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Fundamental role of angiotensin-converting enzyme inhibitors in the management off congestive heart failure
Fundamental Role of Angiotelrsin-ConGbting Enz@nb Inhibiiors in the Management o# Congestive Hear& Failure Lionel
H. Opie,
MD,
DPhil,
FRCP
Angiotensin-converting enzyme (ACE) inhibition thempy has now become firmly ensconced in the modem thempeutic approach to all stages of iongestive heart failure (CHF), including the early presymptomatic phase. Although its benefit is abundantly proven as add-on thempy in established CHF, after digitalis and diuretics, smaller and shorter studies have shown that, as second-line thempy and combined with diuretics, it may be prefemble to digoxin with an undoubted benefit in postinfarction failure. As first-line thempy in early presymptomatic CHF, the evidence is also good, based on the prevention arm of the Studies of Left Ventricular Dysfunction (SOLVD), albeit in predominantly postinfarction patients, and on the Survival and Ventricular Enlargement (SAVE) study on postinfarction patients. ACE inhibitors given prophylactically or therapeutically helped to prevent clinical heart failure in the SOLVD and SAVE studies. These data suggest a role for ACE inhibitors as effective first-
line monothempy in early heart failure, acting on left ventriclular function to avoid or lessen unfavorable remodeling. There are some contmindications or cautions for the use of ACE inhibitors in CHF, such as preexisting hypotension, high-renin states such as bilateml renal artery stenosis with hypertens’we heart failure, aortic stenosis combined with CHF, overdiuresis with excess sodium depletion, and significant preexisting renal failure. ACE inhibition thempy may have deleterious effects on renal function in heart failure, for example, by decreasing the glomerular filtration rate. In geneml, it is likely that serum urea and creatinine will rise slightly and the glomerular filtmtion rate fall slightly during ACE inhibition therapy, which means that a clinical judgment must be made, balancing the expected ovemll benefits of ACE inhibition against any possible aggravation of preexisting renal failure. (Am J Cardioll995;75:3F-6F)
C
tion may be caused by: (1) systemic hypotension (Harris3 has proposed that “the syndrome of CHF may be regarded as one which arises when the heart becomes chronically unable to maintain an appropriate arterial pressure without support”); (2) poor renal perfusion, which activates the stretchsensitive cells of the juxtaglomerular apparatus to release renin; (3) evocation of other ill-understood reflexes arising in poorly perfused peripheral tissues. Compensatory vasoconstrictive and volumeretaining mechanisms overwhelm an opposing vasodilatory system mediated through atrial natriuretic peptide and having its origin in atria1 distension.4 In postinfarction patients, there is increased wall stress on the noninfarcted myocardium. This mechanical factor stimulates myocardial hypertrophy through a mechanism thought to involve angiotensin II. The stimulus to release angiotensin II, which ultimately evokes an increase in protooncogenes such as c-fos, is thought to be nonspecific stretch.5 At present, it is not known whether the benefit of ACE inhibitors in preventing postinfarction remodeling is a specific effect or a nonspecific reduction of stretch because of arterial and venous unloading.
ongestive heart failure (CHF), once the “Cinderella” of cardiology, has now become the focus of intense interest, particularly with the use of angiotensin-converting enzyme (ACE) inhibitors. Studies have shown that, as second-line therapy and combined with diuretics, ACE inhibitors may be prefereable to digoxin with an undoubted benefit in postinfarction failure.’ However, new knowledge that ACE inhibitors can prevent development of clinically evident CHF in those at risk shifts the emphasis from symptomatic to preventive therapy. Meerson* has proposed that excess mechanical loading of the left ventricle leads to myocardial failure through 3 phases: an acute adaptation to the hemodynamic load, which leads to compensatory ventricular hypertrophy, and eventually to myocardial failure. In the last phase of left ventricular failure, the well known neurohumoral stimula-
From the Heart Research Unit, University of Cape School, Cape Town, South Africa. Address for reprints: Lionel H. Opie, M.D., Heart University of Cape Town Medical School, Observatory Town, South Africa.
Town Research 7925,
Medical Unit, Cape
A SYMPOSIUM:
NEW
ACE
INHIBITOR
3F
ACE INHIBITORS AS FIRST-LINE PREVENTlVE THERAPY FOR EARLY MYOCARDIAL FAILURE Preventive role in the postinfarction Survival and Ventricular Enlargement
phasestudy: In
patients with recent acute myocardial infarction, ACE inhibitors given to those with low ejection fractions but without symptoms improved the depressed left ventricular function better than did furosemide.6 Presumably, load reduction was helping to prevent adverse left ventricular remodeling. In the large Survival and Ventricular Enlargement (SAVE) study7 on > 2,000 patients, captopril achieved some striking benefits. It was given to patients 3-16 days after myocardial infarction who had ejection fractions < 40% but were not in overt heart failure, at an initial dose of 6.25 mg and titrated up to 50 mg three times daily. The benefits over an average of 42 months were several. Most importantly, mortality from all causes was reduced by 19%, the development of severe heart failure was down by 37%, and (a surprise) recurrent myocardial infarction was reduced by 25%. ACE inhibitors do not appear to act beneficially in postinfarction remodeling by arteriolar dilation alone+.g., hydralazine fails to improve postinfarction remodeling in rats.s Thus, another effect, possibly venous dilation or possibly direct inhibition of a growth factor, may be involved. Studies of Left Ventricular Dysfunction: New York Heart Association class I: In the large Studies
of Left Ventricular Dysfunction9 (SOLVD) in >4,000 patients, only 17% were taking diuretics and 66% were in New York Heart Association (NYHA) class I-so that the question was whether enalapril could prevent overt heart failure. Not surprisingly, the most striking benefits were found in patients with the lowest initial ejection fractions, <28%, with only borderline results in those with values of 33-35%. Enalapril in a mean daily dose of 17 mg was associated with less hospitalization and less development of symptomatic heart failure. Of note is that 80% of these patients have had a myocardial infarction, so that the prophylactic benefit of an ACE inhibitor in other types of asymptomatic early heart failure has not been established.
to get rid of the fluid retention that is causing the symptoms. This section details studies in which patients already treated with diuretics were given additionally an ACE inhibitor or digoxin. ACE inhibition versus digoxin versus their combination in early left ventricular failure: This impor-
tant question has been studied by Kromer et allo in 19 patients, all treated with hydrochlorothiazide 25 mg and having mild CHF with NYHA class II symptoms. In these patients, ACE inhibition therapy was markedly more effective than digoxin, as it increased exercise tolerance, decreased heart size, and decreased circulating norepinephrine and aldosterone levels. All of these were left unchanged by digoxin therapy. Combination therapy gave virtually identical results to ACE inhibition except that, in addition, fractional shortening increased significantly. Captopril-digoxin multicenter moderate heart failure: Three
study in mild-to-
hundred patients with mild-to-moderate heart failure and an average functional classification (NYHA) of 2.3 were randomly allocated in a double-blind manner to captopril, digoxin, or placebo.” Most were maintained on furosemide. Captopril was better than digoxin in increasing the effort tolerance and functional classification as well as decreasing ventricular premature beats. Only digoxin increased the ejection fraction. The long-term outcome of captopril versus digoxin in such patients needs study.
I
ACE INHIBITORS AS THIRD COMPONENT THERAPY IN COMBINATION WITH DIURETICS AND DlGOXlN
Diuretic therapy is universally accepted as firststep and first-line therapy in CHF when it is logical
Can ACE inhibition reduce diuretic requirements in CHF? In patients with NHYA class III heart failure, about half of a small series required a lower diuretic dose.lz Likewise, the addition of enalapril to patients already treated with digoxin and a diuretic required reduction of the diuretic dose in about half but eventually the diuretic dose was increased in the other half.13 The fundamental logic for triple therapy (diuretic, ACE inhibitor, inotropic agent) lies in the self-evident different mode of action of these 3 types of agents. From the hemodynamic point of view, the combination ACE inhibitor and inotropic agent gives better results than either therapy alone both in mildlo and in severe14 heart failure. Withdrawal of digoxin from triple therapy results in deterioration.15
4F
JUNE
ACE INHIBITORS AS SECOND-LINE THERAPY WITH DIURETICS FOR CONGESTIVE HEART FAILURE
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
75
16, 1995
In a series of 20 studies (reviewed by Opie16), mostly in patients already receiving diuretics or digoxin, nearly consistent effects of ACE inhibition are the increase in exercise time, the reduction of the preload and afterload, the decreased echocardiographic size, and the increased indices of function, such as fractional shortening, as well as an increased ejection fraction measured by radionuelide techniques. Administration of ACE inhibitors has, on the whole, a consistent effect in increasing plasma renin (by virtue of the inhibition of the converting enzyme), decreasing angiotensin II (the consequence of the enzyme inhibition), with also a decrease in aldosterone (which is stimulated by angiotensin II), and a fall in norepinephrine and vasopressin, the elevation of which are among the consequences of severe CHF. Parasympathetic activity, reduced in heart failure, is improved by ACE inhibition. Although there are some exceptions to the patterns noted, most of the results are reasonably consistent.
ACE INHIBITION AS PART OF QUADRUPLE THERAPY INCLUDING DIURETICS, DIGOXIN, AND VASODllATORS A question only recently answered is whether ACE inhibition confers any specific advantages over nonspecific vasodilators in advanced heart failure. A retrospective analysis of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) proposed that enalapril was most effective in patients with neuroendocrine and reninangiotensin activation. l7 The Veterans Administration Heart Failure Trial (V-HeFT-II) showed the expected advantage for ACE inhibition over hydralazine and nitrate therapy.‘* Logically, there should be scope for added vasodilator therapy to the now standard triple therapy in CHF, the latter consisting of diuretics, digoxin, and ACE inhibition. In the well-known CONSENSUS9 47% of patients were already receiving nitrates, and in the treatment arm of SOLVDzO 40% were on nitrates. In the Hy-C trialzl 84% of the patients were on nitrate therapy. Thus, in nitrate-treated patients, ACE inhibition can produce further clinical benefit. It should also be considered that in the V-HeFT-I trialz2 the combination of nitrates and hydralazine was superior to placebo. Hydralazine may help avoid nitrate tolerance.23
PREDICTORS OF POOR RESPONSE TO ACE INHIBITION THERAPY Because of activation of the renin-angiotensinaldosterone axis, it is often supposed that the higher the initial renin value, the better the response to ACE inhibition therapy. That expectation has not been met in at least 4 studies.2”27 A number of indicators of poor response have been proposed: 1. Hyponatremia: A very low sodium (about 130 mmol/liter) may indicate excess diuresis or a very severe neurohumoral response, or both. 2. Excess dietary sodium: This could suppress renin and aldosterone value in CHF without changing peripheral resistance. Thus, a nonrenin but sodium-related mechanism must be able to regulate arterial constriction. A captopril challenge with an acute dose evoked no response during a normal sodium intake, but a large response occurred after sodium depletion in patients with CHF.28 As in many studies in CHF, the exact sodium intake is not stipulated. Variations in the sodium status could help determine the response to ACE inhibitor therapy. Thus, dietary sodium restriction appears highly desirable. 3. Atria1 natriuretic peptide: One reason why a patient might not respond to ACE inhibition therapy is that, with a decrease in circulating angiotensin II,29 a vasodilatory fall in atria1 natriuretic peptide could follow. 4. Renal impairment: Whereas hemodynamic and hormonal effects of ACE inhibition are uniformly favorable, some of the renal effects can be construed as being unfavorable. Angiotensin II increases efferent renal arteriolar tone. Thus, it is not surprising that ACE inhibition may cause urea and creatinine to rise as well as the glomerular filtration rate and creatinine clearance. In several studies,7,20 a high plasma creatinine even before giving the ACE inhibitor has been an exclusion criterion. Typical values for exclusion were: a serum creatinine level > 177 ~mol/liter or 2 mg/dL in SOLVD, and values 221 lJ,mol/liter or 2.5 mg/dL in the SAVE study.7 A serum creatinine level > 1.5 mg/dL with elevated right atria1 pressure is another predictor of poor response to ACE inhibition therapy.30 1. AIRE (Acute Infarction Ramipril Efficacy) Study Investigators. Effect of ramipril on mortality and morbidity of suwivors of acute myocardial infarction with cliiical evidence of heart failure. Lance? 1993;342:821-828
A SYMPOSIUM:
NEW ACE INHIBITOR
!#
2. Meetson FZ. The myocardium in hyperfunction, hypertrophy and heart failure. Circ Res 1%9;25(suppl2):1-163. 3. Harris P. Congestive cardiac failure: central role of the arterial blood pressure. Er Heari I 1987;58:19&203. 4. Harris P. Congestive cardiac failure: the syndrome of volume expansion. Gmiiovasc mugs Thm 1989;3:941-945. 5. Malhotra R, Sadoshiia J, lzumo S. Mechanical stretch upregulates expression of the local renin-angiotensin system genes in cardiac mymes in vitro. (Abstr.) Circulation 1994,90+194. 6. Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancer 1988;i:255-259. 7. Pfeffer MA, Braunwald E, Moy& LA, Basta L, Brown Jr. ET, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins M on behalf of the SAVE Investigators. Effect of captoprii on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the S&&al and Ventricular Enlargement Trial. N Engi .I Med 1992,327zffiM77. 8. Raya TE, Gay RG, Aguirre M, Goldman S. Importance of venodilatation in prevention of left ventricular dilatation after chronic large myocardial infarction in rats: a comparison of captopril and hydralazine. Circ Res 1989;64:33&337, 9. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular fractions. N Engl J Med 1992;327:685-691. 10. Kramer EP, Elsner D, Riegger GAJ. Digoxin, converting-enzyme inhibition (quinapril), and the combination in patients with congestive heart failure function class II and sinus rhythm. J Carciiovasc Phnmuzcol1990;16:9-14. 11. Captoprii-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988,259:53!&544. 12. Odemuyiwa 0, Giiartin J, Kenny D, Hall RJC. Captopril and the diuretic requirements in moderate and severe chronic heart failure. Eur Heart J 1989;10:58&590. 13. Sharpe N, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled, randomized, double-blind study. Circularion 1984;70:271-278. 14. Gheorghiade M, Hall V, Lakier JB, Goldstein S. Comparative hemodynamic and neumhmnoral effects of intravenous captopril and digoxin and their combinations in patients with severe heart failure. JAm Coil Cardid 1989;13:134142. 15. Packer M, Gheorghiade M, Young JB, Smith K, Cstantini PJ, Adams KF, Cody RJ, Butman SM, Gourley LG Jolly MK on behalf of the RADIANCE study. Randomized, double-blind, placebo-controlled, withdrawal study of digoxin in patients with chronic heart failure treated with converting-enzyme inhibitors. (Abstr.) JAm Coil Car&l 1992;19:22’+238. 16. Opie LH. Angiotensti-Converting Enzyme Inhibitors: Scientific Basis for Clinical Use. New York: Authors’ Publishing House/Wiley-L& 1994229-238. 17. Swedberg K, Eneroth P, Kjekshus J, Wilhehnxn L, for the CONSENSUS Trial Study Group. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circularion 1990;8231730-1736.
18. Cohn JN, Johnson G, Ziesche S Cobb F, Grancis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Retcher RD, Doherty J, Hughes CV, Carson P, Cmtron G, Shabetai R, Haakenson C. Comparison of enalaprii with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:302-310. 19. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435. 20. SOLVD Investigators. Effect of enalapril on sunival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:29>302. 21. Fonarow GC, Chelinsky-Fallick C, Stevenson LW, Luu M, Hamilton MA, Moriguchi JD, Till&h JH, Walden JA, Albanese E. Effect of direct vasodilation with hydralazine versus angiotensin-converting enzyme inhibition with captopril on mortality in advanced heart failure: the Hy-C Trial. J Am Coil Cardi 1992$9:842-850. 22. Cohn JN, Archibald DG, Ziexhe S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Eff& of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552. 23. Gogia H, Mehra A, Parikh S, Ajit-Uppai J, Johnson JV, Elkayam U. A randomized study to evaluate the effect of hydralazine on the development of nitrate tolerance in patients with heart failure. (Abstr.) Circulahbn 1994;!Xl Part 2:1-601. 24. Davis R, Ribner HS, Keung E, Sonnenblick EH, L.eJemtel TH. Treatment of chronic congestive heart failure with captopril, an oral inhibitor of angiotensinconverting enzyme. N EnglJ Med 1979;301:117-121. 25. Packer M, Medina N, Yushak M. Efficacy of captopril in low-renin congestive heart failure: importance of sustained reactive hyperreninemia in diitinguishing responders from nonresponders. Am J Cma’io~ 1984;54:29%304. 26. Packer M, Medina N, Yushak M, Lee WH. Usefulness of plasma renin activity in predicting hemodynamic and clinical responses and survival during long term converting enzyme inhibition in severe chmnic heart failure. Experience in 100 consecutive patients. Br Hearf J 1985;54:298-304. 27. Mettauer B, Rouleau J-L, Bichet D, Kortas C, Mazini C, Tremblay G, Chatterjee K. Differential long-term intrarenal and neurohormonal effects of captopril and prazosin in patients with chronic congestive heart failure: importance of initial plasma renin activity. Cizulufion 1986;73:492-502. 28. L.aragh JH. Endocrine mechanisms in congestive cardiac failure: renin, aldosterone and atria1 natriuretic hormone. Drugs 1986,32(suppl5):1-12. 29. Ferrari R, Anand I. Neurohumoral changes in untreated heart failure. Cmiiovasc Drugs Ther 1989;3:979-986. 30. Packer M, Lee WH, Yushak M, Medina N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986,315: 847-853. 31. Sutton M&J, Pfeffer MA, Plappert T, Rouleau J-L, Moyk LA, Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S, Menapace Jr. FJ, Parker JO, Lewis S, Sestier F, Gordon DF, McEwan P, Bernstein V, Braunwald E, for the SAVE Investigators. Quantitative hv@dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circular& 1994;89:68-75.
6F
JUNE
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
75
16, 1995
H. Opie,
MD,
DPhil,
FRCP
Angiotensin-converting enzyme (ACE) inhibition thempy has now become firmly ensconced in the modem thempeutic approach to all stages of iongestive heart failure (CHF), including the early presymptomatic phase. Although its benefit is abundantly proven as add-on thempy in established CHF, after digitalis and diuretics, smaller and shorter studies have shown that, as second-line thempy and combined with diuretics, it may be prefemble to digoxin with an undoubted benefit in postinfarction failure. As first-line thempy in early presymptomatic CHF, the evidence is also good, based on the prevention arm of the Studies of Left Ventricular Dysfunction (SOLVD), albeit in predominantly postinfarction patients, and on the Survival and Ventricular Enlargement (SAVE) study on postinfarction patients. ACE inhibitors given prophylactically or therapeutically helped to prevent clinical heart failure in the SOLVD and SAVE studies. These data suggest a role for ACE inhibitors as effective first-
line monothempy in early heart failure, acting on left ventriclular function to avoid or lessen unfavorable remodeling. There are some contmindications or cautions for the use of ACE inhibitors in CHF, such as preexisting hypotension, high-renin states such as bilateml renal artery stenosis with hypertens’we heart failure, aortic stenosis combined with CHF, overdiuresis with excess sodium depletion, and significant preexisting renal failure. ACE inhibition thempy may have deleterious effects on renal function in heart failure, for example, by decreasing the glomerular filtration rate. In geneml, it is likely that serum urea and creatinine will rise slightly and the glomerular filtmtion rate fall slightly during ACE inhibition therapy, which means that a clinical judgment must be made, balancing the expected ovemll benefits of ACE inhibition against any possible aggravation of preexisting renal failure. (Am J Cardioll995;75:3F-6F)
C
tion may be caused by: (1) systemic hypotension (Harris3 has proposed that “the syndrome of CHF may be regarded as one which arises when the heart becomes chronically unable to maintain an appropriate arterial pressure without support”); (2) poor renal perfusion, which activates the stretchsensitive cells of the juxtaglomerular apparatus to release renin; (3) evocation of other ill-understood reflexes arising in poorly perfused peripheral tissues. Compensatory vasoconstrictive and volumeretaining mechanisms overwhelm an opposing vasodilatory system mediated through atrial natriuretic peptide and having its origin in atria1 distension.4 In postinfarction patients, there is increased wall stress on the noninfarcted myocardium. This mechanical factor stimulates myocardial hypertrophy through a mechanism thought to involve angiotensin II. The stimulus to release angiotensin II, which ultimately evokes an increase in protooncogenes such as c-fos, is thought to be nonspecific stretch.5 At present, it is not known whether the benefit of ACE inhibitors in preventing postinfarction remodeling is a specific effect or a nonspecific reduction of stretch because of arterial and venous unloading.
ongestive heart failure (CHF), once the “Cinderella” of cardiology, has now become the focus of intense interest, particularly with the use of angiotensin-converting enzyme (ACE) inhibitors. Studies have shown that, as second-line therapy and combined with diuretics, ACE inhibitors may be prefereable to digoxin with an undoubted benefit in postinfarction failure.’ However, new knowledge that ACE inhibitors can prevent development of clinically evident CHF in those at risk shifts the emphasis from symptomatic to preventive therapy. Meerson* has proposed that excess mechanical loading of the left ventricle leads to myocardial failure through 3 phases: an acute adaptation to the hemodynamic load, which leads to compensatory ventricular hypertrophy, and eventually to myocardial failure. In the last phase of left ventricular failure, the well known neurohumoral stimula-
From the Heart Research Unit, University of Cape School, Cape Town, South Africa. Address for reprints: Lionel H. Opie, M.D., Heart University of Cape Town Medical School, Observatory Town, South Africa.
Town Research 7925,
Medical Unit, Cape
A SYMPOSIUM:
NEW
ACE
INHIBITOR
3F
ACE INHIBITORS AS FIRST-LINE PREVENTlVE THERAPY FOR EARLY MYOCARDIAL FAILURE Preventive role in the postinfarction Survival and Ventricular Enlargement
phasestudy: In
patients with recent acute myocardial infarction, ACE inhibitors given to those with low ejection fractions but without symptoms improved the depressed left ventricular function better than did furosemide.6 Presumably, load reduction was helping to prevent adverse left ventricular remodeling. In the large Survival and Ventricular Enlargement (SAVE) study7 on > 2,000 patients, captopril achieved some striking benefits. It was given to patients 3-16 days after myocardial infarction who had ejection fractions < 40% but were not in overt heart failure, at an initial dose of 6.25 mg and titrated up to 50 mg three times daily. The benefits over an average of 42 months were several. Most importantly, mortality from all causes was reduced by 19%, the development of severe heart failure was down by 37%, and (a surprise) recurrent myocardial infarction was reduced by 25%. ACE inhibitors do not appear to act beneficially in postinfarction remodeling by arteriolar dilation alone+.g., hydralazine fails to improve postinfarction remodeling in rats.s Thus, another effect, possibly venous dilation or possibly direct inhibition of a growth factor, may be involved. Studies of Left Ventricular Dysfunction: New York Heart Association class I: In the large Studies
of Left Ventricular Dysfunction9 (SOLVD) in >4,000 patients, only 17% were taking diuretics and 66% were in New York Heart Association (NYHA) class I-so that the question was whether enalapril could prevent overt heart failure. Not surprisingly, the most striking benefits were found in patients with the lowest initial ejection fractions, <28%, with only borderline results in those with values of 33-35%. Enalapril in a mean daily dose of 17 mg was associated with less hospitalization and less development of symptomatic heart failure. Of note is that 80% of these patients have had a myocardial infarction, so that the prophylactic benefit of an ACE inhibitor in other types of asymptomatic early heart failure has not been established.
to get rid of the fluid retention that is causing the symptoms. This section details studies in which patients already treated with diuretics were given additionally an ACE inhibitor or digoxin. ACE inhibition versus digoxin versus their combination in early left ventricular failure: This impor-
tant question has been studied by Kromer et allo in 19 patients, all treated with hydrochlorothiazide 25 mg and having mild CHF with NYHA class II symptoms. In these patients, ACE inhibition therapy was markedly more effective than digoxin, as it increased exercise tolerance, decreased heart size, and decreased circulating norepinephrine and aldosterone levels. All of these were left unchanged by digoxin therapy. Combination therapy gave virtually identical results to ACE inhibition except that, in addition, fractional shortening increased significantly. Captopril-digoxin multicenter moderate heart failure: Three
study in mild-to-
hundred patients with mild-to-moderate heart failure and an average functional classification (NYHA) of 2.3 were randomly allocated in a double-blind manner to captopril, digoxin, or placebo.” Most were maintained on furosemide. Captopril was better than digoxin in increasing the effort tolerance and functional classification as well as decreasing ventricular premature beats. Only digoxin increased the ejection fraction. The long-term outcome of captopril versus digoxin in such patients needs study.
I
ACE INHIBITORS AS THIRD COMPONENT THERAPY IN COMBINATION WITH DIURETICS AND DlGOXlN
Diuretic therapy is universally accepted as firststep and first-line therapy in CHF when it is logical
Can ACE inhibition reduce diuretic requirements in CHF? In patients with NHYA class III heart failure, about half of a small series required a lower diuretic dose.lz Likewise, the addition of enalapril to patients already treated with digoxin and a diuretic required reduction of the diuretic dose in about half but eventually the diuretic dose was increased in the other half.13 The fundamental logic for triple therapy (diuretic, ACE inhibitor, inotropic agent) lies in the self-evident different mode of action of these 3 types of agents. From the hemodynamic point of view, the combination ACE inhibitor and inotropic agent gives better results than either therapy alone both in mildlo and in severe14 heart failure. Withdrawal of digoxin from triple therapy results in deterioration.15
4F
JUNE
ACE INHIBITORS AS SECOND-LINE THERAPY WITH DIURETICS FOR CONGESTIVE HEART FAILURE
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
75
16, 1995
In a series of 20 studies (reviewed by Opie16), mostly in patients already receiving diuretics or digoxin, nearly consistent effects of ACE inhibition are the increase in exercise time, the reduction of the preload and afterload, the decreased echocardiographic size, and the increased indices of function, such as fractional shortening, as well as an increased ejection fraction measured by radionuelide techniques. Administration of ACE inhibitors has, on the whole, a consistent effect in increasing plasma renin (by virtue of the inhibition of the converting enzyme), decreasing angiotensin II (the consequence of the enzyme inhibition), with also a decrease in aldosterone (which is stimulated by angiotensin II), and a fall in norepinephrine and vasopressin, the elevation of which are among the consequences of severe CHF. Parasympathetic activity, reduced in heart failure, is improved by ACE inhibition. Although there are some exceptions to the patterns noted, most of the results are reasonably consistent.
ACE INHIBITION AS PART OF QUADRUPLE THERAPY INCLUDING DIURETICS, DIGOXIN, AND VASODllATORS A question only recently answered is whether ACE inhibition confers any specific advantages over nonspecific vasodilators in advanced heart failure. A retrospective analysis of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) proposed that enalapril was most effective in patients with neuroendocrine and reninangiotensin activation. l7 The Veterans Administration Heart Failure Trial (V-HeFT-II) showed the expected advantage for ACE inhibition over hydralazine and nitrate therapy.‘* Logically, there should be scope for added vasodilator therapy to the now standard triple therapy in CHF, the latter consisting of diuretics, digoxin, and ACE inhibition. In the well-known CONSENSUS9 47% of patients were already receiving nitrates, and in the treatment arm of SOLVDzO 40% were on nitrates. In the Hy-C trialzl 84% of the patients were on nitrate therapy. Thus, in nitrate-treated patients, ACE inhibition can produce further clinical benefit. It should also be considered that in the V-HeFT-I trialz2 the combination of nitrates and hydralazine was superior to placebo. Hydralazine may help avoid nitrate tolerance.23
PREDICTORS OF POOR RESPONSE TO ACE INHIBITION THERAPY Because of activation of the renin-angiotensinaldosterone axis, it is often supposed that the higher the initial renin value, the better the response to ACE inhibition therapy. That expectation has not been met in at least 4 studies.2”27 A number of indicators of poor response have been proposed: 1. Hyponatremia: A very low sodium (about 130 mmol/liter) may indicate excess diuresis or a very severe neurohumoral response, or both. 2. Excess dietary sodium: This could suppress renin and aldosterone value in CHF without changing peripheral resistance. Thus, a nonrenin but sodium-related mechanism must be able to regulate arterial constriction. A captopril challenge with an acute dose evoked no response during a normal sodium intake, but a large response occurred after sodium depletion in patients with CHF.28 As in many studies in CHF, the exact sodium intake is not stipulated. Variations in the sodium status could help determine the response to ACE inhibitor therapy. Thus, dietary sodium restriction appears highly desirable. 3. Atria1 natriuretic peptide: One reason why a patient might not respond to ACE inhibition therapy is that, with a decrease in circulating angiotensin II,29 a vasodilatory fall in atria1 natriuretic peptide could follow. 4. Renal impairment: Whereas hemodynamic and hormonal effects of ACE inhibition are uniformly favorable, some of the renal effects can be construed as being unfavorable. Angiotensin II increases efferent renal arteriolar tone. Thus, it is not surprising that ACE inhibition may cause urea and creatinine to rise as well as the glomerular filtration rate and creatinine clearance. In several studies,7,20 a high plasma creatinine even before giving the ACE inhibitor has been an exclusion criterion. Typical values for exclusion were: a serum creatinine level > 177 ~mol/liter or 2 mg/dL in SOLVD, and values 221 lJ,mol/liter or 2.5 mg/dL in the SAVE study.7 A serum creatinine level > 1.5 mg/dL with elevated right atria1 pressure is another predictor of poor response to ACE inhibition therapy.30 1. AIRE (Acute Infarction Ramipril Efficacy) Study Investigators. Effect of ramipril on mortality and morbidity of suwivors of acute myocardial infarction with cliiical evidence of heart failure. Lance? 1993;342:821-828
A SYMPOSIUM:
NEW ACE INHIBITOR
!#
2. Meetson FZ. The myocardium in hyperfunction, hypertrophy and heart failure. Circ Res 1%9;25(suppl2):1-163. 3. Harris P. Congestive cardiac failure: central role of the arterial blood pressure. Er Heari I 1987;58:19&203. 4. Harris P. Congestive cardiac failure: the syndrome of volume expansion. Gmiiovasc mugs Thm 1989;3:941-945. 5. Malhotra R, Sadoshiia J, lzumo S. Mechanical stretch upregulates expression of the local renin-angiotensin system genes in cardiac mymes in vitro. (Abstr.) Circulation 1994,90+194. 6. Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancer 1988;i:255-259. 7. Pfeffer MA, Braunwald E, Moy& LA, Basta L, Brown Jr. ET, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins M on behalf of the SAVE Investigators. Effect of captoprii on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the S&&al and Ventricular Enlargement Trial. N Engi .I Med 1992,327zffiM77. 8. Raya TE, Gay RG, Aguirre M, Goldman S. Importance of venodilatation in prevention of left ventricular dilatation after chronic large myocardial infarction in rats: a comparison of captopril and hydralazine. Circ Res 1989;64:33&337, 9. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular fractions. N Engl J Med 1992;327:685-691. 10. Kramer EP, Elsner D, Riegger GAJ. Digoxin, converting-enzyme inhibition (quinapril), and the combination in patients with congestive heart failure function class II and sinus rhythm. J Carciiovasc Phnmuzcol1990;16:9-14. 11. Captoprii-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988,259:53!&544. 12. Odemuyiwa 0, Giiartin J, Kenny D, Hall RJC. Captopril and the diuretic requirements in moderate and severe chronic heart failure. Eur Heart J 1989;10:58&590. 13. Sharpe N, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled, randomized, double-blind study. Circularion 1984;70:271-278. 14. Gheorghiade M, Hall V, Lakier JB, Goldstein S. Comparative hemodynamic and neumhmnoral effects of intravenous captopril and digoxin and their combinations in patients with severe heart failure. JAm Coil Cardid 1989;13:134142. 15. Packer M, Gheorghiade M, Young JB, Smith K, Cstantini PJ, Adams KF, Cody RJ, Butman SM, Gourley LG Jolly MK on behalf of the RADIANCE study. Randomized, double-blind, placebo-controlled, withdrawal study of digoxin in patients with chronic heart failure treated with converting-enzyme inhibitors. (Abstr.) JAm Coil Car&l 1992;19:22’+238. 16. Opie LH. Angiotensti-Converting Enzyme Inhibitors: Scientific Basis for Clinical Use. New York: Authors’ Publishing House/Wiley-L& 1994229-238. 17. Swedberg K, Eneroth P, Kjekshus J, Wilhehnxn L, for the CONSENSUS Trial Study Group. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circularion 1990;8231730-1736.
18. Cohn JN, Johnson G, Ziesche S Cobb F, Grancis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Retcher RD, Doherty J, Hughes CV, Carson P, Cmtron G, Shabetai R, Haakenson C. Comparison of enalaprii with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:302-310. 19. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435. 20. SOLVD Investigators. Effect of enalapril on sunival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:29>302. 21. Fonarow GC, Chelinsky-Fallick C, Stevenson LW, Luu M, Hamilton MA, Moriguchi JD, Till&h JH, Walden JA, Albanese E. Effect of direct vasodilation with hydralazine versus angiotensin-converting enzyme inhibition with captopril on mortality in advanced heart failure: the Hy-C Trial. J Am Coil Cardi 1992$9:842-850. 22. Cohn JN, Archibald DG, Ziexhe S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Eff& of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552. 23. Gogia H, Mehra A, Parikh S, Ajit-Uppai J, Johnson JV, Elkayam U. A randomized study to evaluate the effect of hydralazine on the development of nitrate tolerance in patients with heart failure. (Abstr.) Circulahbn 1994;!Xl Part 2:1-601. 24. Davis R, Ribner HS, Keung E, Sonnenblick EH, L.eJemtel TH. Treatment of chronic congestive heart failure with captopril, an oral inhibitor of angiotensinconverting enzyme. N EnglJ Med 1979;301:117-121. 25. Packer M, Medina N, Yushak M. Efficacy of captopril in low-renin congestive heart failure: importance of sustained reactive hyperreninemia in diitinguishing responders from nonresponders. Am J Cma’io~ 1984;54:29%304. 26. Packer M, Medina N, Yushak M, Lee WH. Usefulness of plasma renin activity in predicting hemodynamic and clinical responses and survival during long term converting enzyme inhibition in severe chmnic heart failure. Experience in 100 consecutive patients. Br Hearf J 1985;54:298-304. 27. Mettauer B, Rouleau J-L, Bichet D, Kortas C, Mazini C, Tremblay G, Chatterjee K. Differential long-term intrarenal and neurohormonal effects of captopril and prazosin in patients with chronic congestive heart failure: importance of initial plasma renin activity. Cizulufion 1986;73:492-502. 28. L.aragh JH. Endocrine mechanisms in congestive cardiac failure: renin, aldosterone and atria1 natriuretic hormone. Drugs 1986,32(suppl5):1-12. 29. Ferrari R, Anand I. Neurohumoral changes in untreated heart failure. Cmiiovasc Drugs Ther 1989;3:979-986. 30. Packer M, Lee WH, Yushak M, Medina N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986,315: 847-853. 31. Sutton M&J, Pfeffer MA, Plappert T, Rouleau J-L, Moyk LA, Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S, Menapace Jr. FJ, Parker JO, Lewis S, Sestier F, Gordon DF, McEwan P, Bernstein V, Braunwald E, for the SAVE Investigators. Quantitative hv@dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circular& 1994;89:68-75.
6F
JUNE
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
75
16, 1995