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Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients
Marcus D Flather, Salim Yusuf, Lars Kber, Marc Pfeffer, Alistair Hall, Gordon Murray, Christian Torp-Pedersen, Stephen Ball, Janice Pogue, Lemuel Moy, Eugene Braunwald, for the ACE-Inhibitor Myocardial Infarction Collaborative Group

Summary
Background We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensinconverting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure. Methods Three of the trials enrolled patients within a week after acute myocardial infarction. Data were combined by use of the Peto-Yusuf method. Findings Overall 12 763 patients were randomly assigned treatment or placebo and followed up for an average of 35 months. In the three post-infarction trials (n=5966), mortality was lower with ACE inhibitors than with placebo (702/2995 [234%] vs 866/2971 [291%]; odds ratio 074 [95% CI 066083]), as were the rates of readmission for heart failure (355 [119%] vs 460 [155%]; 073 [063085]), reinfarction (324 [108%] vs 391 [132%]; 080 [069094]), or the composite of these events (1049 [350%] vs 1244 [419%]; 075 [067083]; all p<0001). For all five trials the ACEinhibitor group had lower rates of death than the placebo group (1467/6391 [230%] vs 1710/6372 [268%]; 080 [074087]) and lower rates of reinfarction (571 [89%] vs 703 [110%]; 079 [070089]), readmission for heart failure (876 [137%] vs 1202 [189%]; 067 [061074]), and the composite of these events (2161 [338%] vs 2610 [410%]; 072 [067078]; all p<00001). The benefits were observed early after the start of therapy and persisted long term. The benefits of treatment on all outcomes were independent of age, sex, and baseline use of diuretics, aspirin, and blockers. Although there was a trend towards greater reduction in risk of death or readmission for heart failure in patients with lower ejection fractions, benefit was apparent over the range examined.
Preventive Cardiology and Therapeutic Research Program, Hamilton Health Sciences Corporation Research Centre (M D Flather MRCP, Prof S Yusuf FRCP, J Pogue MSc) and Division of Cardiology (Prof S Yusuf, J Pogue), McMaster University, Hamilton, Ontario, Canada; Clinical Trials and Evaluation Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK (M D Flather); Department of Cardiology, Gentofte Hospital, Hellerup, Denmark (L Kber MD, C Torp-Pedersen MD); Cardiovascular Division, Brigham and Womens Hospital, Boston, MA, USA (Prof M Pfeffer MD, Prof E Braunwald MD); Institute for Cardiovascular Research, Yorkshire Heart Centre, Leeds, UK (A Hall MRCP, Prof S Ball FRCP); Public Health Sciences, University of Edinburgh, Edinburgh, UK (Prof G Murray PhD); and University of Texas, Houston, TX, USA (L Moy PhD) Correspondence to: Prof Salim Yusuf, Hamilton General Hospital, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada (e-mail: yusufs@fhs.mcmaster.ca)

Interpretation This systematic overview shows that ACE inhibitors lower rates of mortality, myocardial infarction, and hospital admission for heart failure in patients with leftventricular dysfunction or heart failure with or without a recent myocardial infarct. The use of ACE inhibitors should be part of routine practice in these patients. Lancet 2000; 355: 157581

Introduction
Several large randomised trials have assessed the role of angiotensin-converting-enzyme (ACE) inhibitors for patients with acute myocardial infarction. Some trials started ACE inhibitors within 2436 h of the onset of acute myocardial infarction in unselected patients and continued treatment for a few weeks or months (short-term trials).1 Other trials24 started treatment a few days or weeks after the onset of acute myocardial infarction in patients with heart failure or left-ventricular dysfunction, and continued treatment for at least a year (long-term trials). In addition, two trials of patients with low ejection fractions5,6 included a substantial number of patients with previous myocardial infarction and randomly assigned them long-term therapy with an ACE inhibitor or placebo. Although each trial provides useful data on mortality and morbidity, many important questions remain unanswered. Uncertainty remains about the size of the treatment benefit on mortality, hospital admission for heart failure, and reinfarction; whether the benefits occur soon after randomisation and persist on long-term treatment; and whether the benefits of treatment vary in different subgroups of patients or those taking different medications concomitantly. Systematic overviews (meta-analyses) of large randomised trials improve estimates of treatment effects because they have greater statistical power than the individual trials. Overviews that use data from individual patients can provide more information than those that use published collective data because they have greater flexibility in analysis. In particular, more reliable information on the estimated overall treatment effect size, the effects of treatments in subgroups of patients, the riskbenefit ratios in these patients, and the time course of the treatment effect can be obtained by use of data from individuals in each trial compared with a meta-analysis based on published data. A systematic overview of the short-term ACE-inhibitor trials has been reported previously.1 We report a collaborative overview of the long-term trials, which sought to estimate more precisely the overall benefits (on deaths, admission for heart failure, and reinfarction) and risks of ACE inhibitors, and to assess treatment effects in clinically important subgroups.

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Trial

Eligibility

Timing of first dose after AMI 316 days 310 days 37 days >1 month >1 month

Agent and regimen

Average follow-up (months) 42 15 36 41 37

SAVE AIRE TRACE SOLVD treatment SOLVD prevention

LVEF <40% Clinical heart failure Wall motion index <12 (LVEF <35%) CHF; LVEF 35% No treatment for CHF; LVEF 35%

Captopril or placebo 125 mg initial dose, up to 2550 mg three times daily Ramipril or placebo 25 mg twice daily initial dose, up to 5 mg twice daily for at least 6 months Trandolapril or placebo 1 mg daily initial dose, up to 4 mg daily Enalapril or placebo initial dose 25 or 5 mg twice daily up to 10 mg twice daily Enalapril or placebo initial dose 25 or 5 mg twice daily up to 10 mg twice daily

AMI=acute myocardial infarction; LVEF=left-ventricular ejection fraction; CHF=congestive heart failure. All trials were double blind.

Table 1: Key design features of trials

Methods
Data collection
Experience from previous overviews has shown that most of the clinically useful information comes from the large randomised trials. Thus, this overview was prospectively limited to randomised trials of more than 1000 patients in which the intention was to treat patients with ACE inhibitors or control after myocardial infarction for at least 12 months and to examine their consistency with the SOLVD (Studies of Left Ventricular Dysfunction) trials.5 We carried out a literature search of randomised trials of ACE inhibitors in patients with acute myocardial infarction using MEDLINE and OVID. We identified three large long-term trials that enrolled more than 1000 patients and had an average followup of longer than 1 year. We cross-checked our findings by consulting other researchers and colleagues in the pharmaceutical industry, and by scrutinising reference lists from review articles, to find out about any other published or unpublished trials. Principal investigators from each of the large randomised trials (short-term and long-term) of ACE inhibitors in myocardial infarction and the SOLVD trials were invited to form a collaborative group, which agreed on the data to be collected, and to review the analyses and manuscripts. The group agreed that the overview would collect data from each individual randomised patient. A prospective protocol was written before data collection. It summarised the methods to be used, the main prespecified analyses, and a common data-set of 88 variables. The contents of the protocol were agreed by the collaborative group. Data-sets from each trial were sent to the coordinating centre at the Preventive and Therapeutic Cardiology Research Programme, Hamilton Health Sciences Corporation in Hamilton, Canada. The data-sets were rigorously checked for completeness and consistency to ensure that no errors had occurred in reformatting of the data, and to check for agreement with the original publications. Queries were resolved by communication with the principal investigators. After such checking, the data-sets were incorporated into the master data-base, which was used for analysis. Results of analyses were discussed at several meetings.

z values, and the SD (the square root of this variance) were calculated. Results are presented by the typical odds ratio (the ratio of the odds of an unfavourable outcome among treatmentallocated patients to the corresponding odds among controls). The typical log odds ratio is estimated by the formula z/SD, so the odds ratio is given by the exponential (exp) of z/SD, with approximate 95% CI exp(z/SD196/SD). Standard statistical tests for heterogeneity were used to assess whether results from trials were significantly different from each other. For survival analyses and analyses involving regression principles, the data-set was treated as if it came from one trial. Odds ratios and 95% CI are presented with corresponding two-sided p values. Definitions of myocardial infarction, readmission for heart failure, and side-effects differed among trials. After discussion we accepted that the only practical and unbiased approach was to use the definitions in the original trials. However, in all cases an intention-to-treat approach was used, so events occurring after withdrawal of study medication were included if available.

Results
Patients The three long-term, randomised double-blind placebocontrolled trials of total sample size greater than 1000 patients (table 1) were SAVE (Survival and Ventricular Enlargement), AIRE (Acute Infarction Ramipril Efficacy), and TRACE (trandolapril in patients with reduced leftventricular function after acute myocardial infarction). A total of 5966 patients with evidence of left-ventricular dysfunction or clinical heart failure were randomly assigned ACE-inhibitor treatment or placebo control between 3 days and 16 days after acute myocardial infarction. The distribution of baseline characteristics of patients in these trials and in the SOLVD trials is given in table 2.

Variable

Consistency of results
From the outset we recognised that there was substantial overlap between the trials of patients with left-ventricular dysfunction after myocardial infarction and the SOLVD treatment and prevention trials of enalapril in chronic heart failure, because all these trials had investigated the effects of ACE inhibitors in patients with leftventricular dysfunction and most of the patients in SOLVD had experienced a myocardial infarction previously. In this overview we first analysed the main clinical outcomes (death, death or readmission for heart failure, death or myocardial infarction) for the three studies of patients after myocardial infarction and for the two SOLVD trials separately and examined the consistency of results across these data-sets. Subsequently, to increase statistical power for subgroup analyses we combined data from all five studies, especially when significant proportions of data were missing.
Demography Mean (SD) age (years) F M History Previous myocardial infarction Diabetes Hypertension Current smoker* Clinical Mean (SD) time from onset of symptoms to randomisation (days) Anterior myocardial infarction Mean (SD) ejection fraction (%) Mean (SD) heart rate (bpm) Mean (SD) systolic blood pressure (mm Hg) Mean (SD) diastolic blood pressure (mm Hg) Aspirin Diuretics -blockers

SAVE, AIRE, TRACE (n=5966) 63 (11) 1416 (237%) 4550 (763%) 1859 (312%) 969 (162%) 1791 (300%) 1766 (444%) 8 (4) 3159 (529%) 32 (8) 79 (13) 116 (17) 72 (10) 4444 (745%) 3119 (523%) 1510 (253%)

SOLVD (n=6797)

All trials (n=12 763)

59 (10) 980 (144%) 5817 (856%) 5069 (746%) 1310 (193%) 2652 (390%) 1562 (294%) 27 (6) 77 (13) 125 (17) 78 (10) 3153 (464%) 2901 (427%) 1212 (178%)

61 (11) 2396 (188%) 10 367 (812%) 6928 (543%) 2279 (179%) 4443 (348%) 3328 (358%) 8 (4) 3159 (547%) 29 (7) 78 (13) 122 (17) 76 (10) 7597 (595%) 6020 (472%) 2722 (213%)

Statistics
The statistical principles have been described in detail previously. The Mantel-Haenszel method,7 modified by Peto and Yusuf,8 was used to combine dichotomous variables across different trials. The standard quantity, observed minus expected, was calculated for the number of events among treatment-allocated patients and controls. The variance of the total of the individual observed minus expected

*Information on smoking not available for 3471 patients.

Table 2: Baseline characteristics of patients in trials

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Deaths Information on vital status for patients in the five trials was 999% complete. The median treatment duration in SAVE, AIRE, and TRACE was 31 months (IQR 1941). There were 702 (234%) deaths of 2995 in the ACE-inhibitor group compared with 866 (291%) of 2971 in the control group (odds ratio 074 [95% CI 066083], p<00001; figure 1; table 3). The absolute event-rate difference was 57%. For every 1000 patients treated, about 60 deaths would be avoided (or, to avoid one death, about 15 patients would have to be treated for about 30 months). 6 weeks after randomisation, the proportion of deaths in the ACEinhibitor group was 61% compared with 79% in the control group; thus, the benefits of treatment were apparent very soon after the start of treatment. The results in the SOLVD trials were similar, with no apparent heterogeneity in results between the two categories of trials when the data were examined at the same time point (p values for interaction between trial type and event by time-to-event analysis 0087 for deaths, 083 for readmission for heart failure, 082 for reinfarction, 052 for death or reinfarction, 083 for death or readmission, 036 for death/reinfarction/ readmission, 019 for stroke). For the five trials together the proportion of deaths was 230% in the ACE-inhibitor
40 Cumulative mortality (%) SAVE, AIRE, and TRACE
ACE inhibitor Placebo

group and 268% in the control group (080 [074087], p<00001). Figure 1 shows the continuing divergence in the mortality curves during follow-up that exceeds 4 years. Readmission for heart failure In SAVE, AIRE, and TRACE, 119% of the ACE-inhibitor group and 155% of the control group were readmitted for heart failure (073 [063085], p<00001; figure 2); for all five trials the rates were 137% and 189% (067 [061074], p<00001). The combination of death or hospital admission for heart failure occurred in 305% of the ACE-inhibitor group and 370% of the control group of SAVE, AIRE, and TRACE (074 [067083], p<00001), the results in the SOLVD trials were similar. Overall the rate of death or readmission was 369% in the control group and 307% in the ACE-inhibitor group (074 [069080], p<00001). Myocardial infarction 108% of the ACE-inhibitor group and 132% of the control group in SAVE, AIRE, and TRACE had recurrent
Variable Events ACE-1 SAVE, AIRE, TRACE n Death At 6 weeks At 1 year At 2 years At 4 years Overall Reinfarction* Readmission for CHF Death or reinfarction Death or readmission for CHF Death/MI/or readmission for CHF Stroke SOLVD n Death At 6 weeks At 1 year At 2 years At 4 years Overall Reinfarction* Readmission for CHF Death or reinfarction Death or readmission for CHF Death/MI/or readmission for CHF Stroke All trials n Death At 6 weeks At 1 year At 2 years At 4 years Overall Reinfarction* Readmission for CHF Death or reinfarction Death or readmission for CHF Death/MI/or readmission for CHF Stroke 2995 184 (61%) 458 (153%) 575 (192%) 679 (227%) 702 (234%) 324 (108%) 355 (119%) 876 (292%) 914 (305%) 1049 (350%) 121 (40%) 3396 28 (08%) 266 (78%) 463 (136%) 740 (218%) 765 (225%) 247 (73%) 521 (153%) 849 (250%) 1048 (309%) 1112 (327%) 118 (35%) 6391 212 (33%) 724 (113%) 1038 (162%) 1419 (222%) 1467 (230%) 571 (89%) 876 (137%) 1725 (270%) 1962 (307%) 2161 (338%) 239 (37%) Control 2971 236 (79%) 523 (176%) 695 (234%) 833 (280%) 866 (291%) 391 (132%) 460 (155%) 1054 (355%) 1100 (370%) Odds ratio (95% CI) p

076 (062092) 084 (073097) 077 (068088) 075 (066084) 074 (066083) 080 (069094) 073 (063085) 075 (067083) 074 (067083)

00059 00142 00001 <00001 <00001 00057 <00001 <00001 <00001 <00001 048 0045 0086 00019 00109 0021 00043 <00001 00001 <00001 <00001 0185 00009 00028 <00001 <00001 <00001 00001 <00001 <00001 <00001 <00001 063

30

20

10

1244 (419%) 075 (067083) 110 (37%) 3401 45 (13%) 305 (90%) 553 (163%) 826 (243%) 844 (248%) 312 (92%) 742 (218%) 989 (291%) 1254 (369%) 110 (084143) 062 (039099) 086 (072102) 081 (070092) 086 (076097) 087 (078098) 078 (065092) 063 (056072) 080 (072090) 074 (067083)

0 0
Number at risk ACE-I Placebo 2995 2971 2250 2184 1617 1521 892 853 223 138

40 Cumulative mortality (%)

All trials

1366 (402%) 070 (064078) 139 (41%) 6372 281 (44%) 828 (130%) 1248 (196%) 1659 (260%) 1710 (268%) 703 (110%) 1202 (189%) 2043 (321%) 2354 (369%) 084 (066108) 073 (061088) 085 (076094) 079 (072086) 080 (074087) 080 (074087) 079 (070089) 067 (061074) 077 (072084) 074 (069080)

30

20

10

0 0 1 2 3 4 5

2610 (410%) 072 (067078) 249 (39%) 096 (080115)

Time since randomisation (years)

Number at risk ACE-I Placebo 6391 6372 5378 5279 4204 4025 2457 2364 892 742

CHF=congestive heart failure; MI=myocardial infarction. *If only the adjudicated MI from SAVE are included, the odds ratio is 083 (95% CI 071098) for SAVE, AIRE, and TRACE and 081 (072091) for all trials.

Figure 1: Mortality

Table 3: Summary of major clinical events

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Cumulative death/readmission (%)

60 50 40 30 20 10 0

SAVE, AIRE, and TRACE

ACE inhibitor Placebo

60
Cumulative death/reinfarction (%)

SAVE, AIRE, and TRACE ACE inhibitor Placebo

50 40 30 20 10 0

0
Number at risk ACE-I 2995 Placebo 2971

1
2128 2025

2
1529 1425

3
818 802

4
184 173

5
ACE-I

0
Number at risk 2995

1
2131 2057

2
1502 1393

3
819 760

4
214 183

Placebo 2971

60 Cumulative death/readmission (%) 50 40 30 20 10 0

All trials

50

All trials

Cumulative death/reinfarction (%)

40

30

20

10

0
Number at risk ACE-I 6391 Placebo 6372

0 0 1 2 3 4 Time since randomisation (years) 5

Time since randomisation (years)

5094 4809 3877 3575 2212 2042 786 624

Number at risk ACE-I 6391 5206 5079 4029 3796 2330 2187 856 729 Placebo 6372

Figure 2: Death or readmission for heart failure

myocardial infarction (080 [069094], p=00057). The SOLVD results were similar. In combination with the SOLVD studies the rates were 89% in the ACE-inhibitor group and 110% in the control group (079 [070089], p=00001). Counting the first event only, the proportion with death or myocardial infarction in SAVE, AIRE, and TRACE was 292% in the ACE-inhibitor group and 355% in the control group (075 [067083], p<00001, figure 3), and in combination with SOLVD the corresponding rates were 270% and 321% (077 [072084], p<00001). The results were unchanged if only the adjudicated myocardial infarctions from SAVE were included or if any single trial was omitted. This finding suggests that although the definition of myocardial infarction varied among the trials, the overall conclusions were not greatly affected. For the endpoint death, myocardial infarction, and readmission for heart failure, the overall rate was 410% in the control group and 338% in the ACE-inhibitor group (072 [067078], p<00001; figure 4). Thus, treatment of 100 patients could prevent seven major events. Furthermore, the upper 95% confidence limit shows that a clinically important 22% risk reduction is highly likely. Stroke Stroke rates in the ACE-inhibitor and control groups were similar (table 3). However, the 95% CI are wide and these

Figure 3: Death or reinfarction

data do not conclusively exclude a clinically worthwhile benefit. A further analysis among patients with a history of hypertension or baseline systolic blood pressure of 140 mm Hg or higher showed 119 (44%) events in 2677 patients in the ACE-inhibitor group and 134 (51%) in 2615 in the control group (086 [067111], p=025). Outcomes stratified by baseline characteristics Ejection fraction at randomisation was available for all patients in the SAVE and SOLVD studies. In TRACE, ejection fraction was derived from the wall motion index (a value of 12 is roughly equal to an ejection fraction of 35%). In AIRE, ejection fraction was available for only 25% of patients. We analysed the effects of ACE inhibitors initially in four strata of baseline ejection fraction (<23%, 2327%, 2835%, >35%). Risk of death was strongly correlated with baseline ejection fraction. Patients in the lowest stratum had the worst outcome. For each stratum of ejection fraction, there was a benefit observed with ACE inhibitors, but the greatest proportional benefits were observed in the lowest stratum. A regression analysis of all five trials comparing the effects of ACE inhibitor and placebo showed a strong correlation between baseline ejection fraction and odds reduction of the composite outcome of death, readmission for congestive heart failure, or myocardial infarction with ACE inhibitors (p=0004, table 4).

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Cumulative death/readmission/ reinfarction (%)

70 60 50 40 30 20 10 0

SAVE, AIRE, and TRACE

ACE inhibitor Placebo

Endpoint and Events EF stratum ACE-1 SAVE, AIRE, TRACE Mortality <23% 121/263 (460%) 2327% 133/351 (379%) 2835% 209/949 (220%) >35% 116/714 (162%) CHF readmission <23% 52/263 (198%) 2327% 57/351 (162%) 2835% 94/949 (99%) >35% 63/714 (88%)

Control

Odds ratio (95% CI)

153/262 (584%) 164/385 (426%) 257/899 (286%) 133/714 (186%) 67/262 (256%) 81/385 (210%) 125/899 (139%) 78/714 (109%) 41/262 (156%) 53/385 (138%) 137/899 (152%) 93/714 (130%) 179/262 (683%) 213/385 (553%) 366/899 (407%) 231/714 (324%)

060 (043085) 082 (061111) 068 (055084) 087 (066114) 071 (047107) 073 (050105) 069 (052091) 078 (055111) 062 (037103) 066 (042103) 086 (067112) 079 (057109) 063 (044089) 081 (061109) 074 (061089) 078 (062098)

026

054

0
Number at risk ACE-I Placebo 2995 2971

1
2027 1916

2
1431 1314

3
771 721

4
198 151

MI <23% 2327% 2835% >35%

27/263 (103%) 33/351 (94%) 128/949 (135%) 75/714 (105%)

031

70 Cumulative death/readmission/ reinfarction (%) 60 50 40 30 20 10 0

All trials

Death/CHF readmission/MI <23% 151/263 (574%) 2327% 176/351 (501%) 2835% 322/949 (339%) >35% 192/714 (269%) SOLVD Mortality <23% 2327% 2835% >35%

049

266/824 (323%) 167/714 (234%) 331/1854 (179%) NA

319/813 (392%) 211/787 (268%) 313/1799 (174%) NA 279/813 (343%) 184/787 (234%) 278/1799 (155%) NA 84/813 (103%) 73/787 (93%) 154/1799 (86%) NA 453/813 (557%) 310/787 (394%) 490/1799 (272%) NA

073 (059089) 079 (062100) 105 (088125)

0015

CHF readmission <23% 191/824 (232%) 2327% 114/714 (160%) 2835% 215/1854 (116%) >35% NA MI <23% 2327% 2835% >35% 68/824 (83%) 47/714 (66%) 132/1854 (71%) NA

057 (046071) 058 (044075) 072 (059087)

0085

0
Number at risk ACE-I Placebo 6391 6372

1 2 3 4 Time since randomisation (years)

4950 4635 3735 3386 2118 1901 759 604

078 (056109) 069 (048100) 082 (065105)

081

Figure 4: Death, readmission for heart failure, or reinfarction

Death/CHF readmission/MI <23% 352/824 (427%) 2327% 227/714 (318%) 2835% 468/1854 (252%) >35% NA All trials Mortality <23% 2327% 2835% >35%

057 (047070) 066 (053083) 091 (078106)

00008

However, for myocardial infarction alone, there was no trend for a differential treatment effect at different ejectionfraction values. With stratification for age (<55 years, 5564 years, 6574 years, >75 years) there was no heterogeneity in the benefits of treatment for the combined outcomes of death or myocardial infarction and death or readmission for heart failure. There was no heterogeneity in the benefits on this composite endpoint between men and women (test for interaction p=034; table 5). Benefits of ACE inhibitors were not related to baseline systolic blood pressure or heart rate and benefits were observed over a range of values (data not shown). The benefits of ACE inhibitors in terms of mortality or the composite of death, readmission for heart failure, or myocardial infarction were consistent among patients receiving or not receiving diuretics, aspirin, or -blockers at randomisation. Within each of these subgroups there was clear and statistically significant odds reduction on both outcomes (table 5). Side-effects Data on the adverse effects associated with treatment were available from SAVE, TRACE, and SOLVD. Hypotension occurred in 791 (147%) of 5387 ACE-inhibitor-group patients and 466 (86%) of 5390 placebo-group patients (186 [165210], p<00001). Renal dysfunction occurred in 281 (52%) and 194 (36%), respectively (149 [123179], p<00001).

387/1087 (356%) 300/1065 (282%) 540/2803 (193%) 116/715 (162%)

472/1075 (439%) 375/1172 (320%) 570/2698 (211%) 133/714 (186%) 346/1075 (322%) 265/1172 (226%) 403/2698 (149%) 78/714 (109%) 125/1075 (116%) 126/1172 (108%) 291/2698 (108%) 93/714 (130%) 652/1075 (607%) 549/1172 (468%) 922/2698 (342%) 231/714 (324%)

069 (058083) 080 (066097) 088 (077101) 087 (066114) 060 (049072) 062 (050077) 071 (060083) 078 (055111) 073 (055096) 068 (051090) 084 (070100) 079 (057109) 057 (048067) 069 (058082) 080 (072090) 078 (062098)

0066

CHF readmission <23% 243/1087 (224%) 2327% 171/1065 (161%) 2835% 309/2803 (110%) >35% 63/715 (88%) MI <23% 2327% 2835% >35% 95/1087 (87%) 80/1065 (75%) 260/2803 (93%) 75/715 (105%)

0052

038

Death/CHF readmission/MI <23% 514/1087 (473%) 2327% 415/1065 (390%) 2835% 831/2803 (296%) >35% 192/715 (269%)

00039

EF=ejection fraction; NA=not available; CHF=congestive heart failure; MI=myocardial infarction. *For heterogeneity. In SOLVD, a patient with an EF between 36% and 40% could be enrolled if there was a measure in the previous 3 months with a value below 35%. Comparison of the regression slopes comparing EF with treatment benefit by trial type (SOLVD vs Post Mi) for each outcome is as follows: Death p=043, CHF Hosp p=051, MI p=062, Death/CHF hosp/MI p=0078.

Table 4: Outcomes according to ejection-fraction stratum

Discussion
Overall there was a 28% reduction in death, myocardial infarction, and hospital admission for heart failure in patients with left-ventricular dysfunction after myocardial infarction treated with ACE inhibitors. The upper

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Subgroup Sex Men Women Age (years) <55 5564 6575 >75 Diuretics at baseline Yes No Aspirin at baseline Yes No -blockers at baseline Yes No

Number of patients 10 367 2396 3165 4315 4194 1066 6020 6737 7597 5158 2722 10 034

Deaths

Odds ratio (95% CI)

p*

Death/CHF/MI

Odds ratio (95% CI)

p*

2506 671 495 994 1227 454 2109 1065 1699 1475 422 2752

079 (072087) 085 (071102) 076 (062093) 084 (073097) 075 (066086) 095 (074122) 080 (072089) 083 (073094) 085 (076095) 075 (067085) 068 (055084) 083 (076091)

054

3759 1012 878 1534 1761 590 2988 1780 2571 2197 749 4019

071 (065077) 079 (067093) 077 (066091) 071 (062081) 067 (059076) 089 (069113) 070 (063077) 076 (068085) 076 (069084) 068 (060076) 067 (056079) 074 (068080)

034

047

095

072

035

023

020

008

030

CHF=congestive heart failure; MI=myocardial infarction. *For heterogeneity.

Table 5: Effects of ACE inhibitors on outcomes in selected subgroups from all five trials

confidence limit indicated at least a 22% risk reduction. Given the high absolute risks among the patients included in these trials, this relative risk reduction translates into 70 patients with at least one event prevented for every 1000 patients treated. These data complement a systematic overview of 100 000 patients randomly assigned treatment in the large trials of ACE inhibitors within 36 h of the onset of acute myocardial infarction, which showed a proportional reduction in mortality of 7% (95% CI 211; p=0004) at 5 weeks.1 The benefit was observed in a wide range of patients within the first few days after the start of treatment. Patients with clinical heart failure or significant leftventricular dysfunction after myocardial infarction are at high risk of death and major morbidity. In these patients, treatment with ACE inhibitors produced a proportional reduction in death of 25% (absolute reduction about 6%) for an average of 25 years of treatment. Thus about 60 deaths would be avoided for every 1000 patients treated (or, to avoid one death, 15 patients would need to be treated). The beneficial effects on mortality were observed rapidly within a few weeks of the start of treatment and increased with duration of treatment. An important 20% relative risk reduction was observed in the rate of myocardial infarction with ACE inhibitors compared with placebo in the three trials after myocardial infarction. This effect was also observed in the SOLVD trials. Changing the definition of myocardial infarction (clinically reported versus adjudicated in SAVE) did not greatly affect the conclusions. These analyses indicate that the results are insensitive to specific categorisation or definitions within a trial and robustly confirm that ACE inhibitors lower rates of myocardial infarction in patients with left-ventricular dysfunction. The lack of a relation between the reduction in myocardial infarction and ejection fraction suggests that ACE inhibitors are valuable in patients who have preserved left-ventricular function, a hypothesis that has now been confirmed.9 There was no apparent effect on stroke with ACE inhibitors in SAVE, AIRE, and TRACE (the entry systolic blood pressure was 116 mm Hg). The SAVE study reported decreases in systolic and diastolic blood pressure of 6 mm Hg and 3 mm Hg in the ACE-inhibitor group, which were similar to those in the SOLVD studies. The lack of effect on stroke is surprising because epidemiological data indicate a continuous relation

between blood pressure and stroke even in the normal range of blood pressure.10 However, mean entry blood pressure was already low (116/72 mm Hg in SAVE, AIRE, and TRACE). The 95% CI of the odds ratio is wide and a 15% relative risk reduction in this outcome with ACE inhibitors cannot be excluded (a 3 mm Hg lowering in diastolic blood pressure would be expected to reduce the risk of strokes by about 1020%). This possibility is supported by a trend towards lower stroke rates with ACE inhibitors in the subgroup of patients with a history of hypertension or systolic blood pressure above 140 mm Hg. Recent data from the HOPE Study confirm that ACE inhibitors reduce the risk of strokes in patients who are not hypertensive.9 By pooling the data, we could demonstrate a clear and graded relation between the degree of baseline leftventricular dysfunction (measured by ejection fraction) and the effects of ACE inhibitors. Greater benefits on mortality and hospital admission for heart failure were observed in patients with lower ejection fractions. The interaction was most clearly apparent in SOLVD (which generated the hypothesis), but less clear in SAVE, AIRE, and TRACE (which tested the hypothesis). The overall analysis including all trials shows a less clear interaction, although on the composite outcome of death, myocardial infarction, or admission for heart failure, there seemed to be a greater benefit among patients with the lowest ejection fractions. These data suggest that even among patients with relatively preserved ejection fractions, there is a clinically important benefit. ACE inhibitors are thought to exert their beneficial effects after myocardial infarction by favourably modifying functional and structural changes in the myocardium that occur in response to myocardial damage and necrosis (remodelling). Ventricular dilatation carries an adverse prognosis. Experimental and clinical studies have shown that the benefits of ACE inhibitors are mostly found in large infarcts, which are prone to cause ventricular dilatation. Thus the relation between benefit of ACE inhibitors and ejection fraction is consistent with these observations. Taking all the evidence from animal and clinical studies, we conclude that, whenever treatment is started, there may be greater benefits of ACE inhibitors in patients with impaired left-ventricular function than in those with preserved function. There may be other important benefits from longterm ACE inhibition on the arterial vessel wall, as indicated by prevention of myocardial infarction that appears to be

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independent of the ejection fraction. This hypothesis has been confirmed in one large trial9 and is being tested in two other large trials,11,12 which are confined to high-risk patients who have no evidence of left-ventricular dysfunction or heart failure. Previous reports from the SOLVD13 and CONSENSUS II trials14 suggested that the effects of ACE inhibitors in chronic heart failure or in acute myocardial infarction were decreased in the presence of aspirin. These data-derived observations required independent assessment. In this overview, the proportional benefits of ACE inhibitors were similar whether or not patients were taking aspirin at baseline (table 5). These data refute the hypothesis of a major aspirin interaction with ACE inhibitors. The analysis does not take into account interactions after randomisation (ie, on-treatment effects), but such postrandomisation subgroup analyses are potentially biased.15 The overview data also indicate an additive effect of an ACE inhibitor in patients receiving -blockers. This possibility is supported by the RESOLVD trial data and SAVE, which indicated an additive effect of ACE inhibitors and -blockers in preventing ventricular dilatation.16 There was an increase in both symptomatic hypotension and renal dysfunction in patients assigned ACE inhibitors compared with those assigned placebo. In general, these effects were not life-threatening and were reversible when the medication was stopped or the dose lowered. The clear benefits of ACE inhibitors outweigh the small risks associated with the drug. Our results show that for the important clinical outcomes of death, hospital admission for heart failure, and recurrent myocardial infarction, the pooled results of the trials after myocardial infarction show great consistency with the SOLVD trials (table 3). These data tend to reinforce each other and justify the current practice of use of ACE inhibitors in patients with left-ventricular dysfunction or heart failure irrespective of the proximity to a myocardial infarction. These observations also justify the approach of pooling the two sets of trials especially for subgroup analyses, in which the data from SOLVD help to increase the reliability of the estimates. We postulated that the cause of heart failure was the same in patients in the SOLVD trials who had previously had myocardial infarction (75% of the total) and patients in the SAVE, AIRE, and TRACE trials. The results in this subset of SOLVD patients are almost identical to those in SAVE, AIRE, and TRACE and the overall results (data not shown). Furthermore in the trials that included patients within few weeks of a myocardial infarction, the median time to event was several months to years after the index event. Therefore, there is substantial overlap in the populations among the various trials. This systematic overview differs from other overviews in several respects. First, a prospective protocol was developed. Second, individual data per patient were collected and analysed. Third, this process allowed analyses of composites of outcomes over time, so a more comprehensive and consistent assessment of treatment effect was possible. Fourth, we were able to explore reliably whether there was significant heterogeneity of the effects of ACE inhibitors in subgroups defined by baseline characteristics and other drug use. From all the available evidence (including a previous overview1), we have conclusively shown that use of ACE

inhibitors after an acute myocardial infarction provides clear benefit to a wide range of patients. Those at high risk, especially with clinical heart failure or left-ventricular dysfunction, can expect substantial reductions in mortality and morbidity. ACE inhibitors should therefore be routinely used long term in all eligible high-risk patients.
Study organisation
Steering committee(early and late trials) L Tavazzi, G Tognoni (GISSI3); R Collins, C Baigent, M Flather, P Sleight (ISIS-4); L S Liu (CCS-1); J Kjekshus, K Swedberg (CONSENSUS II); S Ball (AIRE); L Kber, C Torp-Pedersen (TRACE); E Braunwald, L Moy, M Pfeffer (SAVE); S Yusuf (SOLVD). Coordinating centresEarly trials: M G Franzosi, R Latini, A P Maggioni, E Santoro, L Santoro, G Zuanetti (GISSI). Late trials: M Flather, J Pogue, Y Wang, S Yusuf (Canadian Cardiovascular Collaboration).

Acknowledgments
This project was funded by a grant from the Medical Research Council of Canada and support from Merck Frosst Canada, Merck Sharpe and Dohme, USA, Bristol Myers, Squibb, USA, Zeneca, UK, and Hoechst Marion Roussel, Frankfurt, Germany. S Yusuf is supported by a senior scientist award of the MRC, Canada, and a Heart and Stroke Foundation Research Chair. We thank Judy Lindeman, for typing the paper, and Yong Wang, for statistical help.

References
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