Ramipril for the prevention and treatment of cardiovascular disease

OBJECTIVE: To evaluate the effectiveness of ramipril in the prevention and treatment of cardiovascular disease and determine its need for inclusion on a formulary. DATA SOURCES: A MEDLINE and PubMed database search was conducted (1987-May 2002). Only journals written in the English language were selected for review. DATA EXTRACTION AND STUDY SELECTION: Articles reporting the use of ramipril in humans were evaluated. Emphasis was placed on randomized, controlled trials assessing efficacy. DATA SYNTHESIS: Ramipril is an angiotensin-converting enzyme (ACE) inhibitor that exerts its effects through inhibition of the renin-angiotensin-aldosterone system. It exhibits a safety profile that is similar to that of other ACE inhibitors and is comparable in cost to the majority of the available agents. Clinical trials have proven the effectiveness of ACE inhibitors in the treatment of hypertension, heart failure, and nephropathy. Ramipril, however, is the only ACE inhibitor currently approved for the prevention of cardiovascular events in high-risk patients without evidence of left-ventricular dysfunction or heart failure, based on the results of the HOPE (Heart Outcomes Prevention Evaluation) trial. Whether this effect is specific to ramipril has yet to be proven. This article emphasizes the major trials involving ramipril including the AIRE (Acute Infarction Ramipril Efficacy), REIN (Ramipril Efficacy in Nephropathy), and HOPE trials. CONCLUSIONS: Although similar to other ACE inhibitors in many aspects, it cannot be assumed that the benefits shown with ramipril in the HOPE trial are a class effect. Ongoing trials should help to clarify this matter. Until this time, current evidence justifies the inclusion of ramipril on a formulary.     

A study of the efficacy and safety of irbesartan in combination with conventional therapy, including ACE inhibitors, in heart failure. Irbesartan Heart Failure Group

Because heart failure therapy with angiotensin-converting enzyme (ACE) inhibitors may not be optimal, owing to persistent levels of angiotensin II occurring through incomplete blockade and alternate pathways, the benefit of adding irbesartan, an angiotensin receptor antagonist, to conventional therapy, including ACE inhibitors, was examined. In this multicentre, randomised, double-blind, placebo-controlled study, 109 patients with heart failure (New York Heart Association functional class II and III) and left ventricular ejection fraction (LVEF) < or = 40% received stable doses of ACE inhibitors and diuretics before and throughout the study. Irbesartan was titrated as tolerated to 150 mg once daily in all patients. Exercise tolerance time (ETT), LVEF and clinical status were assessed at baseline and after 12 weeks. Compared with placebo, irbesartan in combination with conventional therapy, including ACE inhibitors, produced favourable trends in ETT and LVEF and was well tolerated in patients with mild to moderate heart failure.     

Reducing readmissions for congestive heart failure

Hospital admission for congestive heart failure is extremely common and quite expensive, although it is frequently preventable. New drugs and therapies have been reported to reduce admissions, decrease morbidity and mortality, and improve the quality of life for these patients. Patients with an ejection fraction less than 40 percent (decreased systolic function) should be treated with medication to improve symptoms and prevent progression of heart failure. Angiotensin-converting enzyme (ACE) inhibitors are a mainstay of treatment in patients who can tolerate them; in patients who cannot take these drugs, angiotensin II receptor blocking agents offer an alternative. Patients with New York Heart Association class II or III heart failure should also receive a beta blocker (metoprolol, carvedilol or bisoprolol). Recent research has shown that treatment with spironolactone improves mortality and hospital readmission rates. An exercise program should also be recommended for all patients with heart failure unless their condition is unstable.     

Neurohumoral Mechanisms in Congestive Heart Failure and the Role of Drugs with Multiple Actions: A Review of Carvedilol

Treatments based on mechanistic models of heart failure, although entirely rational, have not succeeded in reducing mortality. A more holistic view, based on the concept that the neurohumoral environment is a common factor, encompasses all the previous theoretical models and extends them to provide a new approach to treatment. Vasodilators, inotropes, and angiotensin-converting enzyme (ACE) inhibitors all modify hemodynamics favorably and improve cardiac-performance. Only the vasodilators and ACE inhibitors have been shown to reduce morbidity and mortality. With the ACE inhibitors, this effect is related to changes in the levels of circulating angiotensin II and noradrenaline rather than to improved hemodynamics. There is direct evidence that adrenergic receptor density is reduced in chronic heart failure. Vasodilating beta-blockers, like carvedilol, that suppress adrenergic overactivity and reduce preload and afterload, offer a new approach to treatment, but the exploitation of this new opportunity is inhibited by the widely held belief that beta-blockers should be avoided in heart failure. This mistaken view is based on the experience of beta-blockers in angina pectoris and after myocardial infarction, experience that should not exclude their use in patients with congestive heart failure. Vasodilating beta-blockers, introduced at an appropriate dosage, may have an important role to play in the overall management of congestive failure.     

Heart failure: highlights from new consensus guidelines

New guidelines for managing heart failure urge physicians to identify patients likely to benefit from therapy, obtain an echocardiogram to measure the ejection fraction, and, in patients with systolic dysfunction (i.e., an ejection fraction < or = 40%), institute therapy with an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker if at all possible. Digoxin and diuretics can relieve symptoms but do not affect the mortality rate. Spironolactone in low nondiuretic doses may reduce mortality when added to baseline drug regimens. The proper role of angiotensin II receptor blocking agents has yet to be determined.     

Novel therapies in acute and chronic heart failure

Despite past advances in the pharmacological management of heart failure, the prognosis of these patients remains poor, and for many, treatment options remain unsatisfactory. Additionally, the treatments and clinical outcomes of patients with acute decompensated heart failure have not changed substantially over the past few decades. Consequently, there is a critical need for new drugs that can improve clinical outcomes. In the setting of acute heart failure, new inotrops such as cardiac myosin activators and new vasodilators such as relaxin have been developed. For chronic heart failure with reduced ejection fraction, there are several new approaches that target multiple pathophysiological mechanism including novel blockers of the renin-angiotensin-aldosterone system (direct renin inhibitors, dual-acting inhibitors of the angiotensin II receptor and neprilysin, aldosterone synthase inhibitors), ryanodine receptor stabilizers, and SERCA activators. Heart failure with preserved ejection fraction represents a substantial therapeutic problem as no therapy has been demonstrated to improve symptoms or outcomes in this condition. Newer treatment strategies target specific structural and functional abnormalities that lead to increased myocardial stiffness. Dicarbonyl-breaking compounds reverse advanced glycation-induced cross-linking of collagen and improve the compliance of aged and/or diabetic myocardium. Modulation of titin-dependent passive tension can be achieved via phosphorylation of a unique sequence on the extensible region of the protein. This review describes the pathophysiological basis, mechanism of action, and available clinical efficacy data of drugs that are currently under development. Finally, new therapies for the treatment of heart failure complications, such as pulmonary hypertension and anemia, are discussed.     

Angiotensin converting enzyme inhibition. Unique and effective therapy for hypertension and congestive heart failure

Major developments in the use of angiotensin converting enzyme (ACE) inhibition for the treatment of hypertension and congestive heart failure have occurred since the discovery of captopril in June 1975. Early in the past decade, this oral ACE inhibitor was restricted to refractory and severe cases of hypertension. By July 1985, the Food and Drug Administration approved its use not only for all degrees of hypertension but also for the initial treatment of hypertensive patients with uncomplicated disease. New information has confirmed the effectiveness of twice-daily administration (which favorably influences compliance) and the lack of a need to monitor blood or urine levels to assure safety. The renin-mediated and non-renin-mediated mechanisms of action of captopril-induced ACE inhibition have been fully delineated, as has its side effect profile, which does not include various CNS, sympathetic reflex, and metabolic side effects seen with other antihypertensive agents. As the first vasodilator to prove its efficacy in the acute and chronic treatment of congestive heart failure to the FDA, captopril is now widely used throughout the United States. ACE inhibition reduces symptoms, enhances exercise capacity, and favorably affects sodium, water, and potassium homeostasis in patients with heart failure. Also, recent but as yet unconfirmed evidence suggests that ACE inhibition may prolong survival in these patients. The success of captopril, the first oral agent of this class, promises to hold true for other ACE inhibitors (such as enalapril), which have similar activities but differing pharmacokinetic properties and will soon be available for clinical use. Further information on these newer agents is anxiously awaited. In the near future, the clinician will undoubtedly be able to choose from a large selection of ACE inhibitors for the treatment of hypertension and heart failure. Therefore, it is important to learn about any meaningful differences among ACE inhibitors and to contrast this class of agents with older, standard therapies. This learning process is crucial as we assess whether newer agents offer clinical advantages over the old.     

Prescribing of ACE inhibitors for cardiovascular disorders in general practice

Objective: To investigate the prescribing patterns for angiotensin converting enzyme (ACE) inhibitors in the management of patients with heart failure and other cardiovascular disorders as part of a local project on heart failure using information collected from a Primary Care Information Initiative Method: Patients from a large city-centre practice, who were receiving an ACE inhibitor or with a diagnosis of heart failure at the time of the study, were identified from medical records. Details of concomitant medical conditions and drug treatment were also recorded Results: There was extensive prescribing of ACE inhibitors alone, in the treatment of patients with hypertension, where no contraindications for the use of thiazide diuretics or beta-blockers could be identified. ACE inhibitors were being prescribed for post-myocardial infarction patients, but the time for the initiation of treatment was rarely within that recommended in the literature. For those patients diagnosed with heart failure, 60% were not being treated with ACE inhibitors even where there were no contraindications Conclusion: It is clear from the results of this study that overall prescribing patterns for ACE inhibitors are not always in accord with evidence from the literature. These findings provide valuable information for the initiation and development of clinical guidelines for prescribers     

Surviving heart failure: Robert L. Frye lecture

Heart failure is increasing in both incidence and prevalence and is associated with a high mortality. In patients with heart failure, coronary artery disease is the cause for about two thirds. Pathophysiologic changes have been linked to altered muscle function and hemodynamics, elevated neurohormones, and, more recently, cellular mechanisms, including apoptosis. Standard triple therapy for symptomatic heart failure consists of an angiotensin-converting enzyme (ACE) inhibitor, digoxin, and a diuretic. In patients with severe heart failure, spironolactone should be added. In large clinical trials, ACE inhibitors, spironolactone, and beta-blockers have reduced mortality. Other drugs may be helpful in the treatment of heart failure. Amiodarone is the antiarrhythmic drug of choice in patients with symptomatic arrhythmias and also has a role in the treatment of dilated cardiomyopathy. Angiotensin II receptor blockers are being compared with ACE inhibitors and appear promising. Newer agents being tested include antagonists to endothelin and tumor necrosis factor. Overall, it is clear that polypharmacy is the standard of care for patients with heart failure. A future challenge will be to prevent heart failure from occurring.     

Native mitral valve regurgitation. Proactive management can improve outlook.

Mitral regurgitation is a common valvular abnormality that can result in substantial morbidity. Primary care physicians should maintain a high index of suspicion for this disorder, especially in patients with symptoms of heart failure. The paramount concern is early identification of patients with mitral regurgitation and prompt referral to a cardiologist when symptoms occur or if evidence of ventricular enlargement or reduction in ejection fraction is found. Echocardiography is an invaluable tool in determining the severity of regurgitation, the integrity of the mitral valve apparatus, the extent of left ventricular enlargement, and the ejection fraction. Although no standard medical treatment has been established for mitral regurgitation, use of ACE inhibitors is appropriate. Patients presenting with severe, acute mitral regurgitation from papillary muscle rupture should be evaluated for ischemia and treated expediently. The preferred operative procedure in patients with severe mitral regurgitation and left ventricular dysfunction is mitral valve repair, if possible, or mitral valve replacement with posterior chordal preservation, if feasible.     

Do all patients with coronary artery disease benefit from angiotensin converting enzyme inhibitors?

Cumulative evidence supports the use of angiotensin-converting enzyme (ACE) inhibitors for stable coronary artery disease in patients with and without heart failure. The dose and unique properties of ACE inhibitors, trial data, differences in trial design and demographics, may all contribute to variable responses in clinical outcomes. Pending direct comparator clinical trials between a tissue ACE inhibitor vs a plasma ACE inhibitor, evidence indicates that both ramipril and perindopril can be recommended for secondary risk prevention.     

Valsartan in chronic heart failure

OBJECTIVE: To evaluate the evidence for valsartan in the treatment of heart failure and determine its need for formulary inclusion. DATA SOURCES: OVID and PubMed databases were searched (1983-June 2004) using the key words angiotensin-receptor blocker, heart failure, valsartan, Diovan, and angiotensin-converting enzyme inhibitor. Only English-language literature was selected. STUDY SELECTION AND DATA EXTRACTION: Pharmacology and pharmacokinetic evaluations for valsartan were selected. Prospective, randomized clinical trials investigating the use of valsartan and other angiotensin-receptor blockers (ARBs) in chronic heart failure were evaluated. DATA SYNTHESIS: Valsartan, a selective antagonist for angiotensin receptor subtype 1, is the first ARB to be approved for use in chronic heart failure. Clinical trial data support valsartan as an alternative to angiotensin-converting enzyme (ACE) inhibitors in ACE inhibitor-intolerant patients with chronic heart failure. Valsartan is generally well tolerated, with renal impairment, elevated serum creatinine and potassium levels, and dizziness being the most common adverse effects; consequently, patients experiencing those adverse events while taking ACE inhibitors are likely to experience them with valsartan. Although further study is needed, differences in effectiveness among races may exist with use of valsartan; however, at this time, valsartan is recommended as an alternative to ACE inhibitors regardless of race. Candesartan and losartan have been studied in similar settings. Candesartan's data support its use in heart failure; however, losartan's data have been less consistent. CONCLUSIONS: Valsartan is a safe and effective alternative for heart failure patients intolerant of ACE inhibitors. Valsartan has not been shown to be safe and effective when used in combination with ACE inhibitors.     

Effects of renin-angiotensin system inhibition on end-organ protection: can we do better?

BACKGROUND: The renin-angiotensin system (RAS) is a major regulator of blood pressure (BP) and vascular response to injury. There is increasing evidence that RAS inhibition may provide end-organ protection independent of BP lowering. Two drug classes directly target angiotensin II through complementary mechanisms. Angiotensin-converting enzyme (ACE) inhibitors block the conversion of angiotensin I to the active peptide angiotensin II and increase the availability of bradykinin. Angiotensin receptor blockers (ARBs) selectively antagonize angiotensin II at AT 1 receptors and may also increase activation of the AT 2 receptor and modulate the effects of angiotensin II breakdown products. OBJECTIVES: This paper presents an overview of clinical data supporting the use of RAS inhibitors (ACE inhibitors and ARBs) as monotherapy or combination therapy based on the known role of the RAS in BP regulation and the vascular response to injury, and considers the implications of the data for future treatment. METHODS: Relevant experimental and clinical studies were identified by searching MEDLINE (1969-June 30, 2007) using the primary search terms renin-angiotensin system, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and dual RAS blockade. Trials included in the review were large (>200 patients), prospective, randomized controlled studies evaluating the effect of RAS inhibition on end-organ protection in various high-risk populations. RESULTS: Eleven clinical trials each were identified that evaluated the effect of ACE-inhibitor and ARB monotherapy on end-organ protection. Five trials were identified that evaluated the effects of combination therapy with an ACE inhibitor and an ARB compared with treatment with either agent alone in different patient populations using different end points. In hypertensive patients with type 2 diabetes and microalbuminuria, combination ACE-inhibitor/ARB therapy resulted in better BP control than either agent alone (mean difference, 11.2 mm Hg systolic [P = 0.002], 5.9 mm Hg diastolic [P = 0.003]), as well as greater reductions in microalbuminuria (mean difference in albumin:creatinine ratio, 34%; P = 0.04). Compared with monotherapy, dual RAS inhibition reduced the occurrence of a doubling of the serum creatinine concentration or end-stage renal disease by 60% to 62% in patients with nondiabetic renal disease (P = 0.018 vs ACE inhibitor alone; P = 0.016 vs ARB alone). A recently published study reported a nonsignificant benefit for combination therapy over monotherapy only in a subset of hypertensive patients with high levels of microalbuminuria at baseline (58.1% vs 43.4% reduction, respectively). In patients with heart failure and left ventricular ejection fraction 相似文献   

A review of the current evidence for the use of angiotensin-receptor blockers in chronic heart failure

Angiotensin-converting enzyme (ACE) inhibitors have a central role in the management of heart failure, reflecting the contribution of the renin-angiotensin-aldosterone system to the pathophysiology of the condition. Angiotensin-receptor blockers (ARBs) bind specifically to the angiotensin type 1 receptor and may offer further benefits compared with ACE inhibitors. Candesartan, losartan and valsartan have all been evaluated in large clinical outcome trials in heart failure. They display marked differences in pharmacokinetics and receptor-binding properties that may contribute to observed differences in outcome. ELITE II found no significant difference in outcome with losartan as compared with captopril. In the Val-Heft trial, valsartan reduced heart failure hospitalisations when added to conventional therapy including an ACE inhibitor in most patients, but had no effect on mortality. The CHARM programme showed that candesartan reduced morbidity and mortality in heart failure with reduced systolic function, both when added to ACE inhibitor therapy or when used as an alternative in patients who are intolerant to ACE inhibitors. Moreover, the CHARM-preserved study suggested that candesartan is beneficial in patients with heart failure and preserved left-ventricular systolic function. A growing body of evidence show that ARBs are an important contribution to the pharmaceutical management of patients with heart failure.     

Drug and drug-device therapy in heart failure patients in the post-COMET and SCD-HeFT era

Reduced left ventricular ejection fraction and heart failure are the most important risk factors for sudden cardiac death. Recent trials have contributed to the knowledge base of critical therapies for the treatment of left ventricular systolic dysfunction and heart failure as it relates to arrhythmic and sudden cardiac death. Both pharmacologic and device therapies can reduce sudden cardiac death. The trials discussed in this paper have identified the pharmacologic and device interventions that are likely to improve the length and quality of life of the patient with left ventricular dysfunction and reduce the risk of sudden cardiac death. The mortality and anti-arrhythmic effects of angiotensin-converting enzyme inhibitors and beta-blockers have been confirmed in large-scale controlled clinical heart failure trials. Recent trials have evaluated which agents are most effective and which patients will derive the most benefit from device therapy in terms of the reduction in the risk of sudden cardiac death and in the amelioration of heart failure. The recent data from the Carvedilol or Metoprolol European Trial (COMET) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) are discussed as the latest in the series of landmark studies that have shaped the current approaches to treating patients with heart failure and that have altered the heart failure treatment paradigm.     

RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection

Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, target organ damage, and ultimately to myocardial infarction, heart failure, stroke or death. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT(1)-receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Both classes of agent can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. Such a reduction has been shown mainly for ACE inhibitors in patients with coronary artery disease, but recent studies revealed that ARBs are not inferior in this respect. However, no such data are currently available on the combination of these drugs. Both ACE inhibitors and ARBs have been shown to reduce target organ damage in organs such as the kidney, brain and heart, and to decrease cardiovascular mortality and morbidity in patients with congestive heart failure. Experimental data point to an influence of ACE inhibitors and ARBs on the number and function of endothelial progenitor cells revealing additional mechanisms of action of these drugs. The VALIANT trial has shown equivalent effects of ARB valsartan and the ACE-inhibitor captopril in patients post myocardial infarction, but the dual RAS-blockade, compared to monotherapy, did not further reduce events. In secondary prevention, the most-recently published ONTARGET study provides evidence that on top of a better tolerability AT(1)-receptors antagonists are equal to ACE inhibitors in the prevention of clinical endpoints like cardiovascular mortality and morbidity, myocardial infarction and stroke. The combined RAS blockade, however, achieved no further benefits in vascular high-risk patients and was associated with more adverse events. In chronic heart failure, ValHeFT and CHARM-ADDED have shown that combined RAS inhibition with ACE inhibitor and valsartan or candesartan reduced morbidity and mortality in certain patient subgroups. Accumulating evidence also points to benefits of the combination therapy in individuals with proteinuric nephropathies. In conclusion, while combined RAS-inhibition is not generally indicated in patients along the cardio-reno-vascular continuum, it has already proven to be effective in heart failure patients with incomplete neuroendocrine blockade. In secondary prevention, monotherapy with either RAS inhibitor is equally efficacious. Furthermore, novel pharmacologic agents such as renin inhibitors may prove useful in preventing common side effects of RAS blockade such as angiotensin escape and AT(1)-receptor upregulation, giving clinicians additional therapeutic tools to optimally treat the individual patient.     

Effect of angiotensin-converting enzyme therapy on QT interval dispersion

Patients with chronic heart failure (CHF) have an increased risk for sudden death. This increased risk has been associated with increased QT dispersion (QTd), a reflection of the heterogeneity in ventricular repolarization. Angiotensin-converting enzyme (ACE) inhibitors have been reported to decrease heart size as well as decreasing morbidity and mortality in moderate-to-severe CHF. The aim of this study was to determine if ACE therapy is associated with a decrease in QTd, a marker for increased electrical instability. Ninety-seven patients were evaluated. The normalized QTd after 2 months of ACE therapy decreased from 16 +/- 4 to 12 +/- 3, a 25% reduction in dispersions. QTd also decreased from 61 +/- 14 to 47 +/- 12 (P < .001) and QTc dispersions decreased from 71 +/- 18 to 52 +/- 14 (P < .001). After 2 months of ACE inhibitor therapy, heart rate slowed significantly (RR intervals 765 +/- 198 before and 838 +/- 186 after ACE). There was a negative correlation between ejection fraction and QTd (r = -0.8; P < .001). The study also found no correlation between ACE level, percent converting enzyme inhibition, and QTd. The effects of ACE therapy appear early on in terms of repolarization changes. The reduction in QTd may explain the reduced sudden death mortality in patients with heart failure who are treated with ACE inhibitor therapy.     

The role of losartan in the management of patients with heart failure

BACKGROUND: Heart failure places a burden on patients and health care systems worldwide. Although the advent of angiotensin-converting enzyme (ACE) inhibitors markedly improved management of this chronic disorder, treatment is still not optimal, and morbidity and mortality remain high. OBJECTIVE: This review summarizes existing data on losartan, an angiotensin II (AII)-receptor antagonist, and compares its potential role with that of ACE inhibitors in the management of patients with heart failure. METHODS: Relevant primary studies and review articles were identified through a MEDLINE search of the English-language literature for the past 5 years and through examination of the reference lists of the articles so identified. Search terms included, but were not limited to, angiotensin-converting enzyme inhibitors, angiotensin II-receptor antagonists, and losartan. RESULTS: Preclinical and clinical studies of losartan have demonstrated consistent hemodynamic effects (via selective antagonism of the AII type 1 receptor) and a safety profile similar to that of placebo (presumably a reflection of the selective approach to AII blockade). In addition, large-scale end-point studies have shown losartan to have comparable efficacy to ACE inhibitors on a number of morbidity and mortality measures. CONCLUSIONS: There is strong evidence for the broad applicability of AII-antagonists in heart failure and for the use of AII-antagonists in the treatment of a broader population of patients with heart failure, not only those who are unable to tolerate treatment with ACE inhibitors.     

Recent developments in the design of angiotensin-converting enzyme inhibitors

Orally-active angiotensin-converting enzyme inhibitors are rapidly establishing themselves in the therapy of hypertension and congestive heart failure. Concerted efforts in a number of laboratories have now led to the discovery or synthesis of an unparalleled variety of potent inhibitors. The manner in which several of these inhibitors bind to ACE is beginning to be understood. It is hoped that some of the insights to be derived from the SAR and structural studies done with ACE inhibitors will be applicable to other enzyme targets as well. The success of ACE inhibitors as pharmacological tools and in the clinic will also quite certainly encourage future efforts to develop new enzyme inhibitor approaches to drug therapy.     

ACE Inhibition in secondary prevention: are the results controversial?

Summary Results from the HOPE and EUROPA trials showed that ACE inhibitors lower cardiovascular mortality of patients with atherosclerosis and preserved left ventricular function. However, despite apparently adequate study design, the recently conducted PEACE trial detected no benefit of an additional ACE inhibitor treatment in patients with coronary artery disease and no heart failure with respect to cardiovascular risk reduction. One of the main reasons for this discrepancy might be the lower cardiovascular baseline risk of the PEACE study population, which was more intensively treated with lipid lowering drugs and myocardial revascularization prior to enrollment than patients in HOPE or EUROPA. Another reason for the negative results of PEACE might be substance-specific differences between individual ACE inhibitors (trandolapril in PEACE, ramipril in HOPE, and perindopril in EUROPA) in their clinical efficacy to reduce cardiovascular end-points. The PEACE trial did not achieve the originally projected sample size and the addition of a soft end-point of revascularization has not been helpful. While the results from the PEACE trial suggest that low-risk patients with coronary artery disease and with preserved left ventricular function who receive intensive standard therapy including lipid lowering and coronary revascularization may not benefit from additional ACE inhibition therapy, this conclusion should be made with caution. A number of reasons, other than drug treatment efficacy, may explain the neutral results in the PEACE trial. Further studies are needed to try to resolve this issue. In the meantime, the overwhelming data still support the use of ACE inhibitors in patients with coronary artery disease with preserved left ventricular function.