The long-term impact of the angiotensin-converting enzyme inhibitor trandolapril on mortality and hospital admissions in patients with left ventricular dysfunction after a myocardial infarction: follow-up to 12 years
Pernille Buch1,*,
Søren Rasmussen2,
Steen Z. Abildstrom2,
Lars Køber3,
Jan Carlsen4 and
Christian Torp-Pedersen1 on behalf of the TRACE investigators
1Department of Cardiology, Bispebjerg University Hospital, Bispebjerg Bakke 23, Building 40, DK-2400 Copenhagen NV, Denmark
2National Institute of Public Health, Copenhagen, Denmark
3Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
4Medicon, Allerod, Denmark
Received 14 September 2004; revised 14 September 2004; accepted 23 September 2004; online publish-ahead-of-print 8 December 2004.
* Corresponding author. Fax: +45 39751803. E-mail address: pb{at}heart.dk
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Abstract
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Aims To investigate the long-term benefits of treatment with angiotensin-converting enzyme (ACE)-inhibitors in patients with myocardial infarction (MI) and left ventricular dysfunction (LVD).
Methods and results In the trandolapril cardiac evaluation (TRACE) study, 1749 patients with LVD (ejection fraction
35%) were randomized to trandolapril (n=876) or placebo (n=873) 37 days post-MI. Enrolment lasted from 1990 to 1994; on-treatment follow-up ranged from 2 to 4 years. At study closure, all patients were recommended continued ACE-inhibitor use. National registries were used to track deaths and hospitalizations until 2002. Mortality was analysed with Cox proportional hazard models and hospitalization with Poisson regression models (models adjusted for observation time). Over 1012 years of follow-up, a total of 1283 deaths and 9220 hospitalizations were registered. Compared with the placebo group, the trandolapril group had a significantly reduced risk of all-cause mortality (relative risk 0.89, 95% CI 0.800.99, P=0.03), all-cause hospitalizations (rate ratio 0.92, 95% CI 0.880.96, P<0.001), and cardiovascular hospitalizations (rate ratio 0.95, 95% CI 0.911.00, P=0.047), including congestive heart failure hospitalizations (rate ratio 0.85, 95% CI 0.770.93, P<0.001).
Conclusion In patients with LVD, use of trandolapril shortly after an MI for 24 years has long-term benefits. The beneficial effect on mortality and hospitalization rates is maintained for at least 1012 years.
Key Words: ACE-inhibitors Myocardial infarction Mortality Morbidity Follow-up Prognosis
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Introduction
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The management of cardiovascular disease frequently requires the long-term use of pharmacological agents, yet management recommendations are often based on clinical trials with follow-up lasting only a few years. Several clinical trials have documented the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients with left ventricular dysfunction (LVD) after a myocardial infarction (MI) during the initial years of treatment.14 However, data on the long-term benefits of treatment with ACE-inhibitors are limited.5,6
The trandolapril cardiac evaluation (TRACE) study demonstrated that the use of the ACE-inhibitor trandolapril shortly after an MI in patients with LVD reduces mortality and morbidity over 4 years of on-treatment follow-up.7 A subsequent analysis, post-treatment, found that the use of trandolapril increased life expectancy after 6 years of follow-up.8 If the benefits of trandolapril treatment observed over these 6 years of follow-up were sustained into the long-term, then it would provide additional support for the use of an ACE-inhibitor shortly after an MI in patients with LVD.
In the present study we have analysed the survival status and hospital admission rates for patients participating in the TRACE study for a minimum of 10 years of follow-up.
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Methods
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Patients
A detailed description of the TRACE study has been published elsewhere.7,9 Briefly, it was a multi-centre, double-blind, randomized, placebo-controlled, parallel group trial of the ACE-inhibitor trandolapril in patients with enzyme-verified MI and echocardiographic signs of LVD. The TRACE study was conducted in 27 Danish coronary units and was approved by all regional ethics committees in Denmark, and all patients had given written consent before inclusion in the trial.
A total of 6676 consecutive patients were screened for entry between May 1990 and July 1992. LVD was defined as a wall motion index of 1.2 or less, corresponding roughly to an ejection fraction of 35% or lower. Of 2606 patients with LVD, 1749 were randomized in the study. The reasons for exclusion were: mandatory ACE-inhibition (150 patients), cardiogenic shock (101), death during screening (70), renal failure or having a single kidney (65), intolerance to the test dose of 0.5 mg trandolapril (39), lack of informed consent (218), or other reasons (216).
Treatment was started with placebo or trandolapril 37 days after an MI. Trandolapril was administered in stepwise increasing doses with a target dose of 4 mg once daily. If the target dose of trandolapril could not be reached due to intolerance, patients either continued treatment at lower doses with a minimum dose of 1 mg/day or were withdrawn from treatment with study medication. At the close of the TRACE study on 30 June 1994, investigators were advised to use an ACE-inhibitor routinely for patients based on results published during the TRACE study that demonstrated the treatment benefit of an ACE-inhibitor in patients with LVD.10,11
Follow-up and outcome
The current study was a retrospective analysis in which national registries were used to track all deaths and hospitalizations from the day of randomization until 15 July 2002, resulting in a follow-up period of 1012 years for those still alive in 2002. Follow-up was divided into two time periods: first period (study-treatment phase) from day of inclusion until 30 June 1994, and second period (post-study treatment phase) from 1 July 1994 until 15 July 2002. On-treatment follow-up ranged from 2 to 4 years.
Information on survival status was obtained from the Danish Central Personal Register. In Denmark, all residents are issued a unique personal register number; in case of death, this number is recorded in the Register within 2 weeks.
Hospital discharge diagnoses were obtained from the National Patient Register where each individual hospitalization was identified by the personal registration number. Detailed information on The National Patient Register has been described elsewhere.12 The register has been validated against the Danish MONICA (Monitoring Trends and Determinants of Cardiovascular Disease) Register. For 4536 admissions with acute MI (AMI) as the primary diagnosis in the National Patient Registry, 93% were verified as definite or possible AMI in MONICA (79% as definite).13 The International Classification of Diseases (ICD) was used to classify diagnoses into the following two categories (the classification system in Denmark changed in 1994, and so both ICD-8 and ICD-10 codes were used): cardiovascular (ICD-8 codes 390458 or ICD-10 codes I0052 and I6099) and non-cardiovascular (all other diagnoses). Also cardiac diagnoses (ICD-8 codes 390429 or ICD-10 codes I0025 and I3052) and vascular diagnoses (ICD-8 codes 430458 or ICD-10 codes I2628 and I6099) were listed separately. Cardiac diagnoses were further subclassified into congestive heart failure (CHF), MI, and other cardiac diagnoses. Both primary and secondary discharge diagnoses were used. Cardiovascular and non-cardiovascular hospitalizations were exclusive groups. Within cardiovascular hospitalizations and non-cardiovascular hospitalizations, subcategories were not exclusive.
Statistics
Differences in baseline variables for patients assigned to placebo or trandolapril were compared with the CochranMantelHaenszel test.14,15 Mortality curves for the two treatment groups were generated by means of KaplanMeier estimates and compared by the log-rank test. Patients still alive at 15 July 2002 were censored at that time. After 10 years, a considerable number of patients were censored due to the inclusion period of 2 years and therefore mortality curves were cut after 10 years. Cox proportional-hazards regression models were formed with treatment allocation as the only covariate to estimate the relative risk (RR) of all-cause mortality and the corresponding 95% confidence interval (CI).16 A Poisson regression model was used to calculate rate ratios for hospital admissions. It was assumed that long-term survivors were more likely to be hospitalized during follow-up compared with patients who died shortly after the end of the trial; thus, all rate ratios were adjusted for observation time (i.e. years from day of randomization until death or end of follow-up). Calculations were made with the Statistical Analysis System software version 8.2 (SAS Institute, Cary, NC, USA). For all analyses, a P-value <0.05 was considered significant.
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Results
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Demographics
Table 1 shows the baseline characteristics of the study population. Mean age was 67 years, 72% were men, and one-third had had a previous MI. The groups were well matched in all aspects, and no important clinical differences were found between the placebo and the trandolapril groups. For those who survived to the start of the post-study treatment phase (501 in the placebo group and 572 in the treatment group), no difference was found in baseline characteristics between the two treatment groups with respect to age, sex, body mass index, infarct position, thrombolysis, and clinical history, except for a history of angina which was more common in the trandolapril group (58 vs. 42%, P=0.02).
Mortality
During the 1012 years of follow-up, a total of 1283 deaths were registered, 652 in the placebo group and 631 in the trandolapril group. Six patients who had emigrated were lost to follow-up. For the rest of the population, follow-up was complete. Mean follow-up length was 5.6 years. The KaplanMeier curves are depicted in Figure 1. The mortality curves diverged within the first year, favouring trandolapril and remained distinct over the 10 years of follow-up. The KaplanMeier estimate of mortality at 10 years was 71.5% in the placebo group and 69.5% in the trandolapril group. For the entire follow-up, trandolapril significantly reduced the risk of death from any cause compared with placebo (RR 0.89, 95% CI 0.800.99, P=0.031). During the on-treatment follow-up, the risk of mortality was significantly reduced in the trandolapril group compared with the placebo group (RR 0.78, 95% CI 0.670.91, P=0.001), but no difference was observed between groups during the remaining post-treatment period (RR 1.03, 95% CI; 0.881.21; P=0.75). There was a borderline significant interaction between treatment and time period (P=0.050 for interaction), such that the benefit of trandolapril was most prominent during on-treatment follow-up.

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Figure 1 Cumulative mortality from all causes in the trandolapril group compared with the placebo group over 10 years of follow-up.
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Hospital admissions
A total of 9220 hospitalizations were registered during the entire follow-up period. Of these, 4634 occurred in the trandolapril group and 4586 in the placebo group. Tables 24 show unadjusted cumulative hospitalizations in each treatment group as well as adjusted rate ratios, where adjustment was made for the time being alive (observation years). The adjusted rate ratio for all-cause hospitalizations was 0.92 (95% CI, 0.880.96, P<0.001) for the trandolapril group as compared with placebo and the reduction was significant for both the study-treatment phase and the post-study treatment phase (Table 2). This represents an 8% reduction in hospital admissions during the 1012 years of follow-up for patients randomized to trandolapril. Figure 2 shows the cumulative number of hospitalizations per patient per 10 years of observation (total time alive) as a function of time after enrolment into the study. There was a difference of
1 hospitalization per patient between the two groups, which occurred early and was maintained throughout the 12 years.
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Table 4 Distribution of diagnoses for all non-cardiovascular hospital admissions during 1012 years of follow-up with rate ratios, adjusted for observation years
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Figure 2 Cumulative hospitalizations from all reasons in the trandolapril group compared with the placebo group over 12 years of follow-up.
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Cardiovascular hospitalizations
There was a significant reduction in cardiovascular hospitalizations during the entire follow-up period for patients treated with trandolapril with an adjusted rate ratio of 0.95 (95% CI 0.911.00, P=0.047), as compared with placebo (Table 2). Further analysis showed that this reduction was the result of decreased rates in hospital admission for cardiac reasons (Table 3). The decreased rate of cardiac hospitalizations in the trandolapril group was particularly evident for CHF hospitalizations (P<0.001). Also of note, the rate of hospitalizations for vascular diagnoses was greater in the trandolapril group during the study-treatment phase. In sub-analyses (not shown) vascular diagnoses were subclassified into venous, arterial, and cerebrovascular disorders. Only the rate of hospitalizations for peripheral arterial disorders was found to be significantly higher in the trandolapril group (adjusted rate ratio 1.43, 95% CI 1.111.86, P=0.006).
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Table 3 Distribution of diagnoses for all cardiovascular diagnoses during 1012 years of follow-up with rate ratios, adjusted for observation years
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Non-cardiovascular hospitalizations
There was a significant reduction in hospitalizations due to non-cardiovascular causes in the trandolapril group over the 1012 years of follow-up (Table 2), but only during the post-study treatment phase. To investigate whether there was any dominating discharge diagnosis that could explain the reduction in non-cardiovascular hospital admissions, the diagnoses were further subclassified as shown in Table 4. Only main hospital discharge diagnoses were included. It is evident that there was no leading diagnosis, but a general reduction in all non-cardiovascular diagnoses in the trandolapril group except for kidney diseases and pulmonary diseases, which were more prominent in the trandolapril group during the study-treatment phase and the post-study treatment phase, respectively.
However, no systematic excess of these diseases was found in the trandolapril group during the 1012 year follow-up as there was a considerable variation in rate ratios, probably due to the small numbers of patients. For diagnoses classified as miscellaneous, the most prominent diagnoses were benign tumours, observation for no specific reasons, diabetes, and prostatic hypertrophy. There were no differences between groups except for benign tumours which was significantly reduced in the trandolapril group (42 cases in the trandolapril group vs. 75 cases in the placebo group) (adjusted rate ratio 0.51, 95% CI 0.350.74, P<0.001).
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Discussion
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We found that post-MI treatment with the ACE-inhibitor trandolapril in patients with impaired left ventricular function had a long-term beneficial effect on survival and hospital admission rates. Patients treated with trandolapril for 24 years had reduced risk of death over 1012 years of follow-up compared with placebo-treated patients. Both cardiovascular and non-cardiovascular hospital admissions were also significantly reduced in the trandolapril group. The lower morbidity in the trandolapril group was mainly achieved through a reduction in CHF hospital admissions during the on-treatment phase and a reduction in non-cardiovascular hospitalizations during the post-treatment phase. The reductions in mortality and morbidity associated with trandolapril were more evident during the treatment phase of the study than during the post-treatment phase.
This analysis is one of the few studies to demonstrate a sustained benefit in mortality with ACE-inhibitor treatment during long-term follow-up. A prolonged effect of ACE-inhibitors on survival during long-term follow-up has been found in studies in patients with CHF in which the majority had a history of MI.5,6 This study complements previous findings and suggests that ACE-inhibitors as a class will provide similar benefits during long-term follow-up. Although the mortality benefit decreased over time, we estimate that post-MI treatment with trandolapril for a minimum of 2 years will save
20 lives per 1000 people over a span of 10 years.
This analysis is the first study to demonstrate a sustained benefit in morbidity with ACE-inhibitor treatment during long-term follow-up. The reduction in hospitalization rates observed in the trandolapril group for the various categories usually occurred during treatment. The preservation of the initial effects of ACE-inhibition during many years of follow-up gives some indication of the kind of benefit such treatment provides. If the major mechanism had been only to keep very ill patients alive for a marginally longer time period, then the initial benefit would be expected to taper off quickly. In contrast, we found that the risk of death was identical in the two treatment groups after the blind phase. This, together with the continued decrease in hospitalization rates indicates that the benefit is truly enduring. Therefore, patients who were saved by treatment in terms of hospitalization or mortality are not left at an increased risk of these events.
We cannot explain the increase in hospitalizations for peripheral arterial diseases during the study treatment phase. One possible mechanism could be related to hypotension, a well-known side effect of ACE-inhibitors, which could have potentially led to insufficient perfusion in patients with severe atherosclerosis.
The reduction in rates of hospitalizations from non-cardiovascular causes observed in the trandolapril group has no obvious pharmacological explanation. However, this may have been related to a decrease in signs and symptoms of CHF,17 and thereby an improvement in the general health of the patients such that medical care was administered in outpatient clinics. Another explanation could be a misclassification of diagnoses so that symptoms of heart diseases were hidden in non-cardiovascular diagnoses. However, when non-cardiovascular hospital admissions were subdivided by the reason for admission, no striking diagnosis was evident that could be linked to symptoms of CHF or other cardiac symptoms.
This study had some limitations. We were not able to establish the medical treatment of patients after the end of the trial, which could have caused bias if considerably more patients in the trandolapril group were treated with ACE-inhibitors or beta-blockers compared with the placebo group. Although nearly 40% of patients had stopped the randomized treatment at the end of the double-blind period,7 this would nevertheless only underestimate the true effect of ACE-inhibition. We found that the survival population was balanced at the beginning of the post-study treatment phase with regard to baseline variables. However, because not all patients contribute information on hospitalizations because of death, the possibility of survival bias exists and this potential bias increases with time. Any analysis of first events would be an incomplete description of the long observation period because many late hospitalizations are second or later events. Including all hospitalizations and adjusting for observation time (time alive) was the chosen method to overcome the survival bias, but the result must be viewed in conjunction with the survival results. Therefore, by conducting analyses of mortality and hospitalizations in parallel, a composite evaluation of events during the entire 1012 year follow-up was possible.
In conclusion, this study demonstrates that treatment with trandolapril for 24 years, when started shortly after an MI in patients with LVD, contributes to reduced mortality and morbidity for at least 10 yearsthe benefit derived from 24 years of treatment is maintained for at least 1012 years. These findings are particularly relevant to clinical practice and emphasize the importance of initiating treatment with ACE-inhibitors after an MI.
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Acknowledgements
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The TRACE study was supported by grants from Abbott Laboratories (Abbott Park, IL, USA), Roussel-Uclaf (Paris, France), Knoll (Ludwigshafen, Germany), and the Danish Heart Foundation.
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