studied and effectively inhibited neurohormonal system has been the reninangiotensin-aldosterone system ACE inhibitors have been studied in many large prospective randomized trials in adults with heart failure, in which more than 7000 adults have been enrolled.68–71 These studies conclusively demonstrated that these agents improve symptoms and survival in adults with HFrEF and delay the onset of symptoms in asymptomatic patients They work through the inhibition of ACE, which inhibits the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor ACE identical to kininase II, thus having an additional action of increasing bradykinin levels This is thought to be responsible for the relatively frequent side effect of cough seen in some patients who take these agents They also reduce afterload, preload, and systolic wall stress ACE inhibitors are currently recommended for all adult patients with stage 3 heart failure (those with current or previously symptomatic HFrEF58 unless the patient is intolerant of them The data on the efficacy of ACE inhibitors in children with heart failure are less robust Many small studies from the 1980s and 1990s suggested that they may be beneficial in children with heart failure due to left-to-right shunts.72–74 A few small retrospective reports also suggested a possible benefit in children with decreased systolic ventricular function.75,76 One prospective randomized trial compared the effects of enalapril with placebo in children who had undergone the Fontan operation The primary end point was exercise capacity, and no difference was found between the two groups after 10 weeks of therapy In fact, the mean percent change from rest to maximal exercise was significantly decreased in the enalapril group compared with those on placebo.77 Another study compared two groups of postoperative patients at two different hospitals, one receiving ACE inhibitors and one not Those receiving the ACE inhibitors had a decreased duration and amount of pleural drainage.78 ARBs have been shown to be beneficial in the treatment of heart failure in adults but not superior to ACE inhibitors Thus, ARBs are currently recommended for the treatment of HFrEF in adults, primarily those who are intolerant of ACE inhibitors There is very little experience with ARBs in children Studies of ACE inhibitors and ARBs in young adults with congenital heart disease and heart failure due to dysfunction of a systemic right ventricle have failed to show a clear clinical benefit.79–81 β-Blockers Waagstein and colleagues first reported the beneficial effects of β-blockade in a small group of adults with heart failure in 1975.82 Many small studies over the next 20 years suggested some benefit from metoprolol, bisoprolol, and carvedilol in adults with stable, chronic HFrEF.82–84 However, it was not until 1996 that two large prospective randomized trials of carvedilol conclusively demonstrated that β-blockers improve symptoms, survival, and ventricular remodeling in adults with mild to moderate HFrEF (Fig 65.5).84 FIG 65.5 Mortality rates at 6 months (deaths per 100 patients randomized) (From Bristow MR, Gilbert EM, Abraham WT, et al Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure MOCHA Investigators Circulation 1996;94:2807–2816.) Subsequent studies have shown that other β-blockers, the long-acting metoprolol and bisoprolol, have similar effects to carvedilol in adults with mild to moderate HFrEF.85,86 Carvedilol was also shown to improve survival in adults with severe HFrEF (Fig 65.6).87 Based on these studies, β-blockers are now recommended for all adults with stable HFrEF unless they have a contraindication to their use or have been shown to be intolerant to these drugs FIG 65.6 Analysis of time to death in patients receiving either placebo or carvedilol in the COPERNICUS trial The 35% lower risk in the carvedilol group was significant: P = 00013 (unadjusted) and P = 0014 (adjusted) (From Packer M, Fowler MB, Roecker EB, et al Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival [COPERNICUS] study Circulation 2002;106:2194–2199.) Not all β-blockers are equally effective in the treatment of HFrEF In one large randomized trial, bucindolol failed to show a survival benefit in adults with HFrEF.88 The reason for this is unclear but may be at least in part due to some interesting pharmacogenomic reasons that are discussed later Some comparisons of metoprolol and carvedilol have demonstrated improved survival after carvedilol compared with metoprolol (Fig 65.7).89 This was thought to possibly be due to the broader actions of carvedilol, affecting the β-1, β-2, and α-1 receptors, compared to metoprolol, which is selective only for the β-1 receptor.90 However, more recent registry analyses have failed to demonstrate any benefit of carvedilol over metoprolol in adults with heart failure.91