Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Abstract

Overview There are 3 primary issues that must be considered when treating heart failure (HF) patients with left ventricular (LV) systolic dysfunction: (1) improving symptoms and quality of life, (2) slowing the progression of cardiac and peripheral dysfunction, and (3) reducing mortality. General measures, such as salt restriction, weight loss, lipids control, and other nonpharmacologic measures are addressed in Section 6. Pharmacologic approaches to symptom control, including diuretics, vasodilators, intravenous inotropic drugs, anticoagulants, and antiplatelet agents are discussed at the end of this section. Two classes of agents have become the recommended cornerstone of therapy to delay or halt progression of cardiac dysfunction and improve mortality: angiotensin-converting enzyme (ACE) inhibitors and β-blockers. Even while these agents are underused in the treatment of HF, new classes of agents have been added that show an impact on mortality, complicating decisions about optimal pharmacologic therapy. These include angiotensin receptor blockers (ARBs), aldosterone antagonists, and the combination of hydralazine and an oral nitrate, all of which are considered in the following recommendations. ACE Inhibitors Recommendation 7.1ACE inhibitors are recommended for routine administration to symptomatic and asymptomatic patients with LVEF ≤40%. (Strength of Evidence = A)ACE inhibitors should be titrated to doses used in clinical trials, as tolerated during concomitant uptitration of β-blockers. (Strength of Evidence = C). Background There is compelling evidence that ACE inhibitors should be used to inhibit the renin-angiotensin system (RAS) in all HF patients with LV systolic dysfunction, whether or not they are symptomatic. A number of large clinical trials have demonstrated improvement in morbidity and mortality in HF patients with LV dysfunction, both chronically and post-MI.1Packer M. Cohn J.N. Consensus recommendations for management of chronic heart failure.Am J Cardiol. 1999; 83: 1A-38AAbstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 2Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.N Engl J Med. 1987; 316: 1429-1435Crossref PubMed Google Scholar, 3Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.N Engl J Med. 1991; 325: 293-302Crossref PubMed Google Scholar The mortality benefit is strongest across New York Heart Association (NYHA) class II-IV HF, but appears present in patients who are NYHA class I as well.4Konstam M.A. Kronenberg M.W. Rousseau M.F. Udelson J.E. Melin J. Stewart D. et al.Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. SOLVD (Studies of Left Ventricular Dysfunction) Investigators.Circulation. 1993; 88: 2277-2283Crossref PubMed Google Scholar The major side effects of ACE inhibitors in patients with HF are hypotension and azotemia. Both are usually well tolerated and do not indicate the need to lower the dose or discontinue the ACE inhibitor. The azotemia commonly is related to the relative volume-depleted state caused by diuretic therapy. The major symptomatic side effect is a dry cough that usually does not require discontinuation of the drug. Care should be taken to distinguish between a cough that is ACE inhibitor–related and one that is due to worsening pulmonary congestion. If the cough impairs the patient's quality of life, alternative therapy, such as an ARB, may be considered. Recommendation 7.2It is recommended that other therapy be substituted for ACE inhibitors in the following circumstances:•In patients who cannot tolerate ACE inhibitors from cough, ARBs are recommended. (Strength of Evidence = A)The combination of hydralazine and an oral nitrate may be considered in such patients not tolerating ARB therapy. (Strength of Evidence = C)•Patients intolerant to ACE inhibitors from hyperkalemia or renal insufficiency are likely to experience the same side effects with ARBs. In these cases, the combination of hydralazine and an oral nitrate should be considered. (Strength of Evidence = C) Background The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative trial prospectively tested the effect of an ARB in an ACE inhibitor intolerant population of patients with chronic HF and a LV ejection fraction (LVEF) <40%. The addition of candesartan in these patients resulted in a reduction in the composite endpoint of cardiovascular death or hospital admission for HF from 40% in the control group to 33% in the candesartan group over a mean follow-up of 34 months with a trend toward decreased all-cause mortality.5Granger C.B. McMurray J.J. Yusuf S. Held P. Michelson E.L. Olofsson B. et al.Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial.Lancet. 2003; 362: 772-776Abstract Full Text Full Text PDF PubMed Scopus (900) Google Scholar ARBs should be considered instead of ACE inhibitors primarily in patients who are intolerant of ACE inhibitors from intractable cough. ARBs appear as likely as ACE inhibitors to produce hypotension, worsening renal function, and hyperkalemia See background to Recommendations 7.19–7.20 for information about isosorbide dinitrate/hydralazine. β-Adrenergic Receptor Blockers β-blocker therapy, advocated for HF by some investigators since the 1970s,6Waagstein F. Bristow M.R. Swedberg K. Camerini F. Fowler M.B. Silver M.A. et al.Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group.Lancet. 1993; 342: 1441-1446Abstract PubMed Scopus (957) Google Scholar remains a major advance in the treatment of patients with LV systolic dysfunction. Several large-scale clinical trials, involving more than 10,000 patients, have provided unequivocal evidence of important reductions in both mortality and morbidity.7Lechat P. Packer M. Chalon S. Cucherat M. Arab T. Boissel J.P. Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials.Circulation. 1998; 98: 1184-1191Crossref PubMed Google Scholar, 8Heidenreich P.A. Lee T.T. Massie B.M. Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials.J Am Coll Cardiol. 1997; 30: 27-34Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar This class of drug is now established as routine therapy in patients with LV systolic dysfunction. This therapy is well tolerated by a large majority of patients with HF, even those with comorbid conditions like diabetes mellitus, chronic obstructive lung disease and peripheral vascular disease. A general summary of the recommendations for beta-blocker therapy is shown in Table 7.1.Table 7.1Summary of Recommendations for the Administration of β-Blocker Therapy∗See Recommendations 7.3–7.9 for specific recommendations and conditions.GeneralInitiate at low dosesUptitrate gradually, generally no sooner than at 2-week intervalsUse target doses shown to be effective in clinical trialsAim to achieve target dose in 8–12 weeksMaintain at maximum tolerated doseConsiderations if symptoms worsen or other side effects appearAdjust dose of diuretic or other concomitant vasoactive medicationContinue titration to target dose after symptoms return to baselineConsiderations if uptitration continues to be difficultProlong titration intervalReduce target doseConsider referral to a HF specialistIf an acute exacerbation of chronic HF occursMaintain therapy if possibleReduce dosage if necessaryAvoid abrupt discontinuationIf discontinued or reduced, reinstate gradually before discharge∗ See Recommendations 7.3–7.9 for specific recommendations and conditions. Open table in a new tab Recommendation 7.3β-blockers shown to be effective in clinical trials of patients with HF are recommended for patients with an LVEF ≤40%. (Strength of Evidence = A) Background The marked beneficial effect of β-blockade on many clinical outcomes has been well demonstrated in large-scale clinical trials of symptomatic patients with NYHA class II–III HF (Table 4.7) using carvedilol, bisoprolol, or metoprolol controlled release/extended release (CR/XL).9Packer M. Bristow M.R. Cohn J.N. Colucci W.S. Fowler M.B. Gilbert E.M. et al.The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group.N Engl J Med. 1996; 334: 1349-1355Crossref PubMed Scopus (3225) Google Scholar, 10The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) a randomised trial.Lancet. 1999; 353: 9-13Abstract Full Text Full Text PDF PubMed Scopus (2917) Google Scholar, 11Rationale, design, and organization of the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF). The International Steering Committee.Am J Cardiol. 1997; 80: 54J-58JAbstract Full Text Full Text PDF PubMed Google Scholar These trials added β-blockade to background therapy that included ACE inhibitors and diuretics in more than 90% of patients. The trial results support benefit from both B1 selective and nonselective β-blockers, whether ancillary properties are present or not. β-blocking agents with intrinsic sympathomimetic activity are likely to worsen survival and should be avoided in patients with HF. Recommendation7.4The combination of a β-blocker and an ACE inhibitor is recommended as routine therapy for asymptomatic patients with a LVEF ≤40%•Post-MI (Strength of Evidence = B)•Non Post-MI (Strength of Evidence = C) Background Randomized controlled data support the efficacy of ACE inhibitors in reducing both the likelihood of developing HF and the need for treatment or hospitalization in asymptomatic patients with an LVEF ≤35%.12Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors.N Engl J Med. 1992; 327: 685-691Crossref PubMed Google Scholar Similar data are not available to support the use of β-blocker therapy in asymptomatic patients with systolic dysfunction. Nevertheless, a number of arguments support the routine use of β-blockade in these patients. Guidance is provided by studies indicating the effectiveness of β-blocker therapy in patients following MI with good symptomatic and functional recovery, yet residual ventricular systolic dysfunction. These studies enrolled a number of patients without clinical HF. Multiple studies suggest myocardial remodeling following β-blocker therapy in patients with symptomatic HF as well. Recommendation7.5β-blocker therapy is recommended for patients with a recent decompensation of HF after optimization of volume status and successful discontinuation of intravenous diuretics and vasoactive agents, including inotropic support. Whenever possible, β-blocker therapy should be initiated in the hospital setting at a low dose prior to discharge in stable patients. (Strength of Evidence = B) Background Ongoing clinical experience and current trial data indicate that beginning β-blockade at low dose in the hospital is possible in patients with improved congestion and other symptoms.13Gattis W.A. O'Connor C.M. Gheorghiade M. The Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) Study: design and implications.Rev Cardiovasc Med. 2002; 3: S48-S54PubMed Google Scholar, 14Gattis W.A. O'Connor C.M. Gallup D.S. Hasselblad V. Gheorghiade M. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial.J Am Coll Cardiol. 2004; 43: 1534-1541Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar Initiation of therapies in hospital is well known to result in better utilization and the attainment of more optimal doses of a variety of cardiovascular drugs. β-blocker therapy should not be initiated in patients with acute decompensated heart failure (ADHF) with persistent symptoms and congestion. However, many patients hospitalized for HF are NYHA functional class IV from volume overload, and will improve sufficiently with standard therapy to allow introduction of β-blockade. The Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) provides strong evidence in a prospective, randomized trial that patients with advanced HF, treated aggressively to reduce congestion and improve symptoms, benefit substantially from the introduction of β-blockade.15Packer M. Coats A.J. Fowler M.B. Katus H.A. Krum H. Mohacsi P. et al.Effect of carvedilol on survival in severe chronic heart failure.N Engl J Med. 2001; 344: 1651-1658Crossref PubMed Scopus (1908) Google Scholar Recommendations7.6β-blocker therapy is recommended in the great majority of patients with LV systolic dysfunction, even if there is concomitant diabetes, chronic obstructive lung disease, or peripheral vascular disease. β-blocker therapy should be used with caution in patients with diabetes with recurrent hypoglycemia, with asthma, or with resting limb ischemia. Considerable caution should be used if β-blockers are initiated in patients with marked bradycardia (<55 beats/min) or marked hypotension (systolic blood pressure <80 mm Hg). β-blockers are not recommended in patients with asthma with active bronchospasm. (Strength of Evidence = C)7.7It is recommended that β-blockade be initiated at low doses and uptitrated gradually, typically no sooner than at 2-week intervals. Doses found to be effective in HF trials are generally achieved in 8 to 12 weeks. Patients developing worsening HF symptoms or other side effects during titration may require a dosage adjustment of diuretic or concomitant vasoactive medications. If side effects resolve with medication adjustment, patients can subsequently be titrated to target or maximally tolerated doses. Some patients may require a more prolonged interval during uptitration, a temporary reduction in β-blocker dose, or, in rare cases, withdrawal of therapy. (Strength of Evidence = B)7.8It is recommended that β-blocker therapy be continued in most patients experiencing a symptomatic exacerbation of HF during chronic maintenance treatment. (Strength of Evidence = C)A temporary reduction of dose in this setting may be considered. Abrupt discontinuation in patients with symptomatic exacerbation should be avoided. (Strength of Evidence = C)If discontinued or reduced, β-blockers should be reinstated or the dose should be gradually increased before the patient is discharged. Background Clinical deterioration during stable maintenance therapy with β-blockers rarely is related to administration of these agents. Noncompliance with medications, progression of underlying LV dysfunction and the adverse influence of a number of comorbid factors, including the occurrence of ischemia, hemodynamic instability from arrhythmia, and pulmonary complications such as pneumonia, are much more likely to be responsible for clinical deterioration. The best course is to use standard therapy to relieve congestion and treat exacerbating factors, rather than reduce or discontinue β-blockade. A retrospective review of patients enrolled in the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) trial of patients hospitalized with ADHF, found that continuation of β-blockade did not interfere with symptomatic improvement during admission,16Felker G.M. Benza R.L. Chandler A.B. Leimberger J.D. Cuffe M.S. Califf R.M. et al.Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study.J Am Coll Cardiol. 2003; 41: 997-1003Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar supporting the continuation of β-blockade in patients hospitalized with an episode of decompensation. This same observation was made in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial.17Binanay C. Califf R.M. Hasselblad V. O'Connor C.M. Shah M.R. Sopko G. et al.Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial.JAMA. 2005; 294: 1625-1633Crossref PubMed Scopus (472) Google Scholar Abrupt withdrawal of β-blockade should be avoided, especially in patients with coronary artery disease. Studies of the withdrawal of β-blockade in patients with persistent LV systolic dysfunction, but improved and stable clinical HF, have revealed a substantial risk of worsening HF and early death after β-blocker discontinuation.18Waagstein F. Caidahl K. Wallentin I. Bergh C.H. Hjalmarson A. Long-term beta-blockade in dilated cardiomyopathy. Effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol.Circulation. 1989; 80: 551-563Crossref PubMed Google Scholar, 19Morimoto S. Shimizu K. Yamada K. Hiramitsu S. Hishida H. Can beta-blocker therapy be withdrawn from patients with dilated cardiomyopathy?.Am Heart J. 1999; 138: 456-459Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Recommendation7.9It is recommended that patients in whom difficulty is encountered in initiating, uptitrating or maintaining β-blocker therapy be referred to clinicians with special expertise in HF. (Strength of Evidence = B) Background In certain patients, frequent return visits for dose titration may be difficult to accommodate in a busy clinical practice. Trained personnel, including nurse practitioners, physician assistants, and pharmacists, with physician supervision, may more efficiently perform patient education and reevaluation during uptitration. HF specialty programs are more likely to have the resources to provide this follow-up and education.20Uretsky B.F. Pina I. Quigg R.J. Brill J.V. MacInerney E.J. Mintzer R. et al.Beyond drug therapy: nonpharmacologic care of the patient with advanced heart failure.Am Heart J. 1998; 135: S264-S284Abstract Full Text Full Text PDF PubMed Google Scholar Consultation or referral may be particularly beneficial when the clinical HF status of the patient is uncertain or problems arise during initiation of therapy or dose titration that may cause unwarranted discontinuation of therapy. Patients for β-blocker therapy should be compliant and have a good understanding of their disease and overall treatment plan. Patients should be aware that symptomatic deterioration is possible early in therapy and that symptomatic improvement may be delayed weeks to months. Unresolved Issues Implantation of Cardiac Pacemakers in Patients with Baseline Bradycardia. Given the strength of evidence supporting β-blocker therapy in patients with symptomatic HF, some physicians would consider pacemaker implantation when symptomatic bradycardia or heart block occurs during the initiation of this therapy. No data are available to support this practice. However, ventricular pacing alone may result in deterioration of ventricular function, negating any potential benefit from β-blockade.21Wilkoff B.L. Cook J.R. Epstein A.E. Greene H.L. Hallstrom A.P. Hsia H. et al.Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial.JAMA. 2002; 288: 3115-3123Crossref PubMed Scopus (1065) Google Scholar Consideration should be given to the withdrawal of other drugs that may have bradycardic effects. Angiotensin Receptor Blockers Both ACE inhibitors and ARBs inhibit the renin-angiotensin-aldosterone system (RAAS), but by different mechanisms. ACE inhibitors block the enzyme responsible for converting angiotensin I to angiotensin II and for degrading various kinins. However, during chronic therapy, angiotensin II levels are not completely suppressed by ACE inhibitors for at least 2 reasons. Instituting an ACE inhibitor increases renin levels, resulting in higher levels of angiotensin I, which will tend by mass action to produce greater angiotensin II levels. Production of angiotensin II may also occur through non-ACE enzyme systems not blocked by inhibitors of this enzyme.22Wolny A. Clozel J.P. Rein J. Mory P. Vogt P. Turino M. et al.Functional and biochemical analysis of angiotensin II-forming pathways in the human heart.Circ Res. 1997; 80: 219-227Crossref PubMed Google Scholar, 23Petrie M.C. Padmanabhan N. McDonald J.E. Hillier C. Connell J.M. McMurray J.J. Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease.J Am Coll Cardiol. 2001; 37: 1056-1061Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Thus, despite treatment with ACE inhibitors in patients with chronic HF, angiotensin II levels may remain elevated and increase over time.24Jorde U.P. Ennezat P.V. Lisker J. Suryadevara V. Infeld J. Cukon S. et al.Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure.Circulation. 2000; 101: 844-846Crossref PubMed Google Scholar, 25Kawamura M. Imanashi M. Matsushima Y. Ito K. Hiramori K. Circulating angiotensin II levels under repeated administration of lisinopril in normal subjects.Clin Exp Pharmacol Physiol. 1992; 19: 547-553Crossref PubMed Google Scholar ARBs block the effects of angiotensin II on the AT1 receptor, independent of the source of angiotensin II production. Coupled with angiotensin II “escape,” this led to the hypothesis that ARBs might be superior to ACE inhibitors in HF and that the addition of ARBs to ACE inhibitors in patients with chronic HF might provide additional blockade of the RAAS and greater therapeutic benefit. The role of the kinin system as a mediator of the beneficial effects of ACE inhibitors in cardiovascular disease is becoming increasingly clear. ACE inhibitors reduce the degradation of kinins, which may lead to important therapeutic benefits not provided by ARBs, making the potential combination of the two agents more attractive.26Witherow F.N. Helmy A. Webb D.J. Fox K.A. Newby D.E. Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure.Circulation. 2001; 104: 2177-2181Crossref PubMed Google Scholar, 27Witherow F.N. Dawson P. Ludlam C.A. Fox K.A. Newby D.E. Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy.J Am Coll Cardiol. 2002; 40: 961-966Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar ACE inhibitors can have some troublesome side effects, including cough and angioedema, which may limit therapy with these agents. ARBs have been demonstrated to be well tolerated in randomized trials of patients judged to be intolerant of ACE inhibitors by their clinicians, although these primarily reflect intolerance from cough, skin rashes, and angioedema. Both drugs have similar effects on blood pressure, renal function, and potassium. Recommendation7.10ARBs are recommended for routine administration to symptomatic and asymptomatic patients with an LVEF ≤40% who are intolerant to ACE inhibitors for reasons other than hyperkalemia or renal insufficiency. (Strength of Evidence = A) Background The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative trial prospectively tested the effect of an ARB in an ACE inhibitor intolerant population of patients with chronic HF and an LVEF <40%. The addition of candesartan in these patients resulted in a reduction in the composite endpoint of cardiovascular death or hospital admission for HF from 40% in the control group to 33% in the candesartan group over a mean follow-up of 34 months with a trend toward decreased all-cause mortality.5Granger C.B. McMurray J.J. Yusuf S. Held P. Michelson E.L. Olofsson B. et al.Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial.Lancet. 2003; 362: 772-776Abstract Full Text Full Text PDF PubMed Scopus (900) Google Scholar Post-hoc subgroup analysis of a small subgroup of patients in the Valsartan in Heart Failure Trial (Val-HeFT) also found that patients intolerant to ACE inhibitors had fewer HF hospitalizations and a trend toward improved mortality with the addition of valsartan.28Cohn J.N. Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.N Engl J Med. 2001; 345: 1667-1675Crossref PubMed Scopus (1927) Google Scholar These data suggest that an ARB should be used in ACE inhibitor intolerant patients with chronic HF and LVEF <40%. ARBs should be titrated as tolerated, in conjunction with β-blocker therapy, to target doses used in clinical trials. ARBs should be considered instead of ACE inhibitors primarily in patients who are intolerant of ACE inhibitors because of intractable cough. ARBs appear as likely as ACE inhibitors to produce hypotension, worsening renal function, and hyperkalemia. Recommendation7.11Individual ARBs may be considered as initial therapy rather than ACE inhibitors for patients with the following conditions:•HF Post-MI (Strength of Evidence = A)•Chronic HF and systolic dysfunction (Strength of Evidence = B) Background Support for the use of the ARB, valsartan, in patients post-MI is provided by The Valsartan in Acute Myocardial Infarction Trial (VALIANT), which randomized 14,703 patients 0.5 to 10 days post-MI to valsartan, valsartan plus captopril, or captopril alone. Patients enrolled had clinical or radiologic signs of HF, evidence of LV systolic dysfunction, or both.29Pfeffer M.A. McMurray J.J. Velazquez E.J. Rouleau J.L. Kober L. Maggioni A.P. et al.Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.N Engl J Med. 2003; 349: 1893-1906Crossref PubMed Scopus (1478) Google Scholar The primary end point was all-cause mortality. There were no statistical differences among the 3 groups at a mean follow-up of 24.7 months. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group. The authors concluded that monotherapy with valsartan was equivalent to monotherapy with captopril. OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) randomized 5477 patient with heart failure or LV dysfunction post-MI to captopril or losartan.30Dickstein K. Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan.Lancet. 2002; 360: 752-760Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar The primary endpoint was all-cause mortality. There were 946 deaths during a mean follow-up of 2.7 years: 499 (18%) in the losartan group and 447 (16%) in the captopril group (relative risk 1.13 [95% CI 0.99–1.28], P = .07). Thus valsartan appears equivalent to captopril in patients with HF or LV dysfunction post-MI. The data do not clearly support equivalence of losartan to captopril in these patients. In patients with chronic HF and LV dysfunction, 2 recent reviews have addressed the equivalence of ARBs and ACE inhibitors.31Lee V.C. Rhew D.C. Dylan M. Badamgarav E. Braunstein G.D. Weingarten S.R. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction.Ann Intern Med. 2004; 141: 693-704Crossref PubMed Google Scholar, 32Gring C.N. Francis G.S. A hard look at angiotensin receptor blockers in heart failure.J Am Coll Cardiol. 2004; 44: 1841-1846Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar One meta-analysis concluded that ARBs should be considered “suitable alternatives” to ACE inhibitors. CMS (Centers for Medicare and Medicaid Services) has used this review to consider both ARBs and ACE inhibitors as acceptable to satisfy performance standards in patients with HF.33McClellan M.B. Loeb J.M. Clancy C.M. Francis G.S. Jacobs A.K. Kizer K.W. et al.Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in chronic heart failure.Ann Intern Med. 2005; 142 (author reply 388–9): 386-387Crossref PubMed Google Scholar A second review suggested that ACE-inhibitors remain first line therapy, whereas ARBs were recommended for ACE-intolerant patients.32Gring C.N. Francis G.S. A hard look at angiotensin receptor blockers in heart failure.J Am Coll Cardiol. 2004; 44: 1841-1846Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Recommendation7.12ARBs should be considered in patients experiencing angioedema while on ACE inhibitors based on their underlying risk and with recognition that angioedema has been reported infrequently with these agents. (Strength of Evidence = B)The combination of hydralazine and oral nitrates may be considered in this setting in patients who do not tolerate ARB therapy. (Strength of Evidence = C) Background Angioedema and ARBs. Nearly three-quarte