Acute Infarction Ramipril Efficacy Research Articles

Long-term survival benefit of ramipril in patients with acute myocardial infarction complicated by heart failure

AimsACE inhibition reduces mortality and morbidity in patients with heart failure after acute myocardial infarction (AMI). However, there are limited randomised data about the long-term survival benefits of ACE inhibition...

Ramipril

Ramipril

Thromboembolism and Antithrombotic Therapy in Patients With Heart Failure in Sinus Rhythm

Heart failure (HF) represents a major and growing public health problem because of its prevalence, incidence, morbidity, mortality, and economic costs. The prevalence of HF is 2% to 3% of the general population.1 Five million Americans are affected, with >550 000 cases diagnosed each year.2 The mortality rate from severe HF remains >60% within 5 years of diagnosis, and 50% of hospitalized patients with HF require readmission within 6 months of discharge. In the US estimated costs amount to > $35 billion per year.3 Although several therapies (eg, β-blockers, angiotensin-converting enzyme [ACE] inhibitors, and cardiac resynchronization therapy) have been proven effective in improving HF outcomes, many unanswered questions about optimal treatment remain. One area of ongoing uncertainty is the appropriate role for antithrombotic therapy in patients with HF. Observational data suggest that patients with HF have an increased venous thromboembolism (VTE) risk (deep venous thromboembolism [DVT], pulmonary embolism [PE], peripheral arterial thromboembolism, and stroke).4 These epidemiological findings are supported by multiple mechanisms that can contribute to a hypercoagulable state in patients with HF. Despite this increased risk of VTE, the role of antithrombotic therapy remains unclear. In this article, we provide an overview of epidemiology, pathophysiology, clinical trial data, and therapeutic recommendations for prevention of thromboembolism in HF. We searched PubMed for articles published between 1958 and 2010 using the following search terms: epidemiology of heart failure , thromboembolism and heart failure , thrombogenesis and heart failure , anticoagulation in heart failure , antiplatelet agent and heart failure , aspirin and heart failure , bleeding risk and anticoagulation , and aspirin and angiotensin-converting enzyme inhibitors . We also studied abstracts from national and international cardiovascular meetings to identify unpublished studies using the key words anticoagulation and dilated cardiomyopathy . Data from published observational studies and secondary …

Determining the cost-effectiveness of preventing cardiovascular disease: Are estimates calculated over the duration of a clinical trial adequate?

Economic analyses of randomized clinical trials often focus only on the results that are observed during the study. However, for many preventive interventions, associated costs and benefits will accrue over a patient's remaining lifetime. To determine the importance of the chosen time horizon, the cost-effectiveness (C/E) of ramipril therapy was calculated and compared in the Heart Outcomes Prevention Evaluation (HOPE), the Microalbuminuria, Cardiovascular, and Renal Outcomes in HOPE (MICRO-HOPE) and the Acute Infarction Ramipril Efficacy (AIRE) study versus the entire life expectancy (L/E) of potential patients. The Cardiovascular Disease Life Expectancy model, a validated Markov model, was calibrated to accurately forecast the results of each trial. These results were then extrapolated over the remaining L/E of hypothetical patients 55 to 75 years of age. The predicted change in L/E and associated direct health care costs for Canadians were calculated and discounted 3% annually. In HOPE, the forecasted increased L/E averaged 0.06 years during the five-year study versus 1.3 years over the remaining years of L/E. The associated C/E of ramipril was $15,000 per year of life saved (YOLS) over the study duration and $8,500/YOLS over the remaining lifetime. For hypothetical patients, the C/E of ramipril over 4.5 years ranged from $6,700/YOLS to more than $58,300/YOLS and was lowest among elderly men. When the remaining L/E was considered, the C/E of ramipril was similar for men and women of all ages, ranging from $8,100/YOLS to $10,200/YOLS. The analyses of MICRO-HOPE and AIRE provided similar results. The estimated efficacy and associated C/E of ramipril in HOPE, MICRO-HOPE and the AIRE study is extremely sensitive to the selected time horizon. Economic analyses beyond the duration of randomized clinical trials are required to fully evaluate the potential costs and benefits of long-term preventive therapies.

Prevention of cardiovascular events in end-stage renal disease: Results of a randomized trial of fosinopril and implications for future studies

Cardiovascular events (CVEs) are the leading cause of death in chronic hemodialysis patients. Results of trials in non-end-stage renal disease (ESRD) patients cannot be extrapolated to patients with ESRD. It is critical to test cardiovascular therapies in these high-risk patients who are usually excluded from major cardiovascular trials. The study objective was to evaluate the effect of fosinopril on CVEs in patients with ESRD. Eligible patients were randomized to fosinopril 5 mg titrated to 20 mg daily (n=196) or placebo (n=201) plus conventional therapy for 24 months. The primary end point was combined fatal and nonfatal first major CVEs (cardiovascular death, resuscitated death, nonfatal stroke, heart failure, myocardial infarction, or revascularization). No significant benefit for fosinopril was observed in the intent to treat analysis (n=397) after adjusting for independent predictors of CVEs (RR=0.93, 95% confidence interval (CI) 0.68-1.26, P=0.35). The per protocol secondary supportive analysis (n=380) found a trend towards benefit for fosinopril (adjusted RR=0.79 (95% CI 0.59-1.1, P=0.099)). In the patients who were hypertensive at baseline, systolic and diastolic blood pressures were significantly decreased in the fosinopril as compared to the placebo group. After adjustment for risk factors, trends were observed suggesting fosinopril may be associated with a lower risk of CVEs. These trends may have become statistically significant had the sample size been larger, and these findings warrant further study.

Ramipril for the prevention and treatment of cardiovascular disease.

To evaluate the effectiveness of ramipril in the prevention and treatment of cardiovascular disease and determine its need for inclusion on a formulary. 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. 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. 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.

Angiotensin II and trials of cardiovascular outcomes

Proven cardiovascular benefit from angiotensin-converting enzyme (ACE) inhibition is a cornerstone of evidence-based medicine. The first study to show dramatic benefits from ACE inhibition was the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS-I), in which a 31% decrease in the rate of death was observed in patients with severe heart failure at the end of 1 year of enalapril treatment (p = 0.001). This result led to large long-term studies—including Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), Trandolapril Cardiac Evaluation (TRACE), and Study of Left Ventricular Dysfunction (SOLVD)—which verified that ACE inhibition decreases heart failure, myocardial infarction (MI), and mortality, and that striking benefit could be observed within 30 days. Short-term studies of patients in the acute phase of a heart attack verified that ACE inhibition provided rapid benefits. A meta-analysis of short-term (up to 8 weeks) studies of ACE inhibition (including CONSENSUS-II, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico [GISSI]-3, International Study of Infarct Survival [ISIS]-4, and the Chinese Captopril Study [CCS]-1) demonstrated that post-MI risk was reduced by 10% within the first day of treatment. The immediacy of the benefit suggested that ACE inhibition not only improved cardiovascular function in failing hearts but also affected important mechanisms in patients without overt heart failure. Effects on more general mechanisms of heart disease suggested that patients with problems other than hypertension or heart failure might benefit from ACE inhibitors. The Heart Outcomes Prevention Evaluation (HOPE) study investigated the hypothesis that ACE inhibition would confer benefits to patients who were at high risk for cardiovascular events, but who were without left ventricular dysfunction or heart failure. Long-term reductions in MI, stroke, cardiac arrest, and heart failure, as well as improvements in mortality, were observed in this population after treatment with ACE inhibitors. Substudies of the HOPE study revealed that ACE inhibition reduced progression of atherosclerosis and improved myocardial remodeling. Taken together, these studies provide evidence that supports treatment of a broad population of patients at risk for cardiovascular events with ACE inhibitors. The next step is to combine ACE inhibition with other treatments to maximize patient benefit. The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) will compare the efficacy of an ACE inhibitor (ramipril) with an angiotensin receptor blocker (telmisartan), and determine whether these treatments in combination will further reduce morbidity and mortality from cardiovascular disease.

INTRODUCTION

This issue addresses the use of angiotensin-converting enzyme (ACE) inhibition in acute myocardial infarction (AMI), and particularly the use of zofenopril, which has been validated in the SMILE (Survival of Myocardial Infarction Long-term Evaluation) study, a large, randomized, placebo-controlled trial in patients within 24 h of the onset of an anterior AMI and not eligible for thrombolytic therapy. Dr Ambrosioni summarizes this data and also the comparison of zofenopril tested against lisinopril, the only ACE inhibitor currently licensed for use early in AMI [as a result of the GISSI-3 (Gruppo Italiano per lo Studio della Streptochinasi nell'infarto Miocardico) study]. Zofenopril was found to be as effective as lisinopril, and possibly with greater safety in the rather slower (5 day) titration regimen tested in the SMILE study. The safety of this regimen is now confirmed in a new study (SMILE-2) which has tested zofenopril in a large population of patients with AMI in any location, who also received thrombolytics. The biology of angiotensin, particularly the newer information on the effects of angiotensin-II (A-II) blockers on the vasculature and on smooth muscle growth, and the differing actions of ACE inhibitors and A-II blockers (ARBs) is reviewed by George Ertl from Würzburg, while Thomas F. Lüscher from Zürich discussed the work of his group on the interplay of A-II, bradykinin and nitric oxide on endothelial function. These two papers underline the sound theoretical and experimental background for these extended actions of angiotensin, and hence the clinical importance of reducing the impact of angiotensin in clinical states with overt or potential left ventricular dysfunction (LVD) such as heart failure or myocardial infarction. The experimental basis for the use of ACE inhibitors in AMI is reviewed by Scott Solomon from the Harvard team of Mark Pfeffer, whose pioneering work demonstrated the benefit of ACE inhibitors in experimental infarction. There has been considerable debate about whether ACE inhibitors should be given early to most patients with infarction, followed by longer term treatment only in those with LVD, or whether the initial treatment should also only be given to the latter group. The recently released preliminary results of the HOPE (Heart Outcomes Prevention Evaluation) suggest that ACE inhibitors are also beneficial in long-term use in high risk patients without LVD or hypertension. This may therefore encourage the practice [tested in ISIS-4 (Fourth International Study of Infarct Survival) and GISSI-3] of using ACE inhibition in a wider group of patients than just those with LVD [as in the SAVE (Survival and Ventricular Enlargement), AIRE (Acute Infarction Ramipril Efficacy) or TRACE (Trandolapril Cardiac Evaluation) studies]. Finally, Edward Frolich, from the Ochsner Medical Foundation in New Orleans reviews the latest information on the importance of LV hypertrophy and reduced LV compliance for the genesis of so-called diastolic heart failure, an increasingly important source of disability, especially in the elderly. ACE inhibition is a particularly effective strategy in reducing LV hypertrophy. At first sight it might appear dangerous, particularly in AMI, to block the action of the sympathetic and renin-angiotensin systems. Harris pointed out many years ago (1) that the activation of these powerful reflexes by baroreceptor sensing of poor LV function, is an inappropriate evolutionary hangover from the days when an inappropriately low blood pressure was a result of bleeding. Reflexes designed to aid survival after accident or trauma are harmful in the setting of LV damage. We older clinicians have been fascinated to witness the development of the widening clinical applications of ACE inhibition over the last three decades.

Manipulation of the renin-angiotensin system.

Since the initial description of angiotensin II–mediated hypertension >40 years ago, basic and clinical investigations of the renin-angiotensin system (RAS) have resulted in a broader understanding of cardiovascular pathophysiology and significant advances in therapy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists are now widely prescribed for the treatment of hypertension and left ventricular (LV) dysfunction; more recently, the aldosterone receptor antagonist, spironolactone, has proven beneficial in severe heart failure. This article will focus on our current understanding of the RAS and how pharmacological manipulation of this system can improve clinical outcomes in patients with cardiovascular disease. ### Pathophysiological Rationale for RAS Manipulation Renin is released by juxtuloglomerular cells in the kidney in response to renal hypoperfusion, decreased sodium delivery, and sympathetic activation (Figure 1). Angiotensinogen produced by the liver is cleaved by renin to yield the inactive decapeptide angiotensin I. Circulating angiotensin I is, in turn, converted to angiotensin II in the lungs by the action of ACE. ACE, or kininase II, also plays a key role in the kallikrein-kinin system by cleaving bradykinin to inactive peptides. In addition to the hormonal effects of circulating angiotensin II, all of the necessary components of the RAS exist in several organs and tissues, including the heart, kidneys, and vasculature. Figure 1. Pathophysiology of the RAS. SMC indicates smooth muscle cell. Angiotensin II exerts its actions in target organs and tissues by binding to both angiotensin II type 1 and 2 (AT1 and AT2) receptors, although adverse effects in humans seem to be mediated primarily by the AT1 receptor (Figure 1). In the kidney, angiotensin II causes sodium and water retention and efferent arteriolar vasoconstriction. Constriction of the systemic vasculature by angiotensin II causes hypertension, whereas coronary vasoconstriction may cause myocardial ischemia and arrhythmias. Angiotensin II–stimulated secretion of aldosterone by the adrenal cortex and arginine …

Ramipril reduces QT dispersion in patients with acute myocardial infarction and heart failure

In a cohort of 67 patients from the Acute Infarction Ramipril Efficacy study, we showed that ramipril therapy was associated with a significant reduction in QT dispersion over a 2-month period after acute myocardial infarction. This reduction of ventricular repolarization inhomogeneity indicates an antiarrhythmic effect and may be an important additional mechanism for the reduced all-cause mortality and sudden death incidence achieved with angiotensin-converting enzyme inhibition after acute myocardial infarction.

β Blocker treatment and other prognostic variables in patients with clinical evidence of heart failure after acute myocardial infarction: evidence from the AIRE study

ObjectivesTo examine clinical outcomes associated with optional β blockade in a population of patients with evidence of heart failure after myocardial infarction.Design and patientsData from the acute infarction ramipril efficacy...

Cost-effectiveness analysis of ramipril in heart failure after myocardial infarction. Economic evaluation of the Acute Infarction Ramipril Efficacy (AIRE) study for Germany from the perspective of Statutory Health Insurance.

Data from the Acute Infarction Ramipril Efficacy (AIRE) study were used in a cost-effectiveness analysis to determine the incremental cost per life-year gained (LYG) when the ACE inhibitor ramipril was added to conventional treatment in patients with heart failure after acute myocardial infarction. In the AIRE trial, the addition of ramipril significantly lowered rates of total mortality and rehospitalisation due to heart failure. The cost-effectiveness analysis was conducted from the perspective of the Statutory Health Insurance (SHI) provider in Germany. A modelling approach was used which was based on secondary analysis of existing data, and costs were those incurred by SHI (i.e. expenses of SHI). In the base-case analysis, average case-related expenses of SHI were applied and LYG were quantified by the method of Kaplan and Meier. The incremental cost-effectiveness ratios of ramipril varied between 2500 and 8300 deutschmarks (DM) per LYG (1993 values for inpatient and 1995 values for outpatient treatment; DM1 approximately $US0.70), according to the treatment periods of 3.8 years and 1 year, respectively. In the sensitivity analysis, the robustness of the model and its results was shown when the extent of influence of different model variables on the base-case results was investigated. First, survival probability and LYG were estimated according to the Weibull method. Second, the dependency of the target variable (i.e. incremental cost per LYG) on random variables was described in a simulation. Third, the influence of the model variables on the target variable was quantified using a deterministic model. The variance of the target variable was broad and the hospitalisation impact of adding ramipril to conventional treatment was an independent variable with much greater influence on the target variable than the parameter of clinical effectiveness, i.e. the number of LYG. Results of this evaluation showed that ramipril has a favourable incremental cost-effectiveness ratio for the treatment of heart failure in post myocardial infarction patients and can be considered an economical therapeutic agent from the perspective of SHI (third-party payer) in Germany.

Is preventive medicine responsible for the increasing prevalence of heart failure?

infarction. Risk factor~, responsible for the development and progression of atherosclerotic coronary artery disease are well known. The factors that predispose patients with coronary disease to the development of heart failure are not clear, but recurrent infarction is a major factor. Hoffman and colleagues 3 studied all patients with documented coronary artery disease eligible for the multicentre, randomised, controlled Coronary Artery Surgery Study to find out which modifiable cardiovascular risk factors predispose to heart failure. At the 12-year follow-up, the cumulative incidence of heart failure was 20.6%. Cigarette smoking, high body-mass index, myocardial infarction during follow-up, older age, female sex, and baseline left-ventricle dysfunction were risk factors for the development of heart failure. Other factors have also been implicated such as: myocardial wall stress, uncorrected myocardial ischaemia, persistent coronary artery occlusion, and neurohormonal (particularly renin-angiotensin and sympathetic) overactivity. The Framingham study ~ also identified the following independent risk factors for the development of heart failure: low vital capacity, rapid heart rate, diabetes, cardiac enlargement, high body-mass index (in women), high serum cholesterol (in men aged <65 years), cigarette smoking, proteinuria, and high haematocrit. These risk factors were in addition to hypertension, evidence of leftventricle hypertrophy on electrocardiogram (ECG), and coronary disease. The findings of this study would suggest that conventional strategies for secondary prevention of coronary artery disease may work as primary preventive measures of heart failure. There is evidence showing this effect in a number of settings.

Follow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension (AIREX) Study

In the Acute Infarction Ramipril Efficacy (AIRE) Study, the effect of angiotensin-converting-enzyme (ACE) inhibition on the survival of patients with clinical heart failure after acute myocardial infarction (AMI), was assessed. At an average follow-up time of 15 months after randomisation, all-cause mortality was reduced from 22.6% (placebo group) to 16.9% (ramipril group) representing an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (95% CI 11-40%; p = 0.002). Our aim in this study was to assess the long-term (3 years after the AIRE Study closed) magnitude, duration, and reliability of the survival benefits observed after treatment with ramipril (target dose 5 mg twice a day) when compared with placebo. We investigated the mortality status of all 603 patients recruited from the 30 UK centres involved in the AIRE Study. Through government records we were able to confirm the death or survival of all 603 patients exactly 3 years after the close of the AIRE Study. Follow-up was for a minimum of 42 months and a mean of 59 months. The average duration of treatment with masked trial medication was 13.4 months for placebo and 12.4 months for ramipril. By 0000 h March 1, 1996, death from all causes had occurred in 117 (38.9%) of 301 patients randomly assigned placebo and 83 (27.5%) of 302 patients randomly assigned ramipril, representing a relative risk reduction of 36% (95% CI 15-52%; p = 0.002) and an absolute reduction in mortality of 11.4% (114 additional 5-year survivors per 1000 patients treated for an average of 12.4 months). Our data provide robust evidence that administration of ramipril to patients with clinically defined heart failure after AMI results in a survival benefit that is not only large in magnitude, but also sustained over many years.

How ACE inhibitors reduce death from myocardial infarction: hypotheses from the AIRE study. Acute Infarction Ramipril Efficacy study.

Doctors treat patients, not populations. 'Evidence-based' practice is essential but extrapolation to the individual patient is always necessary and this fact is well illustrated by data from trials of ACE inhibitors post-myocardial infarction. In the AIRE (Acute Infarction Ramipril Efficacy) study, 2,006 patients with some evidence of heart failure, even if transient, after a myocardial infarction, were randomised to receive oral ramipril or placebo in addition to standard treatment. Follow-up was for a minimum of six and an average of 15 months. The risk reduction in total mortality was 27% (95% CI 11-40%; p = 0.002); approximately 40 lives might be expected to be saved for every 1000 patients treated for one year. Benefit was apparent within weeks of starting treatment. Additional data from the AIRE study are considered in relation to the findings of other mortality trials. It is argued that ACE inhibitors offer most to those patients with impaired left ventricular function through a mechanism not related to the prevention of myocardial re-infarction.

Who should be treated with angiotensin-converting enzyme inhibitors after myocardial infarction?

Angiotensin-converting enzyme (ACE) inhibitors are now established drugs in the treatment of hypertension and heart failure. However, their use in patients after a myocardial infarction has occurred remains controversial. The major clinical question regarding ACE inhibitors is whether they should be given to all patients immediately after thrombolysis or whether their use should be restricted to a particular subgroup. This question has now been addressed in several large-scale trials of mortality after myocardial infarction, and no important new information seems likely to emerge on the issue. Clinicians must therefore decide what their practice will be on the basis of data that are currently available. The authors of the recently published Gruppo italiano per lo Studio delta Sopravvlvenza nell' infarcto Miocardico (GISSI-3) and Fourth International Study of Infarct Survival (ISIS-4) mega-trials advocate a policy of widespread and early use of ACE inhibitors in all patients after myocardial infarction occurs. However, the small mortality benefit observed from use of ACE inhibitors in these studies lacks certainly and may prove difficult to reproduce in the general population of patients who have had an infarct outside the setting of a trial. Although patients were essentially not selected apart from the exclusion of those with marked hypotension, the low 6-month and 1-year mortality figures indicate "selection" compared with the typical population of patients who have had a myocardial infarction. Furthermore, a significant long-term mortality benefit was not observed with the short-term (4- to 6-week) use of ACE inhibitors in these trials. In contrast, in the Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), and Trandopril Cardiac Evaluation (TRACE) trials, where evidence of impairment of ventricular function was used to select patients, both a marked and certain benefit regarding mortality was apparent from long-term prescription of these drugs. Importantly, the marked benefit observed in these selected patients may have been "diluted out" in the larger scale trials of unselected patients where the majority may have gained little and some may have been harmed by treatment or its withdrawal. In most of the large mortality trials the rationale for use of ACE inhibitors after myocardial infarction was stated to be their likely beneficial effect on "remodeling" of the heart after "Infarct expansion." Because adverse remodeling occurs in only a proportion of patients after a heart attack, the benefits of ACE inhibitor therapy might be predicted to be largely limited to this group, which would favor a selective policy. However, strong claims have been made that ACE inhibitors have other important actions, including prevention of myocardial infarction. If this is confirmed in a number of ongoing large-scale trials. then an even ore widespread use of these agents can be expected.

Angiotensin-converting enzyme inhibitors after myocardial infarction: Indications and timing

A number of major studies have examined the impact of angiotensin-converting enzyme inhibitors on mortality in patients with ischemic heart disease. However, in these studies, selection of patients, choice of agent and timing of treatment after myocardial infarction have differed. In the Second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS II), all patients, unless hypotensive, were treated immediately after thrombolysis with placebo or intravenous enalaprilat followed by oral therapy. In contrast, in the Survival and Ventricular Enlargement (SAVE) study, patients were selected with a reduced radionuclide ejection fraction and without overt ongoing ischemia. Despite these different approaches, both studies were based on the rationale that angiotensin-converting enzyme inhibition would beneficially affect infarct expansion and subsequent remodeling. The SAVE study reported a significant reduction in mortality rate (19% risk reduction, 95% confidence interval [CI] 3% to 32%) over an average follow-up period of 42 months, but with no observable impact on mortality rate until almost 1 year into treatment. The CONSENSUS II trial closed prematurely, with no benefit (a 10% increase in risk, 95% CI 7% reduction to 29% increase) apparent from enalapril after 6 months of follow-up. The recently reported but unpublished findings of Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) and the Fourth International Study of Infarct Survival (ISIS-4) indicate a small benefit from early (within 24 h) short-term (4 to 6 weeks) treatment of all patients, unless hypotensive, after a myocardial infarction. In contrast, the Acute Infarction Ramipril Efficacy (AIRE) study demonstrated a marked reduction in mortality rate (27% risk reduction, 95% CI 11% to 40%) when the angiotensin-converting enzyme inhibitor ramipril was given to patients manifesting some clinical evidence of heart failure, even if transient, 3 to 10 days after myocardial infarction for an average period of 15 months. Extrapolation from the findings of the AIRE study and from subgroup analyses of GISSI-3 and ISIS-4 indicate that patients manifesting clinical evidence of heart failure after myocardial infarction derive most of the benefit to be gained from the use of angiotensin-converting enzyme inhibitors. Appropriate selection of patients and careful timing of treatment after myocardial infarction to allow patients to achieve clinical stability will maximize potential benefit against potential harm from these effective agents.

Angiotensin-converting enzyme inhibitors after myocardial infarction: Indications and timing

A number of major studies have examined the impact of angiotensin-converting enzyme inhibitors on mortality in patients with ischemic heart disease. However, in these studies, selection of patients, choice of agent and timing of treatment after myocardial infarction have differed. In the Second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS II), all patients, unless hypotensive, were treated immediately after thrombolysis with placebo or intravenous enalaprilat followed by oral therapy. In contrast, in the Survival and Ventricular Enlargement (SAVE) study, patients were selected with a reduced radionuclide ejection fraction and without overt ongoing ischemia. Despite these different approaches, both studies were based on the rationale that angiotensin-converting enzyme inhibition would beneficially affect infarct expansion and subsequent remodeling. The SAVE study reported a significant reduction in mortality rate (19% risk reduction, 95% confidence interval [CI] 3% to 32%) over an average follow-up period of 42 months, but with no observable impact on mortality rate until almost 1 year into treatment. The CONSENSUS II trial closed prematurely, with no benefit (a 10% increase in risk, 95% CI 7% reduction to 29% increase) apparent from enalapril after 6 months of follow-up. The recently reported but unpublished findings of Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) and the Fourth International Study of Infarct Survival (ISIS-4) indicate a small benefit from early (within 24 h) short-term (4 to 6 weeks) treatment of all patients, unless hypotensive, after a myocardial infarction. In contrast, the Acute Infarction Ramipril Efficacy (AIRE) study demonstrated a marked reduction in mortality rate (27% risk reduction, 95% CI 11% to 40%) when the angiotensin-converting enzyme inhibitor ramipril was given to patients manifesting some clinical evidence of heart failure, even if transient, 3 to 10 days after myocardial infarction for an average period of 15 months. Extrapolation from the findings of the AIRE study and from subgroup analyses of GISSI-3 and ISIS-4 indicate that patients manifesting clinical evidence of heart failure after myocardial infarction derive most of the benefit to be gained from the use of angiotensin-converting enzyme inhibitors. Appropriate selection of patients and careful timing of treatment after myocardial infarction to allow patients to achieve clinical stability will maximize potential benefit against potential harm from these effective agents.

Ramipril. An updated review of its therapeutic use in essential hypertension and heart failure.

Ramipril is a second generation angiotensin converting enzyme (ACE) inhibitor. Like enalapril, it is a prodrug and is hydrolysed in vivo to release the active metabolite, ramiprilat, which has a long elimination half-life, permitting once-daily administration. The antihypertensive efficacy of ramipril has been confirmed in large-scale noncomparative studies conducted in general practice as well as in more rigorously controlled clinical trials. In the former, approximately 85% of patients with mild to moderate essential hypertension have responded successfully to treatment with ramipril 2.5 or 5 mg/day, while comparative trials indicate that the antihypertensive efficacy of the drug is equivalent to that of other established ACE inhibitors and the beta-adrenoceptor antagonist atenolol. As expected, the response rate to ramipril monotherapy is lower in patients with severe hypertension (around 40%), although the blood pressure lowering effect can be enhanced with the addition of a diuretic such as hydrochlorothiazide or piretanide. The antihypertensive efficacy of ramipril is maintained in patients with diabetes mellitus and preliminary data indicate that the drug has the beneficial effect of decreasing urinary albumin excretion in diabetic patients with nephropathy. Ramipril is superior to atenolol in causing regression of left ventricular hypertrophy, although the clinical significance of this effect per se remains to be established. The large-scale Acute Infarction Ramipril Efficacy (AIRE) study demonstrated that ramipril 5 or 10 mg/day significantly decreased the risk of all-cause mortality by 27% in patients with clinical evidence of heart failure after acute myocardial infarction, even if transient. The beneficial effect of ramipril was apparent by 30 days of treatment and appeared to be greatest in patients with more severe ventricular damage after infarction. Ramipril is well tolerated in general practice, with 5% or fewer patients discontinuing therapy because of drug intolerance. The data available suggest that ramipril shares a similar tolerability profile to that of other established ACE inhibitors. Thus, clinical data confirm ramipril as a useful alternative ACE inhibitor for the treatment of patients with mild to moderate hypertension, and indicate a beneficial effect of the drug in patients with clinical evidence of heart failure after acute myocardial infarction. It is also reasonable to assume that ramipril will be of value in the treatment of patients with more established heart failure or asymptomatic left ventricular dysfunction.

Reduction of ischemic events with angiotensin-converting enzyme inhibitors: lessons and controversy emerging from recent clinical trials.

Angiotensin-converting enzyme (ACE) inhibitor therapy has been associated with a substantial (> or = 20%) reduction in the risk of major ischemic events in two recent clinical trials with long-term follow-up: Studies of Left Ventricular Dysfunction (SOLVD) and the Survival and Ventricular Enlargement (SAVE) study. Participants in these studies included patients with a low ejection fraction (< or = 0.35 in SOLVD and < or = 0.40 in SAVE), generally without symptoms of congestive heart failure. Approximately 80% of patients enrolled in SOLVD and all participants in SAVE had histories of ischemic heart disease or acute myocardial infarction (SAVE). In both SOLVD and SAVE the risk of experiencing a major ischemic event such as myocardial infarction was reduced significantly following prolonged ACE inhibitor therapy. In the SOLVD trial, this effect was evident across a range of patient subgroups, including varying concomitant drug therapies. In both studies, several months elapsed before this benefit became apparent, suggesting an effect on underlying ischemic pathophysiology. A third trial of ACE inhibitor therapy postinfarction, the Acute Infarction Ramipril Efficacy (AIRE) Study, demonstrated a 27% reduction in all cause mortality but no effect on myocardial infarction after a 15-month mean follow-up. No effect of ACE inhibition on risk of survival or reinfarction was reported in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS-II), which began the drug within 24 hours of infarction and terminated follow-up at 6 months, a time not likely to demonstrate infarction reduction benefit based on the SOLVD and SAVE observations. Neither AIRE nor CONSENSUS-II had objectively determined left ventricular dysfunction as an entry criterion, as did SOLVD and SAVE, but AIRE mandated "clinical" congestive heart failure prior to randomization. More recently, preliminary results from the third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3), the Fourth International Study of Infarct Survival (ISIS-4), and the Chinese Captopril Trial suggested that angiotensin-converting enzyme (ACE) inhibitor mortality benefits post-myocardial infarction would be detected in these megatrials as early as 35 days after the event.(ABSTRACT TRUNCATED AT 400 WORDS)