Di Filippo With reference to adult trials (Lechat et al 1998), carvedilol was highlighted as the beta-blocker of choice to treat chronic HF (Spicer 2001). Bruns et al (2001) ﬁrst reported multicenter (6 centers) retrospective experience with the use of carvedilol in pediatric HF patients, to assess efﬁcacy, safety, and tolerability. The data from 46 patients (aged 3 months to 19 years) with congestive HF due to dilated cardiomyopathy (80%) or chronic heart disease (20%) were collected and analyzed. Third-month evalua- tion showed improvement in both clinical NYHA class and shortening fraction. Severe adverse outcomes occurred in 30% (death, transplantation, mechanical ventricular sup- port). This study, although limited by retrospective analysis, was the ﬁrst report of consistent data about carvedilol use in pediatric patients with chronic HF. Since heart transplanta- tion is the only ﬁnal option in cases with uncontrolled HF, and facing the shortage of donors and serious post-transplant difﬁculties, one major advantage of beta-blockers is that they enable heart transplant to be delayed. Azeka et al (2002) showed that carvedilol may even allow delisting patients from the waiting list. Two further retrospective studies also conﬁrmed the beneﬁcial effect of beta-blockers on functional outcomes and echo Doppler left ventricle function (Williams et al 2002; Rusconi et al 2004). One main issue is the difﬁculty of differentiating beta-blocker effect from the natural fa- vorable evolution of the disease. Left ventricle has been shown to spontaneously recover in dilated cardiomyopathy or myocarditis or after surgery of abnormal origin of the left main coronary artery from the pulmonary artery. Irrevers- ible systemic ventricle dysfunction should not be assumed too soon. Two years is probably the optimal threshold for myocardial function to recover; however, follow-up does not exceed 6 months in most of the available published studies. Data from prospective studies about carvedilol in children with ventricular dysfunction are very limited. One large multicenter, prospective, double-blind, placebo-controlled study was conducted by Shaddy et al (2002). Patients aged 0–17 years were included, diagnosed with ejection fraction less than 40% at least 4 weeks prior to inclusion, and treated with conventional therapy (angiotensin converting enzyme inhibitors with one or more other medications). Patients were designed to receive either placebo or carvedilol, and were followed-up over an 8-month period. Primary end-point was a composite of clinical outcomes, determined as worsened, improved, or unchanged status (Shaddy et al 2002). Fifty-ﬁve patients were included in the placebo group and 106 in the 852 carvedilol group, recruited from 20 centers. Results showed no difference at 8 months between placebo and treated groups for the primary end-point. This study highlighted a higher- than-expected placebo response rate (Cleland et al 2006). Several conclusions can be drawn from these results: 1) the heterogeneicity of the population regarding cardiac disease and age of the patients may have led to excessive dispari- ties; 2) we hypothesize that systemic right or single ventricle may not act like left ventricle in response to beta-blockers; 3) neonates have different cardiac physiology, in particular lower myocardial compliance, that may have inﬂuenced the results; 4) cases may have been included that would have recovered spontaneously (myocarditis, ischemic injury in coronary artery disease); and 5) the length of follow-up between diagnosis and onset of beta-blockers may have been too short. Conversely, length of follow-up after onset of beta-blockers may also be too short to draw conclusions on the effectiveness of these agents compared with conven- tional therapy. Most recently, Blume et al (2006) reported their results of a single-arm protocol of carvedilol in children with ven- tricular dysfunction lasting for at least 3 months on maximal medical treatment including angiotensin converting enzyme inhibitors. Twenty carvedilol-treated patients were recruited according to clinical and echocardiographic criteria, and were compared with historical matched controls. Primary end-point was echocardiographic parameters of function measured at the sixth month. This study showed a signiﬁcant increase in ejection fraction in the treated group with dilated cardiomyopathy. No conclusion could be drawn in the group with congenital heart disease, although some cases experi- enced echocardiographic improvement similar to patients with dilated cardiomyopathy. In summary, though beta-blockers have been proven to affect survival in adults, such an evidence is not yet available in the pediatric population. Current practice has nevertheless increasingly added beta-blockers to the armamentarium, in an attempt to optimize therapy for HF in children. Only limited experience has been reported, mostly from retrospective analysis of heterogeneous data. Prospective studies are very scarce and results are still a matter of dis- cussion. The only large-scale, prospective, double-blind and placebo-controlled study failed to demonstrate the efﬁcacy of carvedilol on a composite end-point of clinical outcomes. However, one may intuitively predict some beneﬁcial impact of these agents in pediatric HF patients. Further progress will be needed to assess this issue. Therapeutics and Clinical Risk Management 2007:3(5)