Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. beta-Blockers decrease this risk, but studies... Show moreBackground: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. beta-Blockers decrease this risk, but studies comparing individual beta-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of beta-blocker in a large cohort of symptomatic children with CPVT. Methods: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before beta-blocker initiation and age at start of beta-blocker therapy <18 years), treated with a beta-blocker were included. Cox regression analyses with time-dependent covariates for beta-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective beta-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a beta 1-selective beta-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial beta-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for beta 1-selective compared with nonselective beta-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55]). Conclusions: beta 1-selective beta-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective beta-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred beta-blocker for treating symptomatic children with CPVT. Show less
Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. beta-Blockers decrease this risk, but studies... Show moreBackground: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. beta-Blockers decrease this risk, but studies comparing individual beta-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of beta-blocker in a large cohort of symptomatic children with CPVT. Methods: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before beta-blocker initiation and age at start of beta-blocker therapy <18 years), treated with a beta-blocker were included. Cox regression analyses with time-dependent covariates for beta-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective beta-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a beta 1-selective beta-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial beta-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for beta 1-selective compared with nonselective beta-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55]). Conclusions: beta 1-selective beta-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective beta-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred beta-blocker for treating symptomatic children with CPVT. Show less
Metoprolol is among the most frequently prescribed beta-blockers for the treatment of various cardiovascular diseases. Genetic polymorphism within CYP2D6 has been shown to affect the rate of... Show moreMetoprolol is among the most frequently prescribed beta-blockers for the treatment of various cardiovascular diseases. Genetic polymorphism within CYP2D6 has been shown to affect the rate of metabolism of metoprolol. Whether metoprolol dose adjustments are indicated in CYP2D6 poor metabolizers (PMs) has thus far not well been studied. The aim of this study was to determine the effect of the CYP2D6 genotype on the metoprolol maintenance dose in a chronic Dutch patient population. Patients were included if they were treated with metoprolol and in whom CYP2D6 genotype status was known. Patient and treatment characteristics were obtained retrospectively from the electronic healthcare records. Metoprolol maintenance dose was the primary endpoint and was defined as the last known dose that the patients had been treated with. Genotype data were categorized into four phenotypes, that is, PMs, intermediate metabolizers, extensive metabolizers, and ultra-rapid metabolizers (UMs). The endpoints were analyzed as PM versus non-PM. A total of 105 patients were included. The mean +/- SD maintenance dose in PMs (n = 12) was significantly lower compared with non-PMs (n = 93), that is, 48 +/- 20 versus 84 +/- 53 mg, respectively (P = 0.019). No association of the CYP2D6 genotype with the incidence of side effects was observed, although there was a trend for increased risk of drowsiness (P = 0.053). The results of this study show that the CYP2D6 genotype is associated with the maintenance dose of metoprolol. Patients with the CYP2D6 PM phenotype may benefit from a lower metoprolol starting dose, followed by further dose titration to provide patient-tailored therapy and thereby increase the effectiveness of treatment. Show less
Aim Method Metoprolol (a CYP2D6 substrate) is often co-prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug-drug interaction (DDI) is still unclear... Show moreAim Method Metoprolol (a CYP2D6 substrate) is often co-prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug-drug interaction (DDI) is still unclear. This review aimed to systematically evaluate the available evidence and quantify the clinical impact of the DDI. Pubmed, Web of Science, Cochrane Library and Embase were searched for studies reporting on the effect of the DDI among adults published until April 2018. Data on pharmacokinetics, pharmacodynamics and clinical outcomes from experimental, observational and case report studies were retrieved. The protocol of this study was registered in PROSPERO (CRD42018093087). Results Conclusion We found nine eligible articles that consisted of four experimental and two observational studies as well as three case reports. Experimental studies reported that paroxetine increased the AUC of metoprolol three to five times, and significantly decreased systolic blood pressure and heart rate of patients. Case reports concerned bradycardia and atrioventricular block due to the DDI. Results from observational studies were conflicting. A cohort study indicated that the DDI was significantly associated with the incidence of early discontinuation of metoprolol as an indicator of the emergence of metoprolol-related side effects. In a case-control study, the DDI was not significantly associated with bradycardia. Despite the contradictory conclusions from the current literature, the majority of studies suggest that the DDI can lead to adverse clinical consequences. Since alternative antidepressants and beta-blockers with comparable efficacy are available, such DDIs can be avoided. Nonetheless, if prescribing the combination is unavoidable, a dose adjustment or close monitoring of the metoprolol-related side effects is necessary. Show less
