A randomized trial of carvedilol after renin-angiotensin system inhibition in chronic Chagas cardiomyopathy. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. Delisting of infants and children from the heart transplantation waiting list after carvedilol treatment. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Results of the flosequinan-ACE inhibitor trial (FACET). Propranolol treatment of congestive heart failure in infants with congenital heart disease: The CHF-PRO-INFANT Trial. Congestive heart failure in infants treated with propanol. Meta-analysis of observed mortality data from all-controlled, double-blind, multiple-dose studies of losartan in heart failure. Losartan Heart Failure Mortality Meta-analysis Study Group.
The objective of this study was to determine the safety and efficacy of renin-angiotensin system (RAS) inhibitors and beta-blockers in chronic Chagas cardiomyopathy.
                Chronic Chagas cardiomyopathy causes substantial morbidity and mortality in Latin America. Whether RAS inhibitors and beta-blockers are safe and beneficial has been challenged because of the lack of formal trials.
                We conducted a double-blind, placebo-controlled, and randomized trial in 42 patients with Trypanosoma cruzi infection and cardiomyopathy. All patients received enalapril (up-titrated to 20 mg BID) and spironolactone (25 mg QD). Subsequently, the patients were randomly assigned to receive placebo (n = 20) or carvedilol up-titrated to 25 mg BID (n = 19). The primary end points were change in left ventricular ejection fraction (LVEF) after RAS inhibition and that after the addition of carvedilol. The secondary end points were changes in other echocardiographic parameters, Framingham score, quality of life (36-item Short-Form Health Survey), New York Heart Association class, radiographic indices, brain natriuretic peptide levels, and chemokines as well as safety end points.
                Optimization of RAS inhibition was safe, hemodynamically well tolerated, and associated with improvements in Framingham score (P = .001) and quality of life as well as reductions in the cardiothoracic index (P = .002), brain natriuretic peptide level (P = .032), and RANTES (regulated on activation, normal T expressed and secreted) level (P = .001). Left ventricular ejection fraction increased by 2.3% (P = .25); in patients with an LVEF < or = 45% at baseline, it increased by 2.8% (P = .017). Treatment with carvedilol was associated with a trend toward an increase in LVEF (absolute difference between groups, 2.3%; P = .094). The addition of carvedilol was safe, hemodynamically well tolerated, and not associated with symptomatic bradycardia.
                In patients with chronic Chagas cardiomyopathy, optimization of treatment with enalapril and spironolactone and subsequent addition of carvedilol were safe and associated with benefits in cardiac function and clinical status. Larger trials are needed to show effects on mortality and/or hospitalization. Although beta-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents.
                To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction.
                A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months).
                Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight > or =62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight > or =62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not.
                The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels.
                There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend).
                These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology.
                clinicaltrials.gov Identifier: NCT00052026. We performed a prospective, randomized, double-blind, placebo-controlled study of carvedilol effects in children with severe, chronic heart failure (HF), despite the use of conventional therapy.
                Little is known about the effects of carvedilol in youngsters with chronic HF and severe left ventricular (LV) dysfunction.
                We conducted a double-blind, placebo-controlled study of 22 consecutive children with severe LV dysfunction. The children had chronic HF and left ventricular ejection fraction (LVEF) <30%. Patients were randomly assigned to receive either placebo (8 patients) or the beta-blocker carvedilol (14 patients) at 0.01 mg/kg/day titrated up to 0.2 mg/kg/day, followed-up for six months.
                During the follow-up and the up-titration period in the carvedilol group, four patients died and one underwent heart transplantation. In patients receiving carvedilol evaluated after six months, a significant increase occurred in LVEF, from 17.8% (95% confidence interval [CI], 14.1 to 21.4%) to 34.6% (95% CI, 25.2 to 44.0%); p = 0.001. Modified New York Heart Association (NYHA) functional class improved in nine patients taken off the transplant waiting list. All nine patients were alive at follow-up. In the placebo group, during the six-month follow-up, two patients died, and two underwent heart transplantation. Four patients persisted with HF symptoms (NYHA functional class IV). No significant change occurred in LVEF or fractional shortening.
                Carvedilol added to standard therapy may reduce HF progression and improve cardiac function, allowing some youngsters to be removed from the heart transplantation waiting list. The aim of this study was to determine the protective effect of carvedilol in anthracycline (ANT)-induced cardiomyopathy (CMP).
                Despite its broad effectiveness, ANT therapy is associated with ANT-induced CMP. Recent animal studies and experimental observations showed that carvedilol prevented development of CMP due to chemotherapeutics. However, there is no placebo-controlled clinical trial concerning prophylactic carvedilol use in preventing ANT-induced CMP.
                Patients in whom ANT therapy was planned were randomized to administration of carvedilol or placebo. We enrolled 25 patients in carvedilol and control groups. In the carvedilol group, 12.5 mg once-daily oral carvedilol was given during 6 months. The patients were evaluated with echocardiography before and after chemotherapy. Left ventricular ejection fraction (EF) and systolic and diastolic diameters were calculated.
                At the end of 6 months of follow-up, 1 patient in the carvedilol group and 4 in the control group had died. Control EF was below 50% in 1 patient in the carvedilol group and in 5 in the control group. The mean EF of the carvedilol group was similar at baseline and control echocardiography (70.5 vs. 69.7, respectively; p = 0.3), but in the control group the mean EF at control echocardiography was significantly lower (68.9 vs. 52.3; p < 0.001). Both systolic and diastolic diameters were significantly increased compared with basal measures in the control group. In Doppler study, whereas E velocities in the carvedilol group decreased, E velocities and E/A ratios were significantly reduced in the control group.
                Prophylactic use of carvedilol in patients receiving ANT may protect both systolic and diastolic functions of the left ventricle. Current therapy for preventing the first variceal bleed includes beta-blocker and variceal band ligation (VBL). VBL has lower bleeding rates, with no differences in survival, whereas beta-blocker therapy can be limited by side effects. Carvedilol, a non-cardioselective vasodilating beta-blocker, is more effective in reducing portal pressure than propranolol; however, there have been no clinical studies assessing the efficacy of carvedilol in primary prophylaxis. The goal of this study was to compare carvedilol and VBL for the prevention of the first variceal bleed in a randomized controlled multicenter trial. One hundred fifty-two cirrhotic patients from five different centers with grade II or larger esophageal varices were randomized to either carvedilol 12.5 mg once daily or VBL performed every 2 weeks until eradication using a multibander device. Seventy-seven patients were randomized to carvedilol and 75 to VBL. Baseline characteristics did not differ between the groups (alcoholic liver disease, 73%; median Child-Pugh score, 8; median age, 54 years; median follow-up, 20 months). On intention-to-treat analysis, carvedilol had lower rates of the first variceal bleed (10% versus 23%; relative hazard 0.41; 95% confidence interval 0.19-0.96 [P = 0.04]), with no significant differences in overall mortality (35% versus 37%, P = 0.71), and bleeding-related mortality (3% versus 1%, P = 0.26). Six patients in the VBL group bled as a result of banding ulcers. Per-protocol analysis revealed no significant differences in the outcomes. Conclusion: Carvedilol is effective in preventing the first variceal bleed. Carvedilol is an option for primary prophylaxis in patients with high-risk esophageal varices. The aim of this study was to assess the efficacy of flosequinan in chronic heart failure.
                Flosequinan is a new vasodilator drug that acts by interfering with the inositol-triphosphate/protein kinase C pathway, an important mechanism of vasoconstriction. The drug dilates both peripheral arteries and veins, is orally active and has a long duration of action that permits once-daily dosing. Previous studies have shown that flosequinan produces sustained hemodynamic benefits in heart failure, but large scale studies evaluating its clinical efficacy have not been reported.
                One hundred ninety-three patients with chronic heart failure (New York Heart Association functional class II or III and left ventricular ejection fraction < 40%) receiving digoxin and diuretic drugs were randomly assigned (double-blind) to the addition of flosequinan (100 mg once daily, n = 93) or placebo (n = 100) for 3 months. The clinical status and exercise tolerance of each patient was evaluated at the start of the study and every 2 to 4 weeks during the trial while background therapy remained constant.
                After 12 weeks, maximal treadmill exercise time increased by 96 s in the flosequinan group but by only 47 s in the placebo group (p = 0.022 for the difference between groups). Maximal oxygen consumption increased by 1.7 ml/kg per min in the flosequinan group (n = 17) but by only 0.6 ml/kg per min in the placebo group (n = 23), p = 0.05 between the groups. Symptomatically, 55% of patients receiving flosequinan but only 36% of patients receiving placebo benefited from treatment (p = 0.018). In addition, fewer patients treated with flosequinan had sufficiently severe worsening of heart failure to require a change in medication or withdrawal from the study (p = 0.07). By intention to treat, seven patients in the flosequinan group and two patients in the placebo group died.
                These findings indicate that flosequinan is an effective drug for patients with chronic heart failure who remain symptomatic despite treatment with digoxin and diuretic drugs. The effect of the drug on survival remains to be determined. Angiotensin converting enzyme inhibitors, diuretics, and digoxin are each effective in treating congestive heart failure, but many patients remain symptom-limited on all three medications. This trial was designed to determine whether the addition of oral flosequinan, a new direct-acting arterial and venous vasodilator with possible dose-dependent positive inotropic effects, improves exercise tolerance and quality of life in such patients.
                In a randomized, double-blind multicenter trial, 322 patients with predominantly New York Heart Association class II or III congestive heart failure and left ventricular ejection fractions of 35% or less, who were stabilized on a diuretic, angiotensin converting enzyme inhibitor, and digoxin, were treated with 100 mg flosequinan once daily, 75 mg flosequinan twice daily, or matching placebo. Efficacy was evaluated with serial measurements of treadmill exercise time, responses to the Minnesota Living With Heart Failure Questionnaire (LWHF), and clinical assessments during a baseline phase and a 16-week treatment period. After 16 weeks, 100 mg flosequinan once daily produced a significant increment in median exercise time (64 seconds at 16 weeks) compared with placebo (5 seconds), whereas the higher-dose flosequinan group did not show a statistically significant increase. Flosequinan (100 mg once daily) also improved the overall LWHF score significantly compared with placebo; both active therapies decreased the physical component, but 75 mg flosequinan twice daily was associated with a trend toward worsening of the emotional component. Most clinical assessments tended to improve on active therapy.
                These results indicate that additional symptomatic benefit can be attained by adding flosequinan to a therapeutic regimen already including a converting enzyme inhibitor. Because in the future most patients will fall into this category, flosequinan is a potential adjunctive agent in the management of severe congestive heart failure. However, because recent evidence indicates that the flosequinan dose studied in the present trial has an adverse effect on survival, the benefit-to-risk ratio must be assessed in individual patients. Infants with congenital heart disease and left-to-right shunts may develop significant clinical symptoms of congestive heart failure in spite of therapy with digoxin and diuretics. We investigated the effects of beta-blockade in infants with severe heart failure.
                We performed a prospective, randomized, open monocenter trial in infants treated with digoxin and diuretics (n=10) in comparison to 10 infants receiving additional beta-blocker therapy. After 17 days on average beta-blocker treated infants (propranolol:1,6 mg/kg/day) improved significantly with respect to Ross heart failure score (3.3+/-2.3 vs. 8.3+/-1.9, P=0.002), lower renin levels (338+/-236 vs. 704+/-490 microU/l, P=0.008) and lower mean heart rates in Holter ECG (118+/-10 vs. 142+/-11 beats/min, P<0.001). While digoxin and diuretic treated infants had unchanged mean heart rate (149+/-8 vs. 148+/-10 beats/min), less decrease of symptoms (Ross Score: 8.5+/-1.7 vs. 6.8+/-2.3, P=0.02) but a significant increase of renin levels (139+/-102 vs. 938+/-607 microU/l, P=0.001).
                Additional propranolol treatment but not digoxin and diuretics alone can effectively reduce clinical symptoms of heart failure in infants with congenital heart disease, who suffer from increased neurohormonal activation. Clinical studies of heart failure utilizing losartan, an angiotensin-II receptor antagonist, found that this drug is well tolerated and demonstrates hemodynamic, neurohormonal, and symptomatic improvement. To assess all-cause mortality in heart failure patients treated with losartan, a meta-analysis including 1,896 patients was performed on 6 controlled, double-blind, multiple-dose studies, regardless of sample size or duration of follow-up. A combination of logarithmic (log) odds ratios with a continuity correction was utilized for the meta-analysis. Treatment groups were comparable with regard to demographic characteristics, heart failure characteristics, and concomitant cardiovascular therapies. Concomitant use of open-label angiotensin-converting enzyme (ACE) inhibitors was not allowed in any study. The mean left ventricular ejection fraction obtained in individual studies ranged from 23% to 31%. Seven hundred forty patients were randomized to control therapy and 1,154 patients were randomized to losartan therapy. There were 36 deaths (3.12%) in the losartan groups compared with 47 in the control groups (6.35%) during the double-blind periods. The odds of dying in the losartan groups were 0.51 times (0.31 to 0.81) that of dying in the control groups (p = 0.004). In this analysis, treatment with losartan provided a beneficial effect upon survival. However, because the number of deaths in these studies is relatively small and the follow-up relatively short, a large confirmatory study is needed to assess the mortality benefit of losartan compared with an ACE inhibitor.
This Cochrane review has found a lack of evidence on the effects of carvedilol for treating heart failure in patients with Chagas disease. The two included trials were underpowered and had a high risk of bias. There are no conclusive data to support the use of carvedilol for treating Chagas cardiomyopathy. Unless randomized clinical trials provide evidence of a treatment effect, and the trade off between potential benefits and harms is established, policy-makers, clinicians, and academics should be cautious when recommending and administering carvedilol for treating heart failure in patients with Chagas disease. The efficacy and safety of other pharmacological interventions for treating heart failure in patients with Chagas disease is unknown.