ß-Blocker Use and Risk of Mortality in Heart Failure Patients Initiating Maintenance Dialysis.

RATIONAL & OBJECTIVE: Beta-blockers are recommended for patients with heart failure (HF) but their benefit in the dialysis population is uncertain. Beta-blockers are heterogeneous, including with respect to their removal by hemodialysis. We sought to evaluate whether ß-blocker use and their dialyzability characteristics were associated with early mortality among patients with chronic kidney disease with HF who transitioned to dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults patients with chronic kidney disease (aged≥18 years) and HF who initiated either hemodialysis or peritoneal dialysis during January 1, 2007, to June 30, 2016, within an integrated health system were included. EXPOSURES: Patients were considered treated with ß-blockers if they had a quantity of drug dispensed covering the dialysis transition date. OUTCOMES: All-cause mortality within 6 months and 1 year or hospitalization within 6 months after transition to maintenance dialysis. ANALYTICAL APPROACH: Inverse probability of treatment weights using propensity scores was used to balance covariates between treatment groups. Cox proportional hazard analysis and logistic regression were used to investigate the association between ß-blocker use and study outcomes. RESULTS: 3,503 patients were included in the study. There were 2,115 (60.4%) patients using ß-blockers at transition. Compared with nonusers, the HR for all-cause mortality within 6 months was 0.79 (95% CI, 0.65-0.94) among users of any ß-blocker and 0.68 (95% CI, 0.53-0.88) among users of metoprolol at transition. There were no observed differences in all-cause or cardiovascular-related hospitalization. LIMITATIONS: The observational nature of our study could not fully account for residual confounding. CONCLUSIONS: Beta-blockers were associated with a lower rate of mortality among incident hemodialysis patients with HF. Similar associations were not observed for hospitalizations within the first 6 months following transition to dialysis.

Supraventricular tachycardias in the first year of life: what is the best pharmacological treatment? 24 years of experience in a single centre.

BACKGROUND: Supraventricular tachycardias (SVTs) are common in the first year of life and may be life-threatening. Acute cardioversion is usually effective, with both pharmacological and non-pharmacological procedures. However, as yet no international consensus exists concerning the best drug required for a stable conversion to sinus rhythm (maintenance treatment). Our study intends to describe the experience of a single centre with maintenance drug treatment of both re-entry and automatic SVTs in the first year of life. METHODS: From March 1995 to April 2019, 55 patients under one year of age with SVT were observed in our Centre. The SVTs were divided into two groups: 45 re-entry and 10 automatic tachycardias. As regards maintenance therapy, in re-entry tachycardias, we chose to start with oral flecainide and in case of relapses switched to combined treatment with beta-blockers or digoxin. In automatic tachycardias we first administered a beta-blocker, later combined with flecainide or amiodarone when ineffective. RESULTS: The patients' median follow-up time was 35 months. In re-entry tachycardias, flecainide was effective as monotherapy in 23/45 patients (51.1%) and in 20/45 patients (44.4%) in combination with nadolol, sotalol or digoxin (overall 95.5%). In automatic tachycardias, a beta-blocker alone was effective in 3/10 patients (30.0%), however, the best results were obtained when combined with flecainide: overall 9/10 (90%). CONCLUSIONS: In this retrospective study on pharmacological treatment of SVTs under 1 year of age the combination of flecainide and beta-blockers was highly effective in long-term maintenance of sinus rhythm in both re-entry and automatic tachycardias.

Use of beta-blockers for rosacea-associated facial erythema and flushing: A systematic review and update on proposed mode of action.

BACKGROUND: Flushing and erythema are frequent skin symptoms in rosacea. Because their adequate treatment remains a clinical challenge, new treatment options are explored, such as oral ß-blockers. OBJECTIVES: To evaluate the efficacy of oral ß-blockers for rosacea-associated facial flushing and erythema. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched, including studies providing original data on the efficacy of oral ß-blockers in rosacea patients with facial flushing and/or persistent erythema. Risk of bias was assessed using the Cochrane Risk of Bias tool, Newcastle-Ottawa scale, and Quality in Prognosis Studies tool. RESULTS: Nine studies evaluating the use of carvedilol, propranolol, nadolol, and ß-blockers in general were included. Articles studying carvedilol and propranolol showed a large reduction of erythema and flushing during treatment with a rapid onset of symptom control. Bradycardia and hypotension were the most commonly described adverse events. LIMITATIONS: Most studies had a retrospective design with a small sample size, and outcome measurement was often subjective. CONCLUSIONS: Oral ß-blockers could be an effective treatment option for patients with rosacea with facial erythema and flushing that does not respond to conventional therapy. Larger prospective trials with objective outcome assessment are needed to validate the promising results of these studies.

Ventricular arrhythmia suppression with ivabradine in a patient with catecholaminergic polymorphic ventricular tachycardia refractory to nadolol, flecainide, and sympathectomy.

Conventional treatment strategies for catecholaminergic polymorphic ventricular tachycardia (CPVT) include avoidance of strenuous exercise and competitive sports, drugs such as ß-blockers and flecainide and, cervical sympathectomy. An implantable cardioverter-defibrillator (ICD) has been utilized if the response to these strategies is inadequate; however, ICD use in CPVT patients, in addition to usual complications, is associated with an increased risk of life-threatening electrical storm. Ivabradine is a selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 generated funny current (If ), which has been shown to be efficacious in suppression of inappropriate sinus tachycardia, junctional tachycardia, atrial tachycardia, and ventricular ectopy in humans. We report an 18-year-old male with a severe CPVT phenotype refractory to flecainide, nadolol, and sympathectomy who exhibited suppression of ventricular arrhythmias after initiation of ivabradine. These findings are of importance as ivabradine could be an important add-on therapy in CPVT patients who are drug refractory or are unable to continue conventional therapies at the recommended doses.

A large deletion in RYR2 exon 3 is associated with nadolol and flecainide refractory catecholaminergic polymorphic ventricular tachycardia.

We report a 17-year-old boy with a large RYR2 exon 3 deletion who has a severe catecholaminergic polymorphic ventricular tachycardia (CPVT) phenotype characterized by refractoriness to both nadolol and flecainide which has previously not been reported in this subgroup of CPVT patients. Treatment options in a patient like ours are therefore limited and sympathectomy and implantable cardioverter-defibrillator implantation should be considered early in the treatment course as was done in this patient. In contrast to other CPVT patients who do not usually have structural cardiac abnormalities, these patients are at a high risk of developing left ventricular noncompaction or dilated cardiomyopathy and therefore might benefit from cardiac imaging at regular intervals.

Efficacy of ivabradine to control ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal hereditary disease characterized by complex ventricular arrhythmias provoked by exercise or emotional stress and by a high mortality rate in young individuals. Nadolol alone or in combination with flecainide is the most effective therapy. However, compliance to treatment is often low due to side effects. We report two patients with CPVT in whom side effects of treatment prompted discontinuation of flecainide or nadolol and in whom ivabradine was successfully added to therapy. In these two patients, ivabradine in combination with nadolol or flecainide was well tolerated and successfully suppressed nonsustained polymorphic ventricular tachycardia and couplets. Thus, ivabradine could limit the use of implantable cardioverter-defibrillators or left cardiac sympathetic denervation in CPVT patients with uncontrollable ventricular arrhythmias.

Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices.

BACKGROUND: Non-selective beta-blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non-selective beta-blocker with additional intrinsic alpha1-blocking effects, which may be superior to traditional, non-selective beta-blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of carvedilol compared with traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices. SEARCH METHODS: We combined searches in the Cochrane Hepato-Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018. SELECTION CRITERIA: We included randomised clinical trials comparing carvedilol versus traditional, non-selective beta-blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices. DATA COLLECTION AND ANALYSIS: Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the quality of the evidence with GRADE. MAIN RESULTS: Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I2 = 0%, low-quality evidence). There appeared to be no differences between carvedilol versus traditional, non-selective beta-blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I2 = 45%, very low-quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I2 = 14%, low-quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long-term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non-selective beta-blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non-serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I2 = 88%; very low-quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non-selective beta-blockers both in absolute (MD -1.75 mmHg, 95% CI -2.60 to -0.89; 368 participants; 6 trials; I2 = 0%; low-quality evidence) and percentage terms (MD -8.02%, 95% CI -11.49% to -4.55%; 368 participants; 6 trials; I2 = 0%; low-quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I2 = 42%; very low-quality evidence) or in clinical outcomes. AUTHORS' CONCLUSIONS: We found no clear beneficial or harmful effects of carvedilol versus traditional, non-selective beta-blockers on mortality, upper gastrointestinal bleeding, serious or non-serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long-term, double-blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.

Risk and Predictors of Variceal Bleeding in Cirrhosis Patients Receiving Primary Prophylaxis With Non-Selective Beta-Blockers.

OBJECTIVES: Prior studies have demonstrated the efficacy of non-selective beta-blockers (NSBB) in preventing first variceal bleeding in patients with cirrhosis. However, little is known about the overall effectiveness of NSBB in routine clinical care. METHODS: We conducted a retrospective cohort study of cirrhotic patients without prior bleeding who initiated a NSBB (propranolol, nadolol) at any Veterans Administration facility between 2008 and 2013. The primary outcome was variceal bleeding within 12 months. We conducted Cox-proportional hazards analyses to identify demographic, clinical, and NSBB-related (type of NSBB, mean dose, dose change, and heart rate response) factors associated with variceal bleeding. RESULTS: Of 5,775 patients, 678 (11.7%) developed variceal bleeding. Mean daily dose of NSBB was <40 mg in 58.8%, 18.1% had either upward or downward titration in NSBB dose, and 9.8% had hemodynamic response. Patients who were younger, with ascites, greater medical comorbidity, and higher MELD (Model for end-stage liver disease) scores had a higher risk of variceal bleeding. Patients on a higher daily dose (>60 vs. <40 mg, adjusted hazard ratio (HR) 0.64; 95% confidence interval (CI): 0.51-0.81), who had either upward or downward dose titration (adjusted HR 0.69; 95% CI: 0.52-0.90 and 0.64; 95% CI 0.45-0.90, respectively), and those who achieved hemodynamic response (adjusted HR 0.75; 95% CI=0.57-1.0) had lower risk. CONCLUSIONS: Approximately 12% of patients bled while being on NSBB for primary prophylaxis. A higher NSBB dose and dose titration were protective; yet most patients did not have the NSBB dose titrated to the recommended levels. Our data highlight the need for careful monitoring of cirrhotic patients on NSBB.

Oral Nadolol for the Treatment of Infantile Hemangiomas: A Single-Institution Retrospective Cohort Study.

BACKGROUND: Beta-blockers have become the treatment of choice for problematic infantile hemangiomas (IHs). Nadolol, a nonselective beta-blocker with potential dosing advantages and a better safety profile than that of other beta-blockers, has been studied as an alternative therapeutic option. Our objective was to characterize the efficacy and safety of oral nadolol in the treatment of proliferating IHs. METHODS: A retrospective cohort study was conducted at the Hospital for Sick Children between February 2010 and April 2012 in patients treated with nadolol for proliferating IHs causing functional impairment or cosmetic disfigurement. The primary outcome was the percentage involution measured independently by two assessors who scored changes in the extent of IHs by comparing serial photographs using a 100-mm visual analogue scale (VAS), on which 5 mm represented 10% change. RESULTS: Forty-four patients treated with nadolol for IHs with adequate photographic documentation were identified. The median age at presentation was 4.5 months (interquartile range 1.5-7.9 mos). There was a mean improvement of 91.8 ± 11.1%. At least 50% improvement was noted in 42 (95%) patients and 75% improvement in 39 (89%) patients. The mean time to 50% and 75% improvement was 2.9 and 3.7 months, respectively. Analysis of variance showed that younger age at the time of treatment start was associated with a higher mean VAS score (% involution) (p < 0.05). Treatment duration (mean 9.5 ± 5.6 months) had no significant effect on VAS score. Test of interobserver correlation showed good agreement (intraclass correlation coefficient = 0.86, p = 0.001). CONCLUSIONS: Oral nadolol is efficacious in patients with problematic IHs. Further large-scale prospective comparative studies are warranted to compare nadolol with other beta-blockers.

Beta blocker treatment for infantile hemangiomas.

Infantile hemangiomas (IH) are common childhood vascular tumors.  Treatment of IH has undergone rapid change in recent years.  Since 2008, oral propranolol has been used to treat complicated IH and has proven superior to previously used therapies.  More recently, the efficacy of other systemic beta blockers, specifically atenolol and nadolol, has been reported.  In addition, topical timolol solution has been effective for treatment of smaller, more superficial IH.  The purpose of this article is to review the current literature of beta-blocker therapy for IH.

Combined therapies versus monotherapies for the first variceal bleeding in patients with high-risk varices: a meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: The effect of combined therapies (among non-selected beta-blockers [NSBB], endoscopic therapy, and other treatments) on the first variceal bleeding has been evaluated in several randomized controlled trials previously, and the results were controversial. We performed this meta-analysis to assess the effect of combined therapies in patients with high-risk varices without previous variceal bleeding. METHODS: The Cochrane Library, The Cochrane Hepato-Biliary Group Controlled Trials Register, MEDLINE, and EMBASE were searched for eligible trials. Manual searches were also performed for additional studies. Upper gastrointestinal bleeding, variceal bleeding, mortality, and adverse events were evaluated as end-points by meta-analysis. RESULTS: Twelve randomized controlled trials with 1571 patients were included. Compared with the NSBB (propranolol or nadolol) or endoscopic therapy alone, all of the combined therapies did not demonstrate significant improvements in variceal bleeding, total upper gastrointestinal bleeding, and mortality. Only the combinations of isosorbide-mononitrate or spironolactone with NSBB tended to decrease the risk of variceal bleeding when compared with the use of NSBB alone (isosorbide-mononitrate plus NSBB vs NSBB: odds ratio = 0.67, 95% confidence interval 0.40-1.13, P = 0.13; spironolactone plus NSBB vs NSBB: odds ratio = 0.41, 95% confidence interval 0.10-1.69, P = 0.22). Adverse events were more frequently observed in the combined therapy groups. CONCLUSIONS: Based on the available evidences, no combined therapy can be recommended as the first-line treatment for the primary prevention of variceal bleeding currently. Further studies with large sample sizes and long-term follow up are warranted.

Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding.

BACKGROUND AND AIM: Carvedilol has been shown to be more effective than propranolol in decreasing portal pressure. Sufficient data from controlled trials remains limited. This trial compared the relative safety and efficacy between carvedilol and nadolol plus isosorbide mononitrate in preventing variceal rebleeding. METHODS: After successful control of acute esophageal variceal bleeding, eligible patients were randomized to the carvedilol group, 61 patients, using carvedilol 6.25-12.5 mg daily or the N + I group, 60 patients, using nadolol 40-80 mg plus isorsorbide-5-mononitrate 20 mg daily. The end points were rebleeding from varices, adverse events or death. RESULTS: After a median follow up of 30 months, recurrent upper gastrointestinal bleeding developed in 37 patients (61%) in the carvedilol group and 37 patients (62%) in the N + I group (P = 0.90). Recurrent bleeding from esophageal varices occurred in 31 patients (51%) in the carvedilol group and in 26 patients (43%) in the N + I group (P = 0.46). Recurrent bleeding from gastric varices occurred in two patients (3%) in the carvedilol group and in eight patients (13%) in the N + I group (P = 0.05). Severe adverse events occurred in one patient in the carvedilol group and 17 patients in the N + I group (P < 0.0001). Fifteen patients of the carvedilol group and 17 patients in the N + I group died (P = 0.83). Two patients in the carvedilol group and three patients in the N + I group died of variceal bleeding. CONCLUSIONS: Carvedilol was as effective as nadolol plus isorsorbide-5 -mononitrate mononitrate in the prevention of gastroesophageal variceal rebleeding with fewer severe adverse events and similar survival.

Outcomes of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia Treated With ß-Blockers.

Importance: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) may experience life-threatening arrhythmic events (LTAEs) despite ß-blocker treatment. Further complicating management, the role of implantable cardioverter defibrillator (ICD) in CPVT is debated. Objective: To investigate the long-term outcomes of patients with RYR2 CPVT treated with ß-blockers only and the cost to benefit ratio of ICD. Design, Settings, and Participants: This prospective cohort study conducted from January 1988 to October 2020 with a mean (SD) follow-up of 9.4 (7.5) years included patients who were referred to the Molecular Cardiology Clinics of ICS Maugeri Hospital, Pavia, Italy. Participants included consecutive patients with CPVT who were carriers of a pathogenic or likely pathogenic RYR2 variant with long-term clinical follow-up. Exposures: Treatment with selective and nonselective ß-blocker only and ICD implant when indicated. Main Outcome and Measures: The main outcome was the occurrence of the first LTAE while taking a ß-blocker. LTAE was defined as a composite of 3 hard end points: sudden cardiac death, aborted cardiac arrest, and hemodynamically nontolerated ventricular tachycardia. Results: The cohort included 216 patients with RYR2 CPVT (121 of 216 female [55%], median [IQR] age 14, [9-30] years). During a mean (SD) follow-up of 9.4 (7.5) years taking ß-blockers only, 28 of 216 patients (13%) experienced an LTAE (annual rate, 1.9%; 95% CI, 1.3-2.7). In multivariable analysis, experiencing either an LTAE (hazard ratio [HR], 3.3; 95% CI, 1.2-8.9; P = .02) or syncope before diagnosis (HR, 4.5; 95% CI, 1.8-11.1; P = .001) and carrying a C-terminal domain variant (HR, 18.1; 95% CI, 4.1-80.8; P < .001) were associated with an increased LTAE risk during ß-blocker therapy only. The risk of LTAE among those taking selective ß-blockers vs nadolol was increased 6-fold (HR, 5.8; 95% CI, 2.1-16.3; P = .001). Conversely, no significant difference was present between propranolol and nadolol (HR, 1.8; 95% CI, 0.4-7.3; P = .44). An ICD was implanted in 79 of 216 patients (37%) who were followed up for a mean (SD) of 8.6 (6.3) years. At the occurrence of LTAE, ICD carriers were more likely to survive (18 of 18 [100%]) than non-ICD carriers (6 of 10 [60%]; P = .01). Conclusions and Relevance: In this cohort study, selective ß-blockers were associated with a higher risk of LTAE as compared with nadolol. Independently from treatment, LTAE and syncope before diagnosis and C-terminal domain variants identified patients at higher risk of ß-blocker failure, and the ICD was associated with reduced mortality in high-risk patients with CPVT.

Contemporary maternal and fetal outcomes in the treatment of LQTS during pregnancy: Is nadolol bad for the fetus?

BACKGROUND: ß-Blocker therapy, specifically nadolol, is the recommended treatment for long QT syndrome (LQTS). Previous studies assessing maternal and fetal outcomes were published before the nadolol era. OBJECTIVE: The purpose of this study was to examine contemporary maternal and fetal outcomes in the treatment of LQTS during pregnancy. METHODS: We queried the Inherited Arrhythmia Database at Cleveland Clinic and identified all pregnant patients with LQTS from January 2001 through January 2020. Collected data included use and timing of ß-blockers, maternal arrhythmic events, fetal growth restriction, neonatal hypoglycemia, and bradycardia. RESULTS: Among 68 live-birth pregnancies in 31 women with LQTS (mean age 29 ± 5.9 years; mean corrected QT interval 468 ± 39 ms), there were 5 arrhythmic events in 4 mothers. All arrhythmic events occurred in the postpartum period, and there were no arrhythmic events in patients taking ß-blockers. In patients diagnosed with LQTS and treated with ß-blockers (n = 27 [41%]), nadolol was the most commonly prescribed agent throughout pregnancy and the postpartum period (n = 16 [60%]). The rate of intrauterine growth restriction was not significantly different in fetuses exposed to ß-blockers vs unexposed (P = .08). In the postnatal period, hypoglycemia was not seen and 1 patient in the exposure group had bradycardia. CONCLUSION: Arrhythmic events were only seen in the postpartum period in those not treated with ß-blockers. Events occurred as late as 9 months postpartum. ß-Blocker therapy, specifically nadolol, was not associated with a higher incidence of intrauterine growth restriction. Moreover, neonatal bradycardia was rare and hypoglycemia was not observed.

Controlled trial of ligation plus nadolol versus nadolol alone for the prevention of first variceal bleeding.

UNLABELLED: Both nadolol and ligation have proved to be effective in the prophylaxis of first variceal bleeding. This study was conducted to evaluate the effects and safety of combining nadolol with ligation. Cirrhotic patients with high-risk esophageal varices but without a bleeding history were considered for enrolment. Eligible patients were randomized to receive band ligation plus nadolol (Combined group, 70 patients) or nadolol alone (Nadolol group, 70 patients). In the Combined group multiligators were applied. Patients received regular ligation treatment at an interval of 4 weeks until variceal obliteration. Nadolol was administered at a dose to reduce 25% of the pulse rate in both the Combined group and the Nadolol group. Both groups were comparable in baseline data. In the Combined group 50 patients (71%) achieved variceal obliteration. The mean dose of nadolol was 52 +/- 16 mg in the Combined group and 56 +/- 19 mg in the Nadolol group. During a median follow-up of 26 months, 18 patients (26%) in the Combined group and 13 patients (18%) in the Nadolol group experienced upper gastrointestinal bleeding (P = NS). Esophageal variceal bleeding occurred in 10 patients (14%) in the Combined group and nine patients (13%) in the Nadolol group (P = NS). Adverse events were noted in 48 patients (68%) in the Combined group and 28 patients (40%) in the Nadolol group (P = 0.06). Sixteen patients in each group died. CONCLUSION: The addition of ligation to nadolol may increase adverse events and did not enhance effectiveness in the prophylaxis of first variceal bleeding.

Germline and somatic mosaicism for a mutation of the ryanodine receptor type 2 gene: implication for genetic counselling and patient caring.

We identified a heterozygous p.Arg2401His mutation of RYR2 by sequencing the DNA of a 7-year-old girl who was referred for catecholaminergic polymorphic ventricular tachycardia (CPVT). Using high-resolution melting assay, we have demonstrated a mosaicism for this mutation in her asymptomatic mother which illustrates the benefit of extensive genetic analysis in CPVT, in particular regarding genetic counselling.

Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.

BACKGROUND & AIMS: Studies of variceal bleeding have shown that a hemodynamic response to treatment of portal hypertension is appropriate when the hepatic venous pressure gradient (HVPG) decreases below 12 mmHg or by > 20% from baseline. However, in primary prophylaxis, many nonresponders do not bleed and 2 invasive procedures are needed to assess response. We investigated the long-term prognostic value of an acute response to beta-blockers and whether the target reduction in HVPG can be improved in primary prophylaxis. METHODS: An initial hemodynamic study was performed in patients with large varices and without previous bleeding. After baseline measurements were made, propranolol was administered intravenously and measurements were repeated 20 minutes later. Patients were given nadolol daily and a second hemodynamic study was performed. RESULTS: Of 105 patients, 15% had variceal bleeding. Using receiver operating characteristic curve analysis, a decrease of HVPG > or = 10% was the best value to predict bleeding. In the initial study, 75 patients (71%) were responders (HVPG decreased to < or = 12 mmHg or by > or = 10%) and had a lower probability of first bleeding than nonresponders (4% vs 46% at 24 months; P < .001). Acute responders also had a lower risk of developing ascites (P = .001). Chronic responders had a lower probability of bleeding than nonresponders (P < .001). There was a correlation between acute and chronic changes in HVPG (r = 0.62; P = .01). CONCLUSION: The acute hemodynamic response to beta-blockers can be used to predict the long-term risk of first bleeding. An HVPG reduction > 10% from baseline is the best target to define response in primary prophylaxis.