ACE Inhibitor Use in Patients With Myocardial Infarction
1995; Lippincott Williams & Wilkins; Volume: 92; Issue: 10 Linguagem: Inglês
10.1161/01.cir.92.10.3132
ISSN1524-4539
AutoresRoberto Latini, Aldo P. Maggioni, Marcus Flather, Peter Sleight, Gianni Tognoni,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeCirculationVol. 92, No. 10ACE Inhibitor Use in Patients With Myocardial Infarction Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBACE Inhibitor Use in Patients With Myocardial Infarction Summary of Evidence From Clinical Trials Roberto Latini, Aldo P. Maggioni, Marcus Flather, Peter Sleight, Gianni Tognoni and Roberto LatiniRoberto Latini From the Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy (R.L., A.P.M., G.T.); the Associazione Nazionale Medici-Cardiologi Ospedalieri, Firenze, Italy (A.P.M.); the Division of Cardiology, McMaster University, Hamilton, Canada (M.F.); and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK (P.S.). , Aldo P. MaggioniAldo P. Maggioni From the Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy (R.L., A.P.M., G.T.); the Associazione Nazionale Medici-Cardiologi Ospedalieri, Firenze, Italy (A.P.M.); the Division of Cardiology, McMaster University, Hamilton, Canada (M.F.); and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK (P.S.). , Marcus FlatherMarcus Flather From the Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy (R.L., A.P.M., G.T.); the Associazione Nazionale Medici-Cardiologi Ospedalieri, Firenze, Italy (A.P.M.); the Division of Cardiology, McMaster University, Hamilton, Canada (M.F.); and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK (P.S.). , Peter SleightPeter Sleight From the Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy (R.L., A.P.M., G.T.); the Associazione Nazionale Medici-Cardiologi Ospedalieri, Firenze, Italy (A.P.M.); the Division of Cardiology, McMaster University, Hamilton, Canada (M.F.); and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK (P.S.). , Gianni TognoniGianni Tognoni From the Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy (R.L., A.P.M., G.T.); the Associazione Nazionale Medici-Cardiologi Ospedalieri, Firenze, Italy (A.P.M.); the Division of Cardiology, McMaster University, Hamilton, Canada (M.F.); and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK (P.S.). and From the Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy (R.L., A.P.M., G.T.); the Associazione Nazionale Medici-Cardiologi Ospedalieri, Firenze, Italy (A.P.M.); the Division of Cardiology, McMaster University, Hamilton, Canada (M.F.); and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK (P.S.). and for the meeting participants Originally published15 Nov 1995https://doi.org/10.1161/01.CIR.92.10.3132Circulation. 1995;92:3132–3137Experimental evidence for the beneficial effects on heart failure of chronic treatment with ACE inhibitors accumulated from early 1980 in experimental models of LV dysfunction secondary to AMI. These studies demonstrated an improvement in hemodynamics, LV remodeling,1234 and mortality with ACE inhibitor treatment.56 The effect of ACE inhibitors during the acute phase of AMI was less clear, although there was evidence of protection from ischemic damage, possibly mediated by an increase in collateral coronary blood flow.7891011Clinical DataThe striking beneficial results of prolonged ACE inhibitor therapy in the CONSENSUS-I trial12 on mortality of patients with advanced CHF have been followed by a series of trials in patients with less severe heart failure or asymptomatic LV dysfunction of any origin131415 or limited to AMI.161718 Consistent with the experimental data, the latter studies showed that ACE inhibition clearly produces favorable effects on mortality and LV function in selected high-risk post-AMI populations. More recent trials have addressed the role of ACE inhibition in relatively unselected patients19202122 or in those with anterior AMI2324 in whom treatment was initiated during the first day of AMI. Overall, these trials indicate a small but definite benefit of about 5 lives saved for every 1000 patients treated (Table 1).21Table 2 summarizes the evidence available from the literature (the results of the TRACE18 and SMILE24 studies were not available at the time of the meeting but are included for completeness, and their findings confirm previous evidence). Table 2 and Fig 1 summarize the background information: a decrease in the relative size of the beneficial effects is associated with a broadening of the population who might derive a clinically relevant benefit. Although the results of these trials are complementary in many ways, they also are a potential source of contradictory interpretation.252627282930 For example, are the populations randomized in CONSENSUS II,19 GISSI-3,20 and ISIS-421 concordant or discordant with respect to those of the other trials? Although ongoing trials31 are addressing the issue of long-term secondary prevention with ACE inhibitors in patients at high risk of vascular events, no other placebo-controlled trials in the acute phase of AMI are planned. Thus, there is a need to translate the available evidence into reasonable and coherent recommendations for the use of ACE inhibitors in AMI and post-AMI patients.To address these issues, a meeting of investigators actively involved in the principal published ACE inhibitor trials was convened to reach a consensus on ACE inhibitor use in patients with AMI.Methods and ParticipantsThe GISSI group invited the coordinating groups and/or principal investigators of the CONSENSUS, AIRE, SAVE, SOLVD, ISIS-4, GISSI-3, and V-HeFT trials. A few other experts were invited, to provide a wide range of opinions, and representatives of collaborative research groups from Latin America participated, to allow discussion of the problems of transferability and relevance in different health care settings.The meeting was held in Berlin during the XII World Congress of Cardiology and the XVI Congress of the European Society of Cardiology, September 10, 1994. The members of the panel are listed in the "Appendix."A summary of the existing data from the randomized clinical trials of ACE inhibitors in AMI was sent to all participants 1 month before the meeting to allow proper consideration and to avoid repetitive presentations. Confidential unpublished data from the GISSI-3, ISIS-4, and CCS-1 trials were also included.The following questions were submitted to the panel at the same time to facilitate a productive and practice-oriented debate.1. Is the primary indication for ACE inhibitor the treatment of the patients with AMI syndrome or with LV dysfunction that at any time complicates AMI? In the first case, should all patients or only those at higher risk be treated (ie, anterior AMI, large AMI)?2. When should ACE inhibitor treatment be started?3. What are the criteria of initial exclusion and subsequent withdrawal or continuation of ACE -inhibitor treatment of AMI patients?4. Do known or suggested pathophysiological mechanisms provide a satisfactory explanation of the observed clinical effects of ACE inhibitor therapy?Summary of Panel Discussion and ConclusionsQuestions 1 and 2Is primary indication for ACE inhibitor the treatment of the patients with AMI syndrome or with LV dysfunction that at any time complicates AMI? In the first case, should all patients or only those at higher risk be treated (ie, anterior AMI, large AMI)?When should ACE inhibitor treatment be started?The two questions are presented together because the answer to question 1 is integrally related to question 2. The evidence available from the trials on ACE inhibitors is documented in detail in Tables 1 and 2 and may be summarized as follows. Treatment with ACE inhibitors has a beneficial effect in patients selected for the presence of LV dysfunction after AMI and in relatively unselected patients presenting with AMI. The benefit increases in patients with clinical or laboratory evidence of LV dysfunction. There is still uncertainty about treating all AMI patients without contraindications to ACE inhibitors or targeting a selected higher-risk group.The extension of the indication of early treatment to an unselected AMI population is supported by the consideration of the following. In the absence of absolute predictive criteria, short-term treatment is likely to offer protection from LV dysfunction to many patients before they develop it. There is evidence in the GISSI-3 and ISIS-4 trials of a very early benefit (Fig 2) when reliable, objective measurement of LV dysfunction may be impractical. A beneficial effect of ACE inhibitor treatment in GISSI-3 and ISIS-4 is observed across a wide range of patients, although as expected the benefit was less in patients at lower risk. For example, the GISSI-3 results show that 33 patients with an impaired hemodynamic state at entry (Killip class >1) had to be treated for 1 life to be saved; 333 patients without complications (Killip class 1) had to be treated for 1 life to be saved. Nevertheless, the number of lives saved in the group of lower-risk patients is important in absolute terms because of the greater prevalence of this group of patients (ie, 24 lives saved in Killip class 1 versus 39 in Killip class >1 in GISSI-3). The potential risk of an ACE inhibitor therapy started early after AMI is small and does not obscure its net benefit, as shown by GISSI-3 results: persistent hypotension and renal dysfunction were significantly more common among lisinopril-treated patients than among control subjects (Fig 3), and most of the cases of persistent hypotension (>80%) and more than half of those of renal dysfunction occurred within 7 days of randomization. However, a subsidiary analysis of GISSI-3 and ISIS-4 showed that in the same period (days 0 through 7) mortality was lower in the ACE inhibitor–allocated patients (Fig 2).In conclusion, evidence of an early benefit in unselected AMI patients was considered complementary to the favorable effects in patients with LV dysfunction by some members of the panel but disputed by others. All agreed that patients with a clinically large AMI and/or current or previous LV failure should certainly be considered for early treatment with an ACE inhibitor in the absence of contraindications (eg, hypotension).Question 3What are the criteria for initial exclusion and subsequent withdrawal or continuation of ACE inhibitor treatment of AMI patients?Exclusion CriteriaThe safety profile of patients treated within 24 hours from the onset of symptoms appears acceptable if the following exclusion criteria are applied: high risk of further serious hemodynamic deterioration (systolic blood pressure ≤100 mm Hg) and specific contraindications (history of clinically relevant renal failure, history of bilateral stenosis of the renal arteries, or documented allergy to ACE inhibitors).Patients with low systolic blood pressure (100 to 110 mm Hg) in the first 24 hours after the onset of symptoms should be monitored carefully.No specific additional risk was shown in GISSI-3 or ISIS-4 for elderly patients or women, so ACE inhibitors are not contraindicated in these populations.Withdrawal or ContinuationThe consistency of data on the role of ACE inhibitors from trials in patients with LV dysfunction or heart failure complicating AMI (as in the AIRE, SAVE, and TRACE studies) strongly indicates that ACE inhibitors should be given to these patients. For this reason, if at any time after AMI clinical signs and/or symptoms of LV dysfunction occur or are diagnosed instrumentally, treatment should be continued over a long period of time. In other words, as soon as a patient becomes an "AIRE- or SAVE-like patient," he or she should be treated according to the indications of these studies (this recommendation was applied in the GISSI-3 and ISIS-4 trials).On the other hand, if a patient does not show signs or symptoms of LV dysfunction, it is likely that treatment can be stopped safely after 4 to 6 weeks (based on existing evidence from GISSI-3 and ISIS-4). In this case, the patients should ideally be reevaluated after a reasonable period (ie, 4 to 6 months) to check for evidence of LV function. The appearance of persistent hypotension or clinically relevant renal dysfunction should be considered an indication for ACE inhibitor dose reduction or withdrawal (at least temporarily).Question 4Do the suggested pathophysiological mechanisms provide a satisfactory explanation of ACE inhibitor clinical effects?Even if randomized clinical trials alone cannot provide answers on specific pathophysiological mechanisms, the results of ACE inhibitor trials in patients with LV dysfunction do appear to fit the remodeling hypothesis based on experimental studies and represent a good example of the consistency of a mechanistic hypothesis with the clinical data. The exploratory analysis of echo data from GISSI-332 supports this hypothesis in a large, relatively unselected population of patients treated very early after AMI. Although the changes observed in LV volumes are small, they are statistically and clinically significant, as already shown in a subgroup of patients from the SAVE trial.33 A small decrease in LV volume in the whole population is consistent with a reduction in the incidence of LV dysfunction.20Post hoc analyses of randomized clinical trials suggest that additional mechanisms (vasodilator and neurohormonal effects), in addition to the effect on long-term remodeling, might contribute substantially to the favorable effect of ACE inhibitors. This is suggested by the early beneficial effects (days 0 through 7, Fig 2) documented in GISSI-3 and ISIS-4 and the reduced number of ischemic events reported by the SOLVD and SAVE trials after long-term ACE inhibition (although as expected no evidence of such an effect has been found with the short-term treatments in GISSI-3 and ISIS-4).In particular, activation of the renin-angiotensin system in the first few days after AMI34 may increase heart rate and systemic vascular resistance and decrease coronary artery perfusion,35 which may lead to infarct expansion. The early benefit observed in GISSI-3, ISIS-4, and CSI-1 could be explained in this way.Summary Statements1. Patients with signs or symptoms of LV dysfunction at any time after AMI warrant prompt initiation of long-term (lifelong?) ACE inhibitor treatment unless contraindications exist.2. Treatment of AMI patients with ACE inhibitors may be started the first day after timely and careful observation of their hemodynamic and clinical status and after administration of routinely recommended treatments (thrombolysis, aspirin, and β-blockers). No absolute "efficacy" criteria currently are available to recommend selection of preferential subgroups in the early phase of AMI.3. Within the time frame of 24 hours after AMI, there is no evidence that in relatively unselected AMI patients early treatment with ACE inhibitors provides more efficacy. However, because mortality is highest in the acute phase of AMI, treatment should not be delayed unnecessarily.4. Discontinuing ACE inhibitor treatment that was begun in the early phase of AMI should be considered in patients without asymptomatic LV dysfunction after 4 to 6 weeks. Further reassessment of LV function might be considered 4 to 6 months after AMI.5. The dose of an ACE inhibitor can be individualized on the basis of safety criteria (eg, hemodynamic response) because simple criteria of efficacy, especially in the early phase, are not available. However, the target dose should be that used in the clinical trials.6. A planned meta-analysis of existing trials should allow more reliable focusing on predefined subgroups of patients at higher risk of side effects or with better-defined profiles of potential benefit.AppendixInternational PanelStephen Ball, University of Leeds (AIRE); Jay N. Cohn, University of Minnesota (V-HeFT); Rory Collins, Radcliffe Infirmary (ISIS); Henry J. Dargie, University of Glasgow; Rafael Diaz, Instituto Cardiovascular de Rosario (ECLA); Alistair Hall, University of Leeds (AIRE); Peter Held, Astra Hässle (CONSENSUS); Bodh I. Jugdutt, University of Alberta; John Kjekshus, University of Oslo (CONSENSUS); Marc A. Pfeffer, Harvard Medical School (SAVE); Philip A. Poole-Wilson, National Heart & Lung Institute; Thomas Ryan, Boston University; Edgardo Sandoya, Sociedad Uruguaya de Cardiologia (ECLA); Rolf Schroeder, Berlin University (ISIS); Maarten Simoons, Erasmus Universiteit; Peter Sleight, cochair, University of Oxford (ISIS); Leopoldo Soares Piegas, Instituto Dante Pazzanese (ECLA); Carlos Tajer, Instituto Medico Antartida (ECLA); and Salim Yusuf, McMaster University (SOLVD, ISIS, and HOPE). Drs Ball and Hall actively participated in the meeting but did not share all the views expressed in the Summary Statements, particularly statement 2.GISSI Group, ItalyErnesto Correale, Maria Grazia Franzosi, Enrico Geraci, Stefano Ghio, Paolo Marino, Francesco Mauri, Gian Luigi Nicolosi, Fausto Rovelli, Eugenio Santoro, Luigi Tavazzi, Alberto Volpi, and Giulio Zuanetti.RapporteursMarcus Flather, McMaster University (ISIS); Roberto Latini, Istituto Mario Negri (GISSI); and Aldo P. Maggioni, Istituto Mario Negri and ANMCO (GISSI).Selected Abbreviations and AcronymsACE=angiotensin-converting enzymeAIRE=Acute Infarction Ramipril Efficacy StudyAMI=acute myocardial infarctionCCS=Chinese Cardiac StudyCHF=congestive heart failureCONSENSUS=Cooperative New Scandinavian Enalapril Survival StudyECLA=Estudios Cardiologicos LatinoAmericaGISSI-3=Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico 3HOPE=Heart Outcomes Prevention EvaluationISIS-4=International Study of Infarct Survival–4LV=left ventricularSAVE=Survival and Ventricular Enlargement TrialSMILE=Survival of Myocardial Infarction: Long-term EvaluationSOLVD=Studies of Left Ventricular DysfunctionTRACE=Trandolapril Cardiac Evaluation StudyV-HeFT=Veterans Administration Cooperative Vasodilator–Heart Failure TrialParticipants in the meeting, held September 10, 1994, in Berlin, Germany, are listed in the "Appendix."Download figureDownload PowerPoint Figure 1. Chart showing randomized clinical trials on ACE inhibitors from CHF to coronary artery disease. Length of each bar represents the time span from the first to the last patient enrolled in each trial. LVD indicates left ventricular dysfunction; CAD, coronary artery disease.Download figureDownload PowerPoint Figure 2. Bar graphs showing that in GISSI-3 and ISIS-4 ACE inhibitors saved lives during the very early phases. A, In the GISSI-3 lisinopril-allocated patients (cross-hatched bar), there were 76 fewer deaths than in the control-allocated group (open bar): 21 fewer for days 0 through 1, 43 fewer for days 2 through 7, and 12 fewer for the following days of treatment. B, In the ISIS-4 captopril-allocated patients (cross-hatched bar), there were 143 fewer deaths than in the control-allocated group (open bar): 44 fewer for days 0 through 1, 37 fewer for days 2 through 7; and 62 fewer for the following days of treatment. Absolute reductions and percent contribution to total benefit are shown for each time interval.Download figureDownload PowerPoint Figure 3. Bar graphs showing that in GISSI-3 persistent hypotension (A) occurred chiefly during the acute phase of AMI, with >80% of the cases occurring within day 2 from randomization, while excessive renal dysfunction (B; clinically defined by attending cardiologists) occurred throughout the hospitalization. These two events were consistently more frequent in patients treated with lisinopril (patterned bar) than in control subjects (open bar). Absolute increase of events and percent contribution to total increase are shown for each time interval. Data on timing of the event are missing for 12 patients with persistent hypotension and 1 with renal dysfunction. Table 1. Overview of ACE Inhibitor Trials on Patients With AMITrialPatients Treated With ACE Inhibitors (%)Control Subjects, deaths/treated (%)Agent, deaths/treated (%)11 small trials150/2175153/2119Various(6.9)(7.2)CONSENSUS-II219/3044192/3046Enalapril, IV and oral(7.2)(6.3)GISSI-3597/9435673/9460Lisinopril, oral(6.3)(7.1)ISIS-42088/29 0282231/29 022Captopril, oral(7.2)(7.7)CCS-1617/6814654/6820Captopril, oral(9.1)(9.6)Overview3671/50 4963903/50 467P=.006(7.27)(7.73)4.6 lives saved per 1000 treated patients. ACE inhibitors reduced mortality in all trials, except for CONSENSUS II, in which 1-month mortality (reported in the table) was not significantly higher in enalapril-allocated patients. The plan for this trial was to recruit 9000 patients, but the study was stopped after randomization of 6090 patients. In this trial, the ACE inhibitor was administered in the first 24 hours after AMI by intravenous (IV) infusion (enalaprilat) and then orally for 6 months.Modified from Reference 21 with permission. Table 2. Summary of Randomized Clinical TrialsRandomized Clinical Trials of ACE Inhibitors in Heart FailureRandomized Clinical Trials of ACE Inhibitors in High-Risk AMI PatientsCONSENSUS-ISOLVD TreatmentV-HeFT IISOLVD PreventionSAVEAIRETRACERandomization, yApril 1985- December 1986June 1986- March 1989March 1986- September 1990July 1986- May 1990January 1987- January 1990April 1991- August 1992July 1991- August 1993Patients randomized, n25325698044228223120061749Patients screened1…39 9242741. . .36 63030 7177010Randomized/screened, %66.525PopulationNYHA IV (CAD, 73%; previous MI 47%)NYHA II-III, EF ≤35% (CAD 71%; previous MI, 66%)NYHA II-III, EF <45% (CAD, 54%; previous MI, 47%)NYHA I-II, EF ≤35% (CAD, 83%; previous MI, 80%)MI, EF ≤40%MI, clinical HFMI, WMI ≤1.2Exclusion criteriaAPE, MI 300 μmol/LNYHA IV, MI≤1 mo, age>80 y, Cr>177 μmol/LMI 80 y, Cr>177 μmol/LACE inhibitor for CHF or HBP, age>80 y, Cr>221 μmol/LNYHA IV, clinical severe RF0.5 mg trandolopril not tolerated, Cr>200 μmol/LDrug initiation from MI>60 d>30 d>90 d>30 d3-16 d (mean, 11 d)3-10 d (mean, 5.4 d)3-7 d (median, 4 d)Drug and dose, mgEnalapril, 5 to 20 bidEnalapril, 2.5 to 10 bidEnalapril 5 to 20 dailyEnalapril, 2.5 to 10 bidCaptopril, 12.5 to 50 tidRamipril, 2.5 to 5 bidTrandolapril, 1 to 4 dailyFollow-up duration1 d-20 mo (mean, 188 mo)22-55 mo (mean, 41.4 mo)6-68 mo (mean, 30 mo)14.6-62 mo (mean, 37.4 mo)24-60 mo (mean, 42 mo)6-30 mo (mean, 15 mo)24-? moOverall mortality, %Control5439.738.2115.824.62362.3Treated3935.232.814.820.41734.7Reduction, %271611.18192718P.003.0036.08.30.019.002.001Lives saved per 1000 patients per month323.61.11.7. . .1.03.52.9Needed to be treated to save 1 life, n72219. . .241713CATS indicates Captopril and Thrombolysis Study; NYHA, New York Heart Association class; HF, heart failure; WMI, wall motion index; EF, ejection fraction; CAD, coronary artery disease; APE, acute pulmonary edema; Cr, serum creatinine; HBP, high blood pressure; RF, renal failure; and SBP, systolic blood pressure.1Figures are not comparable with post-AMI trials because of different screening procedures.2Hydralazine plus isosorbide dinitrate.3The figures should be compared with caution between studies of different durations. Table 2B. ContinuedRandomized Clinical Trials of ACE Inhibitors in High-Risk AMI PatientsRandomized Clinical Trials of ACE Inhibitors in Relatively Unselected AMI PatientsSMILECATSCONSENSUS-IIGISSI-3ISIS-4CCS-1January 1991- December 1992April 1990- December 1991March 1990- March 1991June 1991- July 1993July 1991- August 1993January 1990- April 19951556298609019 39458 05013 63420 261…10 38743 047……8…5945……Anterior MI, nonthrombolyzedAnterior MI, thrombolyzedMIMIMIMISBP 186 μmol/LBP≤100/55 mm Hg, RFBP 105/65 mm Hg, clinical severe RFKillip 4, SBP 177 μmol/LSBP <90-100, Killip 4SBP<90 mm Hg, chronic diuretic6-24 h (mean, 15 h)≤6 h≤1 d≤1 d≤1 d≤36 hZofenopril, 7.5 to 30 bidCaptopril, 6.25 to 25 bidEnalaprilat IV, po 5 to 20 bidLisinopril, 2.5 to 10 once dailyCaptopril, 6.25 to 50 bidCaptopril, 6.25 to 12.5 tid12 mo3 mo41-180 d (mean, 6 mo; 2952 patients)42 d1 mo4 weeks6.54.09.47.17.79.64.96.010.26.37.29.124……117.06.0.198.03.020.311.2005.44.95.363……125200200All the participants listed in the Appendix contributed to the present paper by attending the meeting in Berlin and/or carefully revising two versions of the manuscript. We thank Luisa Galbiati for the secretarial help in organizing the meeting and preparing the manuscript.FootnotesCorrespondence to Gianni Tognoni, MD, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea, 62, 20157 Milano, Italy. Email [email protected] References 1 Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res.1985; 57:84-95. CrossrefMedlineGoogle Scholar2 Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation.1990; 81:1161-1172. CrossrefMedlineGoogle Scholar3 Raya TE, Gay RG, Aguirre M, Goldman S. Importance of venodilatation in prevention of left ventricular dilatation after chronic large myocardial infarction in rats: a comparison of captopril and hydralazine. Circ Res.1989; 64:330-337. CrossrefMedlineGoogle Scholar4 Capasso JM, Anversa P. 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Cardiovasc Res.1992; 26:232-236. CrossrefMedlineGoogle Scholar9 Van Gilst WH, De Graeff PA, Wesseling H, de Langen CDJ. Reduction of reperfusion arrhythmias in the ischemic isolated rat heart by angiotensin converting enzyme inhibitors: a comparison of captopril, enalapril, and HOE 498. J Cardiovasc Pharmacol.1986; 8:722-728. MedlineGoogle Scholar10 Liang CS, Gavras H, Black J, Sherman LG, Hood WB Jr. Renin-angiotensin system inhibition in acute myocardial infarction in dogs: effects on systemic hemodynamics, myocardial blood flow, segmental myocardial function and infarct size. Circulation.1982; 66:1249-1255. CrossrefMedlineGoogle Scholar11 Ertl G, Kloner RA, Alexander RW, Braunwald E. Limitation of experimental infarct size by an angiotensin-converting enzyme inhibitor. Circulation.1982; 65:40-48. CrossrefMedlineGoogle Scholar12 The CONSENSUS Trial Group. 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N Engl J Med.1992; 327:685-691. CrossrefMedlineGoogle Scholar16 Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM, for the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial (SAVE). N Engl J Med.1992; 327:669-677. CrossrefMedlineGoogle Scholar17 The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet.1993; 342:821-828.MedlineGoogle Scholar18 The TRACE Study Group. The Trandolapril Cardiac Evaluation (TRACE) Study: rationale, design, and baseline characteristics of the screened population. Am J Cardiol.1994; 73:44C-50C. CrossrefMedlineGoogle Scholar19 Swedberg K, Held P, Kjekshus J, Rasmussen K, Rydén L, Wedel H, for the CONSENSUS II Study Group. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. N Engl J Med.1992; 327:678-684. CrossrefMedlineGoogle Scholar20 Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet.1994; 343:1115-1122. MedlineGoogle Scholar21 ISIS-4 Collaborative Group. ISIS-4
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