Hemodynamic and neuroendocrine effects for candoxatril and frusemide in mild stable chronic heart failure.

OBJECTIVES: The study aimed to assess the hemodynamic and neuroendocrine effects of candoxatril and frusemide compared with placebo in patients with mild chronic heart failure. BACKGROUND: Candoxatril is an atriopeptidase inhibitor. It increases circulating levels of atrial natriuretic peptide leading to natriuresis and diuresis, which alleviate the symptoms of a failing heart. METHODS: This was a multicenter, randomized, double-blind study. Forty-seven patients with mild stable chronic heart failure received candoxatril 400 mg/day, frusemide 40 mg/day or placebo for up to six weeks. Cardiac indices were determined at rest and during exercise, and blood samples were taken for laboratory analysis. Assessments were performed at baseline (day 0) and after six weeks (day 42). RESULTS: In comparison with placebo, both drugs significantly reduced mean pulmonary capillary wedge pressure following the first dose administration. Only candoxatril significantly reduced pulmonary capillary wedge pressure during exercise on day 0, while both drugs significantly reduced this parameter on day 42. Changes in the remaining hemodynamic parameters were comparable for both drugs relative to placebo. Frusemide significantly increased mean plasma renin activity (days 0 and 42), and the mean aldosterone concentration (day 42) in comparison with placebo, whereas candoxatril caused no significant changes in any of the hormonal parameters assessed. CONCLUSIONS: These results show that candoxatril, 400 mg/day, has a similar hemodynamic profile to frusemide, 40 mg/day, but it does not induce adverse neuroendocrine effects. Candoxatril therefore appears to offer a clinically significant advantage over frusemide, providing an alternative therapeutic approach to the treatment of patients with mild stable chronic heart failure.

Ventricular Arrhythmia Suppression by Magnesium Treatment after Coronary Artery Bypass Surgery.

Ventricular arrhythmias occur frequently shortly after coronary artery bypass grafting (CABG), and their occurrence coincides with the postoperative decline in serum magnesium (Mg) levels. To examine if this decline causes ventricular arrhythmias and if their appearance could be reduced by intravenous Mg administration, 140 consecutive CABG patients were randomized to receive 70 mmol of Mg sulphate (N = 69) or placebo (N = 71) over two days. Serum Mg concentration fell to 0.77 mmol/l in the control group but rose to 1.09 mmol/l in the Mg group (p < 0.001). On 48 h Holter, the number of ventricular premature complexes (VPC) on the third postoperative day was reduced in the Mg group (4 +/- 5 vs 12 +/- 21 VPCs/h; p < 0.05) and the incidence of complex ventricular arrhythmias (Lown grade 2-5) was significantly diminished (19% vs 41% of the patients; p < 0.05). In multivariate analysis, high risk ventricular arrhythmias (repetitive polymorphic ventricular complexes, couplets, R-on-T complexes or operative tachycardia) were independently predicted by high number of bypassed vessels (p = 0.01), poor NYHA functional class (p = 0.06), preoperative diuretic use (p = 0.07), and low postoperative Mg levels (p = 0.08). In conclusion, correction of the postoperative decline in serum Mg concentration decreases the occurrence of early VPCs and complex ventricular arrhythmias. Patients with extensive underlying coronary artery disease and prior diuretic therapy appear to benefit greatest from Mg treatment.http://link.springer-ny.com/link/service/journals/00547/bibs/8n3p165.html

Comparison of sotalol and metoprolol in the prevention of atrial fibrillation after coronary artery bypass surgery.

New-onset atrial fibrillation (AF) is frequent after coronary artery bypass grafting (CABG), and beta-blockers decrease its incidence. To examine whether a beta-blocker with class III properties is superior to a pure one, 191 consecutive patients undergoing CABG were randomized to receive oral sotalol, 120 mg daily (n = 93), or metoprolol, 75 mg daily (n = 98), postoperatively. The doses were adjusted if beta-blockade was inadequate or excessive. AF occurred in 16 (16%) of 98 sotalol patients and in 30 (32%) of 93 metoprolol patients (p < 0.01). Symptoms related to beta-blockade or proarrhythmia did not appear. After CABG, sinus heart rate increased in both groups (p < 0.001) but less in the sotalol patients (p < 0.001) throughout the postoperative period. Corrected QT duration (by the Bazett equation) was prolonged after the operation in both groups (p < 0.001), whereas uncorrected QT duration at similar heart-rate levels were prolonged only in sotalol patients (mean increase, 31 ms; 95% confidence interval, 2042 ms; p < 0.01). Uncorrected QT durations at similar heart-rate levels were longer during sotalol (compared with metoprolol) treatment (p < 0.05). Heart rates or QT durations did not differ between the patients with or without AF. In conclusion, sotalol significantly reduces the incidence of AF after CABG. Although a marked class III effect is demonstrated with relatively low doses (as prolonged ventricular repolarization) in direct comparison unbiased by any rate correction, its contribution as an enhanced antifibrillatory mechanism in the postoperative state remains unconfirmed.

The influence of intravenous magnesium sulphate on the occurrence of atrial fibrillation after coronary artery by-pass operation.

To examine the influence of magnesium (Mg) on hypomagnesaemia and atrial fibrillation (AF) following coronary artery by-pass surgery, 140 consecutive patients were randomized to receive 70 mmol of magnesium sulphate intravenously (n = 69) or placebo (n = 71). Serum magnesium concentrations fell to 0.77 +/- 0.10 mmol.l-1 in the control group but rose to 1.09 +/- 0.17 mmol.l-1 in the Mg group (P < 0.001). The incidence of AF was 29% in the Mg group and 26% in the placebo group (NS). The AF patients were older, more of them had had prior AF episodes, their sinus rates (SR) were slower (78 +/- 10 vs 86 +/- 12 beats.min-1; P < 0.01) and serum Mg concentrations higher (0.89 +/- 0.21 vs 0.80 +/- 0.11 mmol.l-1; P < 0.05). The incidence of AF was 43% in the highest quartile of serum Mg and 23% among the rest (P = 0.056). In patients experiencing AF during the first three post-operative days, serum Mg concentrations were higher and SR slower on each day compared with non-AF patients. SR increased post-operatively less with high Mg levels (P = 0.044). In the Mg group, serum Mg and SR were the only independent predictors of AF. In conclusion, the incidence of post-operative AF is not decreased with magnesium. High Mg levels are likely to provoke AF probably by mechanisms that modify SR.