Data comparing the effect of renal denervation (RD) with those of maximal medical therapy (MMT) have shown conflicting results. Also, effect of RD on pulse pressure (PP) has not been evaluated. The aim of this meta-analysis was to compare the effect of RD with that of MMT on blood pressure (BP) and PP at 6-month follow-up in patients with resistant hypertension. Randomized controlled trials and nonrandomized controlled trials reporting systolic BP, diastolic BP, and PP results in RD and MMT groups at 6-month follow-up in patients with resistant hypertension were systematically reviewed, and eligible citations were pooled using a random-effects model. Five studies (3 randomized controlled trials, 2 nonrandomized controlled trials, n = 800) met the inclusion criteria. In the pooled analysis, RD was associated with a significant decrease in systolic BP (weighted mean difference −19.4 mm Hg, 95% confidence interval −32.8 to −5.9, p = 0.005), diastolic BP (weighted mean difference −6.4 mm Hg, 95% confidence interval −10.7 to −2.0 mm Hg, p = 0.004), and PP (weighted mean difference −12.7 mm Hg, 95% confidence interval −22.3 to −3.1 mm Hg, p = 0.009) compared with MMT at 6-month follow-up. Sensitivity analysis limited to randomized controlled trials showed a borderline significant difference in lowering systolic BP, a significant difference in lowering diastolic BP, and a nonsignificant difference in lowering PP when RD was compared with MMT. In conclusion, this meta-analysis shows that RD is superior to MMT in lowering BP, but heterogeneity among study populations in this pooled sample is high, and further data are needed to better compare these treatment strategies.
Highlights
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A meta-analysis using data from controlled trials shows that renal denervation decreases systolic blood pressure, diastolic blood pressure, and pulse pressure at 6-month follow-up.
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Data restricted to randomized controlled trials, although confirming the association of renal denervation with improvement in diastolic blood pressure, show an attenuated association with systolic blood pressure and pulse pressure.
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Methodologic and procedural limitations in the included studies suggest a need for further exploration, in studies with superior methodologies and standardized procedural techniques, to accurately determine the association of renal denervation and blood pressure.
Sympathectomy, a historical surgical procedure, showed promise in significantly reducing blood pressure (BP). Because of its associated postsurgical morbidities, this procedure was phased out of clinical practice. There has been recent renewed interest and encouraging early findings using catheter-based renal denervation (RD) as a potential therapeutic option for resistant hypertension (RH). Evidence from observational studies, randomized controlled trials, and 3 systematic reviews strongly supports the unprecedented BP-lowering effect of RD, leading to its approval as a therapeutic option for RH in Europe and Canada. However, dampening this enthusiasm associated with RD are the results of a recent randomized controlled trial (RCT), with a larger sample size and the methodologic advantage of the control group’s receiving sham treatment, reporting conflicting results. A pooled analysis comparing the BP-lowering effects of RD versus maximal medical therapy (MMT) in RH, including this new RCT and the other newer controlled trials, is lacking. Pulse pressure (PP), an important cardiovascular risk stratification tool, has not been evaluated systematically in RD trials. Hence, in this systematic review and meta-analysis, we have pooled data from available controlled trials published so far to assess the effect of RD compared with MMT on systolic BP, diastolic BP, and PP change at 6-month follow-up.
Methods
The Preferred Reporting Items for Systemic Reviews and Meta-Analysis method was followed for planning, conducting, and reporting of this systematic review and meta-analysis. We searched MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, OVID, the Cochrane Library database, the Web of Science, and Google Scholar for studies that assessed the effect of RD on systolic BP and diastolic BP. The search terms and strategy are detailed in the online supplement . Titles and abstracts of retrieved citations were reviewed. Full texts of relevant citations were assessed for eligibility for inclusion into the review. Inclusion criteria for studies were (1) controlled trials or RCTs that involved patients who presented with RH, defined as uncontrolled hypertension (systolic BP ≥160 mm Hg) despite treatment with 3 maximally dosed antihypertensive medications from 3 different classes that include a diuretic; (2) one of the intervention groups received RD; (3) the other group (control group) received MMT for RH; (4) reported systolic BP and diastolic BP; and (5) reported BP change at 6-month follow-up, the rationale being that important RCTs had used 6-month follow-up BP change as their primary outcomes. We excluded observational studies, uncontrolled trials, and case reports. We included conference abstracts if they reported data relevant to our research question. Two reviewers independently assessed studies for eligibility. Discrepancy was resolved by consensus. Two reviewers independently extracted data from the included full-text citations and entered into electronic datasheets using standardized protocol. Discrepancy was resolved by consensus. The following information was abstracted: the last name of the first author, publication year, the country where the study was performed, study design (RCTs or nonrandomized controlled trials [CTs]), total participants in the study, number of participants who received RD, number of participants in the control group, baseline mean systolic BP and diastolic BP (office and/or ambulatory measurement), details regarding antihypertensive agents used in the RD group and MMT group at baseline, type of catheter used for performing RD, RD procedure–related complications if reported in the included studies, and mean systolic BP and diastolic BP at 6-month follow-up in the RD and MMT groups.
Because we included only RCTs and CTs in our review, we used the Cochrane Collaboration’s risk for bias assessment tool to determine the quality of the included studies. Two investigators individually assessed study quality, and differences were resolved by consensus.
Abstracted data from the included studies were entered into RevMan version 5.1 (Nordic Cochrane Center, Copenhagen, Denmark). Weighted mean differences (WMDs) in systolic BP, diastolic BP, and PP change at 6-month follow-up in the RD group were compared with those in the MMT group, pooling all included studies (RCTs and CTs). Considering the clinical and statistical heterogeneity among studies, data were combined using a DerSimonian and Laird random-effects model with inverse variance weighting. Estimates were reported as WMDs comparing the RD group with the MMT group, with 95% confidence intervals (CIs). Differences were considered significant at a 2-sided p value <0.05. Then, we performed 2 sensitivity analyses, (1) assessing WMDs in systolic BP, diastolic BP, and PP at 6-month follow-up comparing the RD group with the MMT group using data restricted to RCTs and (2) removing 1 study at a time and assessing the effect on the WMDs. Heterogeneity was assessed with Cochran’s Q statistic (chi-square), with a p value <0.10 for significance, and with the I 2 test. An I 2 value <25% was considered to indicate low heterogeneity, 25% to 50% moderate heterogeneity, and >50% substantial heterogeneity. Considering the significant statistical heterogeneity, we performed meta-regression for systolic BP, diastolic BP, and PP change, investigating the sources of heterogeneity in the included studies; the potential sources assessed were differences in age, gender, body mass index, prevalence of diabetes mellitus, and prevalence of coronary artery disease. These variables were chosen because of their potential to affect BP outcomes. Publication bias was assessed using Egger’s linear regression test, visual inspection of funnel plots, and Begg-Mazumdar’s test. These analyses were performed using Stata version 11 (StataCorp LP, College Station, Texas). A p value <0.05 was considered statistically significant.
Results
Study selection details are described in Figure 1 . From a total of 1,409 citations identified, 5 studies were included in the meta-analysis. The study by Fadl et al, although an RCT, used the European Society of Hypertension guidelines definition for RH (systolic BP ≥140 mm Hg), whereas other included studies uniformly used standard criteria systolic BP ≥160 mm Hg) to define RH. Hence, suspecting the possibility of participant misclassification due to differential definitions, by consensus, we decided to exclude this study from our analysis. Study characteristics and participant details are listed in Tables 1 and 2 and Supplementary Tables 1 and 2 .
| First Author | Year | Region | Design | BP Assessment | Catheter Type | RD (n) | Controls (n) | Non-Responders |
|---|---|---|---|---|---|---|---|---|
| Esler (Simplicity 2) | 2010 | Er, Aust, NZ | RCT | O and A | Simplicity catheter | 52 | 53 | 16% |
| Ewen | 2014 | Germany | CT | O | Simplicity catheter | 50 | 10 | 14% |
| Mahfoud | 2014 | Germany, Aust | CT | O | Simplicity Flex system | 55 | 17 | NR |
| Pokusholav | 2012 | Russia | RCT | O | Navistar ThermoCool | 13 | 14 | 0% |
| Bhatt (Simplicity 3) | 2014 | USA | RCT | O and A | Simplicity catheter | 364 | 171 | NR |
| First Author | Year | Treatment Group | Age (Yrs) | Males | BMI (Kg/m 2 ) | DM | CAD | GFR (ml/min/1.73 m 2 ) |
|---|---|---|---|---|---|---|---|---|
| Esler (Simplicity 2) | 2010 | RD | 58 ± 12 | 65% | 31 ± 5 | 40% | 19% | 77 ± 19 |
| MMT | 58 ± 12 | 50% | 31 ± 5 | 28% | 7% | 86 ± 20 | ||
| Ewen | 2014 | RD | 64.7 ± 7 | 78% | 30.7 ± 4 | 50% | 24% | NR |
| MMT | 68.4 ± 8 | 80% | 28.6 ± 4 | 30% | 40% | NR | ||
| Mahfoud | 2014 | RD | 65 ± 10 | 71% | 29.2 ± 4.3 | 47% | NR | NR |
| MMT | 70 ± 9 | 59% | 28.6 ± 5.3 | 41% | NR | NR | ||
| Pokusholav | 2012 | RD | 57 ± 8 | 85% | 28 ± 6 | 8% | 15% | 78 ± 6.1 |
| MMT | 56 ± 9 | 71% | 28 ± 5 | 14% | 14% | 80 ± 4.2 | ||
| Bhatt (Simplicity 3) | 2014 | RD | 57 ± 10 | 59% | 34.2 ± 6.5 | 47% | 28% | 72 ± 15.7 |
| MMT | 56 ± 11 | 64% | 33.9 ± 6.4 | 41% | 25% | 74 ± 18.7 |
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