a Department of Cardiology, Gentofte University Hospital, Copenhagen, Denmark
b National Institute of Public Health, Copenhagen, Denmark
c Rigshospitalet Heart Centre, Department of Medicine, Division of Cardiology, Copenhagen, Denmark
d Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark
* Corresponding author. Jawdat Abdulla, Lyovej 18, 3TV, DK-2000 Copenhagen F, Denmark. Tel.: +45-38113340; fax: +45-39760107
E-mail address: jawab{at}dadlnet.dk
Received 17 November 2002; revised 6 August 2003; accepted 4 September 2003
Abstract
Aims To study the effect of angiotensin-converting enzyme (ACE) inhibitor trandolapril on exercise tolerance time (ETT) and New York Heart Association (NYHA) classification in patients with reduced left ventricular systolic dysfunction (LVSD) after acute myocardial infarction (AMI).
Methods and results The TRAndolapril Cardiac Evaluation (TRACE) was a randomized controlled study designed to evaluate the effect of trandolapril on mortality in 1749 consecutive Danish patients with LVSD after AMI. NYHA class was recorded every 3 months in all patients. In a prospective sub-study, 254 patients underwent exercise tolerance tests at 1, 3 and 12 months. The two treatment arms showed equal improvement in NYHA class both in the entire and exclusively symptomatic population over 4 years of follow-up (P=ns). ETT increased equally in both treatment arms at 1, 3, 12 months (P=ns). A mean of 12mg/day of furosemide was spared in trandolapril arm (P=0.001).
Conclusions Trandolapril had a mild diuretic-sparing effect. These results emphasis the importance of explaining to patients that ACE inhibitors provide protection against death and hospitalisation for heart failure but do not have any significant effect upon symptoms.
Key Words: Systolic function ACE inhibitor ETT
1. Introduction
Angiotensin-converting enzyme (ACE) inhibitors are mainstay drugs for treatment of congestive heart failure and acute myocardial infarction (AMI) accompanied by left ventricular systolic dysfunction (LVSD). This concept is supported by an array of randomized trials, which show that ACE inhibitor therapy results in a significant reduction in mortality and morbidity in these patients.14Since the introduction of ACE inhibitors in the beginning of 1980s, many placebo-controlled trials have provided conflicting results concerning the effect of ACE inhibitors on exercise tolerance and New York Heart Association (NYHA) class. Narang et al. presented results of 35 studies on exercise tolerance in a review in 1996.5The conclusion was that ACE inhibitors improved both exercise tolerance time and NYHA class in the majority of studies. In contrast, several later studies showed no beneficial effects of ACE inhibitors on exercise tolerance or NYHA class.69Some mortality studies of ACE inhibitors have also assessed changes in NYHA class, but the results have not provided a clear answer whether ACE inhibitor therapy results in functional improvement.1,10,11
The TRAndolapril Cardiac Evaluation (TRACE) study was designed to evaluate the effect of trandolapril in patients with LVSD after AMI. TRACE was performed in the period 19901994, when beta-blockers and spironalactone were yet not established as conventional treatments in heart failure. Thus, a correct estimation of the isolated effect of ACE inhibitors could be anticipated. We present new data evaluating the effect of the ACE inhibitor-trandolapril- on exercise tolerance time on both short- (3 months) and long-term (12 months) of follow-up in a sub-population and further data on effect of trandolapril on NYHA class in the entire randomized TRACE study population.
2. Patients and methods
2.1. Patients
TRACE was a study designed to assess the effect of trandolapril on mortality and morbidity in patients with moderate to severe LVSD after AMI. Consecutive patients (n=6676) were admitted in 27 Danish departments from May 1990 until July 1992 and were screened for entry. Of 2606 eligible patients, 1749 patients were randomized to receive either placebo or trandolapril. The design, baseline characteristics and main results have been published previously.4,12
2.2. Exercise tolerance sub-study
In a prospective sub-study 305 patients (planned number 300) from five centres were enrolled in an exercise tolerance study. In- and exclusion criteria, and dose titration of trandolapril were the same as in the main study,4and all patients in these five centres were asked to participate in the exercise sub-study unless they were unable to perform bicycle test or it was considered unethical (Table 3). Fifty-one patients wereexcluded; thus only 254 (126 placebo vs 128 trandolapril) patients were scheduled for exercise tolerance tests at 1, 3 and 12 months after discharge from hospital.
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2.4. NYHA class follow-up in the main study
At baseline, before hospital discharge and at each visit, which took place after 1 month and thereafter every 3 months, NYHA class,13angina and use of diuretic treatment were registered at every visit for each patient in the main study. Diuretic treatment was recorded in milligrams of furosemide and angina as 0 for no angina, 1 for angina on exertion or 2 for angina at rest.
3. Statistical analyses
Patient characteristics, exercise tolerance, NYHA class, and dose of furosemide at each time-point were examined using the Wilcoxon rank sum test for continuous variables, whilst discrete variables and angina were examined using chi-square test. The overall analysis of changes in exercise time, NYHA class, dose of furosemide and angina over time in the two treatment groups was performed using mixed models. These models can be viewed as an extension of an analysis of variance with repeated measures. As opposed to this method, mixed models can handle missing values without removing that individual from the analyses. Trandolapril treatment (or placebo) and patient were entered in these models as fixed effects and random effects respectively. Time and its interaction with treatment were entered in the model to account for any differences between time-points. Then the time and treatment nested in patient (subject effect) were also entered as random effects to account for differences within patients as well. In these models angina was entered as a dichotomous variable (present/absent) using a logit transfer function and SAS procedure GENMOD was used. The other variables were analysed as continuous variables using SAS procedure MIXED. A plot of predicted values vs residuals indicated a normal distribution of residuals and no systematic relation between residuals and the predicted values. Plots using general linear model were used to check the linearity of the random effects. The covariance structure (variance component) was checked also using the previous model in further three different covariance structures to ascertain that the results were similar. Differences in survival were compared with the log-rank test. All calculations were done using the Statistical Analysis System version 8 (SAS, Institute, Cary Inc., North Carolina, U.S.A.). All P-values are two-sided and a P-value below 0.05 indicatedstatistical significance.
4. Results
4.1. Exercise tolerance sub-study
Baseline demographics for the two treatment groups did not differ (Table 1).
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4.4. Survival in subgroups
Life tables for patients who were excluded (not performed exercise test, n=51) and who were included (performed exercise tests, n=254) showed no statistically difference in mortality between placebo and trandolapril arms, neither in the first year as mentioned above(Table 3), nor after four years of follow-up. Amongst the excluded subgroup, 4-years mortality analysis showed that 14 (58%) patients in placebo compared with 11 (40%) patients in trandolapril arm died. While, in the included subgroup, 32 (25%) patients in placebo compared with 26 (20%) patients in trandolapril arm died, respectively. Though these mortality rates were higher among placebo patients than trandolapril, particularly in the excluded group, these differences did not reach statisticallysignificant levels (P-values >0.05). However, the total mortality rate in the excluded patients was higher compared with the included patients (49% vs 22%). In the entire randomized TRACE population (n=1749) the mortality rates during the study period were 42.3% in the placebo arm vs 34.7% in the trandolapril, which were higher than the mortality rates in exercise sub-study patients, however, the difference between treatment and placebo arms was statistically significant with a relative risk reduction to 0.78 (95% confidence interval 0.670.91; P=0.001).
4.5. NYHA class, angina and diuretic treatment in the entire randomized population
There was no significant difference between the two treatment groups in NYHA class over 24 years of follow-up in the entire randomized TRACE population with LVSD, P=0.45 at 1 month, P=0.51 at 6 month, P=0.90 at 12 month, P=0.60 at 48 month and by the mixed model P=0.12 (Fig. 2). Importantly, we found also that there was no significant difference between the two treatment groups in patients with clinically overt heart failure and Killip class 2 (n=367, 21% of the total), P=0.43 at 1 month, P=0.09 at 6 month, P=0.17 at 12 month, P=0.31 at 48 month and by the mixed model P=0.51 (Fig. 3). There was also no significant difference in the incidence of angina pectoris during follow-up between the two treatment groups in patients with NYHA class
II, P=0.80 at 1 month, P=0.86 at 6 months, P=0.55 at 12 month, P=0.28 at 48 months and by the mixed model P=0.37 (Fig. 4). The only significant difference between the two treatment groups was in the use of furosemide in the entire population, P=0.006 at 1 month, P=0.02 at 6 month, P=0.04 at 12 months, P=0.14 at 48 months and by the mixed model P=0.001 (Fig. 5). In the patients with clinically overt heart failure (Killip class
2) there was a similar significant use of furosemide, P=0.01 at 1 month, P=0.008 at 6 months, P=0.01 at 12 months, P=0.38 at 48 months and by the mixed model P=0.001 (Fig. 6). The placebo group used a significantly higher dose of furosemide than trandolapril group; a mean of 12mg/day (520mg/day 95% CI, P=0.001). Fig. 5shows use of dose of furosemide in the entire randomized TRACE population throughout the study, while Fig. 6shows use of a slightly higher dose in patients with clinically overt heart failure (Killip class
2) at entry into the trial.
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This study demonstrates that in a large population of patients with LVSD after an AMI, the ACE inhibitor trandolapril had no effect on exercise tolerance or NYHA classin spite of a remarkable effect on survival demonstrated by the entire TRACE study population and other large randomized trials.14A minor effect on symptoms is suggested by the fact that trandolapril treatment was associated with a significant reduction in the need for diuretic therapy. The study is in line with several large exercise studies in patients with heart failure, which neither demonstrated a significant effect on exercise tolerance or functional class.69Not many studies have followed exercise tolerance or functional class for a prolonged period and our findings after at least one year are comparable to other studies with long-term follow-up.1417Our study is the only one, which provides functional class data for up to 24 years.
Failure of an ACE inhibitor-trandolapril- to improve NYHA class in the TRACE study is in contrast with the results reported previously by Cooperative North Scandinavian Enalapril Survival Study-I (CONSENSUS-I, n=253).1A sub-study of CONSENSUS-II (n=428) showed, however, no significant changes in NYHA class over 6 months of follow-up.10In Studies of Left Ventricular Dysfunction (SOLVD), the investigators used dyspnoea as one of the 14 scales of life quality questionnaire in 5025 patients with left ventricular dysfunction.11This scale (05) showed slight improvement only in the Treatment Trial at one year but not in the following year. Compared with these studies the TRACE study gives a clear answer on this issue by providing new data in a large population and in a longer period of follow-up of NYHA class, and is further supported by an exercise tolerance study.
A large number of studies has examined the effect of ACE inhibitors on exercise tolerance and symptom status in patients with congestive heart failure. Early studies predominantly showed that exercise tolerance and functional class improved, but when a dramatic effect of ACE inhibitors was first reported in 1987, subsequent reports were less likely to demonstrate a benefit. Narang et al5observed this interesting trend in their review. They found that the majority of studies demonstrated some improvement of exercise capacity and functional class. A publication bias towards positive studies is likely before 1987but there is also a risk that publication bias in the opposite direction occurred after 1987, namely that studies with an unexpected result are more likely to be submitted and published. These additional results from the TRACE study are of particular value therein that the studies of exercise tolerance and functional class included large number of patients. If there is any effect of ACE inhibitors on exercise tolerance and functional class, these effects are much less pronounced than the effects upon survival and recurrent hospitalisation for heart failure.
In the majority of previous exercise trials on patients with heart failure almost all patients were conventionally treated with both digoxin and diuretics, but this was not the case in our study. LVSD was confirmed initially after AMI and the patients were randomized to either trandolapril or placebo regardless of other medications for heart failure or ischaemia. There were no instructions to investigators regarding concomitant treatment, which was guided by the clinical condition. We examined diuretic therapy in the two treatment groups as a marker of congestive heart failure. The placebo group used an average of 12-mg/day of furosemide more than trandolapril group in the whole population and a greater difference was found in patients with overt heart failure (Fig. 5Fig. 6). This difference may be explained in several ways. The difference may be caused by a minor improvement in the clinical status not evident from NYHA class. This could be caused by a mild diuretic-sparing effect of ACE inhibitors, though this has not been found in studies directly addressing that question. Finally, a very pragmatic explanation may be that placebo patients were more often admitted with worsening of heart failure. Such admissions might easily have led to an increase in the diuretic doses. We have no data to support any of these explanations, but in the context of this study not finding an improvement in NYHA class the possibility that the reduced diuretic dose may be explained by a mild improvement in symptoms is important.
In some studies the significant difference in mortality rates has been considered as one of the possible causes of lack of effect of ACE inhibitors on exercise tolerance.6,7In this study, the higher mortality rate in the placebo group vs trandolapril group (16% vs 12% at the last exercise test) did not reach a significant statistical level, which in contrast to the above-mentioned studies, was helpful in diminishing bias, yet, these bias still can not be excluded. However this trend towards higher mortality in placebo arm was consistent with results of the TRACE study, where a significant reduction of mortality was obtained in the trandolapril arm. This difference in mortality between the entire randomized TRACE study population compared with the current exercise sub-study can be partly attributed to the difference in the baseline characteristics, as the patients who participated in exercise sub-study were younger and the percent of male patients was higher than in TRACE study, and partly because patients of the exercise sub-study constituted only 15% of the entire randomized TRACE study population. On the other hand the survival analysis in subgroups showed higher total mortality rate in the excluded compared with included patients; this finding was not unexpected in such population who experienced AMI. Though a possible trend to higher mortality was found in the placebo arm amongst the excluded patients, against our anticipation even this did not reach statistical significance.
Patients in this study were randomized to receive ACE inhibitor therapy or placebo within few days after AMI and after verification of LVSD by echocardiography. Two previous long-term studies on patients with myocardial infarction randomized to ACE inhibitors failed to find any improving effect in exercise tolerance.15,17We hypothesized also that additional symptoms due to ischaemia, like angina pectoris could have affected the assessment of NYHA class, but the two groups demonstrated similar incidences of angina without any significant difference in the long term (Fig. 6).
Another question that could be raised is whether an ACE inhibitor improves symptoms and exercise tolerance in patients with established congestive heart failure in longer period but not in another population with recent AMI with LVSD, taking into consideration haemodynamic and hormonal changes, and the recently highlighted roll of natriuretic peptides. Firstly, as mentioned above, the results of many previous studies on patients with established congestive heart have been controversial and there is a tendency to more negative results in the later studies.69Secondly, no subgroup analysis indicates that there are differences in the effect of ACE inhibitors based on aetiology. This answer can be determined only by a randomized controlled study.
In this study the majority of the patients did not suffer from severe heart failure as the majority of patients were classified as NYHA III at the entry to the study. In such a population, changes in NYHA class are probably more difficult to evaluate than in a population with more symptoms e.g. NYHA class IIIIV. Therefore a sub-analysis was done to determine whether there was any difference between asymptomatic patients and those with overt heart failure (Killip class2, Figs 3and 4). No such difference was found.
In the exercise sub-study, the first exercise test was done one month after randomisation. Thus some changes in the basic characteristics of patients, particularly NYHA class, were possible. However, we did not find any changes in NYHA class or exercise duration neither after one month nor at any later time point. It thus appears that the delay in performing the first exercise test did not influence the result.
In conclusion, the results of this and other studies616evaluating the effect of ACE inhibitors on symptoms and exercise tolerance conflict with one another and do not support the existence of a significant clinical effect. This conclusion disagrees with the current clinical concepts and guidelines18concerning the use of ACE inhibitors and has important clinical consequences especially in cardiological and medical departments involved in using ACE inhibitors. Physicians should be made aware that while ACE inhibitors are well-documented prophylactic agents in patients with left ventricular systolic dysfunction concerning mortality and hospitalisation, there is no convincing evidence that they affect symptoms and exercise capacity. Patients receiving ACE inhibition for overt heart failure should not have their expectations of an improved functional capacity raised. Their disappointment when they do not sense improvement might lead to unnecessary discontinuation of these life saving agents.
Acknowledgments
The authors thank the Danish Heart Foundation for support to the study by a research grant used for help to statistical analysis.
Footnotes
1 Disclosures: Roussel-Uclaf and Knoll pharmaceutical companies sponsored the TRACE study.
References