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European Journal of Heart Failure 2004 6(7):927-935; doi:10.1016/j.ejheart.2004.02.002
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© 2004 European Society of Cardiology

A meta-analysis of the effect of angiotensin-converting enzyme inhibitors on functional capacity in patients with symptomatic left ventricular systolic dysfunction

Jawdat Abdullaa,*, Steen Z. Abildstromb, Erik Christensenc, Lars Koberd and Christian Torp-Pedersene

a Department of Cardiology P, Gentofte University Hospital Niels Andersensvej 65, DK-2990 Hellerup, Denmark
b National Institute of Public Health Denmark
c Department of Medicine I, Bispebjerg University Hospital Denmark
d Rigshospitalet Heart Centre, Department of Medicine Division of Cardiology B, Denmark
e Department of Cardiology Y, Bispebjerg University Hospital Copenhagen, Denmark

* Correspondent author. Tel.: +45-38113340; Fax: +45-39760107 E-mail address: jawab{at}dadlnet.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 6. Limitations of the...
 References
 
Aim: To determine by meta-analysis whether angiotensin-converting enzyme (ACE) inhibitors improve exercise tolerance in patients with symptomatic left ventricular systolic dysfunction (LVSD).

Methods and results: After literature search 13 multi-centre double blind parallel group trials that evaluated the effect of ACE inhibitors vs. placebo on exercise duration were selected. Ninety-four percent of patients were in New York Heart Association class II–IV. The studies were combined using the Cochrane meta-analysis program (Review manager version 4.1). Analyses according to treatment period, exercise protocols and publication periods were performed. Treatment with ACE inhibitor over 4–12 weeks resulted in a beneficial effect on exercise duration (P=0.003 and P=0.0008 for 4- and 12-weeks treatment, respectively), but the magnitude of improvements did not exceed 30 s corresponding to only 5% compared with placebo.

Conclusion: In addition to the pronounced effect on mortality and morbidity in patients with symptomatic LVSD, ACE inhibitors have improving effect on functional capacity measured as exercise tolerance time.

Key Words: Angiotensin-converting enzyme inhibitor • Congestive heart failure • Exercise tolerance • Exercise capacity • Clinical trial

Received June 11, 2003; Revised November 7, 2003; Accepted February 5, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 6. Limitations of the...
 References
 
Angiotensin-converting enzyme (ACE) inhibition is a cornerstone in the treatment of patients with reduced left ventricular function in either congestive heart failure or acute myocardial infarction. Many randomised studies on ACE inhibitors demonstrate a clear reduction in mortality and hospitalisation for patients with heart failure [1–4]. Compared to these results, data on the other endpoints such as functional capacity are much less clear. The available data on the functional capacity measured by exercise tolerance are conflicting. In 1996 Narang et al. reviewed 35 randomised studies evaluating the effect of ACE inhibitors on functional capacity and found that ACE inhibitors had a beneficial effect on exercise tolerance time and New York Heart Association (NYHA) classification [5]. It is therefore commonly stated that ACE inhibitors improve functional capacity, symptoms and prognosis. Since Narang's review several studies have been published showing no significant beneficial effect on exercise tolerance [6–9]. Therefore, we found it important to perform a meta-analysis of studies evaluating exercise tolerance to determine whether these agents produce any beneficial effect on this variable. It is important to clarify these aspects in order to establish reasonable recommendations, as patients are likely to discontinue long-term therapy if they do not feel relevant functional improvement.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 6. Limitations of the...
 References
 
2.1. Search strategy
We searched medical literature through MEDLINE and EMBASE for all clinical trials on ACE inhibitors using the following keywords: angiotensin-converting enzyme inhibitor, congestive heart failure, exercise tolerance, exercise capacity, clinical trial and human, without time limitation. Additionally, a manual search was conducted using all previous reviews, and meta-analyses on ACE inhibitors. The Cochrane database showed no meta-analysis concerning this subject.

2.2. Criteria and selection of the studies
All randomised controlled studies comparing ACE inhibitors vs. placebo and high vs. low dose of ACE inhibitors on patients with clinically established diagnosis of congestive heart failure with left ventricular dysfunction and concurrently having performed an exercise tolerance test (bicycle ergometer, treadmill, 6-min walk) before and after a certain therapy period, were considered eligible to inclusion into the meta-analysis. A total of 49 studies [6–55] were identified, one study on exclusively non-symptomatic patients [56] and one withdrawal study [57] was excluded to minimize bias. Two previously published meta-analysis including six unpublished studies were also identified [58,59].

The outcome measure was exercise duration because this was the common measured variable in all studies. The reported data on peak oxygen consumption [14,24,26–28] and 6-min walk test [13,14] were heterogeneous and insufficient; and accordingly were not meta-analysed.

The authors and pharmaceutical companies responsible for a number of published studies with insufficient presentation of results and for unpublished studies were contacted, but the authors were unable to provide any data- either because the data were destroyed, not available, or because no replies were given. Consequently, 20 published studies [6,10,38–55] and the six unpublished studies included in the previous meta-analysis [58,59] also had to be excluded. The reason of exclusion in six studies [6,42–44,53,55] was unreported standard deviations, in 13 studies [38–41,45–52] both exercise duration and its standard deviations were unreported, and one study did not precisely report the number of patients in each group [10]. The total excluded population at the end of these 20 studies was 1544 patients. Thus, out of the 49 published studies only 29 studies were retained. Further 11 studies evaluating the effect of ACE inhibitor vs. placebo [11,17–27], three studies evaluating 1-year treatment [9,28,30], and two studies evaluating low vs. high dose without placebo arm [36,37] were also excluded. These 16 studies were characterised by small populations (<50 patient, the vast majority included 10–30 patients) and had a wide range of confidence interval for effect size inducing significant heterogeneity (P=0.0009) together with the large multi-centre studies and possible publication bias (Fig. 1). Therefore, only 13 studies were selected for a meta-analysis of the effect of ACE inhibitors vs. placebo on exercise tolerance time and consequently no eligible data were left to analyse 1-year effect or the high vs. low dose comparison.


Figure 1
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  		Fig. 1 Funnel plots of the 12-weeks studies with (left) and without (right) the small sample studies. The plot to the left shows the small studies spread widely from the mean effect line (punctured midline) and some of them are out of the 95% confidence interval lines (punctured tent-shaped line) because of their large random error in contrast to the large multi-centre studies that are distributed almost normally within the confidence interval limits (right). This skewed distribution of the small studies was associated with significant heterogeneity (P=0.0009) and indicated possible publication bias. In these plots the treatment effects (WMD=weighted mean difference) are plotted against their standard error (S.E.).

 
Because of missing information on allocation concealment it was not possible to score for study quality properly. However, these 13 studies were large multi-centre double blind parallel group trials [7,8,12–16,29,31–35] wherein the allocation concealment might be considered adequate.

2.3. Data analysis
In the studies using two different ACE inhibitors or exercise protocol in two separate arms, each ACE inhibitor or protocol arm was compared independently with placebo [7,12,13]. In the studies comparing different doses of the same ACE inhibitor vs. placebo, the mean result of the ACE inhibitor arms was analysed together with the results of the other studies vs. placebo [7,8,14,15]. The analysis was based on the data provided by the number of patients at the end of each treatment period.

Cochrane Collaboration, Nordic Cochrane Centre's meta-analysis program called Review Manager (Rev Man version 4.1) was used [60]. This program allows selection of different meta-analytic methods. Chi-square method tests homogeneity of studies and Z score tests the overall probability of results. Funnel plots can be made to detect publication bias.

Exercise durations at the end of 4- and 12-weeks treatment were compared between ACE inhibitor and control groups. We chose the random-effects model for continuous data, which provides the weighted mean difference with 95% confidence interval. All values presented as standard error of mean in the original studies [29,31,34] were recalculated to their standard deviations. In case of unreported standard deviations in the post-treatment values the pre-treatment values were substituted [7,8,12,30]. The results of exercise durations in minutes were expressed as means and standard deviations. Z score <2 and P-values >0.05 were considered insignificant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 6. Limitations of the...
 References
 
Characteristics of the selected studies and populations are shown in Tables 1 and 2. Left ventricular systolic dysfunction (LVSD) was reported as reduced ejection fraction or fractional shortening in all studies. Number of participants and values of exercise durations at the end of 4- and 12-weeks treatment are shown in Figs. 2–4. Several studies contributed to both 4- and 12-weeks analysis [12,33–35] (Figs. 2–4).


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  		Table 1 Characteristics of the 13 double blind multi-centre studies included in the meta-analysis

 


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  		Table 2 Basic characteristics of the patients included in the meta-analysis. The values are presented either as range or percent of patients

 


Figure 2
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  		Fig. 2 Meta-analysis of five short-term (4–8-weeks) studies showed a significant effect on exercise duration with an improvement of 0.5 min (=30 s) corresponding to only 5% favouring angiotensin-converting enzyme inhibitor (ACEI). WMD=weighted mean difference, n=number, s.d.=standard deviation, CI=confidence interval.

 


Figure 3
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  		Fig. 3 Meta-analysis of the12-weeks multi-centre studies showed a significant effect on exercise time with an improvement of 0.47 min (28 s) corresponding to only 5% favouring angiotensin-converting enzyme inhibitor (ACEI). WMD=weighted mean difference, n=number, s.d.=standard deviation, CI=confidence interval.

 


Figure 4
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  		Fig. 4 Results of the meta-analysis of 9 of 12 weeks multi-centre studies that used bicycle ergometer showed significant improvement in exercise duration of 0.44 min (=26 s) corresponding to only 5% favouring angiotensin-converting enzyme inhibitor (ACEI). WMD=weighted mean difference, n=number, s.d.=standard deviation, CI=confidence interval.

 
Meta-analysis of five short-term (4–8 weeks) studies showed a significant benefit favouring ACE inhibitor arm with a mean difference of 0.50 (0.17–0.83) min (=30 s) in exercise duration—corresponding to an improvement of 5% (0.5–10%) (Fig. 2).

Meta-analysis of the 12-weeks studies showed a significant benefit favouring ACE inhibitor arm with a mean difference of 0.47 (0.19–0.75) min (=28 s) corresponding to an improvement of 5% (2–9%) (Fig. 3). The studies showed homogenous effects and the funnel plot showed rather symmetric and almost normal distribution (Fig. 1). A meta-analysis of 9 of 12-weeks studies using bicycle ergometer protocol showed a significant benefit with a mean difference of 0.44 (0.19–0.69) min (=26 s)—corresponding to an improvement of only 5% (2–8%) (Fig. 4).

A comparative analysis was done to show the difference in results between studies conducted before and after Narang's review. There was a significant effect of ACE inhibitors in the seven studies [12,13,16,29,31–33] published between 1983 and 1995 with a mean difference of 0.58 (0.18–1.98) min (=35 s), P=0.005. The five studies [7,8,14,15,34,35] published thereafter between 1996 and 2002 showed no significant effect with a mean difference of 0.37(0.003–0.76) min (=22 s), P=0.07. Funnel plots showed possible publication bias in both periods.

All analyses were also tested with fixed-effects model, but the change in the mean differences compared to random-effects model was slight, 1–2 s in each analysis. Despite inclusion of the previously mentioned excluded small sample studies in the above-mentioned analyses, the maximal increase in exercise tolerance time did not exceed 40 s.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 6. Limitations of the...
 References
 
This meta-analysis was the result of a comprehensive data review of many studies evaluating the effect of ACE inhibitors on exercise tolerance in patients with LVSD. The results showed a statistically significant effect favouring ACE inhibitors demonstrated by prolonged mean exercise duration compared with placebo during the 4–12 weeks of treatment. The overall improvement in the magnitude of exercise duration of 30 s corresponding to 5% of the total exercise duration was small compared to that effect of ACE inhibitors on mortality and hospitalisation [1–4]. However, the results should be interpreted cautiously as this meta-analysis depended upon analysis of only one exercise tolerance parameter.

4.1. Confounding factors
Several confounding factors have been argued to influence the results of the controlled studies evaluating exercise tolerance in patients with symptomatic LVSD. An important factor to be mentioned is the outcome of withdrawals—a problem that could be more evident in the studies with longer follow-up. Obviously, this might be due to comparatively higher mortality rate in the placebo arm and probably as a result of more frequent side effects in the ACE inhibitor arm. The lack of improvement in the ACE inhibitor arm has been partly attributed to higher mortality rates in placebo patients and with the assumption that dead patients might have been in worse clinical condition accordingly could have produced worse functional capacity. Hence, the maximal exercise tolerance time was chosen as a primary endpoint rather than mortality in these studies, the dead patients were unable to provide results of the final exercise tolerance tests. An analysis based on data of patients who ended the study would, therefore, provide clinically relevant results as no analysis can accurately account for the missed data concerning the dead patients. Inclusion of all dropouts—inclusive deaths—in an analysis on basis of intention-to-treat with an assumption that dying patients would have provided low response values—least or zero exercise duration—has been suggested [59]. In this case, the investigator has to combine data of two different end-points, which would be confusing and clinically unrealistic. The results are subjected to attrition bias but apparently this is unavoidable.

The other factor is patients’ NYHA class. NYHA class may worsen due to deterioration of heart failure or improve as a result of adjustment of the concomitant therapy. Such changes in NYHA class can affect exercise performance. Generally the studies reported improvement in functional capacity, reported also improvement in NYHA class [5]. However, it could be difficult to perform exercise tests in patients with severe heart failure with NYHA class IV; subsequently these patients are prone to be unqualified to enter exercise studies or eventually become withdrawn during the course of the trial. It is also unlikely to obtain noticeable changes in exercise duration in asymptomatic patients with NYHA class I. Overall, a meta-analysis of such population is prone to some selection and performance biases. However, in this meta-analysis only a minority of the included populations were in NYHA class I or IV, 6% and 4%, respectively.

Another factor that could have affected the results is the use of concomitant medications, particularly diuretics. Only five studies took into account the effect of concomitant diuretic consumption on the exercise tolerance test [18,31,34,36,37]. However, the TRACE study has analysed this problem in details and showed that the placebo arm consumed slightly more furosemide dose (mean 12 mg/day), but this small difference could not explain the similar slight improvements in exercise duration and NYHA classes in both study arms [61].

Several studies [14,17,36] used repeated baseline exercise tests which probably added further performance bias as the investigators perhaps tried to encourage patients to reach maximal capacity to be enrolled; this bias even increases if the same investigator tests the same patient during the study. It can also be argued that repeated exercise tests might reduce variability and introduce a training effect, but attempting to exclude patients with variable exercise times could impair the results.

Methodological problems during exercise protocols may affect the results and its interpretation. Exercise protocols are usually graded; patients may manage one grade but suddenly fail to continue the test when the grade increases. Thus, the difference in magnitude of the performed exercise duration (30 s in this study) crossing a grade could be significantly large, however, the same magnitude at the same grade could be small. Using different exercise protocols seems not to be an important factor affecting the results and the general guidelines recommend individualising the choice of different exercise tests [62].

Finally, various ACE inhibitors could have exerted different effects but there is consensus on that ACE inhibitors have a class effect, thereby different effects are unexpected.

These above-mentioned factors elucidate how difficult it is to perform an ideal exercise study in patients with LVSD.

4.2. Study design and duration
It has previously been suggested that parallel studies designed for 12-weeks period would be reasonable to minimize the effect of some of the above-mentioned confounding factors. Hence, the majority of the studies included in this meta-analysis were parallel and designed for 12-weeks periods. Nevertheless it is still arguable whether 12-weeks period is adequate to make such a conclusion, because the question of maintainability of the effectiveness of ACE inhibitors in the longer term will still not be answered. Although only few studies evaluated exercise tolerance time in 1 year, the results showed no significant effect in all studies, indicating that the effectiveness of ACE inhibitors more likely diminishes and perhaps disappears in the longer terms or the mortality effect becomes more pronounced [9,28,30,35].

4.3. Homogeneity between studies
Some differences between the included studies might have caused heterogeneity and presumably might have affected the results. Using different types of ACE inhibitors or exercise protocols and NYHA class as possible sources of heterogeneity had already been discussed. Other sources of heterogeneity could be attributed to some dissimilarity in the aetiology or duration of the heart failure in the baseline population, however, in this meta-analysis all studies included patients with chronic heart failure except TRACE study whose patients performed the first exercise test 1 month after acute myocardial infarction. Additionally, the included studies were published over 20 years wherein the management of patients with LVSD and myocardial infarction progressed rapidly and might probably have led to some significant differences in concomitant therapy particularly between the earlier and later studies. Nevertheless, ACE inhibition has been the primary choice of treatment in all settings of LVSD since the large mortality studies were published. There is no evidence confirming that the effect of ACE inhibitors should be different due to the aetiology or duration of heart failure. Thus, it is unlikely that these differences between the studies could have created considerable heterogeneity.

4.4. Previous meta-analyses
Two previous meta-analyses have also evaluated the effect of ACE inhibitors on exercise duration in patients with congestive heart failure [58,59]. Lubsen et al. [59] performed a meta-analysis on five studies (n=1095) using ramipril. The studies independently showed no significant effect but the combined data showed a significant effect favouring the ramipril arm but with only 3.5% improvement compared with placebo (P-value <0.05). Another meta-analysis performed by Kiowski et al. [58] included six studies using cilazapril (n=1030); four studies independently showed no effect but the combined data showed a significant effect. The results of these two meta-analyses were limited only to a number of trials using two ACE inhibitors and they could not confirm a marked effect.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
6. Limitations of the...
 References
 
The current meta-analysis included major double blind multi-centre trials; there was a beneficial effect of ACE inhibitors on exercise duration, but this effect appears to be modest compared to the well-documented reducing effect on mortality and hospitalisation in patients with LVSD. We conclude that these patients could by receiving ACE inhibitors improve their functional capacity in addition to the well-documented effect on mortality and hospitalisation. The general guidelines for treatment of these patients should take this point into consideration.


   6. Limitations of the results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 6. Limitations of the...
References
 
This meta-analysis depended upon the available data extracted from the published studies and the efforts we made to collect the unpublished data were not successful. Consequently, a significant number of studies were unfortunately excluded leading to publication bias. There was neither sufficient data on the other exercise tolerance parameters like peak oxygen consumption to support further the analysis on exercise duration. The comparative analyses made according to publication periods also suggested significant difference between the results before and after 1996 indicating possible publication bias towards unpublished papers with negative results before 1996 and unpublished positive results thereafter. The role of confounding factors and their contribution to further bias is discussed above. The overall influence of bias particularly on short-term analysis is perhaps significant.


   References
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 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 6. Limitations of the...
 References
 

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