Continuing uncertainty about the value of percutaneous revascularization in atherosclerotic renovascular disease: a meta-analysis of randomized trials
Natalie J. Ives1,,
Keith Wheatley1,
Rebecca L. Stowe1,
Pieta Krijnen2,
Pierre-Francois Plouin3,
Brigit C. van Jaarsveld4 and
Richard Gray1
1 Birmingham Clinical Trials Unit, The University of Birmingham, Birmingham, UK,
2 Department of Public Health, Erasmus University Rotterdam, Rotterdam, The Netherlands,
3 Hypertension Unit, Hôpital Européen Georges Pompidou, Paris, France and
4 Dianet Dialysis Centers, Utrecht, The Netherlands
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Abstract
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Background. To study the effect of revascularization on blood pressure (BP) and serum creatinine (SCr) in patients with atherosclerotic renovascular disease (ARVD).
Methods. Three randomized studies comparing balloon angioplasty (plus medication if necessary) with medical therapy alone in patients with ARVD were identified. In one study, patients were stratified and analysed according to whether they had unilateral or bilateral disease. Therefore, four sets of results were available for inclusion in a meta-analysis comparing BP and SCr at 6 months and changes from baseline.
Results. The three trials recruited 210 patients. There was no clear benefit for angioplasty when comparing BP at 6 months. Relative to the medical therapy group, the mean (95% CI) systolic/diastolic BP was 2.9 mmHg (-9.1, 3.4)/0.35 mmHg (-3.6, 2.9) lower in the angioplasty group (P=0.4/0.8). There was, however, some suggestion of benefit for angioplasty when changes in BP were compared. There was a greater reduction in the systolic/diastolic BP in the angioplasty group, with a difference of 6.3 mmHg (-11.7, -0.8)/3.3 mmHg (-6.2, -0.4) in the mean change (P=0.02/0.03). There was some suggestion of benefit for angioplasty in terms of changes in SCr, although this was not significant (P=0.06).
Conclusions. The reported trials have been too small to determine reliably the role of angioplasty in ARVD. Although the combined results of three previous trials exclude the possibility of a large improvement in renal function or hypertension after angioplasty, a moderate but clinically worthwhile benefit cannot be ruled out. Further large-scale randomized evidence is needed.
Keywords: angioplasty; ARVD; medical therapy; meta-analysis; revascularization
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Introduction
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Atherosclerotic renovascular disease (ARVD) is a common condition in which proximal atherosclerotic narrowing of renal arteries may lead to hypertension and/or progressive renal dysfunction. ARVD is a frequent, and potentially avoidable, cause of end-stage renal failure and the need for renal replacement therapy among older persons. The procedure used to try to prevent further progression of ARVD is revascularization either by surgical repair or, in more recent years, by percutaneous transluminal balloon angioplasty and/or endovascular stenting. However, whilst the use of balloon angioplasty and stenting has been shown to improve arterial patency, there is currently no clear evidence that such interventions prevent further progressive decline of renal function [1]. To date, there have been only three randomized controlled trials that have evaluated the role of angioplasty compared to medical therapy alone in patients with ARVD [24]. Taken individually, these trials provide no clear evidence that angioplasty improves renal function or blood pressure (BP). This is in part due to the small number of patients recruited into the studies (49106 patients), giving insufficient statistical power to detect realistically modest, but potentially clinically important, differences. To improve statistical reliability and to give a balanced view of the trial evidence, a meta-analysis of these three trials comparing angioplasty and medical therapy alone was undertaken.
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Subjects and methods
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Literature search
A systematic search for randomized trials of revascularization in ARVD was undertaken using an extension of the Cochrane search strategy incorporating the search terms: atherosclerotic, renal, revascularization, angioplasty and stent. For systematic reviews, the Cochrane Library, NHS Centre for Reviews and Dissemination and Health Technology Assessment databases were searched. For primary research, a number of databases were searched including Medline (Ovid version), Embase (Ovid version), PubMed, and the Web of Science. Major journals in the field were hand searched for relevant material. The hand search also involved a search of conference proceedings to identify presentations made at meetings. Experts in the field were contacted in an attempt to identify studies not found by the electronic and hand search (including material presented at conferences and seminars) and to identify trials that have not been formally published. Research registers including the National Research Register (NRR), Controlled Clinical trials, ClinicalTrials.gov and Computer Retrieval of Information on Scientific Projects (CRISP) were searched to identify ongoing research. Additional information was sought from scanning reference lists of already retrieved papers, in particular review papers, and web sites relating to renovascular disease.
Study selection
To be included in the analysis, studies had to meet the following criteria: treatment was assigned by randomization; the treatment group received revascularization with percutaneous balloon angioplasty and/or endovascular stenting (with medication as necessary) and the control group received medical therapy alone.
Outcome measures and statistics
The main outcomes measures were BP and serum creatinine (SCr) at 6 months (at 3 months for the study by van Jaarsveld et al. [4]), and the changes in these measures from baseline. The mean and standard deviations for each outcome measure were extracted (where available) from the published papers [5]. Standard methods for overviews based on published data are described in detail elsewhere [6]. In summary, for each trial the difference (and its variance) between the outcome measure means for each group was calculated (µangioplasty µmedical). From these values, it was possible for each outcome measure to calculate the overall difference and its variance. All P-values stated are two-sided.
Table 1
outlines for each study the number and type of patients included in the trial, the randomized treatment comparison, the end-points and the duration of follow-up. All the trials reported the same endpoints: BP and SCr and/or SCr clearance, which were usually measured at baseline and 1, 3 and 6 months (sometimes also at 12 months). Two studies measured BP using standard or Hawksley random zero sphygmomanometers [2,4], whilst the third measured 24-h ambulatory BP [3]. There was inconsistency in the amount of information that was reported with standard deviations (SD), confidence intervals (CIs) and/or P-values often not presented. For example, Webster did not report any SD for BP, although SD were provided for SCr; Plouin did not provide any information on SCr at 6 months; and van Jaarsveld reported the median SCr (and range) at baseline, and at 3 and 12 months. To address the problem of missing data and to improve the reliability of the analysis, the main authors of the papers were approached and a request made for the missing data. The SCr individual patient data was provided by Plouin, which enabled us to calculate the mean (and SD) for SCr at 6 months and the change in this measure from baseline; and summary data (the mean and SD) for BP and SCr at baseline and follow-up assessments were provided by both the Dutch team (at 3 and 12 months) and by Webster (at 6 months). Unfortunately, Webster was unable to provide any data on the mean change between baseline and 6 months for either BP or SCr. We therefore had to make various assumptions for the analysis of changes over time where SDs were not available. We performed a sensitivity analysis, assuming for the missing SD either the smallest, largest or average of the SDs that were provided. This had little or no effect on the results, so the results presented are reasonably robust. The results presented assume the average SD for missing data.
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Results
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Three randomized controlled trials comparing angioplasty and medical therapy alone in patients with ARVD were identified. Two studies compared percutaneous balloon angioplasty vs medical management [2,4], although two patients in the study by van Jaarsveld et al. also received a stent. The third study compared angioplasty (with or without stent insertion) with medical management [3], although of the 23 patients randomized to angioplasty, only two patients also had a stent inserted. One study included only those patients with unilateral ARVD [3], whilst the other two studies [2,4] included patients with both unilateral and bilateral disease. The study by Webster et al. [2], however, was stratified according to whether the patient had unilateral or bilateral disease, and these patients were analysed separately. Therefore, four sets of results from three trials were included in this meta-analysis.
The three trials recruited 210 patients in total, with the smallest recruiting 27 patients (Websterunilateral disease) and the largest recruiting 106 (van Jaarsveld). One hundred and four patients (49.5%) were randomized to receive angioplasty and 106 patients (50.5%) randomized to receive medical therapy alone. Compliance with the randomized treatment was good in general. All patients randomized to angioplasty received this intervention except for five patients in the study by Webster et al. [unilateral (n=3) nephrectomy (n=2), vein bypass (n=1) and bilateral (n=2) nephrectomy (n=1), vein bypass (n=1)]. In two studies, the number of patients randomized to medical management who had an angioplasty less than 6 months after randomization was small [Webster (n=0) and Plouin (n=7)]. But for the other study, nearly half of the patients randomized to medical management underwent angioplasty between 3 and 12 months post-randomization [4]. However, the results for this trial are presented at 3 months, when there had been no cross-overs from medical management to angioplasty.
Blood pressure
There was no clear benefit for angioplasty when the systolic and diastolic BP was compared for the two groups at 6 months. Compared to the medical therapy group, the mean systolic/diastolic BP was 2.9 mmHg (95% CI=-9.1, 3.4)/0.35 mmHg (95% CI=-3.6, 2.9) lower in the angioplasty group (P=0.4/P=0.8) (Figures 1
and 2
). There was, however, some suggestion of benefit for angioplasty when the mean change (between baseline and 6 months) in BP was compared between groups. There was a greater reduction in the systolic BP in the angioplasty group, with a difference of 6.3 mmHg (95% CI=-11.7, -0.8) in the mean change between the two groups (P=0.02) (Figure 3
). Similarly for diastolic BP, there was a greater reduction in the angioplasty group, with a difference of 3.3 mmHg (95% CI=-6.2, -0.4) in the mean change (P=0.03) (Figure 4
). There was no evidence of heterogeneity between the trials for any of these outcomes.
Serum creatinine
At 6 months, SCr was 9.7 mmol/l (95% CI=-18.7, -0.73) lower (P=0.03) (Figure 5
) and SCr clearance was 0.14 ml/s (95% CI=0.02, 0.3) greater (P=0.03) in the angioplasty group, although only two studies reported SCr clearance [3,4] (data not shown). When change in SCr from baseline was investigated, there was no clear benefit for angioplasty, with a difference of 6.2 mmol/l in the mean change (95% CI=-12.5, 0.15) (P=0.06) (Figure 6
). Moreover, the upper limit of the 95% CI is compatible with no benefit for angioplasty. Similarly, for changes over time in SCr clearance, there was no evidence of a clear benefit for angioplasty (P=0.05) (data not shown). Again, there was no evidence of heterogeneity between the trials for any of these outcomes.
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Discussion
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Even when the results of the three trials of angioplasty compared to medical therapy alone were combined in a meta-analysis, no clear improvement in renal function (as measured by serum creatinine), and no good evidence of a clinically worthwhile improvement in BP were apparent. Whilst the overall results suggested an improvement in systolic and diastolic BP after angioplasty, the true benefit of angioplasty remains unclear. The CIs were wide and compatible either with no (or an unimportantly small) benefit, or with a moderate but clinically worthwhile benefit. Even taking the most positive finding, the CI ranges from a very modest 0.8 mmHg reduction in systolic BP to a much larger 11.7 mmHg benefit. Thus, it is important to try to obtain tighter estimates of the true treatment effect. Similarly, for renal function, whilst a significant improvement in serum creatinine was observed at 6 months, this was not the case when the change in serum creatinine between baseline and 6 months was investigated, where the 95% CI is consistent with no benefit for angioplasty.
As with many fields of medicine, the reported trials have been too small (27106 patients) to determine reliably the role of angioplasty in ARVD. Furthermore, follow-up in all three trials was relatively short (minimum 6 months and maximum 12 months). ARVD is a progressive disease, so it is important to look at the longer-term effects of angioplasty in renal function over years rather than months. The trials have also suffered from a differing quality of reporting. One study compared both BP and serum creatinine at 6 months, and the change in these measures from baseline, although no data for the comparison of these measures over time was provided [2]. Another study compared the BP and serum creatinine at 3 and 12 months, but did not report on the change in either measure over time [4]. By comparing only the BP and serum creatinine at 3 months, the analysis does not take into account the baseline values of these measurements. A potentially more informative analysis is to compare the change in BP (and serum creatinine) over time, which allows for any imbalances in the baseline BP measures in the two groups. An example of this is in the study by Webster et al. [2] (unilateral disease), where the systolic BP at 6 months suggests that medical management is better than angioplasty. However, when the change between the BP at baseline and 6 months is analysed this benefit disappears, and there is little difference between the two groups. This can be explained in part by the fact that at baseline, patients in the medical management arm had lower BP than patients randomized to angioplasty, although this difference was not statistically significant.
In some cases, standard deviations, CIs and/or P-values were not provided, which added further uncertainty to the analyses. We attempted to address this uncertainty by writing to the authors of the papers and requesting the data that were missing. All the authors provided the data that was missing, although the data for the change between baseline and 6 months for BP and serum creatinine was not available for one study [2]. We therefore carried out a sensitivity analysis where various assumptions for the missing data were made. This had little or no effect on the results so we consider that the analysis is robust and is the best estimate of the efficacy of angioplasty that can be obtained from the existing clinical trial evidence. A meta-analysis of individual patient data from all these studies would not materially change our conclusions.
The trials included in this analysis predominantly used angioplasty alone, only the study by Plouin et al. [3] allowed stent insertion, although only two of the 23 patients randomized to angioplasty actually received stents. Since these studies were undertaken, the standard of care has changed slightly with revascularization (balloon angioplasty with stent insertion) having become increasingly popular. This is despite the lack of evidence to support the use of stents in patients with ARVD. There has been only one randomized study of 85 patients with ostial atherosclerotic renal-artery stenosis that has directly compared angioplasty with or without stent placement [1]. They reported clear improvements in arterial patency following stent insertion (primary patency rate at 6 months 75% (angioplasty plus stent) vs 29% (angioplasty)), but were unable to show any corresponding reduction in the rate of decline in renal function or improvement in BP.
As with all published data meta-analyses, there is the potential problem of publication bias. This is, however, unlikely to be a substantial source of bias, as we undertook a comprehensive search of databases, journals and conference proceedings to identify published data, as well as contacting experts in the field to identify unpublished data. The only other relevant randomized controlled trial compared surgical reconstruction and angioplasty in 58 patients with severe hypertension and significant stenosis, and found no significant difference between the two methods with regard to BP response or renal function [7].
This meta-analysis confirms the conclusions of several non-systematic reviews [811] that advocate much larger trials, such as the UK Medical Research Council's ASTRAL trial, comparing revascularization (using balloon angioplasty with or without stent insertion) and medical management, recruiting several hundred patients, to determine more reliably whether or not revascularization leads to clinically worthwhile improvements in renal function and BP in patients with ARVD.
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Acknowledgments
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We would like to thank Dr John Webster for providing the additional data needed for the analysis. We are grateful for the support of the NHS Executive R&D, Medtronic, Medical Research Council, and National Kidney Research Fund (NKRF). Presented in part at the Renovascular Forum, Glasgow, March 2001 and the 39th ERAEDTA Congress, Copenhagen, July 2002.
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Notes
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Correspondence and offprint requests to: Natalie Ives, Birmingham Clinical Trials Unit, The University of Birmingham, Park Grange, 1 Somerset Road, Edgbaston, Birmingham B15 2RR, UK. Email: n.j.ives{at}bham.ac.uk 
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Received for publication: 29. 7.02
Accepted in revised form: 4. 9.02