Subsequent trials with metoprolol (Merit-HF 1999; Hjal- marsen et al 2000) and bisoprolol (CIBIS-II 1999) showed similar survival beneﬁts in adults with HF. CIBIS-II included 2647 patients in NYHA class II or IV with left ventricular fraction of 35% or less receiving diuretics with inhibitors of angiotensin-converting enzyme, who were randomly assigned to receive placebo or bisoprolol: all-cause mortality was signiﬁcantly lower in the treated group (11.8%) com- pared with placebo (17.3%). Similarly Merit-HF enrolled 3991 patients in NYHA class II to IV, with ejection fraction of 40% or less, to receive either metoprolol or placebo, in addition to standard therapy: results also showed a signiﬁcant reduction of all-cause mortality (7.2% vs 11%). From these large-scale randomized double-blind trials, beta-blockers agents were recommended for the treatment of mild to moderate HF, excluding NYHA class IV cases. The COPERNICUS trial (Packer et al 2002) further entered patients with more severe HF: 2289 patients in NYHA class IV, with ejection fraction less than 25%, were randomized to receive either placebo or carvedilol for an average of 10.4 months. The results showed a significant reduction in the number and dura- tion of hospitalizations, and in the occurrence of serious Beta-blockers in pediatric heart failure adverse events (including clinical deterioration, sudden death, arrhythmias, and cardiogenic shock). Experience in children Table 1 summarizes the current literature about the use of beta-blockers in the pediatric HF population. First experience with beta-receptor antagonist agents was reported by Shaddy et al (1999) with the use of meto- prolol in patients with dilated cardiomyopathy. The authors reviewed data from 3 centers. Fifteen patients aged 8.6 ± 1.3 years and treated over the 1986 to 1997 period were included in this study. They received conventional therapy for 22.5 ± 9 months, and subsequently a mean dose of 1.1 ± 0.1 mg/kg/day metoprolol. Eleven patients were responders and 4 non-responders; mean follow-up was 23.2 ± 7 months. Responders showed a signiﬁcant improvement in ejection fraction and shortening fraction, while there was no change under conventional therapy (before initiation of beta-block- ers). Eight of 11 responders also improved their NYHA class. Since the pre-beta-blocker period was prolonged enough, the authors concluded that improvement was more likely related to the beneﬁcial effect of beta-blockers, rather than to spontaneous recovery of left ventricular function. Table 1 Reported studies about beta-receptor antagonists in pediatric heart failure patients Ref N Design Cardiac Beta- FU Pre FU Post Results disease blocker Shaddy 15 Retro CMD 14 metoprolol 22.5 ± 9 23.2 ± 7 Improved EF, SF, NYHA 1999 Multic CHD 1 mos mos (11 responders) Bruns 2001 46 Retro Multic Williams 12 Retro 2002 Rusconi 24 Retro 2004 Azeka 22 Prosp 2002 Shaddy 2002 Cleland 2006 Blume 2006 161 Prosp Multic Rando 20 Pro Multic CMD 37 CHD 9 CMD 10 CHD 2 CMD CMD CMD CHD CMD 12 CHD 8 carvedilol 14 Placebo 8 carvedilol 106 Placebo 55 carvedilol 20 controls 24 carvedilol 3 mos Improved SF, NYHA metoprolol 8.5 ± 21 6 mos and carvedilol mos carvedilol 14 ± 23 9 mos mos Improved EF, SF Improved EF, NYHA 6 mos Improved EF, SF, NYHA 1 mos 6 mos 3 mos 6 mos No signiﬁcant change (composite measure of clinical outcome) Improved EF, improved composite clinical outcome Side effects Outcome Bradycardia 3 dead (1 case) 1 transplant 1 bradycardia 25 cases (54%) 1 dead 12 transplant 1 VAD 5 dead or transplant 5 cases (21%) - 1 death 3 heart transplant 6 dead(4 carvedilol, 2 placebo) 3 transplant (1 carvedilol, 2 placebo) - 12 in 6 patients No difference Abbreviations: CMD, cardiomyopathy; CHD, congenital heart disease; EF, ejection fraction; FU, follow-up; mos, months; Multic, multicenter; NYHA, New York Heart As- sociation; Nb, number of patients; Pre, before onset of beta-blockers; Post, after onset of beta-blockers; Prosp, prospective; Rando, randomized; Ref, reference; SF, shortening fraction;VAD, ventricular assistance device. Therapeutics and Clinical Risk Management 2007:3(5) 851