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.

Randomised trial on episodic cluster headache with an angiotensin II receptor blocker.

OBJECTIVES: The aim of this study was to evaluate the angiotensin II receptor antagonist candesartan as prophylactic medication in patients with episodic cluster headache. METHODS: This study comprised a prospective, placebo-controlled, double-blind, parallel-designed trial performed in seven centres in Scandinavia. Forty (40) patients with episodic cluster headache (ICHD-2) were recruited and randomised over a five-year period to placebo or 16 mg candesartan in the first week, and placebo or 32 mg candesartan in the second and third week. RESULTS: The number of cluster headache attacks (primary efficacy variable) during the three-week treatment period was reduced from 14.3 ± 9.2 attacks in week 1 to 5.6 ± 7.0 attacks in week 3 (-61%) in the candesartan group and from 16.8 ± 14.1 attacks in week 1 to 10.5 ± 11.3 attacks in week 3 (-38%) in the placebo group. The difference between the candesartan and placebo group was not significant with the pre-planned non-parametric ranking test, but a post-hoc exact Poisson test, which takes into account the temporal properties of the data, revealed a significant result ( P < 0.0001). CONCLUSIONS: This was a negative trial. Post-hoc statistics suitable to describe the temporal changes in cluster headache indicate that conduction of future larger studies may be justified.

Endocardial electromechanical mapping in a porcine acute infarct and reperfusion model evaluating the extent of myocardial ischemia.

OBJECTIVE: Catheter-based, left ventricular, electromechanical mapping (EMM) has evolved as a diagnostic tool to characterize ischemic and injured myocardium. In the acute setting, diagnostic criteria for ischemic or infarcted myocardium are not well defined. In the present study, the capacity of separating myocardium with evolving necrosis from viable myocardium was investigated. METHODS AND RESULTS: Pigs were subjected to balloon occlusion of the left anterior descending coronary artery for 45 minutes. Using the NOGATM cardiac mapping system, EMM was performed at the baseline and after two hours of reperfusion. EMMs were evaluated regarding unipolar voltage (UPV), bipolar voltage (BPV) and local linear shortening (LLS). The pigs were sacrificed four hours after reperfusion and morphological estimation of infarct size and localization was performed. Baseline UPV activity was significantly lower in the anterior, lateral and posterior basal segments as compared to the septal and posterior midventricular segments. After reperfusion, UPV, but not BPV, was significantly decreased in the apical, midventricular septal and basal segments. LLS demonstrated significant impairment of mobility in the septal midventricular segment. The thresholds for separating electromechanical activity at baseline from after infarction differed between the myocardial regions. The ability of EMM to correctly detect infarcted myocardium showed a sensitivity and specificity in the order of 50 85%, as compared to the morphological standard. CONCLUSION: In a porcine acute infarct and reperfusion model, electromechanical activity thresholds, for infarct detection, could be established, but there was significant intersegmental threshold variability at baseline and after infarction. Accordingly, applying general thresholds demonstrated a poor correlation between infarct extension evaluated by EMM and morphology.