Tissue angiotensin-converting enzyme inhibitors for the prevention of cardiovascular disease in patients with diabetes mellitus without left ventricular systolic dysfunction or clinical evidence of heart failure: a pooled meta-analysis of randomized placebo-controlled clinical trials

Aim:  The aim of this study was to determine the role of tissue angiotensin-converting enzyme (ACE) inhibitors in the prevention of cardiovascular disease in patients with diabetes mellitus without left ventricular systolic dysfunction or clinical evidence of heart failure in randomized placebo-controlled clinical trials using pooled meta-analysis techniques.
Methods:  Randomized placebo-controlled clinical trials of at least 12 months duration in patients with diabetes mellitus without left ventricular systolic dysfunction or heart failure who had experienced a prior cardiovascular event or were at high cardiovascular risk were selected. A total of 10 328 patients (43 517 patient-years) from four selected trials were used for meta-analysis. Relative risk estimations were made using data pooled from the selected trials and statistical significance was determined using the Chi-squared test (two-sided alpha error <0.05). The number of patients needed to treat was also calculated.
Results:  Tissue ACE inhibitors significantly reduced the risk of cardiovascular mortality by 14.9% (p = 0.022), myocardial infarction by 20.8% (p = 0.002) and the need for invasive coronary revascularization by 14% (p = 0.015) when compared to placebo. The risk of all-cause mortality also tended to be lower among patients randomized to tissue ACE inhibitors, whereas the risks of stroke and hospitalization for heart failure were not significantly affected. Treating about 65 patients with tissue ACE inhibitors for about 4.2 years would prevent one myocardial infarction, whereas treating about 85 patients would prevent one cardiovascular death.
Conclusion:  Pooled meta-analysis of randomized placebo-controlled trials suggests that tissue ACE inhibitors modestly reduce the risk of myocardial infarction and cardiovascular death and tend to reduce overall mortality in diabetic patients without left ventricular systolic dysfunction or heart failure.     

Baseline clinical characteristics of patients recruited into the assessment of treatment with lisinopril and survival study

BACKGROUND: The beneficial effect of ACE inhibitors on mortality has been established in a series of trials. However, in clinical practice, ACE inhibitors are commonly administered in doses much lower than those shown to be effective in the landmark trials. AIMS: This report describes the baseline characteristics of the patients recruited into the ATLAS study by age and gender sub-groups. METHODS: The ATLAS study compared the effects of 'low' dose (2.5-5.0 mg/day) to 'high' dose (32.5-35.0 mg/day) lisinopril in a double-blind study of 3164 patients with moderate to severe heart failure and left ventricular ejection fraction < 30% during a mean follow-up period of 46 months. The primary end-point was all cause mortality and the principal secondary end-point a composite of all-cause hospitalisation or all-cause mortality. RESULTS: Among patients with heart failure selected for the presence of left ventricular systolic function there were few differences among age groups or between genders. Older patients were not so heavy, were more likely to have ischaemic heart disease, hypertension and atrial fibrillation contributing to their heart failure and had a higher blood urea. Women were not so heavy as men. Age and gender had no major influence on mean ejection fraction or baseline treatment in the ATLAS study. CONCLUSIONS: Weight and renal function may alter the plasma concentration of any given dose of an ACE inhibitor. Potential interactions between dose of lisinopril, weight and renal function will be explored after the study is completed.     

Use of beta-blockers in older adults with chronic heart failure

Most heart failure patients are older adults. Angiotensin-converting enzyme (ACE) inhibitors reduce mortality and morbidity in patients with systolic heart failure. However, the annual mortality rate in patients with systolic heart failure receiving ACE inhibitors is about 12%. Beta-blockers further reduce mortality rate by an additional 35% to 65%. Because of potential adverse effects, the rate of beta-blocker use is likely to be low in older adults with systolic heart failure. In this article, we review the findings of the major beta-blocker trials in systolic heart failure and discuss the potential benefits and adverse effects of beta-blockers, along with various practical aspects of their use in older adults with systolic heart failure. Subgroup analyses of these trials suggest that the survival benefits of beta-blockers observed in the main trials are also observed in persons 65 years of age and older. However, data are limited for heart failure patients 85 years of age and older. About half of the older adults with heart failure do not have systolic heart failure, and currently there is no evidence that beta-blockers also improve survival in these patients. Beta-blockers might play a beneficial role in heart failure patients without systolic heart failure by reducing high blood pressure, high heart rate, or myocardial ischemia, conditions known to impair ventricular relaxation. Adequate knowledge of the commonly used beta-blockers, along with careful patient selection and close monitoring for adverse effects will allow safe initiation and continuation of beta-blocker use for older adults with systolic heart failure. It is likely that lower doses of beta-blockers are as effective as higher doses.     

Review of randomized trials of digoxin therapy in patients with chronic heart failure.

Although digitalis glycosides were introduced in the treatment of cardiac maladies greater than 200 years ago, controversy persists regarding the precise role of digoxin in any multidrug approach to the treatment of congestive heart failure (CHF). Despite its widespread use for more than 2 centuries, only recently have double-blind, randomized, placebo-controlled trials of digoxin therapy been conducted in patients with moderate CHF and sinus rhythm. These trials demonstrate that digoxin is superior to placebo in improving left ventricular (LV) ejection fraction, increasing exercise capacity, and preventing CHF worsening. Digoxin produces benefits similar to those seen with angiotensin converting enzyme (ACE) inhibitors with regard to clinical compensation and improvement in LV function. However, improved survival is demonstrated only in response to ACE inhibitors. The recently completed RADIANCE study addresses the value of combining digoxin with ACE inhibitor therapy in patients with mild-to-moderate CHF. Because increased mortality has been reported with the newer oral inotropic agents, it currently appears that digoxin is the only oral inotropic agent useful in clinical practice in the treatment of CHF. However, the effects of digoxin on mortality in patients with CHF remain unknown. In the large, double-blind, randomized trial conducted by the National Heart, Lung, and Blood Institute, the effects of digoxin on mortality in patients with CHF and already being treated with ACE inhibitors are currently being evaluated. Presently, based on the results of placebo-controlled studies, it appears that digoxin, alone or in combination with ACE inhibitors, is beneficial in patients with any signs or symptoms of CHF due to systolic LV dysfunction.     

Angiotensin-converting enzyme inhibition after acute myocardial infarction with special reference to the Fourth International Study of Infarct Survival (ISIS-4)

Role of ACE inhibitors in the management of asymptomatic or symptomatic left ventricular (LV) dysfunction after acute myocardial infarction (AMI) is well established. More recently, large clinical trials have evaluated the use of angiotensin-converting enzyme (ACE) inhibitors early after AMI, ie, within 24 hours of symptom onset. This concept has emerged with the understanding of pathophysiological changes occurring after AMI. Neurohormonal activation and ventricular remodelling after AMI form the basis of these changes, whereas the extent of LV dysfunction remains strongly predictive of poor outcome. The large clinical trials with mortality end point have shown modest benefit with early use of ACE inhibitors in an unselected population. However, the generalized use of ACE inhibitors remains controversial because of an overall small benefit. We review the pathophysiological changes occurring after AMI, the rationale for early use of ACE inhibitors, and the data available from the large clinical trials. We recommend consideration of early ACE inhibitor in all but the lowest risk patients. Clinical features of such a low-risk population would include small and nonanterior infarctions in patients less than 65 years of age and with LV ejection fractions greater than 50%. Objective assessment of LV function is warranted during hospitalization for AMI to appropriately select patients for ACE inhibitor therapy. Dosing should be started carefully to avoid hypotension and should be titrated to the goal of doses used in the large trials. Duration of therapy in patients at high risk for death or ventricular enlargement should be indefinite. Further large-scale secondary prevention trials with long-term treatment are underway to assess the effect of ACE inhibition on coronary disease progression and reinfarction.     

Role and optimal dosing of angiotensin-converting enzyme inhibitors in heart failure

Based on overwhelming data demonstrating reduced morbidity and mortality, ACE inhibitors form a mainstay of therapy in all patients with symptomatic left ventricular systolic dysfunction. Furthermore, ACE inhibitors may be beneficial in the prevention of heart failure in patients with high-risk cardiovascular profiles. However, definite benefit from the use of ACE inhibitors in all patients with heart failure and preserved ejection fraction has not been demonstrated. Even though ACE inhibitors probably have a class effect in patients who have heart failure, it is recommended that ACE inhibitors that have been shown to reduce morbidity and mortality in clinical trials (captopril, enalapril, lisinopril, and ramipril) be used because studies have clearly defined a dose for these agents that is effective in modifying the natural history of the disease. Attempts should be made to up titrate patients to target doses of ACE inhibitors that have been used in clinical trials, if tolerated.     

A remarkable medical story: benefits of angiotensin-converting enzyme inhibitors in cardiac patients

The development of angiotensin-converting enzyme inhibitors (ACE inhibitors) has been one of the most remarkable stories in the treatment of cardiovascular diseases. Angiotensin converting enzyme inhibitors have several acute and sustained hemodynamic effects that are beneficial in the presence of left ventricular (LV) dysfunction. They increase cardiac output and stroke volume and reduce systemic vascular resistance as well as pulmonary capillary wedge pressure. The hemodynamic benefits are associated with improvement in the signs and symptoms of congestive heart failure (CHF) as well as decreased mortality, regardless of the severity of CHF. In patients with asymptomatic LV dysfunction, therapy with ACE inhibitors prevented the development of CHF and reduced hospitalization and cardiovascular death. They also increase survival when administered early after an acute myocardial infarction (MI). Most recently, ACE inhibition was associated with improved clinical outcomes in a broad spectrum of high-risk patients with preserved LV function. The mechanism of ACE inhibitors benefits is multifactorial and includes prevention of progressive LV remodeling, prevention of sudden death and arrhythmogenicity and structural stability of the atherosclerotic process. Evidence suggests that ACE inhibitors are underutilized in patients with cardiovascular diseases. Efforts should be directed to prescribe ACE inhibitors to appropriate patients in target doses. It is reasonable to believe that ACE inhibitors have a class effect in the management of LV dysfunction with or without CHF and acute MI. Whether the same is true for ACE inhibitors in the prevention of ischemic events is not known yet.     

The CARE-HF study (CArdiac REsynchronisation in Heart Failure study): rationale, design and end-points

BACKGROUND: Cardiac resynchronisation is a promising new intervention for patients with heart failure, left ventricular systolic dysfunction and ventricular dyssynchrony. OBJECTIVE: The CARE-HF trial is designed to evaluate the long-term effects of cardiac (atrio-bi-ventricular) resynchronisation on the mortality and morbidity of patients with heart failure due to left ventricular systolic dysfunction already receiving diuretics and optimal medical therapy with ACE inhibitors and beta-blockers (where indicated and tolerated). METHODS AND RESULTS: Approximately 800 patients will be randomised to device therapy or control and followed for a minimum of 18 months. A pragmatic study design has been chosen that does not attempt to conceal allocation from investigators or patients because it is impossible to guarantee maintenance of blinding for the duration of the study. The end-points committee will adjudicate events in a blinded fashion. Since cardiac resynchronisation may alter other aspects of the management of the patient, as would occur in clinical practice, the study should be considered a comparison of strategies rather than simply of a device. The primary end-point is all-cause mortality or unplanned cardiovascular hospitalisation. The study should complete recruitment during 2002 and report in 2004.     

Treatment of High-Risk African American Patients: Left Ventricular Dysfunction, Heart Failure, Renal Disease, and Postmyocardial Infarction

African Americans experience more mortality and morbidity from hypertension-related complications than other racial groups. Although angiotensin-converting enzyme (ACE) inhibitors have clearly been shown to reduce mortality and morbidity in hypertensive white patients with heart failure, renal dysfunction, stroke, and acute myocardial infarction, African American patients have been underrepresented in these trials. The lack of direct evidence of the benefit of ACE inhibitors in these individuals and the suggestion that ACE inhibitors are less efficacious in this group has resulted in a reluctance to use ACE inhibitors in African Americans. However, retrospective analyses in black patients with heart failure and a recent randomized clinical trial in African Americans with renal dysfunction suggest that a regimen based on ACE inhibitors is efficacious in this racial group. Although diuretics remain first-line therapy, data now suggest that ACE inhibitors provide additional benefit and should be considered for use in patients with high-risk complications regardless of race.     

Additive Beneficial Effects of Beta-Blockers to Angiotensin-Converting Enzyme Inhibitors in the Survival and Ventricular Enlargement (SAVE) Study

Objectives. This study assessed whether treatment with a beta-adrenergic blocking agent in addition to the use of the angiotensin-converting enzyme (ACE) inhibitor captopril decreases cardiovascular mortality and morbidity in patients with asymptomatic left ventricular dysfunction after myocardial infarction (MI) and whether the presence of neurohumoral activation at the time of hospital discharge predicts the effects of beta-blocker treatment in these patients.Background. Both beta-blockers and ACE inhibitors have been shown to have beneficial effects in patients with left ventricular dysfunction but no overt heart failure after MI. These patients often have persistent neurohumoral activation at the time of hospital discharge, and one would expect that patients with activation of the sympathetic nervous system derive the most benefit from treatment with beta-blockers. However, beta-blockers are underutilized in this high risk group of patients, and it is unknown whether their beneficial effects are additive to those of ACE inhibitors.Methods. We performed a retrospective analysis of data from the Survival and Ventricular Enlargement (SAVE) study and its neurohumoral substudy. The relations between beta-blocker use at the time of randomization and neurohumoral activation and the subsequent development of cardiovascular events were analyzed by use of Cox proportional hazards models controlling for covariates.Results. After adjustment for baseline imbalances, beta-blocker use was associated with a significant reduction in risk of cardiovascular death (30%, 95% confidence interval [CI] 12% to 44%) and development of heart failure (21%, 95% CI 3% to 36%), but the reduction in recurrent MI (11%, 95% CI 13% to 31%) was not significant. These reductions were independent of the use of captopril. Beta-blockers were not found to have a greater effect in patients with neurohumoral activation at the time of hospital discharge.Conclusions. The beneficial effects of beta-blocker use at the time of hospital discharge in patients with asymptomatic left ventricular dysfunction after MI appear to be additive to those of captopril and other interventions known to improve prognosis. Neurohumoral activation at the time of hospital discharge fails to identify those patients who will derive the greatest benefit from treatment with beta-blockers.(J Am Coll Cardiol 1997;29:229–36)     

Gender differences and practice implications of risk factors for frequent hospitalization for heart failure in an urban center serving predominantly African-American patients

To identify the clinical correlates of recurrent heart failure hospitalization in a large urban hospital serving predominately African-American patients, and to provide further insight into modifiable risks for heart failure readmissions, a retrospective period prevalence review of the records of all adult patients admitted with a primary diagnosis of heart failure (International Classification of Diseases-9 code 428.0) between January and December 1995 was performed.The main outcome was the number of heart failure hospitalizations over 12 months. Twelve hundred patients were identified. Mean age was 64 +/- 16 years, 94% were black, 57% were women, and 40% were > or = 65 years old. Ninety-eight percent had a history of systemic hypertension and 55% had uncontrolled hypertension. Other comorbidities were left ventricular (LV) hypertrophy (64%), coronary artery disease (52%), and tobacco abuse (28%). Sixty-five percent of patients were on angiotensin-converting enzyme (ACE) inhibitors, 51% on calcium antagonists, and 8% on beta blockers. Most patients had suboptimal dosing of ACE inhibitors and there was inappropriate use of calcium antagonists in 56% of patients with moderate or severe systolic dysfunction. Diabetes mellitus and echocardiographic wall motion abnormality were independently associated with frequent admissions for women but not for men. Medication-related increase in heart failure hospitalization was seen for calcium antagonists in patients with severe LV dysfunction (odds ratio 2.24, 95% confidence intervals 1.0 to 5.03; p <0.03). Uncontrolled hypertension, underdosing of ACE inhibitors, and overuse of calcium antagonists in patients with significant LV dysfunction are potential targets for intervention.     

Beta blockers with ACE inhibitors in mild heart failure

ACE inhibitors are standard therapy for treating both symptomatic and asymptomatic patients with left ventricular dysfunction. However, recent clinical trials have shown that beta blockers further reduce mortality in patients with symptomatic heart failure treated with ACE inhibitors. However, the evidence in support of adding beta blockers to ACE inhibitor therapy in patients with asymptomatic left ventricular dysfunction is less certain. The mechanisms by which ACE inhibitors and beta blockers may exert benefit in patients with heart failure are discussed, and studies assessing the association of beta blockade with outcome in patients with mild heart failure receiving ACE inhibitor therapy are reviewed. (c)2000 by CHF, Inc.     

Current perspectives for AT(1)-receptor blockers in the management of heart failure

Despite improvements in therapy, long-term mortality remains high in patients with heart failure and thus there remains a need for new treatment strategies to reduce the burden of mortality and morbidity associated with this condition. AT(1)-receptor blockers represent a rational approach to the management of heart failure, and have been shown to have beneficial effects on heart failure symptoms and exercise tolerance. However, the two outcome trials reported to date have not shown conclusive evidence of improvements in mortality. The potential benefits of AT(1)-receptor blockers in heart failure are currently being investigated in several trials. The CHARM programme (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) is the largest heart failure trial so far. This comprises three trials: CHARM Alternative, in patients with left ventricular dysfunction who are intolerant to ACE inhibitors; CHARM Added, in patients with left ventricular dysfunction who are also receiving ACE inhibitors; CHARM Preserved, in patients with preserved left ventricular systolic function (ejection fraction >40%). The primary end point will be a composite of cardiovascular mortality and hospitalisation for the treatment of heart failure. Other trials are currently investigating the effects of AT(1)-receptor blockers when used as an alternative or in addition to ACE inhibitors. The CHARM programme, together with other studies, should clarify the role of these agents in the management of heart failure.     

Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of the Studies of Left Ventricular Dysfunction

OBJECTIVES: This analysis was performed to assess whether beta-adrenergic blocking agent use is associated with reduced mortality in the Studies of Left Ventricular Dysfunction (SOLVD) and to determine if this relationship is altered by angiotensin-converting enzyme (ACE) inhibitor use. BACKGROUND: The ability of beta-blockers to alter mortality in patients with asymptomatic left ventricular dysfunction is not well defined. Furthermore, the effect of beta-blocker use, in addition to an ACE inhibitor, on these patients has not been fully addressed. METHODS: This retrospective analysis evaluated the association of baseline beta-blocker use with mortality in 4,223 mostly asymptomatic Prevention trial patients, and 2,567 symptomatic Treatment trial patients. RESULTS: The 1,015 (24%) Prevention trial patients and 197 (8%) Treatment trial patients receiving beta-blockers had fewer symptoms, higher ejection fractions and different use of medications than patients not receiving beta-blockers. On univariate analysis, beta-blocker use was associated with significantly lower mortality than nonuse in both trials. Moreover, a synergistic reduction in mortality with use of both a beta-blocker and enalapril was suggested in the Prevention trial. After adjusting for important prognostic variables with Cox multivariate analysis, the association of beta-adrenergic blocking agent use with reduced mortality remained significant for Prevention trial patients receiving enalapril. Lower rates of arrhythmic and pump failure death and risk of death or hospitalization for heart failure were observed. CONCLUSIONS: The combination of a beta-blocker and enalapril was associated with a synergistic reduction in the risk of death in the SOLVD Prevention trial.     

Beta-blockers, angiotensin-converting enzyme inhibitors, and calcium antagonists in treatment of elderly patients with acute myocardial infarction

Administration of beta-blockers reduces mortality among old persons during and after acute myocardial infarction. The American College of Cardiology/American Heart Association guidelines recommend that persons without contraindications to use of beta-blockers should be administered beta-blockers within a few days of myocardial infarction (if administration is not initiated acutely) and that their administration should be continued indefinitely. These guidelines also recommend the use of angiotensin converting enzyme inhibitors in treating persons within the first 24 h of suspected onset of acute myocardial infarction with ST-segment elevation in two or more anterior precordial leads or with congestive heart failure in the absence of significant hypotension or other contraindications to use of ACE inhibitors; and persons during and after convalescence from acute myocardial infarction with congestive heart failure associated with an abnormal left ventricular ejection fraction (LVEF) or with asymptomatic left ventricular systolic dysfunction with a LVEF < 40%. These guidelines state that there are no class I indications for using calcium antagonists after myocardial infarction. If patients have persistent angina pectoris after myocardial infarction despite treatment with beta-blockers and nitrates or hypertension inadequately controlled by other drugs, administration of a nondihydropyridine calcium antagonist such as verapamil or diltiazem should be added to the therapeutic regimen if the LVEF is normal. If the LVEF is abnormal, administration of amlodipine or felodipine should be added to the therapeutic regimen.     

Beta Blocker Therapy After Acute Myocardial Infarction in Patients with Heart Failure and Systolic Dysfunction

The benefit of beta blockade has been well established in acute myocardial infarction for several decades, and its benefit in chronic heart failure has been proven since the early 1990's. Several large retrospective analyses suggested the benefit of beta blockers in post-MI systolic dysfunction. Only recently has the benefit of beta blockers been proven in addition to ACE inhibitors, antiplatelet agents, and reperfusion therapy. In the year 2000, CAPRICORN became the first randomized trial to directly address beta blockade in patients with post-infarction systolic dysfunction. The trial showed a 23% reduction in all-cause mortality with carvedilol, in patients already receiving ACE inhibitors, antiplatelet agents, and reperfusion therapy. This is a review of the literature on the administration of beta blockade in patients after acute myocardial infarction with left ventricular systolic dysfunction, as well as a comment on other current treatment modalities for this subset of patients.