Section 5: Management of Asymptomatic Patients With Reduced Left Ventricular Ejection Fraction

Abstract

Overview Left ventricular (LV) remodeling and reduced ejection fraction (EF) should be distinguished from the syndrome of clinical heart failure (HF). When LVEF is reduced (<40%), but there are no signs and symptoms of HF, the condition frequently is referred to as asymptomatic LV dysfunction (ALVD). It is now well recognized that there may be a latency period when the EF is reduced before the development of symptomatic HF. Although most attention in the HF literature has centered on patients with symptoms, evidence now indicates that ALVD is more common than previously assumed. The recent realization that therapies aimed at symptomatic HF may improve outcomes in patients with ALVD has increased the importance of recognizing and treating patients with this condition. Prevalence. Studies indicate that the prevalence of ALVD ranges from just under 8% to 16% in some populations.1McDonagh T.A. Morrison C.E. Lawrence A. Ford I. Tunstall-Pedoe H. McMurray J.J. et al.Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population.Lancet. 1997; 350: 829-833Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar, 2Mosterd A. Hoes A.W. de Bruyne M.C. Deckers J.W. Linker D.T. Hofman A. et al.Prevalence of heart failure and left ventricular dysfunction in the general population; The Rotterdam Study.Eur Heart J. 1999; 20: 447-455Crossref PubMed Scopus (560) Google Scholar, 3Rodeheffer R.J. Jacobsen S.J. Gersh B.J. Kottke T.E. McCann H.A. Bailey K.R. et al.The incidence and prevalence of congestive heart failure in Rochester, Minnesota.Mayo Clin Proc. 1993; 68: 1143-1150Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 4Lee E.T. Cowan L.D. Welty T.K. Sievers M. Howard W.J. Oopik A. et al.All-cause mortality and cardiovascular disease mortality in three American Indian populations, aged 45–74 years, 1984–1988. The Strong Heart Study.Am J Epidemiol. 1998; 147: 995-1008Crossref PubMed Scopus (135) Google Scholar Some studies suggest that patients with ALVD outnumber those with overt HF. The First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (NHANES I) reported only a 2% prevalence of overt HF in individuals ages 25 to 74 years, though this value likely is an underestimate.5He J. Ogden L.G. Bazzano L.A. Vupputuri S. Loria C. Whelton P.K. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study.Arch Intern Med. 2001; 161: 996-1002Crossref PubMed Scopus (877) Google Scholar The prevalence of both ALVD and overt HF dramatically increase with age. The lifetime risk of developing HF is approximately 20% in octogenarians.6Ho K.K. Pinsky J.L. Kannel W.B. Levy D. The epidemiology of heart failure: the Framingham Study.J Am Coll Cardiol. 1993; 22: 6A-13AAbstract Full Text PDF PubMed Scopus (1824) Google Scholar, 7Lloyd-Jones D.M. Larson M.G. Leip E.P. Beiser A. D'Agostino R.B. Kannel W.B. et al.Lifetime risk for developing congestive heart failure: the Framingham Heart Study.Circulation. 2002; 106: 3068-3072Crossref PubMed Scopus (1133) Google Scholar, 8Remes J. Reunanen A. Aromaa A. Pyorala K. Incidence of heart failure in eastern Finland: a population-based surveillance study.Eur Heart J. 1992; 13: 588-593PubMed Google Scholar Prognosis. Patients with ALVD have approximately half the mortality rate (5% annualized) of those with overt symptoms of HF, but their risk of death is 5 to 8 times higher than a normal age-matched population. In the Study of Left Ventricular Dysfunction (SOLVD) prevention study, patients with untreated ALVD developed overt HF at a 10% annual rate, with a further 8% annual risk of death or hospitalization for HF.9Jong P. Yusuf S. Rousseau M.F. Ahn S.A. Bangdiwala S.I. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study.Lancet. 2003; 361: 1843-1848Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar These data indicate patients with ALVD are at high risk for developing HF. Managing Patients With ALVD. The management of patients with ALVD focuses on controlling cardiovascular risk factors and on the prevention or reduction of progressive ventricular remodeling. A number of risk factors have the potential to promote progression of ventricular remodeling and adverse outcomes in patients with ALVD. These include systemic hypertension, coronary artery disease, diabetes, and obesity. Population-attributable risk for hypertension and myocardial infarction (MI) may be as high as 60% to 70%, underscoring the importance of preventing and managing these two conditions.10Haider A.W. Larson M.G. Franklin S.S. Levy D. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study.Ann Intern Med. 2003; 138: 10-16Crossref PubMed Scopus (387) Google Scholar, 11Kannel W.B. Castelli W.P. McNamara P.M. McKee P.A. Feinleib M. Role of blood pressure in the development of congestive heart failure. The Framingham study.N Engl J Med. 1972; 287: 781-787Crossref PubMed Scopus (487) Google Scholar, 12Kannel W.B. Hjortland M. Castelli W.P. Role of diabetes in congestive heart failure: the Framingham study.Am J Cardiol. 1974; 34: 29-34Abstract Full Text PDF PubMed Scopus (1536) Google Scholar, 13Levy D. Larson M.G. Vasan R.S. Kannel W.B. Ho K.K. The progression from hypertension to congestive heart failure.JAMA. 1996; 275: 1557-1562Crossref PubMed Google Scholar, 14Kenchaiah S. Evans J.C. Levy D. Wilson P.W. Benjamin E.J. Larson M.G. et al.Obesity and the risk of heart failure.N Engl J Med. 2002; 347: 305-313Crossref PubMed Scopus (2055) Google Scholar The 30% or more of patients with ALVD who do not have ischemic heart disease may suffer from hypertension, alcohol overuse, or familial or idiopathic dilated cardiomyopathy. Surveillance studies suggest that relatives of those with idiopathic dilated cardiomyopathy often have asymptomatic LV dilatation and may be at increased risk for developing HF.15Vasan R.S. Larson M.G. Benjamin E.J. Evans J.C. Levy D. Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction.N Engl J Med. 1997; 336: 1350-1355Crossref PubMed Scopus (315) Google Scholar In addition, those exposed to toxins through alcohol overuse or anthracycline activity may develop ALVD, which may progress to HF in the absence of intervention.16Seymour L. Bramwell V. Moran L.A. Use of dexrazoxane as a cardioprotectant in patients receiving doxorubicin or epirubicin chemotherapy for the treatment of cancer. The Provincial Systemic Treatment Disease Site Group.Cancer Prev Control. 1999; 3: 145-159PubMed Google Scholar Recommendations5.1It is recommended that all patients with ALVD exercise regularly according to a physician-directed prescription to avoid general deconditioning; to improve weight, blood pressure, and diabetes control; and to reduce cardiovascular risk. (Strength of Evidence = C)5.2Smoking cessation is recommended in all patients including those with ALVD. (Strength of Evidence = B)5.3It is recommended that alcohol consumption be discouraged in patients with ALVD. Abstinence is recommended if there is a current habit or previous history of excessive alcohol intake. (Strength of Evidence = C)5.4It is recommended that all patients with ALVD with hypertension have aggressive blood pressure control. (Strength of Evidence = B) Background Therapeutic Approaches. Cardiovascular risk factor reduction is advocated in patients with ALVD to decrease the risk of developing overt HF. Control of blood pressure and treatments that slow the progression of ischemic heart disease may have substantial benefit. (See Section 3 for more on the control of cardiovascular risk factors.) Recommendation5.5Angiotensin-converting enzyme (ACE) inhibitor therapy is recommended for asymptomatic patients with reduced LVEF (<40%). (Strength of Evidence = A) Background Twelve-year follow up in SOLVD demonstrated that the initial benefit of enalapril was maintained.9Jong P. Yusuf S. Rousseau M.F. Ahn S.A. Bangdiwala S.I. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study.Lancet. 2003; 361: 1843-1848Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar Survival curve analysis has confirmed an absolute 9.2-month benefit in life expectancy conferred by 40 months of treatment with an ACE inhibitor, a benefit conferred despite the fact that nearly all patients enrolled in SOLVD went on to receive ACE inhibitors after termination of the randomized portion of the trial. The likelihood of death after 12 years in the treatment group remained fairly constant at approximately 5% annually. A substudy of the SOLVD trial found that administration of enalapril reduced the tendency to progressive LV enlargement in patients with ALVD.17Konstam M.A. Kronenberg M.W. Rousseau M.F. Udelson J.E. Melin J. Stewart D. for the SOLVD Investigators et al.Effects of the angiotensin-converting enzyme inhibitor, enalapril, on the long-term progression of left ventricular dilitation in patients with asymptomatic systolic dysfunction.Circulation. 1993; 88: 2277-2283Crossref PubMed Scopus (279) Google Scholar This beneficial effect on LV remodeling, in combination with prevention of MI, most likely explains the mechanism of reduction of both cardiovascular mortality and progression to HF observed in the SOLVD Prevention trial.18Pouleur H. Rousseau M.F. van Eyll C. Melin J. Youngblood M. Yusuf S. Cardiac mechanics during development of heart failure. SOLVD Investigators.Circulation. 1993; 87 (IV14–20)PubMed Google Scholar, 19Pouleur H.G. Konstam M.A. Udelson J.E. Rousseau M.F. Changes in ventricular volume, wall thickness and wall stress during progression of left ventricular dysfunction. The SOLVD Investigators.J Am Coll Cardiol. 1993; 22: 43A-48AAbstract Full Text PDF PubMed Scopus (47) Google Scholar, 20Quinones M.A. Greenberg B.H. Kopelen H.A. Koilpillai C. Limacher M.C. Shindler D.M. et al.Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: significance of left ventricular hypertrophy. Studies of Left Ventricular Dysfunction.J Am Coll Cardiol. 2000; 35: 1237-1244Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar Thus ACE inhibitors are indicated in patients with reduced LVEF, regardless of symptoms. See more about ACE inhibitors in Section 7. Recommendation5.6Angiotensin receptor blockers (ARBs) are recommended for asymptomatic patients with reduced LVEF who are intolerant of ACE inhibitors from cough or angioedema. (Strength of Evidence = C) Routine use of the combination of ACE inhibitors and ARBs for prevention of heart failure is not recommended in this population. (Strength of Evidence = C) Background Randomized clinical trials of ARBs in asymptomatic patients with LV systolic dysfunction who are intolerant of ACE inhibitors have not been conducted. Despite the absence of definitive data, based on the results of CHARM-Alternative and the Valsartan Heart Failure Trial (Val-HeFT) and a variety of pathophysiologic and clinical considerations, it is reasonable to use an ARB in a patient with ALVD if the patient is intolerant to an ACE inhibitor.21Granger 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 (1443) Google Scholar, 22Maggioni A.P. Anand I. Gottlieb S.O. Latini R. Tognoni G. Cohn J.N. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors.J Am Coll Cardiol. 2002; 40: 1414-1421Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar The addition of an ARB to an ACE inhibitor in asymptomatic patients with reduced LVEF has not been investigated. See more about ARBs in Section 7. Recommendation5.7It is recommended that β-blocker therapy be administered to asymptomatic patients with reduced LVEF. (After MI, Strength of Evidence = B; non post-MI, Strength of Evidence = C) Background Ischemic Heart Disease With ALVD. A strong rationale exists for the use of β-blocker therapy in the management of patients with ALVD from ischemic heart disease, based on the benefits seen in patients with cardiac dysfunction and no overt HF after acute MI. The Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) study examined the effects of carvedilol in asymptomatic patients with reduced EF after MI, with concomitant use of ACE inhibitors, aspirin, and statins in the majority of patients. Although there was no difference between the carvedilol and placebo groups in the number of patients meeting the primary endpoint of all-cause mortality or hospital admission, carvedilol use was associated with fewer deaths, as well as a reduction in the combined endpoint of death or recurrent MI, classical end points in previous studies of β-blockade after MI.23Dargie H.J. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.Lancet. 2001; 357: 1385-1390Abstract Full Text Full Text PDF PubMed Scopus (1400) Google Scholar Nonischemic Heart Disease With ALVD. No trial has specifically examined the effect of β-blockers on mortality in asymptomatic patients with reduced EF but no recent MI. Given the consistency of benefit observed with β-blockers across symptomatic populations, with and without ischemic heart disease, and in patients with prior MI, regardless of HF symptoms, it seems reasonable to recommend use of these agents in asymptomatic patients with reduced EF in the absence of identifiable ischemic heart disease. See more about β-blockers in Section 7.