Use of ACE inhibitors for secondary prevention

Opinion statement The role of the renin-angiotensin system as a regulator of blood pressure, body fluids, electrolytes, and neurohormonal activation has been established for more than two decades. The dramatic benefits of angiotensin-converting enzyme (ACE) inhibition on overall mortality, progression to heart failure, and major cardiovascular events were first demonstrated in patients with congestive heart failure (CHF) or left ventricular dysfunction. ACE inhibitors should be prescribed for all patients with symptomatic CHF and for all asymptomatic patients with a left ventricular ejection fraction less than 35% to 40%, unless contraindicated or not tolerated, and therapy should be continued indefinitely. Data have shown that ACE inhibition improves oxidative stress, endothelial and ventricular function, and reduces ventricular remodeling as well as progression of carotid intimal and medial thickening. Current evidence suggests that ACE inhibitors should be prescribed as early as possible for all patients with acute myocardial infarction, unless contraindicated or not tolerated, and that they should be continued for at least 6 weeks; moreover, because these patients automatically qualify as high-risk individuals, indefinite therapy should be considered. Likewise, individuals at increased risk for major cardiovascular events (diabetic patients with additional risk factors and patients with known vascular disease) should be prescribed ACE inhibitors, unless contraindicated or not tolerated, and therapy should be continued indefinitely. There is not sufficient evidence at present to recommend the use of ACE inhibitors after coronary revascularization for the specific goal of preventing restenosis or graft disease, in the absence of decreased ejection fraction, CHF, or a new myocardial infarction.     

Aspects of the Use of Angiotensin-Converting Enzyme Inhibitors and Calcium Antagonists in Treatment of Heart Failure in the Older Patient

The syndrome of congestive heart failure may result from either systolic or diastolic dysfunction of the left ventricle. Diastolic left ventricle dysfunction is particularly common in the geriatric age group, and is associated with left ventricular hypertrophy resulting from aging and hypertension. The clinical differentiation of these two patterns is important in understanding the pathophysiologic process and in selecting appropriate therapy. Angiotensin-converting enzyme (ACE) inhibitors are useful in systolic dysfunction, both in improving clinical manifestations of reduced cardiac output and in actually prolonging survival. ACE inhibitors are also beneficial in diastolic heart failure by promoting regression of left ventricular hypertrophy, thus improving diastolic physiological function. Calcium antagonists improve diastolic function by reducing blood pressure of hypertensive subjects, reducing left ventricular mass, and theoretically, by facilitating the energy-dependent transport of calcium ions from the actin-myosin complex into the sarcoplasmic reticulum. However, because of the negative inotropic properties of the calcium antagonists, they should be used cautiously, if used at all, in patients with significant systolic dysfunction, at least until the results of clinical trials using these drugs in systolic congestive heart failure are available.     

The multifacetted role of angiotensin converting enzyme inhibitors in congestive heart failure

The angiotensin converting enzyme (ACE) inhibitors constitute a major breakthrough in the medical management of congestive heart failure. The incidence of side effects with these agents is surprisingly low when they are used in the appropriate dosage. They produce sustained beneficial hemodynamic and symptomatic improvement in most patients with congestive heart failure and may produce greater symptomatic benefit than digoxin when given as second-line therapy to patients with heart failure on diuretics. Their neurohumoral effects generally are advantageous, resulting in normalization of sodium and potassium balance and a reduction in ventricular arrhythmias. The ACE inhibitors may improve survival in patients with congestive heart failure, and recent data suggest that they may prevent or delay the development of left ventricular dilatation and overt heart failure in patients with asymptomatic left ventricular dysfunction.     

Angiotensin II receptor blockers in the treatment of heart failure

Heart failure treatment centers on antagonism of the renin-angiotensin-aldosterone system and adrenergic nervous system. Angiotensin-converting enzyme (ACE) inhibitors have been shown to benefit patients with left ventricular systolic dysfunction irrespective of symptoms. Despite ACE inhibitor use, left ventricular dysfunction continues to progress in most patients. In addition, ACE inhibitors are substantially underused in patients who would benefit, in large part due to physician concern over potential adverse effects. Angiotensin receptor blockers (ARBs) have been proposed as either potential substitutes for ACE inhibitors or as additive therapy for heart failure patients. The authors will review the importance of the renin-angiotensin-aldosterone system in the progression of heart failure, as well as the mechanisms by which ACE inhibitors and ARBs counteract this effect. The clinical evidence to date supporting the use of ARBs in heart failure also will be reviewed. Based on current trials, ARBs are suitable substitutes for ACE inhibitors in patients who have true ACE inhibitor intolerance, but ACE inhibitors should still be considered first-line therapy in the treatment of left ventricular systolic dysfunction and heart failure. ARBs are a reasonable additive therapy in patients on maximal ACE inhibitor therapy who remain symptomatic, especially in patients unable to tolerate beta blockade.     

Angiotensin-converting enzyme inhibitors in patients with coronary atherosclerosis

Activation of the renin-angiotensin-aldosterone system has been shown to be an independent risk factor for myocardial infarction (MI). The importance of this risk factor has been confirmed by the finding that patients with a DD genotype for the angiotensin-converting enzyme (ACE) gene, which is associated with increased serum ACE levels, have a higher incidence of MI than do patients without this genotype. ACE inhibitors have been shown to significantly reduce the incidence of recurrent MI in patients with left ventricular dysfunction. The mechanism by which activation of the renin-angiotensin-aldosterone system leads to MI has not been ascertained, but it may be related to the effect of angiotensin II or aldosterone on the development of atherosclerosis, endothelial dysfunction, plaque rupture, or thrombosis after plaque rupture. Experimental data suggest that each of these mechanisms may be of importance. Several prospective randomized studies are under way to determine the effect of ACE inhibitors on recurrent ischemic events and the progression of atherosclerosis in patients without left ventricular dysfunction. If these studies yield positive results, ACE inhibitors might assume an important role in the secondary and possibly primary prevention of ischemic heart disease.     

Managing the post-myocardial infarction patient with asymptomatic left ventricular dysfunction

The percentage of post-myocardial infarction (MI) patients with asymptomatic left ventricular dysfunction (ALVD) is now estimated at 10%, and that number is expected to grow as reperfusion procedures increasingly become routine. Since average all-cause mortality risk in these patients is high (up to 27%), definitive diagnostics are recommended to screen all post-MI patients for ALVD, defined as left ventricular systolic dysfunction in the absence of heart failure symptoms. Post-MI management strategies for patients with ALVD target the two routes of progression to heart failure: (1) cardiac remodeling mediated by neurohormonal activation, and (2) continued and recurrent myocardial ischemic events. Clinical trials of neurohormonal antagonists in post-MI ALVD patients have shown that angiotensin-converting enzyme inhibitors attenuate left ventircular remodeling and that beta-blocker therapy reverses remodeling for patients already on angiotensin-converting enzyme inhibitor therapy. Neurohormonal antagonist therapy is also associated with significant reductions in sudden death in post-MI ALVD patients.     

Angiotensin converting enzyme inhibition in cardiovascular risk populations: a practical approach to identify the patient who will benefit most

PURPOSE OF REVIEW: Evidence from clinical trials suggests that angiotensin converting enzyme (ACE) inhibition has the broadest impact of any class of drugs in cardiovascular medicine, reducing cardiovascular morbidity and mortality. This beneficial effect varies across different patient populations, however. This review will summarize the current literature about the therapeutic potential of ACE inhibition and provide a practical approach for clinicians to identify patients who benefit most from ACE inhibition. RECENT FINDINGS: ACE inhibition has been shown to benefit patients with heart failure, left ventricular dysfunction, postmyocardial infarction, nephropathy, peripheral vascular disease, diabetes, stroke or transient ischemic attack. The absolute clinical benefit varies across different risk populations, however, depending on the patient characteristics. ACE inhibitors are most effective in patients with an increased cardiovascular risk associated with an activated renin-angiotensin system and less effective in patients with classical cardiovascular risk factors, but without an activated renin-angiotensin system. SUMMARY: We argue that markers of an activated renin-angiotensin system, such as left ventricular dysfunction, left ventricular hypertrophy, renal dysfunction, as assessed by estimated glomerular filtration rate, or urinary albumin excretion, may be used as targets and act as indicators for ACE-inhibition therapy and also for monitoring purposes. This will help clinicians to guide their therapy and identify patients who benefit most from ACE inhibition.     

Heart failure – from pathophysiology to therapy

Swedberg K et al. (Department of Medicine, Östra University Hospital, Göteborg, Sweden). Heart failure – from pathophysiology to therapy (Minisymposium). J Intern Med 1996; 239 : 305–43. Population studies, together with data from clinical records, reveal a range of estimated heart failure prevalence of 1–10%. Estimated incidence rates vary around 1% per annum. In community studies, the five-year mortality is between 50–60%, while in patients requiring hospital admission, the annual mortality is 10–20% in those with mild–moderate symptoms and as high as 40–60% in severe heart failure. Many definitions of heart failure have been formulated. Making a diagnosis is a complex process. Heart failure is not a diagnosis or even one syndrome, but is a cluster of syndromes. The diagnosis is therefore only part of the assessment process. Essential parts for the diagnosis include symptomatology, objective evidence of important cardiac dysfunction and evaluation of the response to therapy. The cardinal symptom is exertional breathlessness. At present, echocardiography remains the most useful tool for confirming cardiac dysfunction, but determination of atrial natriuretic peptide or magnetic resonance imaging may supersede it. Heart failure has been viewed primarily as an oedematous disorder, in which fluid retention occurs because the heart cannot pump adequate quantities of blood to the kidneys. This model led to the utilization of diuretics for heart failure, but it failed to recognize that heart failure is a chronic progressive disorder that impairs both the quality and quantity of life, even when oedema is adequately controlled. A new model has been developed in which the development and progression of heart failure is viewed as resulting from the interplay of haemodynamic and neurohormonal mechanisms. Both mechanisms support the inotropic state of the heart following an injury to the myocardium, but when sustained for long periods, these mechanisms act to enhance ventricular wall stress, and, thereby, impair ventricular performance. As the heart failure evolves, endogenous mechanisms that are normally activated to control wall stress become exhausted, and peripheral vasoconstriction and sodium retention develop. Unopposed activation of haemodynamic stresses and neurohormonal systems leads to further destruction of myocardium and progression of the underlying disease. The acceptance of this haemodynamic–neurohormonal model has led to the development of vasodilators and neurohormonal antagonists which have been shown to be useful alone  – or added to diuretics – in the treatment of heart failure. Non-pharmacological therapy includes counselling of life style and, for patients with moderate heart failure, light exercise. Within the last decade, pharmacological therapy was improved considerably. Asymptomatic patients with left ventricular dysfunction benefit from acetylsalicylic acid (ASA) and beta-blockers. In patients with progressive dilatation of the left ventricle and with an established left ventricular dysfunction treatment with angiotensin-converting enzyme (ACE) inhibitors has beneficial effects on mortality and morbidity. In symptomatic patients and those with clear systolic left ventricular dysfunction in addition to digitalis and diuretics, ACE inhibitors are clearly indicated in addition to ASA. Beta-blockers may be added but the true benefit is not established. The initiation of both ACE inhibitors and beta-blockers should be careful and the dose titrated slowly. Antiarrhythmic class I agents should be avoided unless clear indications are present, e.g. life-threatening arrhythmias. Amiodarone might be considered as an alternative. The prognosis for patients with heart failure remains serious and the search for even better therapies should continue.     

A hard look at angiotensin receptor blockers in heart failure

Multiple trials over the past several years have examined indications for angiotensin receptor blockers (ARBs) in the treatment of left ventricular dysfunction, both acutely after myocardial infarction and in chronic heart failure. Yet despite these data, there is still confusion regarding the efficacy of ARBs as monotherapy in these patient populations, as well as the specific indications for combination ARB/angiotensin-converting enzyme (ACE) inhibitor therapy. We examine the key differences among the trials-including the ACE inhibitor dose, the ARB and its dose, blood pressure reduction, and patient populations-to present our perspective on ARB use, alone or in combination with ACE inhibitors, in patients with chronic heart failure and post-myocardial infarction left ventricular dysfunction. We conclude that ACE inhibitors remain the first-line therapy for left ventricular dysfunction. Angiotensin receptor blockers should be reserved for monotherapy in ACE intolerant patients and for combination therapy in symptomatic class II/III patients with chronic heart failure.     

Mineralocorticoid receptor antagonism and cardiac remodeling in ischemic heart failure

Aldosterone production in the heart as well as aldosterone plasma levels are increased after myocardial infarction and in congestive heart failure, correlating with the severity of disease. Aldosterone promotes sodium and water retention, sympathoadrenergic activation, endothelial dysfunction, and cardiovascular fibrosis and hypertrophy. Even maximally recommended doses of ACE inhibitors do not completely prevent formation of aldosterone. The Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Post acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS) demonstrated that aldosterone receptor blockade markedly reduces mortality among patients with heart failure. This review summarizes recent clinical and experimental data on the effect of aldosterone antagonists on left ventricular remodeling and function in ischemic heart failure with special emphasis on potential underlying mechanisms. While reduction of excessive extracellular matrix turnover leading to decreased fibrosis appears to be the most important effect of mineralocorticoid receptor antagonism in heart failure, other mechanisms such as regression of hypertrophy, improvement of endothelial function, reduction of superoxide formation, and enhanced renal sodium excretion may contribute. Recent data showed that in rats with left ventricular dysfunction after extensive myocardial infarction, eplerenone on top of ACE inhibition more effectively improved cardiac remodeling and molecular alterations than ACE inhibition alone.     

Dosing of ACE inhibitors in postinfarct protection

Summary ACE inhibitors improve not only symptoms and signs of heart failure in patients with symptomatic left ventricular dysfunction but also lead to a slower progression of heart failure. In asymptomatic patients with left ventricular dysfunction, the progression to symptomatic heart failure is retarded by ACE inhibitors. As heart failure is preceded in about 80% by myocardial infarctions, trials were designed to influence the development of heart failure after myocardial infarction. It could be shown that therapy with ACE inhibitors ameliorates the progressive left ventricular dilatation and that this effect is translated into a significant increase of life expectancy. Mainly based on the CONSENSUS I study, large doses of ACE inhibitors were used in most subsequent trials. The mean daily doses of enalapril were 18.4 mg in the CONSENSUS I trial and 16.6 and 16.7 mg in both arms of the SOLVD trial. There is a trend towards lower doses of ACE inhibitors, as in the SAVE trial only 79% of the patients taking captopril received the target dose of 150 mg daily. Smaller studies used similar target doses, but a beneficial effect on left ventricular enlargement has been shown with a daily dose of only 75 mg captopril. Based on the hypothesis that the left ventricular enlargement is mainly determined by the activation of the local cardiac renin angiotensin system, even lower, and therefore better tolerated, doses of ACE inhibitors may prove effective. However, studies comparing the effect of different doses of ACE inhibitors on left ventricular remodeling are missing. Consequently, the above-mentioned target doses of ACE inhibitors should be aimed at when treating patients after myocardial infarction. Even when the doses have to be reduced because of side effects such as worsening angina or hypotension, there is good evidence that the progressive left ventricular dilatation will still be retarded.     

ACE inhibitors versus diuretics: When to choose which drug?

Summary ACE inhibitors and diuretics should be used in combination in the majority of patients with clinical congestive heart failure. The broad spectrum of heart failure should include the phase of significant left ventricular dysfunction without overt clinical heart failure for which ACE inhibitor treatment alone may be beneficial in selected cases.     

Clinical aspects of ACE inhibition in patients with acute myocardial infarction

Summary The purpose of the present article was to review the current evidence on the use of angiotensin-converting enzyme (ACE) inhibitors in acute myocardial infarction (MI). This article is based on published information as well as on our personal experience derived from an extensive analysis of the SMILE study. All the randomized trials have been included irrespective of the primary endpoint, and the results are presented in terms of either hemodynamic or clinical benefit. Short- and long-term treatment with ACE inhibitors in patients with acute MI results in a significant reduction in mortality, which is more evident in high risk patients (i.e., patients with left ventricular dysfunction, congestive heart failure on admission, or anterior myocardial infarction). Development and progression of congestive heart failure after myocardial infarction was significantly reduced by ACE inhibition, which also reduced the rate of reinfarction, the need for revascularization procedures, as well as the occurrence of ventricular arrhythmias, probably through a mechanism involving some drug-dependent effects. In conclusion, the available data strongly support a wide benefit associated with the use of ACE inhibitors in patients with high-risk acute MI.     

Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of heart failure caused by left ventricular systolic dysfunction

Activation of the renin-angiotensin-aldosterone system (RAAS) in left ventricular systolic dysfunction is a critically important determinant in the pathophysiologic processes that lead to progression of heart failure and sudden death. Angiotensin II, acting at the specific angiotensin receptor (AT1-R), activates a series of intracellular signaling sequences which are ultimately expressed within the cardiovascular system as vasoconstriction and associated vascular hypertrophy and remodeling. Angiotensin converting enzyme (ACE) inhibition leads to increases in the vasodilatory peptides bradykinin and substance P and at least an initial reduction in angiotensin II concentrations. AT1-R blocking drugs prevent access of angiotensin II to the AT1-R and thus prevent cellular activation. ACE inhibitors have clearly been demonstrated through a large number of clinical trials to increase survival in congestive heart failure, primarily by reducing the rate of progression of left ventricular dilatation and decompensation. However, this beneficial effect diminishes over time. Preliminary short-term clinical studies evaluating the efficacy of AT1-R blocking drugs in the treatment of heart failure have suggested that they elicit similar hemodynamic and neuroendocrine effects as do the ACE inhibitors. The combination ACE inhibitors and AT1-R blocking drugs offer the theoretical advantage of increasing bradykinin while blocking the actions of angiotensin II, and thus possibly show a synergistic effect. Again, preliminary studies have yielded encouraging results that are difficult to interpret because neither ACE inhibitor nor the AT1-R blocking drug doses were titrated to tolerance. Pharmacological manipulation of the RAAS has led to better understanding of its role in heart failure and improved clinical outcomes.     

Mechanisms in heart failure and the role of angiotensin-converting enzyme inhibition

The four major diagnostic criteria for the syndrome of congestive heart failure are left ventricular dysfunction, exercise intolerance, pulmonary congestion or edema and ventricular arrhythmias. Activation of norepinephrine, angiotensin II, vasopressin and atrial natriuretic peptide may be a key factor in the vasoconstriction and increased impedance to left ventricular ejection in heart failure. Interventions that interfere with these vasoconstrictor mechanisms should have a salutary effect on left ventricular performance. Treatment with angiotensin-converting enzyme (ACE) inhibitors, alpha-adrenoceptor blockers and vasopressin antagonists has resulted in hemodynamic benefits, but it has been more difficult to demonstrate long-term clinical effectiveness. Reductions in mortality have been demonstrated in patients with heart failure treated with vasodilators and ACE inhibitors. Improvement in the quality of life and prolongation of life are the only two appropriate goals in the management of heart failure. Further understanding of the role of angiotensin II and its interference by ACE inhibition in the tissue processes of heart failure is needed.     

Asymptomatic Left Ventricular Dysfunction

Increasingly, it is recognized that significant ventricular dysfunction can exist in the absence of symptoms for an extended period of time in patients with cardiovascular disease. Recent multicenter trials have demonstrated that therapy during the asymptomatic phase can reduce progression to symptomatic heart failure and mortality. Little is known about the epidemiology of this problem. However, preliminary studies suggest that the prevalence of asymptomatic left ventricular dysfunction may approach that of clinically apparent congestive heart failure. The mechanisms whereby some patients with severe ventricular dysfunction may remain asymptomatic while others with similar degrees of ventricular dysfunction have severe symptoms of heart failure remain unclear. By understanding these mechanisms, we may devise novel therapies which will prolong the asymptomatic phase and hopefully prevent the progression to heart failure. This review focuses on pertinent clinical and pathophysiologic issues pertaining to asymptomatic left ventricular dysfunction. This revised version was published online in July 2006 with corrections to the Cover Date.     

Early neurohormonal effects of trandolapril in patients with left ventricular dysfunction and a recent acute myocardial infarction: a double-blind, randomized, placebo-controlled multicentre study

Angiotensin-converting enzyme inhibitors improve long-term survival in patients with left ventricular dysfunction after a myocardial infarction, but their mechanism of action is not entirely clear. The neurohormonal effects may be important in this respect, as well as an early hemodynamic unloading induced by these drugs. The primary objective was to assess the effect of trandolapril on plasma levels of atrial natriuretic peptide. A secondary objective was to assess the effects of trandolapril on selected neurohormones, vasoactive peptides and enzymes, which may be important in the development of left ventricular remodeling and heart failure following an acute myocardial infarction. A total of 119 patients with an acute myocardial infarction and a wall motion index < or =1.2 (16-segment echocardiographic model) were randomized to double blind treatment with trandolapril or placebo within 3-7 days after the onset of infarction. Blind treatment was discontinued 21 days after the index infarction. Venous blood samples were collected at rest, before randomization and on the day after treatment was discontinued. At the end of the study, there were no differences in plasma levels of atrial natriuretic peptide between the two treatment groups. Angiotensin-converting enzyme activity was suppressed and plasma renin activity was higher in the trandolapril group. No differences in plasma levels of N-terminal pro-atrial natriuretic peptide, brain natriuretic peptide, aldosterone, noradrenaline, adrenaline, vasopressin, big endothelin-1 and neuropeptide Y were found between the two treatment groups. There were positive correlations between several markers of neurohormonal activation at baseline and variables expressing left ventricular dysfunction and clinical heart failure. Neurohormonal activation is related to left ventricular dysfunction. The effects of 2-3 weeks of angiotensin-converting enzyme inhibition on neurohormonal activation does not predict the already established beneficial long-term effects after myocardial infarction. Thus, early modulation of circulatory neurohormone levels may not be a major mechanism for the efficacy of angiotensin-converting enzyme inhibitors in these patients. Selected plasma hormone markers may still be used to identify patients who might get the greatest benefit from treatment.     

Update on therapy for heart failure

The success of angiotensin-converting enzyme (ACE) inhibitors in reducing morbidity and mortality in patients with heart failure has led to investigations of other inhibitors of the renin-angiotensin-aldosterone system. Although ACE inhibitors remain first-line drugs in the treatment of heart failure and left ventricular dysfunction, clinical evidence suggests that a newer class of agents--angiotensin II receptor blockers--may provide additional benefit by blocking the adverse effects of angiotensin II more completely. An improved adverse-effect profile also makes angiotensin II receptor blockers appropriate in patients who cannot tolerate ACE inhibitors. Clinical trials have demonstrated the beneficial effects of angiotensin II receptor blockers on the combined endpoints of morbidity and mortality in patients with heart failure. Aldosterone antagonism with spironolactone has additive benefits in patients receiving an ACE inhibitor. The most recent treatment guidelines for heart failure recommend the use of angiotensin II receptor blockers and spironolactone in selected patients.     

Diuretics in the Prevention and Treatment of Congestestive Heart Failure

Diuretics, either as monotherapy or in combination with other drugs in the management of hypertension, have retarded the development of left ventricular hypertrophy and congestive heart failure in many patients. Diuretics also remain one of the most effective therapies in the treatment of congestive heart failure, when given with an ACE inhibitor and digoxin.