Double-blind comparison between zofenopril and lisinopril in patients with acute myocardial infarction: Results of the Survival of Myocardial Infarction Long-term Evaluation-2 (SMILE-2) study

Double-blind comparison between zofenopril and lisinopril in patients with acute myocardial infarction: Results of the Survival of Myocardial Infarction Long-term Evaluation-2 (SMILE-2) study Claudio Borghi, MD, and Ettore Ambrosioni, MD, on behalf of the SMILE-2 Working Party Bologna, Italy

Background Angiotensin-converting enzyme (ACE) inhibitors have been reported to be effective in placebo-controlled trials in various subsets of patients with acute myocardial infarction (MI). However, no direct comparisons have been performed between different ACE inhibitors in the same patient population.

Methods This phase III, double-blind, parallel-group, multicenter study compared the safety and efficacy of zofenopril and lisinopril in 1024 thrombolyzed patients with acute MI. Patients, aged 18 to 75 years, were randomized to receive oral zofenopril (30-60 mg/day) or lisinopril (5-10 mg/day), starting within 12 hours of completion of thrombolytic therapy and continuing for 42 days. The primary study end point was the incidence of severe hypotension (systolic blood pressure ⬍90 mm Hg), either cumulative or drug-related. Secondary end points included additional safety and efficacy parameters.

Results The overall incidence of severe hypotension was slightly more reduced with zofenopril (10.9%) than with lisinopril (11.7%, P ⫽ .38). The incidence of drug-related severe hypotension was slightly but significantly lower with zofenopril than with lisinopril (6.7 vs 9.8%, 2-tailed P ⫽ .048). The 6-week mortality rate was 3.2% in the zofenopril group and 4.0% in the lisinopril group (P ⫽ .38), and no significant differences were observed in the incidence of major cardiovascular complications or any safety variables between the 2 ACE inhibitors.

Conclusions The SMILE-2 study demonstrates that both zofenopril and lisinopril are safe and associated with a rather low rate of severe hypotension when given in accordance with a dose-titrated scheme to thrombolyzed patients with acute MI. These findings could have a positive clinical impact and increase the proportion of patients with acute MI who can be safely treated with ACE inhibitors. (Am Heart J 2003;145:80-7.)

Angiotensin-converting enzyme (ACE) inhibitors are well-established agents for the treatment of hypertension and congestive heart failure.1 In recent years, the use of ACE inhibitors has been extended to patients with acute myocardial infarction (MI),2 and the results of the Heart Outcome Prevention Evaluation (HOPE) study3 have demonstrated the therapeutic role of ACE inhibition in the large population of patients at risk of cardiovascular events. The clinical evaluation of ACE inhibitors in acute MI has involved thousands of patients1,2 enrolled into several placebo-controlled trials involving a wide range of patients—from those with asymptomatic LV dysfuncFrom the Department of Medicine, University of Bologna, Bologna, Italy. Supported by Menarini Ricerche S.p.A., Firenze, Italy. Submitted September 21, 2001; accepted June 12, 2002. Reprint requests: Claudio Borghi, MD, Divisione di Medicina Interna, Policlinico S.Orsola, Via Massarenti 9, 40138 Bologna, Italy. E-mail: [email protected] Copyright 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1067/mhj.2003.24

tion4,5 to patients with acute MI complicated by overt congestive heart failure (CHF).6,7 The beneficial role of ACE inhibitors has been confirmed in nonselected populations of patients with MI8,9 as well as in selected high-risk patients with anterior MI not undergoing thrombolysis.10 Finally, the use of ACE inhibitors has resulted in a sizeable benefit in patients treated early after the onset of symptoms or in those where drug administration has been delayed for days or weeks after the acute event. Despite this large amount of evidences, no studies have been carried out so far to directly compare ACE inhibitors with different pharmacologic profiles11 in patients with MI. Zofenopril calcium, a prodrug of the active metabolite zofenoprilat,12 is a typical ACE inhibitor producing a longer lasting inhibition of tissue and cardiac ACE activity than captopril.11,13 The clinical efficacy of zofenopril has been evaluated in the treatment of arterial hypertension14,15 and acute MI.16,17 In the SMILE (Survival of Myocardial Infarction Long-term Evaluation) study, zofenopril reduced the 6-week mortality

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and the risk of progression to severe CHF when started within 24 hours of symptom onset in patients with acute anterior MI.10,17 In addition, the SMILE data provided clear-cut evidence of a satisfactory safety profile of zofenopril in patients with MI10,16 where the drug was well tolerated, with a rate of treatment discontinuation due to severe symptomatic hypotension comparable to that observed in patients treated with placebo.10 Conversely, a similar favorable safety profile has not been described in patients with acute MI treated with different ACE inhibitors (enalapril, lisinopril),18,19 suggesting that some drug-specific features of ACE inhibitors can reduce the risk of adverse events and improve individual tolerability and compliance to treatment. The objective of this study was to investigate the safety and tolerability of early administration of the ACE inhibitors zofenopril and lisinopril in patients with acute MI treated with intravenous thrombolysis.

Methods This phase III randomized, double-blind, parallel-group study, involving patients with acute MI undergoing thrombolytic treatment, was conducted at 155 centers in Italy, Poland, Germany, Czech Republic, Romania, Russia, and the Ukraine (see Appendix). The study was performed in agreement with the Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol was reviewed and approved by the ethics committee of each participating center, and written informed consent was obtained from each patient before enrollment in the trial.

Study objectives The primary study end point was the occurrence of severe hypotension (systolic blood pressure [SBP] ⬍90 mm Hg on 2 consecutive measurements, at least 1 hour apart), either cumulative or related to study drug administration. Cumulative severe hypotension was identified by the presence of hypotension (as defined above) occurring at any time during the study. Drug-related severe hypotension was a co-primary end point and was defined by the presence of hypotension considered by the investigator to be either definitely or probably related to the study medication. The diagnosis of drug-related hypotension was confirmed by an independent event committee that directly reviewed patients’ records in a blinded fashion. Secondary study end points were (1) 6-week cumulative mortality, (2) incidence of severe CHF (Killip and New York Heart Association [NYHA] classifications), (3) 6-week left ventricular ejection fraction (determined by echocardiography or isotopic ventriculography), (4) need for rescue revascularization procedures (percutaneous transluminal coronary angioplasty or coronary artery bypass graft), (5) incidence of angina pectoris (Canadian Cardiovascular Society classification), (6) incidence of reinfarction, and (7) proportion of patients with deteriorating renal function (doubling of serum creatinine levels at the end of the treatment period).

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Study population Male and nonpregnant female patients aged 18 to 75 years were enrolled in this study. The inclusion criteria were a confirmed diagnosis of acute MI, SBP ⬎100 mm Hg, and prior thrombolytic treatment with either streptokinase, tissue plasminogen activator, anistreplase, or reteplase initiated within 12 hours of the onset of clinical symptoms of acute MI. The main exclusion criteria were the presence of cardiogenic shock (Killip class IV), diastolic blood pressure (DBP) ⬎115 mm Hg, SBP ⬎200 mm Hg, bilateral renal artery stenosis, prolonged cardiac massage, coronary artery bypass graft performed in the last 3 months, hemodynamically significant valvular disease, current treatment with ACE inhibitors or angiotensin II-receptor antagonists (ARBs), and hypersensitivity to ACE inhibitors. Patients with a history of renal failure (serum creatinine ⬎2.1 mg/dL and/or documented proteinuria ⬎500 mg/day), leukopenia (leukocytes ⬍3500 ⫻ 109/L), or neutropenia (neutrophils ⬍1500 ⫻ 109/L), or who had received high doses of diuretics (furosemide ⬎250 mg/day) in the previous 24 hours were also excluded.

Drug treatment Eligible patients were randomized (using a centralized, computer-generated randomization list) to receive either zofenopril or lisinopril, with the first dose being administered between 90 minutes and 12 hours after completion of thrombolytic therapy. The dose of either study drug was up-titrated during days 1 to 5 to improve individual tolerability and to avoid adverse effects. On days 1 and 2, patients received zofenopril 7.5 mg twice daily or lisinopril 2.5 mg plus 1 placebo tablet according to a single-dummy technique. On days 3 and 4 the drug dose was increased to zofenopril 15 mg twice daily or lisinopril 5 mg plus 1 placebo tablet, and from days 5 to 42 patients were maintained at the final target dose of zofenopril 30 mg twice daily or lisinopril 10 mg plus 1 placebo tablet in the evening. Zofenopril and lisinopril were supplied as indistinguishable oral tablets. In the event of severe hypotension, treatment was discontinued and the patient was withdrawn from the study. The study medications were administered in combination with standard recommended treatments for acute MI (heparin, aspirin, and ␤-blockers) with the exclusion of other ACE inhibitors or ARBs.

Patient assessment Blood pressure and heart rate were measured on day 1, immediately before and at 1, 2, 3, 6, and 12 hours after the first dose of study medication. The same variables were also measured 12 hours after the second dose, and then twice daily (immediately before each dose of study medication) from days 2 to 7. On days 14, 28 and 42, blood pressure and heart rate were measured before the morning dose of zofenopril and lisinopril. Blood pressure was also measured whenever clinical signs or symptoms of hypotension occurred. A physical examination and a 12-lead electrocardiogram were performed before randomization, on day 1 after the first dose of study medication, and at the end of the treatment period. Laboratory tests for hematology, clinical chemistry, and urinalysis were performed before study drugs, on day 14, and

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Table I. Baseline demographic characteristics of the study population (n ⫽ 1024) Characteristics Sex (%) Male Female Age (y) mean ⫾ SD Weight (kg) Ethnic group White Others Clinical history before MI (%) Hypertension Previous MI Diabetes Heart failure Lipid disorders History of smoking Killip class on admission (%) I II–III Infarct type (%) Q type Non-Q type Undefined Infarct location (%) Anterior Antero-lateral Inferior Other

Zofenopril (n ⴝ 504)

Lisinopril (n ⴝ 520)

390 (77.4) 114 (22.6) 58.8 ⫾ 10.4 80.4 ⫾ 12.8

395 (76.0) 125 (24.0) 58.8 ⫾ 10.3 79.9 ⫾ 13.4

502 (99.6) 2 (0.4)

516 (99.2) 4 (0.8)

45.4 12.7 17.5 3 43.5 45

44.6 12.3 17.3 3.1 45.6 46.9

85.8 14.2

85.4 14.6

81.3 15.9 2.8

78.5 18.1 3.4

29.0 14.3 40.3 16.4

27.7 14.6 33.7 24.0

at the end of the treatment period. Additionally, plasma levels of creatine phosphokinase (CPK) and creatine kinase-MB (CK-MB) were measured on day 1 before drug administration, and every 4 hours during the following 24-hour period. From days 2 to 4, CPK and CK-MB were measured once daily. All adverse events were recorded and classified according to their severity (mild, moderate, or severe) as well as to their relationship with the study drug. Patients could be withdrawn from the study for any of the following reasons: severe hypotension, unwillingness to continue, development of any clinical condition requiring openlabel treatment, or onset of significant adverse events.

Statistical analysis The study was planned to include 512 patients per treatment group on the basis of an anticipated 6-week incidence of severe hypotension of 4.7% and 9.7% and of drug-related severe hypotension of 3.7% and 7.9% with zofenopril and lisinopril, respectively9,16,20; an estimated 10% drop-out rate; a statistical power of 80%; and a significance level of 5% (2tailed test). For the evaluation of the primary and secondary measures of safety, the intention-to-treat (ITT) population was defined by the study protocol as those patients who had received ⱖ1 dose of study medication and had subsequently provided ⱖ1 measurement of SBP. The per-protocol (PP) population included all patients who completed the double-

blind phase of the study without major protocol violations and/or treatment discontinuation for reasons other than severe hypotension. The ␹2 test with Mantel-Haenszel extension and the Student t test were used for comparison of the 2 treatment groups at baseline. The Fisher exact test (2-sided at the 2.5% significance level) was used to test the null hypothesis of no difference in the proportions of patients experiencing severe drug-related hypotension in the 2 treatment groups. Confirmatory analysis was performed on the ITT population and an additional exploratory analysis on the PP population. Additional exploratory post-hoc analyses were also performed to investigate the relationship between severe hypotension, the dose of study medication, and the duration of dose titration.

Results Patient population In total, 1024 patients were enrolled into the study and randomized to treatment: 504 patients were assigned to zofenopril and 520 patients to lisinopril. Treatment was discontinued prematurely in 113 (22.4%) patients receiving zofenopril and 129 (24.8%) patients receiving lisinopril. Severe hypotension was the most frequent reason for treatment discontinuation in both treatment groups, accounting for the withdrawal of 50 (9.9%) and 59 (11.3%) patients, respectively. There were no significant differences in baseline demographic characteristics or in concomitant diseases and medications between the treatment groups (Table I). The study population was predominantly white (99%) and male (⬃75%), and had a mean age of 58.8 ⫾ 10.3 years. Because all patients received ⱖ1 dose of study medication and provided ⱖ1 valid measurement of SBP, the ITT population consisted of all 1024 patients. The PP population was reduced to 841 patients as a result of the exclusion of 183 patients who did not complete the 6-week treatment period for reasons other than severe hypotension. At baseline, there were no significant differences between the 2 treatment groups in blood pressure and heart rate (Figure 1). Biochemical, hematologic, and urinary variables or vital signs were also comparable, as was the time course of biochemical markers of MI (CPK and CK-MB, data not shown). Concomitant medication (ie, started before randomization and continued during the study) included heparin (61.9% zofenopril vs 63.7% lisinopril), antiplatelet drugs (98.2% zofenopril vs 98.7% lisinopril), and ␤-blockers (67.4% zofenopril vs 63.9% lisinopril). The most commonly used thrombolytic agent was streptokinase (83.1% vs 84.2%), and there were no clinically relevant differences between treatment groups with respect to site and type of infarction or thrombolytic treatment (Table I).

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Borghi and Ambrosioni 83

Figure 1

SBP and DBP profile at baseline (day 1) in patients treated with zofenopril or lisinopril.

Primary measures of safety SBP and DBP profiles recorded on day 1 in the 2 treatment groups showed a significant reduction with both zofenopril and lisinopril groups (Figure 1), even though a more persistent blood pressure decrease was observed in patients treated with lisinopril. The overall incidence of severe hypotension in the ITT population was lower in zofenopril- than lisinopriltreated patients (10.9% vs 11.7%), although this difference did not achieve statistical significant (Fisher’s exact test, 2-sided P ⫽ .38,) (Figure 2). The same trend was observed in the PP population (zofenopril 11.5% vs lisinopril 13.0%). The average time-interval from randomization to the onset of severe hypotension was largely comparable in the 2 treatment groups (zofenopril 5.9 ⫾ 6.6 days, lisinopril 5.5 ⫾ 6.5 days; Wilcoxon test, 2-sided P ⫽ .59). The incidence of severe drug-related hypotension was significantly lower in zofenopril- than lisinopriltreated patients, both for the ITT population (6.7% vs 9.8%) and the PP population (7.6% vs 11.1%; Fisher’s exact test, 2-sided P ⫽ .048 for both populations) (Figure 3). The difference persisted after adjustment for the main confounding variables. Because hypotension mainly occurred during the initial fixed-dose titration period, we separately determined the incidence of severe drug-related hypotension during the first 48 hours and after 5 days of treatment. The results of this analy-

Figure 2

Overall incidence of severe hypotension (%) with zofenopril (60 mg/day) and lisinopril (10 mg/day) after 42 days of treatment (ITT population, n ⫽ 1024).

sis showed a 48-hour incidence of severe drug-related hypotension of 3.2% with zofenopril and 5.8% with lisinopril, representing a statistically significant intergroup difference for the ITT population (Fisher’s exact test, 2-sided P ⫽ .031). Likewise, after 5 days of therapy, the incidence of severe drug-related hypotension was significantly lower in the zofenopril group (4.4%) than the lisinopril group (7.7%; Fisher’s exact test,

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Table III. Incidence of adverse events during 6 weeks’ treatment with either zofenopril or lisinopril.

Figure 3

Incidence of severe hypotension (%) considered probably or definitely related to treatment with either zofenopril (60 mg/day) or lisinopril (10 mg/day) for 42 days (ITT population, n ⫽ 1024). Asterisk, P ⫽ .048.

Table II. Incidence of secondary safety parameters (%) among patients treated with either zofenopril (60 mg/day) or lisinopril (10 mg/day). Parameter Death (%) Severe heart failure (Killip classification) day 1 to 7 (%) Severe heart failure (NYHA classification) end of treatment period (%) Acute revascularisation (%) Mean LVEF (%) Myocardial reinfarction (%) Renal function deterioration (%) Angina pectoris (%)

Zofenopril (n ⴝ 504)

Lisinopril (n ⴝ 520)

P

3.2 0.8

4.0 0.6

NS NS

4.2

3.5

NS

3.4 51.9 4.2 2.6 20.6

3.3 52.0 3.8 2.7 20.6

NS NS NS NS NS

NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; NS, not significant.

Number of patients Number of adverse events Number of serious adverse events Patients with adverse events (%) Patients with serious adverse events (%) Patients with drug-related adverse events (%) Patients with drug-related serious adverse events (%) Treatment discontinuation due to adverse event (including severe hypotension and serious adverse events) (%)

Zofenopril

Lisinopril

504 1026 95 367 (72.8) 69 (13.7)

520 947 85 370 (71.2) 65 (12.5)

147 (29.2)

148 (28.5)

18 (3.6)

13 (2.5)

83 (16.5)

99 (19.0)

(4.0%). Likewise, no significant differences have been observed in the incidence of CHF either during the inhospital or the overall 6-week treatment period in agreement with the lack of difference in the value of ejection fraction at the end of the treatment period (Table II). The rate of significant deterioration of renal function was comparable between the 2 treatment groups, thereby suggesting a prevalent role of intraglomerular hemodynamic mechanisms over systemic hypotension in the renal effects of ACE inhibition in post-MI patients. The incidence of cumulative as well as serious adverse events tended to be slightly higher in the zofenopril than in the lisinopril group, whereas the rate of treatment discontinuation due to adverse events (including severe hypotension) was higher in the lisinopril group (Table III), although the differences did not achieve statistical significance.

Discussion 2-sided P ⫽ .017). The average time interval between randomization and onset of severe drug-related hypotension was comparable in zofenopril and lisinopril recipients (5.9 ⫾ 11 vs 5.5 ⫾ 12 days, respectively, 2-sided P ⫽ .59), and no relationship was observed between the onset of hypotension and the time of the first administration of study drugs during the day or the night.

Secondary measures of safety and efficacy No statistically significant differences were observed between the treatment groups for any of the secondary measures of safety or efficacy (Table II). During the treatment period, there were 16 deaths in the zofenopril group (3.2%), and 21 deaths in the lisinopril group

Acute myocardial infarction is often associated with activation of the circulating renin-angiotensin-aldosterone (RAA) system, which can cause necrosis of cardiac myocytes21 and systemic vasoconstriction22 leading to deterioration in left ventricular structure and function.19,23 Accordingly, there is a sound rationale for the pharmacologic blockade of the RAA system in the setting of acute MI,1 and the results arising from several large-scale controlled clinical trials have largely confirmed this hypothesis.8-10,24,25 In particular, the results of a systematic overview of 14 randomized studies, involving about 100,000 patients, demonstrated a 7.1% reduction in 30-day mortality and a 4.0% reduction in 30-day incidence of severe CHF in patients treated with ACE inhibitors when compared with controls.2 Most of this benefit occurs during the

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first few days of treatment, when the risk of death is greatest, thus suggesting a prominent role for the acute effects of ACE inhibitors in patients with MI. Despite extensive evidence of benefit,26 the early initiation of ACE inhibitor therapy after acute MI does raise possible safety concerns.20,27 Blockade of angiotensin II production during the acute phase of MI can impair ventricular healing and promote infarct expansion.28 Moreover, ACE inhibition can cause a significant hypotensive response that might lead to expansion of the subendocardial ischemic lesion.29 The reduction in plasma angiotensin II levels might also impair renal function, particularly in patients who rely upon the RAA system for preservation of renal blood flow (eg, those with left ventricular dysfunction or symptomatic CHF).23 Recent large-scale controlled clinical trials have suggested that the use of ACE inhibitors in the acute or subacute phase of MI is associated with an increased risk of adverse events, in particular hypotension.8-10,18,24 The excess in hypotensive risk occurs predominantly during the first week of treatment and may be responsible for the development of clinical complications such as cardiogenic shock and, in particular, renal dysfunction,2 both of which occur predominantly among elderly patients (aged ⱖ75 years) and in those presenting with SBP ⬍100 mm Hg.2 On the basis of these findings, it would appear that the extent of the benefit derived from ACE inhibition in patients with acute MI will be significantly influenced by the degree of blood pressure control. In particular, the risk of hypotension is likely to reduce the use of such drugs in patients with acute myocardial injury. The SMILE study indicated that zofenopril could be safely administered on a forced-dose titration schedule within 24 hours of symptom onset in nonthrombolyzed patients with anterior MI aged ⱕ80 years.10 In particular, in the SMILE study, the rate of treatment discontinuation because of severe or symptomatic hypotension (SBP ⬍90 mm Hg), and the incidence of first-dose hypotension were comparable in patients treated with zofenopril and controls (3.8% vs 2.7% and 0.6% vs 0.3%, respectively). The results of this study extend these earlier findings by demonstrating that zofenopril is well tolerated when initiated on the same titration schedule within 24 hours of symptom onset in a broad population of patients with acute MI (ie, with different infarct sites) undergoing thrombolytic therapy. Overall, the incidence of adverse events observed with zofenopril was comparable to that observed with the reference drug lisinopril, and both drugs showed a tolerability profile that was largely consistent with previous clinical observations in the same field,27 and supports the systematic use of ACE inhibitors during the acute phase of MI. Interestingly, the treatment with zofenopril was associated with a slightly decreased incidence of se-

Borghi and Ambrosioni 85

vere, drug-related hypotension that achieved a marginal statistical significance when compared with that observed with the recommended dose of lisinopril (10 mg/day) and is most pronounced during the acute phase after hospital admission, when the risk of adverse effects from ACE inhibitors is greatest.2 Many different reasons can account for the satisfactory safety profile of both ACE inhibitors in the SMILE-2 trials. In particular, the progressive increase in the dosage of either zofenopril or lisinopril could prevent any extensive blockade of RAA system during the acute phase of MI and improve the extent of blood pressure control. The importance of the dose-titration schedule of ACE inhibitors in patients with acute MI can be inferred by the negative results of the Cooperative New Scandinavian Enalapril Survival (CONSENSUS) II study,18 where the intravenous administration of a fixed dose of enalapril resulted in an excessive risk of severe hypotension. This was avoided in subsequent clinical trials of structurally dissimilar ACE inhibitors by progressively increasing the dosage according to the individual blood pressure response.6-10 The slight but significant difference in the rate of severe drugrelated hypotension we observed in the SMILE-2 study between zofenopril and lisinopril is in agreement with the differences in the extent of hypotension observed in the SMILE and Gruppo Italiano per la Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) 3 studies. We speculate that this trend could be related to the shorter plasma half-life of zofenopril,30 which could contribute to further improve the tolerability of ACE inhibitors and reduce the risk of hypotensive complications during the acute phase of MI. In conclusion, the results of the SMILE-2 study—the first trial to directly compare 2 different ACE inhibitors in patients with acute MI—reached the reassuring confirmatory conclusion that ACE inhibitors can be safely given to patients with MI where the occurrence of hypotension can be largely limited by an adequate dose-titration of drugs, even in the face of a different pharmacologic profile. We thank Professor G. Patrizi for his continuous research support. We also thank Dr Giulio Zuanetti for his invaluable contribution in the preparation of the manuscript.

References 1. Borghi C, Ambrosioni E. Evidence-based medicine and ACE inhibition. J Cardiovasc Pharmacol 1998;32(2 Suppl):S24-35. 2. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. Circulation 1998;97:2202-12. 3. The Heart Outcome Prevention Evaluation Study Investigators. Ef-

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19. McAlpine HM, Morton JJ, Leckie B, et al. Neuroendocrine activation after acute myocardial infarction. Br Heart J 1988;60:117-24. 20. Borghi C, Bacchelli S, Degli Esposti D, et al. Early and late angiotensin-converting enzyme inhibition in acute myocardial infarction. Am J Cardiol 1993;72(G Suppl):169-74G. 21. Tan LB, Jalil JE, Pick R, et al. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991;69:1185-95. 22. Hollenberg NK. The renin-angiotensin system and cardiovascular disease. Blood Press 2000;1(Suppl):5-8. 23. Sigurdsson A, Held P, Swedberg K. Short- and long-term neurohumoral activation following acute myocardial infarction. Am Heart J 1993;126:1068-76. 24. Chinese Cardiac Study Collaborative Group. Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995;345:686-7. 25. Shen W, Gong L. Beneficial effects of captopril on prognosis in patients with acute myocardial infarction. Shanghai Secondary Prevention of Acute Myocardial Infarction Study Group. Chin Med J 1996;109:588-91. 26. Borghi C, Ambrosioni E. Clinical aspects of ACE inhibition in patients with acute myocardial infarction. Cardiovasc Drugs Ther 1996;10:519-25. 27. Borghi C, Ambrosioni E. Risk-benefit assessment of ACE inhibitor therapy post-myocardial infarction. Drug Safety 1996;14:277-87. 28. Sun Y, Weber KT. Infarct scar: a dynamic tissue. Cardiovasc Res 2000;46:250-6. 29. Scharper W, Pasyk S. Influence of collateral flow on the ischemic tolerance of the heart following acute and subacute occlusion. Circulation 1976;66:1143-9. 30. DeForrest JM, Waldron TL, Krapcho J, et al. Preclinical pharmacology of zofenopril, an inhibitor of angiotensin I converting enzyme. J Cardiovasc Pharmacol 1989;13:887-94.

Appendix SMILE-2 Working Party participating centers and clinical investigators Italy: Andreoli L, Bacchelli S, Bacca F, Borgo E, Castellani G, Cecchetti E, Conti U, Corsini G, Degli Esposti D, De Matteis C, De Rinaldis G, Ferrante R, Galati A, Iliceto S, Jacovoni F, Mangiameli S, Marcellini G, Mazzini CA, Napoli A, Pasotti C, Pelini F, Ruggeri G, Scelfo R, Tartagni F, Capelletti D

Czech Republic: Adamec F, Bezdekova´ I, Bican J, Carda J, Dosta´l J, Dusˇek J, Fa´bik L, Filipensky´ B, Go ¨ rner M, Hapla J, Havlı´k V, Charouzek J, Kala M, Kos P, Kotousˇ J, Kladı´vkova´ M, Klı´r J, Kova´r P, Kra´l J, Kroupa J, Luka´ˇsek J, Martı´nek, CSc, Moses K, Mu ¨ nz J, Navra´til J, Nemecek E, Nova´k J, Plocek J, Podzemska´ B, Povolny´ J, Sa´bl P, Semra´d J, Sla´ma J, Stoupenec R, Svoboda J, ˇS´rek ı J, Toma´ˇsek J, Turkova´ N, Wiendl J, Zuvakova´ J, Za´kova´ A

Germany: Bechthold H, Bernsmeyer R, Beyer T, Beythien R, Bleckmann A, Bo ¨ hm K, Dietz A, Dyckmanns J, Frede S, Go ¨ rge G, Greiner A, Gu ¨ tzkow R, Hanraths M, Klocke R, Kohler B, Kunze M, Lipke M, Loos U, Malsch B, Ma¨urer W, Meier M, Mendoza, Mu ¨ gge A, Mu ¨ hling H, Niederer W, Oehler M, Oet-

American Heart Journal Volume 145, Number 1

tel R, Post G, Presser H, Probst M, Sanuri M, Schinke R, Schubotz R, Schwertfeger F, Sehnert W, Simon M, Tebbe U, Wacker P, Walthier J, Wegener M, Westhoff M

Poland: Dudzik-Flis E, Hiczkiewicz J, Juszczyk Z, Kuc K, Kusnierz B, Kuzniar J, Majcher Z, Miarka J, Piotrowski W, Pluta A, Pluta W, Polonski L, Sciborski R, Siedlecki J

Romania: Alexandru I, Carstea D, Christodorescu GR, Cinteza M, Bruckner IV, Georgescu D, Manitiu I, Mihalla M, Olariu C,

Borghi and Ambrosioni 87

Panturu E, Radol M, Sinescu C, Stefanescu M, Tatu-Chitoiu G, Topolnitchi L

Russia: Arutyunov G, Ivanov G, Lusov V, Sidorenko B, Sviridov A, Troshina E (Moscow), Ostrovskly A, Orlova H, Therevko V, Veklenko M

Ukraine: Amosova E, Karpenko A, Orgorodniychuk A, Parkhomenko V, Dutka R, Dykun Y, Goloborodko B, Kubyshkin V, Syvolap V