Effects of omeprazole or anti-reflux surgery on lower oesophageal sphincter characteristics and oesophageal acid exposure over 10 years.

OBJECTIVE: To compare the effect of anti-reflux surgery (ARS) versus proton pump inhibitor therapy on lower oesophageal sphincter (LOS) function and oesophageal acid exposure in patients with chronic gastro-oesophageal reflux disease (GORD) over a decade of follow-up. MATERIAL AND METHODS: In this randomised, prospective, multicentre study we compared LOS pressure profiles, as well as oesophageal exposure to acid, at baseline and at 1 and 10 years after randomisation to either open ARS (n = 137) or long-term treatment with omeprazole (OME) 20-60 mg daily (n = 108). RESULTS: Median LOS resting pressure and abdominal length increased significantly and remained elevated in patients operated on with ARS, as opposed to those on OME. The proportion of total time (%) with oesophageal pH <4.0 decreased significantly in both the surgical and medical groups, and was significantly lower after 1 year in patients treated with ARS versus OME. After 10 years, oesophageal acid exposure was normalised in both groups, with no significant differences, and bilirubin exposure was within normal limits. After 10 years, patients with or without Barrett's oesophagus did not differ in acid reflux control between the two treatment options. CONCLUSIONS: Open ARS and OME were both effective in normalising acid reflux into the oesophagus even when studied over a period of 10 years. Anatomically and functionally the LOS was repaired durably by surgery, with increased resting pressure and abdominal length.

In Silico comparison between metoprolol succinate and bisoprolol on 24-hour systolic blood pressures.

OBJECTIVE: To compare the effects of bisoprolol and metoprolol CR/ZOK (metoprolol succinate controlled release) on systolic blood pressure (bpsys) over a 24-h period in an in silico model. METHODS: On the basis of the observed data from ambulatory blood pressure measurements (ABPM), a model with an appropriate distribution and correlation structure was derived for simulation of 24-h bpsys patterns during treatment with commonly studied doses, assumed to be equipotent, of bisoprolol and metoprolol CR/ZOK. Input into the simulations was aligned with the available data on the diurnal efficacy and pharmacology profiles of these substances. The validity of the model was tested in a bootstrap model. RESULTS: The simulation model reproduced the observed data with high congruence (p = 1.0). The mean 24-h bpsys values did not significantly differ between the two simulated groups (estimated overall change in bpsys [∆bpsys] for metoprolol versus bisoprolol = 2.7 mmHg [95% confidence interval -0.3 to 5.7 mmHg]; p = 0.08). There were clear diurnal differences, with bisoprolol being more effective earlier and metoprolol CR/ZOK being more effective later in the 24-h day. A validity test with 100 repeated samples gave an overall mean group difference of 1.4 ± 3.59 mmHg (p = 0.63 relative to simulation). CONCLUSION: In a robust model for the simulation of 24-h ABPM, comparisons between bisoprolol and metoprolol CR/ZOK indicate a comparable overall blood pressure-lowering effect but different diurnal patterns, consistent with the pharmacokinetics of the two drugs. This difference may be of clinical relevance, given the recognized diurnal pattern of cardiovascular events.

The role of antihypertensive therapy in reducing vascular complications of type 2 diabetes. Findings from the DIabetic REtinopathy Candesartan Trials-Protect 2 study.

BACKGROUND: Recent trials question previously accepted low blood pressure targets in type 2 diabetes to reduce complication risk. We explored this question in the DIabetic REtinopathy Candesartan Trials-Protect 2 clinical trial. METHODS: A total of 1905 normoalbuminuric participants with type 2 diabetes and mild-moderate retinopathy were randomized to candesartan or placebo. Participants were normotensive [untreated, blood pressure (BP) < 130/85 mmHg] or treated hypertensive [(62%), BP < 160/90 mmHg]. The effects of candesartan on microvascular and macrovascular endpoints alone and in combination were analysed, including subgroup analyses by baseline hypertension status. RESULTS: Mean age was 57 ± 8 years, 50% were men, mean diabetes duration was 9 ± 5 years and baseline HbA1c was 8.2 ± 1.6%. Mean randomization BP was 123/75 mmHg in the normotensive, and 139/79 mmHg in the treated hypertensive subgroups. During the median 4.7-year follow-up, achieved systolic pressure on candesartan was 128 mmHg in baseline normotensive individuals, and 136 mmHg in treated hypertensive patients. Candesartan reduced combined macrovascular and microvascular complication risk; the age and baseline SBP overall adjusted hazard ratio for candesartan vs. placebo was 0.85 [95% confidence interval (CI) 0.72-0.99], P = 0.040, reflecting hazard ratios of 0.86 (0.66-1.13) for baseline normotensive individuals and 0.83 (0.68-1.02) for hypertensive patients. Hazard ratios were 0.87 (0.74-1.04) for microvascular and 0.84 (0.57-1.25) for macrovascular complications, when analysed separately. However, an interaction (P = 0.06) between hypertensive [hazard ratio 0.67 (0.42-1.07)] and normotensive (1.45, 0.71-2.94) subgroups was observed for macrovascular events. CONCLUSION: Candesartan modestly reduces vascular complication risk in treated hypertensive diabetic individuals at low risk of cardiovascular disease. Separate analyses of microvascular and macrovascular events suggest that candesartan may not reduce macrovascular events in normotensive persons with type 2 diabetes.

Effects of AZD0837, a novel direct thrombin inhibitor, on the electrophysiological properties of the human heart: a randomized, double-blind, parallel-group, placebo-controlled study.

BACKGROUND: AZD0837 is an investigational oral anticoagulant that is bioconverted to its active form, AR-H067637, a selective direct thrombin inhibitor. OBJECTIVES: The objectives of the present study were to investigate if there are any clinically relevant adverse effects of intravenous AZD0837 on cardiac conduction, refractoriness and repolarization, and to study its safety and tolerability. METHODS: In this randomized, double-blind, parallel-group, placebo-controlled study (study code D1250C00026), invasive electrophysiological measurements were performed twice in 30 subjects with a history of, or ongoing, atrial flutter, starting 30 minutes after successful ablation of atrial flutter and then 60 minutes after start of an intravenous infusion of AZD0837. Pre-study warfarin therapy was not an exclusion criterion. The stimulation protocol was performed mainly at 500 and 400 ms drive cycle length. A 12-lead ECG was also recorded before and during AZD0837 infusion. Plasma concentrations of AZD0837 and its metabolites were obtained at predefined timepoints. RESULTS: Measurements were made at baseline and during stable plasma concentrations of the prodrug AZD0837 (mean +/- standard deviation 7.96 +/- 2.38 micromol/L, approximate target of 10 micromol/L), the intermediate metabolite AR-H69927 (1.26 +/- 0.39 micromol/L, target 1-2 micromol/L) and the active direct thrombin inhibitor AR-H067637 (0.35 +/- 0.14 micromol/L, target 0.5-1.0 micromol/L). There were no clinically relevant effects on cardiac conduction (QRS duration, PR interval, His bundle electrogram, Wenckebach point), refractoriness (atrial, atrioventricular and ventricular effective refractory periods) or repolarization (QT, QT interval corrected for heart rate using Fridericia's formula, QRS onset to the top of the T wave [QT(top)], QRS onset to the end of the T wave [QT(end)] or QT(top) - QT(end)). CONCLUSIONS: AZD0837 was well tolerated, and had no clinically relevant effects on cardiac electrophysiology of the target population, either in subjects previously treated with warfarin or in those without previous treatment.

Comparison of outcomes twelve years after antireflux surgery or omeprazole maintenance therapy for reflux esophagitis.

BACKGROUND & AIMS: It is important to evaluate the long-term effects of therapies for gastroesophageal reflux disease (GERD). In a 12-year study, we compared the effects of therapy with omeprazole with those of antireflux surgery. METHODS: This open, parallel group study included 310 patients with esophagitis enrolled from outpatient clinics in Nordic countries. Of the 155 patients randomly assigned to each arm of the study, 154 received omeprazole (1 withdrew before therapy began), and 144 received surgery (11 withdrew before surgery). In patients who remained in remission after treatment, post-fundoplication complaints, other symptoms, and safety variables were assessed. RESULTS: Of the patients enrolled in the study, 71 who were given omeprazole (46%) and 53 treated with surgery (37%) were followed for a 12-year follow-up period. At this time point, 53% of patients who underwent surgery remained in continuous remission, compared with 45% of patients given omeprazole with a dose adjustment (P = .022) and 40% without dose adjustment (P = .002). In addition, 38% of surgical patients required a change in therapeutic strategy (eg, to medical therapy or another operation), compared with 15% of those on omeprazole. Heartburn and regurgitation were significantly more common in patients given omeprazole, whereas dysphagia, rectal flatulence, and the inability to belch or vomit were significantly more common in surgical patients. The therapies were otherwise well-tolerated. CONCLUSIONS: As long-term therapeutic strategies for chronic GERD, surgery and omeprazole are effective and well-tolerated. Antireflux surgery is superior to omeprazole in controlling overall disease manifestations, but post-fundoplication complaints continue after surgery.

Safe and effective conversion of persistent atrial fibrillation to sinus rhythm by intravenous AZD7009.

BACKGROUND: Acute drug conversion of persistent atrial fibrillation usually fails. OBJECTIVES: The purpose of this study was to test the proarrhythmic potential, safety, and efficacy of the novel antiarrhythmic agent AZD7009 in patients with persistent atrial fibrillation (AF) or atrial flutter (mean duration 43 days) scheduled for direct current (DC) cardioversion. METHODS: Patients were randomized to AZD7009 (3-hour intravenous infusion; n = 86) or placebo (n = 36). AZD7009 was given in doses intended to produce target pseudo-steady-state plasma levels of 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, or 2.5 micromol/L after 30 minutes of infusion. DC cardioversion was performed if conversion to sinus rhythm (SR) did not occur within 2 hours of infusion. RESULTS: AZD7009 in a concentration-dependent manner increased the rate of conversion of AF to SR and shortened the time to conversion. At the three highest target concentrations of AZD7009, 45%, 64%, and 70% of AF patients converted after a mean time of 62, 55, and 26 minutes, respectively, whereas no placebo-treated patients converted. SR was maintained for 24 hours in 21 of 22 patients with drug-associated conversion. AZD7009 treatment was associated with QT-interval prolongation; the increase in QT corrected according to Fridericia typically ranged from 40 to 80 ms at targeted pseudo-steady-state plasma concentrations >or=0.75 micromol/L, but a number of outliers with QT corrected according to Fridericia >550 ms were seen in the higher concentration groups, particularly after conversion to SR and prolonged infusion. None of the patients exhibited torsades de pointes according to predefined criteria; however, one patient exhibited a nonsustained, polymorphic ventricular tachycardia of eight beats with torsades de pointes-like features after AZD7009 infusion (asymptomatic and discovered only upon retrospective Holter tape analysis). Clinical adverse events (primarily dizziness, bradycardia, hypotension, and nausea) were significantly more common in the highest target concentration AZD7009 group vs placebo (P <.001). CONCLUSION: AZD7009 exhibited dose-dependent effects in converting AF to SR in AF patients and appeared to be associated with a low risk of proarrhythmia despite continued administration during a period of heightened vulnerability.

Evaluation of ST-segment changes during and after maximal exercise tests in one-, two- and three-vessel coronary artery disease.

OBJECTIVE: To relate ECG and heart rate (HR) variables during and after exercise testing with the presence of one-, two- or three-vessel disease defined by angiography. DESIGN: Seventy-three male patients with stable angina pectoris and angiographically verified coronary artery disease underwent a maximal exercise test. From 12-lead ECG recordings and computer averaging ST-amplitude and HR data were measured in consecutive 10-s intervals. RESULTS: In univariate analysis, patients with three-vessel disease had lower maximal exercise capacity, a shorter time to >1 mm ST-depression, more often a clockwise ST/HR recovery loop, more frequently a post-exercise downward ST-segment slope, and a greater ST-deficit at 3.5 min after exercise than patients with one-vessel disease. In multivariate analysis, time to >1 mm ST-depression discriminated between patients with three- and one-vessel disease. In patients with an intermediate time to >1 mm ST-depression a clockwise ST/HR recovery loop and/or a downsloping ST-segment in the post-exercise period were significantly more prevalent in severe vessel disease. CONCLUSION: Patients with three-vessel disease had a significantly shorter time to >1 mm ST-depression during exercise and more often an abnormal post-exercise ST/HR reaction than those with one-vessel disease.

Inter- and intraday variability in major electrocardiogram intervals and amplitudes in healthy men and women.

The ECG may vary during the day (intra-day), and between days (interday), for the same subject. Variability in ECG characteristic measurements between different investigators is well documented and is often large. During days 1-6 of each placebo period of a two-way crossover Phase I study, digital ECGs were recorded at about 8 and 12 AM in 16 healthy volunteers (8 men, 8 women). Two observers independently analyzed leads V2 and V6 using EClysis software. The durations and amplitudes of major ECG waves and the intervals between major electrocardiographic events were analyzed in a mixed model ANOVA, in which subject, observer, time, and day were treated as random factors. The influence of various corrections for heart rate on the variability of QT intervals was investigated. The difference among subjects explained between 44-81% of the total variability in ECG intervals and amplitudes. Overall, inter- and intraday variability was not statistically significant for any variable. The individualized exponential correction of the QT interval for heart rate eliminated the QT interval dependence on the RR interval in all subjects. Changes in T wave morphology and shortening of the QT interval from morning to noon were observed in ten subjects. The interobserver variability was close to zero (SD < 0.005 ms) for all variables except the PQ interval (SD 1.4 ms). The various sources of variability in determinations of ECG wave characteristics should be considered in the design of clinical studies. The use of EClysis software for ECG measurements is this study made the results highly observer independent.