excess fatal, severe, or intracranial bleeds caused per 10 000 patients treated per year. Generalisation from CALIBER's target subgroup to all 7238 real world patients who were stable at least one year after acute myocardial infarction showed similar three year risks of ischaemic events (17.2%, 16.0% to 18.5%), with an estimated 92 (86 to 99) events prevented per 10 000 patients treated per year, and similar three year risks of bleeding events (2.3%, 1.8% to 2.9%), with an estimated 58 (45 to 73) events caused per 10 000 patients treated per year. CONCLUSIONS:  This novel use of primary-secondary care linked electronic health records allows characterisation of "healthy trial participant" effects and confirms the potential absolute benefits and harms of dual antiplatelet therapy in representative patients a year or more after acute myocardial infarction.

Carbapenems versus other beta-lactams in treating severe infections in intensive care: a systematic review of randomised controlled trials.

Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN). A systematic review of CENTRAL, EMBASE, MEDLINE and JICST-EPlus for randomised controlled trials was conducted to establish the currently available evidence. Database searching was supplemented by hand searching and contacting conference organisers. Searching was completed in November 2006 and no restriction was placed on the language of publication. Data were extracted on clinical response, bacteriologic response, all-cause mortality and adverse events. Of the 265 papers identified, 12 were appropriate for meta-analysis (four 4GC and eight APP). The results showed that carbapenems are associated with a significant reduction in all-cause mortality (relative risk 0.62, 95% confidence interval: 0.41 to 0.95; p=0.03) compared to APP in the treatment of SI, and withdrawals due to adverse events (RR 0.65, 95% CI: 0.45 to 0.96; p=0.03) are also less common. When compared in the treatment of FN, carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 1.37, 95% CI: 1.09 to 1.74; p=0.008) and bacteriologic response (RR 1.73, 95% CI: 1.03 to 2.89; p=0.04). For all other outcomes, including all comparisons with 4GC, there were no significant differences between treatments. The use of carbapenems rather than APP could reduce mortality and, by simplifying treatment decisions, reduce the time before patients receive appropriate antibiotic treatment. The currently available evidence is insufficient for distinguishing between carbapenems and 4GC.

Trends in the prevalence of diagnosed atrial fibrillation, its treatment with anticoagulation and predictors of such treatment in UK primary care.

OBJECTIVES: To examine trends in the prevalence of diagnosed atrial fibrillation (AF), its treatment with oral anticoagulants between 1994 and 2003, and predictors of anticoagulant treatment in 2003. METHODS: Analysis of electronic data from 131 general practices (about one million registered patients annually) contributing to the DIN-LINK database. RESULTS: From 1994 to 2003 the prevalence of "active" AF rose from 0.78% to 1.31% in men and from 0.79% to 1.15% in women. The proportion of patients with AF taking anticoagulants rose from 25% to 53% in men and from 21% to 40% in women. Most others received antiplatelets. The likelihood of receiving anticoagulants was greater for men and with increasing stroke risk. It decreased sharply with age after 75 years. Socioeconomic status, urbanisation and region had no influence. Non-steroidal anti-inflammatory drugs, antiplatelet drugs and ulcer healing drugs were associated with reduced likelihood of receiving anticoagulants, as were peptic ulcers, chronic gut disorders, anaemias, psychoses and poor compliance. Anticoagulant treatment was associated with several cardiovascular co-morbidities and drugs, possibly due to secondary care treatment. Nevertheless, only 56.5% of patients at very high risk of stroke were taking anticoagulants in 2003, whereas 38.2% of patients at low risk of stroke received anticoagulants. CONCLUSIONS: This study confirms previously observed trends of increasing AF prevalence and warfarin treatment. Many patients who may benefit from anticoagulation still do not receive it, whereas others at lower risk of stroke do. The lower likelihood of women receiving anticoagulants is of particular concern.

Evaluation of survival and ischaemic and thromboembolic event rates in patients with non-valvar atrial fibrillation in the general population when treated and untreated with warfarin.

OBJECTIVE: To compare survival and adverse outcome of patients with non-valvar atrial fibrillation (NVAF) treated with or without warfarin. DESIGN: Record linkage method to identify patients with a previous hospital diagnosis of atrial fibrillation and to link these patients to international normalised ratio (INR) test results and mortality data. SETTING: Cardiff and the Vale of Glamorgan, Wales. MAIN OUTCOME MEASURES: Mortality, specifically from ischaemic and thromboembolic events. RESULTS: 6108 patients were identified with NVAF, of whom 36.4% received warfarin. Mean survival in the warfarin and non-warfarin groups was 52.0 months and 38.2 months, respectively (p < 0.001), and 14.4 months (p < 0.001) after adjustment for confounding factors. Warfarin treated patients in the upper quartile of INR control had significantly longer survival (57.5 months) than did those in the lowest quartile of control (38.1 months, p < 0.001). The risk of stroke in the warfarin group when treated was lower than that in the non-warfarin group (relative rate (RR) 0.74, p < 0.001). The risk of death from ischaemic stroke was lower in the warfarin group (RR 0.43, p < 0.001). The risk of all ischaemic and embolic events in the warfarin group was lower when they were taking warfarin (RR 0.74, p < 0.001). The risk of bleeding in the warfarin group when treated was greater (RR 1.78, p = 0.001). CONCLUSIONS: Patients with NVAF within the recommended target INR range of 2.0-3.0 survive longer and have reduced morbidity. Probably too few people are anticoagulated with warfarin in NVAF.

Omeprazole is more effective than cimetidine in the prevention of recurrence of GERD-associated heartburn and the occurrence of underlying oesophagitis.

BACKGROUND: There is documentation of the long-term use of omeprazole 10 mg o.d. in patients with reflux oesophagitis but not in the large number of gastrooesophageal reflux disease (GERD) patients without oesophagitis. There is also a paucity of data on the long-term use of cimetidine in GERD patients. METHODS: One hundred and fifty-six patients (100 male) who previously had symptomatic non-ulcerative oesophagitis (81%) or symptoms without oesophagitis (19%), were recruited. All patients were in symptomatic remission following 4 weeks of omeprazole 20 mg o.d. or cimetidine 400 mg q.d.s. and, if required, a further 4 weeks of omeprazole 20 mg o.d. Patients were randomized to receive, double-blind, either omeprazole 10 mg o.m. (n = 77) or cimetidine 800 mg nocte (n = 79) for 24 weeks. RESULTS: A greater proportion of patients receiving omeprazole, compared with cimetidine, were in symptomatic remission after 12 (69 vs. 27%) and 24 weeks (60 vs. 24%) (each P < 0.0001). The median time to symptomatic relapse was longer for patients receiving omeprazole (169 vs. 15 days) (P = 0.0001). Of patients leaving the study in symptomatic remission, a greater proportion receiving omeprazole, compared with cimetidine, was free of oesophagitis (84 vs. 53%) (P < 0.05). CONCLUSION: Omeprazole 10 mg o.m. is more effective than cimetidine 800 mg nocte in the prevention of recurrence of GERD-associated heartburn and the occurrence of underlying oesophagitis.

Omeprazole is more effective than cimetidine for the relief of all grades of gastro-oesophageal reflux disease-associated heartburn, irrespective of the presence or absence of endoscopic oesophagitis.

BACKGROUND: Previous studies have demonstrated greater efficacy for omeprazole compared with cimetidine in patients with endoscopically verified oesophagitis, but excluded the substantial group of gastro-oesophageal reflux disease (GERD) patients with reflux symptoms but without endoscopic abnormality. This prospective, randomized, double-blind study compared omeprazole and cimetidine in the treatment of GERD-associated heartburn both in patients with symptomatic non-ulcerative oesophagitis and in those with heartburn but without oesophagitis. METHODS: A total of 221 patients with heartburn and oesophageal mucosa grade 0 (normal, n = 51), 1 (no macroscopic erosions, n = 52), 2 (isolated erosions, n = 97) or 3 (confluent erosions, n = 21) were randomized to receive double-blind either omeprazole 20 mg daily or cimetidine 400 mg q.d.s. for a period of 4 weeks. Those still symptomatic after 4 weeks of treatment received omeprazole 20 mg daily for a further 4 weeks. RESULTS: There was no correlation between severity of heartburn and endoscopic grade at entry (correlation coefficient = 0.196). After 4 weeks of treatment, the proportion of patients in whom heartburn was controlled (no more than mild symptoms on no more than 1 day in the previous 7) on omeprazole (66%; 74/112) was more than double that on cimetidine (31%; 34/109) (P < 0.0001). There was no significant difference between the relief of heartburn in the 47% of patients without unequivocal oesophagitis (endoscopic grade 0 or 1) and in the 53% of patients with erosive oesophagitis (grade 2 or 3) (P = 0.31). Only treatment with omeprazole (P < 0.0001) and lower severity of heartburn at entry (P < 0.01) were significant in predicting heartburn relief. Amongst those patients requiring an additional 4 weeks of treatment with omeprazole, 67% (54/81) reported that their heartburn was controlled after 8 weeks of treatment. CONCLUSION: We conclude that omeprazole is superior to cimetidine for the relief of all grades of heartburn in GERD, whether or not the patient has unequivocal endoscopic oesophagitis.

Addition of metronidazole to omeprazole/amoxycillin dual therapy increases the rate of Helicobacter pylori eradication: a double-blind, randomized trial.

AIMS: To compare the efficacy, safety and tolerability of an omeprazole/amoxycillin (OA) dual therapy Helicobacter pylori eradication regimen with an omeprazole/amoxycillin/metronidazole (OAM) triple therapy regimen. METHODS: In this double-blind trial, conducted in 19 hospitals, 119 patients with symptomatic duodenal ulcer disease were randomized to receive either 14 days treatment with omeprazole 40 mg daily, amoxycillin 500 mg t.d.s. and placebo followed by a further 14 days' treatment with omeprazole 20 mg daily (n = 59) or 14 days treatment with omeprazole 40 mg daily, amoxycillin 500 mg t.d.s., and metronidazole 400 mg t.d.s., followed by a further 14 days' treatment with omeprazole 20 mg daily (n = 60). H. pylori status was assessed by 13C-urea breath test at entry and at 4 weeks post-treatment. RESULTS: H. pylori infection was eradicated in 46% of the OA treated patients and in 92% of the OAM treated patients, a mean difference of 46% (P < 0.0001, 95% CI for the difference: +30 to +62). In only one patient was the duodenal ulcer not endoscopically healed after 4 weeks of treatment (OA 100%; OAM 98% healed). There were no significant differences in speed of symptom relief or improvement in symptoms between the two groups. Both regimens were well tolerated, with 96% of patients completing the course, and only one patient withdrawing due to an adverse event. The only side-effect with a significantly higher incidence in the OAM group was diarrhoea, which occurred in 36% of patients compared to 16% of patients in the OA group (P < 0.05). CONCLUSIONS: A regimen consisting of omeprazole 40 mg daily, amoxycillin 500 mg t.d.s. and metronidazole 400 mg t.d.s. for 14 days gives an appreciably higher H. pylori eradication rate than omeprazole and amoxycillin alone, with acceptable tolerability.

Tamoxifen inhibits growth of oestrogen receptor-negative A549 cells.

The non-steroidal anti-oestrogen tamoxifen inhibits proliferation of the A549 human lung adenocarcinoma cell line (EC50 congruent to 10 nM) yet there was no evidence of oestrogen receptor expression as determined by ligand binding assay and northern blotting. 17-beta-Oestradiol had no effect on A549 cell proliferation (1 pM-1 microM) and moreover a 100-fold excess failed to reverse the effect of 10 nM tamoxifen as did a 100-fold excess of the steroidal anti-oestrogens ICI 164384 and ICI 182780. However, 4-hydroxytamoxifen which had no significant effect on A549 cell growth (1 pM-1 microM) completely antagonized the effect of 10 nM tamoxifen when used at a 100-fold excess. In the presence of oleic acid and stearic acid (10 microM) the growth inhibitory effect of tamoxifen in A549 cells was greatly enhanced, unlike effects mediated by the anti-oestrogen binding protein described in other cells where these fatty acids had no effect. These results indicate the presence of a unique and highly sensitive mechanism in A549 cells whereby concentrations of tamoxifen relevant to classical receptor binding can inhibit cell growth in the absence of the oestrogen receptor.

Effect of ligand binding and DNA binding on the structure of the mouse oestrogen receptor.

We have investigated the effects of ligand and DNA binding on the structure of the oestrogen receptor by performing limited proteolysis and analysing DNA binding activity by gel shift analysis. The effects of oestradiol, 4-hydroxytamoxifen and ICI 164,384 have been examined and we have found that despite differences in the DNA binding activity or relative mobility of the receptor-DNA complex we were unable to detect differences in the cleavage pattern produced by trypsin, chymotrypsin, Staphylococcus aureus V8, papain or elastase. Inhibition of DNA binding by ICI 164,384 was lost in receptor fragments that lacked the hormone binding domain. In contrast to the full-length receptor, proteolytic fragments produced by chymotrypsin differed in their ability to bind to an oestrogen response element (ERE) vs a thyroid response element (TRE). Evidence is presented that this difference can be accounted for by the inability of fragments lacking the hormone binding domain to dimerise on a TRE.