The aim of the study was to compare the efficacy of revascularization versus medical therapy in patients with atherosclerotic renal artery stenosis (ARAS). ARAS is the most common cause of secondary hypertension and is associated with several complications, such as renal failure, coronary artery disease, cardiac destabilization, and stroke. Medical therapy is the cornerstone for management of ARAS; however, numerous trials have compared medical therapy with revascularization in the form of percutaneous renal artery angioplasty (PTRA) or percutaneous renal artery angioplasty with stent placement (PTRAS). Medline (PubMed and Ovid SP), Embase, Cochrane Central Register of Controlled Clinical Trials (CENTRAL), and Cochrane Database of Systematic Review (CDSR) were searched till present (November 2013) to identify clinical trials where medical therapy was compared with revascularization (PTRA or PTRAS). We performed a meta-analysis using a random effects model. The heterogeneity was assessed using I 2 values. The initial database search identified 540 studies and 7 randomized controlled trials, and 2,139 patients were included in the final analysis. Angioplasty with or without stenting was not superior to medical therapy with respect to any outcome. The incidence of nonfatal myocardial infarction was 6.74% in both the stenting and medical therapy group (odds ratio = 0.998, 95% confidence interval 0.698 to 1.427, p = 0.992), and incidence of renal events in stenting population was found to be 19.58% versus 20.53% in medical therapy (odds ratio = 0.945, 95% confidence interval 0.755 to 1.182, p = 0.620). In conclusion, PTRA or PTRAS does not improve outcomes compared with medical therapy in patients with ARAS. Future studies should investigate to identify patient subgroups that may benefit from such an intervention.
Atherosclerotic renal artery stenosis (ARAS) is the most common cause of secondary hypertension accounting for up to 5% of all cases. The prevalence increases with age and the presence of multiple atherosclerotic risk factors. Furthermore, evidence suggests that ARAS is a significant cause of chronic renal failure and is associated with several other long-term complications, such as coronary artery disease, stroke, peripheral vascular disease, and cardiac destabilization. Medical therapy has been the cornerstone of treatment for patients with ARAS. The data from animal studies and early uncontrolled human studies suggested that revascularization with or without stenting leads to better blood pressure control and decreases in using antihypertensive medications. This led to rapid adoption of this procedure in clinical practice. The associated costs and complications warrant robust evidence to support ARAS as a first-line therapy. The 2005 ACC/AHA guidelines strongly recommend percutaneous revascularization for patients with hemodynamically significant ARAS, recurrent unexplained congestive heart failure (CHF), or sudden pulmonary edema and may also be reasonable in patients with hemodynamically significant ARAS and resistant hypertension or progressive chronic kidney disease. Several randomized controlled trials have been undertaken to identify if and which patients would benefit by undergoing therapeutic revascularization with percutaneous renal artery angioplasty (PTRA) or percutaneous renal artery angioplasty with stent placement (PTRAS). The individual trials are limited by several factors, such as sample size, duration of follow-up, methodological issues, heterogeneous end points, lack of clinical end points, and varying degrees of stenosis of the renal artery. The aim of this systematic review was to identify randomized controlled trials comparing revascularization strategies (PTRA and PTRAS) versus medical therapy looking at clinical outcomes (deaths and nonfatal myocardial infarction [MI], CHF, changes in systolic blood pressure from baseline, stroke, and deterioration in renal function).
Methods
Literature search was conducted using methods described in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. Medline (PubMed and Ovid SP), Embase, Cochrane Central Register of Controlled Clinical Trials (CENTRAL), and Cochrane Database of Systematic Review (CDSR) were searched from the inception of these databases till present (November 2013). We used “renal artery stenosis,” “randomized controlled trials,” “angioplasty,” “surgical intervention,” and “medical therapy” as the search terms. No limits of language were applied, and references of the included studies were hand searched to ensure that the eligible studies were not missed.
Only randomized controlled trials where medical therapy was compared with angioplasty and stenting were included in the study. Nonrandomized comparisons, observational studies, and other article types such as editorials were excluded.
Two researchers independently abstracted data in an excel sheet using a structured template. The extracted variables included baseline demographics, clinical characteristics, and outcomes ( Table 1 ). Discrepancies were resolved through mutual consensus.
| Study | Mean Age ∗ (Years) | Patients Enrolled ∗ | DBP (mm Hg) | CC (ml/min) | ARAS (% Stenosis) | Primary Outcome Measures | Duration of follow-up (Months) |
|---|---|---|---|---|---|---|---|
| Plouin et al | 59.2 vs. 59.5 | 49 (23 vs. 26) | ≥95 | ≥50 | — | ↓SBP | 6 |
| Jaarsveld et al | 61 vs. 59 | 106 (56 vs. 50) | ≥95 | — | — | Renal function | 12 |
| Bax et al | 66 vs. 67 | 140 (64 vs. 76) | — | <80 | ≥50 | Renal function | 1, 3, 24 |
| Webster et al | 59.4 vs. 62.6 | 135 (55 25 vs. 30) | ≥95 | — | — | ↓SBP | 1, 3, 6 and every 6 there after |
| ASTRAL Investigators | 70 vs. 71 | 806 (403 vs. 403) | — | — | — | Renal function | 60 |
| CORAL study | 69.3 vs. 69. | 947 (459 vs. 472) | — | — | ≥60 | Clinical end points † | 43 (median) |
∗ Reported as intervention versus control group.
† Mortality, nonfatal MI, stroke, renal function, and hospitalization for CHF.
The Cochrane Collaboration tool was used to ascertain the risk of bias in the included studies. The following domains were assessed: randomization, concealment to treatment allocation, avoidance of co-interventions, similarity of groups at baseline, eligibility criteria, blinding, and intention to treat analysis. Funnel plot was constructed to assess for publication bias.
The primary outcome measures were nonfatal MI and renal events. The secondary outcome measures included changes in systolic blood pressure from baseline, CHF, stroke, and death. We performed separate analyses based on the type of intervention (PTRA or PTRAS).
We performed a meta-analysis using Comprehensive Meta-analysis 2.0 using random effects model. The heterogeneity was assessed using I 2 values, and sensitivity analysis was performed to explain the heterogeneity where present.
Results
We found 540 titles during the initial database search. After screening the titles, 95 studies were eligible for further review, and 7 randomized controlled trials were included in the meta-analysis. The search strategy is shown in the PRISMA sheet ( Figure 1 ).
In the included trials, intensive medical therapy was compared against angioplasty with or without stenting in the patients with ARAS. The primary outcome measure was systolic blood pressure reduction in studies by Plouin et al and Webster et al and deterioration in renal function in the more recent studies (van Jaarsveld et al, Bax et al, and Revascularization versus Medical Therapy for Renal-Artery Stenosis [ASTRAL] Investigators ). The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) Investigators were the first to design a trial specifically aimed at assessing the composite clinical end points (mortality, nonfatal MI, stroke, renal dysfunction, and the need for renal replacement therapy) as the outcome measures. There was variation in the follow-up duration of the included studies (for instance, ≤6 months in Plouin et al and 5 years by the ASTRAL Investigators).
A total of 2,139 patients with ARAS were randomized in the 7 clinical trials. However, the extent of stenosis and the diagnostic methods used to identify ARAS varied significantly across the studies. Bax et al initially aimed to include patients based on the presence of a stenosis of ≥50% by noninvasive means. However, subsequently, it was noticed that many of these patients were not candidates for stenting. To overcome the limitations of earlier studies, the CORAL Investigators conducted a large, multicenter, double-blind, randomized controlled trial. This trial sought to address several shortcomings by enrolling a large population with >60% (average stenosis 73%) degree of renal artery stenosis. However, the findings from the core laboratory showed that mean renal artery stenosis of CORAL was <70%, that is, moderate at best. The CORAL study is the only trial specifically designed to assess clinical end points in ARAS. Moreover, contrary to the earlier studies, its findings were confirmed by core laboratories. Its results showed that stenting did not improve the primary outcome (a composite of renal or cardiovascular outcomes) compared with medical therapy. CORAL demonstrated that for patients with renal artery stenosis and hypertension or chronic kidney disease, a trial of medical therapy was as good as or better than an initial stent attempt. The follow-up revealed a modest benefit in the improvement of blood pressure in the stented group.
The quality assessment of the included studies is summarized in Table 2 , which illustrates the quality assessment of studies performed using the Cochrane collaboration’s tool. Table 2 illustrates temporal trends showing that the risk of bias is low in the recent trials with Cooper et al showing the least bias. Funnel plot showed no publication bias ( Supplementary Figure 1 ).
| Cooper 2014 | ASTRAL 2009 | Jaarsveld 2000 | Bax 2009 | Webster 1998 | Plouin 1998 | |
|---|---|---|---|---|---|---|
| Randomization | + | + | + | + | + ∗ | + |
| Concealment to treatment allocation | + | +/0 | +/0 | 0 | 0 | 0 |
| Avoidance of co-interventions | + | + | + | + | + | + |
| Similarity of groups at baseline | + | + | + | + | + | + |
| Eligibility criteria | + | + | + | + | + | + |
| Blinding criteria | + | 0 | +/0 | 0 | 0 | 0 |
| Intention to treat analysis | + | + | + | + | 0 | 0 |
Results were reported as random effects model. The results show that in patients with ARAS treated with intervention (angioplasty or stenting), the outcomes did not differ compared with those with medical therapy alone.
Pooled estimates from our analysis failed to reveal any benefit of angioplasty or stenting ( Figures 2 and 3 , Table 3 ). The incidence of nonfatal MI was 6.74% in both the stenting and medical therapy group (OR 0.998, 95% confidence interval [CI] 0.698 to 1.427, p = 0.992). The incidence of nonfatal MI in angioplasty group was 1.2%, whereas in medical therapy group it was found to be 2.5%. There was no evidence of heterogeneity among the studies (I 2 = 0%).
| Study | Total (n) | Revascularization | Medical Therapy (MT) | NFMI-Revascularization | NFMI-MT | Mortality-Revascularization | Mortality-MT |
|---|---|---|---|---|---|---|---|
| ASTRAL trial (2009) | 806 | 403 | 403 | 20/403 | 24/403 | 103/403 | 106/403 |
| Bax et al (2009) | 140 | 64 | 76 | 3/64 | 3/76 | 5/64 | 6/76 |
| Scarpioni et al ∗ (2005) | 52 | 24 | 28 | 1/24 | 2/28 | 3/24 | 3/28 |
| VanJaarsveld et al (2000) | 106 | 56 | 50 | 0/56 | 1/50 | 0/56 | 0/50 |
| Webster et al (1998) | 55 | 25 | 30 | 1/25 | 1/30 | 2/25 | 4/30 |
| Cooper et al (2013) | 931 | 459 | 472 | 40/459 | 37/472 | 63/459 | 76/472 |
| Plouin et al (1998) | 49 | 23 | 26 | NA | NA | 0/23 | 0/26 |
| Renal Event-Revascularization | Renal Event-MT | CHF-Revascularization | CHF-MT | Stroke-Revascularization | Stroke-MT | |
|---|---|---|---|---|---|---|
| ASTRAL trial | 73/403 | 80/403 | 44/403 | 55/403 | 19/403 | 18/403 |
| Bax et al | 10/64 | 16/76 | 1/64 | 3/76 | 0/64 | 1/76 |
| Scarpioni et al ∗ | 10/24 | 8/28 | NA | NA | 4/24 | 3/28 |
| VanJaarsveld | 1/56 | 3/50 | NA | NA | NA | NA |
| Webster et al | 2/25 | 2/30 | 3/25 | 4/30 | 1/25 | 4/30 |
| Plouin et al | 0/23 | 1/26 | NA | NA | NA | NA |
| Cooper et al | 93/459 | 97/472 | 39/459 | 39/472 | 16/459 | 23/472 |
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