Accepted Manuscript Meta-Analysis of the Effect of Renal Denervation on Blood Pressure and Pulse Pressure in Patients with Resistant Systemic Hypertension Samir B. Pancholy, MD Ghanshyam Palamaner Subash Shantha, MD Tejas M. Patel, MD Paul A. Sobotka, MD David E. Kandzari, MD PII:

S0002-9149(14)01365-4

DOI:

10.1016/j.amjcard.2014.06.018

Reference:

AJC 20545

To appear in:

The American Journal of Cardiology

Received Date: 4 May 2014 Revised Date:

16 June 2014

Accepted Date: 25 June 2014

Please cite this article as: Pancholy SB, Palamaner Subash Shantha G, Patel TM, Sobotka PA, Kandzari DE, Meta-Analysis of the Effect of Renal Denervation on Blood Pressure and Pulse Pressure in Patients with Resistant Systemic Hypertension, The American Journal of Cardiology (2014), doi: 10.1016/j.amjcard.2014.06.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1 Meta-Analysis of the Effect of Renal Denervation on Blood Pressure and Pulse Pressure in Patients with Resistant Systemic Hypertension Running head: Renal Denervation and Resistant Hypertension Meta-analysis

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Samir B. Pancholy, MDa, Ghanshyam Palamaner Subash Shantha, MDa, Tejas M. Patel, MDb; Paul A. Sobotka, MDc; David E. Kandzari, MDd a

The Commonwealth Medical College, and The Wright Center for Graduate Medical

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Education, Scranton, PA; bApex Heart Institute and Seth N.H.L. Municipal Medical

Institute, Atlanta, GA Address for Correspondence: Samir B. Pancholy, MD

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College, Ahmedabad, India; cOhio State University, Columbus, OH; dPiedmont Heart

Program Director, Fellowship in Cardiovascular Diseases,

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The Wright Center for Graduate Medical Education, Associate Professor of Medicine,

The Commonwealth Medical College,

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501 Madison Avenue, Scranton, PA: 18510.

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Ph: 001-570-587-7817, email: [email protected], Fax: 570-587-7815.

ACCEPTED MANUSCRIPT 2 Abstract Data comparing the effect of renal denervation (RD) to maximal medical therapy (MMT) have shown conflicting results. Also, effect of RD on pulse pressure (PP) has not been

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evaluated. In this meta-analysis we have attempted to compare the effect of RD with MMT on blood pressure (BP) and PP at 6 months follow-up in patients with resistant

hypertension (RH). Randomized controlled trials (RCTs) and non-randomized controlled

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trials (CT) reporting systolic BP, diastolic BP and PP results in RD and MMT groups at 6 months follow-up in patients with RH were systematically reviewed and eligible citations

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were pooled using random effects model. 5 studies (3 RCTs, 2 CTs, n = 800) met inclusion criteria. In the pooled analysis, RD was associated with a significant decrease in systolic BP [weighted mean difference (WMD): -19.4 mmHg, 95% CI: -32.8 to -5.9 mmHg, P = 0.005], diastolic BP (WMD: -6.4 mmHg, 95% CI: -10.7 to -2.0 mmHg, P =

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0.004) and PP (WMD: -12.7 mmHg, 95% CI: -22.3 to – 3.1 mmHg, P = 0.009) when compared to MMT, at 6 months follow-up. Sensitivity analysis limited to RCTs, showed borderline significant difference in lowering systolic BP, significant difference in

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lowering diastolic BP, and non-significant difference in lowering PP when RD was compared to MMT. In conclusion, our meta-analysis shows that RD is superior to MMT

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in lowering BP, however, heterogeneity amongst study populations in this pooled sample is high, and further data are needed to better compare these treatment strategies. Keywords: resistant hypertension, renal denervation, blood pressure, pulse pressure

ACCEPTED MANUSCRIPT 3 Introduction Sympathectomy, a historical surgical procedure, showed promise in significantly reducing blood pressure [1]. Due to its associated post-surgical morbidities, this

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procedure was phased out of clinical practice. There has been a recent renewed interest and encouraging early findings using catheter-based RD as a potential therapeutic option for RH [2, 3]. Evidence from observational studies [3, 4, 5], randomized controlled trials

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[6, 7] and 3 systematic reviews [8, 9, 10] strongly support the unprecedented BP lowering effect of RD, leading to its approval as a therapeutic option for RH in Europe and Canada

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[11]. However, dampening this enthusiasm associated with RD, are the results of a recent RCT [12] with larger sample size and methodological advantage of the control group receiving sham treatment [12] reporting conflicting results. A pooled analysis comparing the BP lowering effects of RD versus MMT in RH including this new RCT [12] and the

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other newer controlled trials [13, 14] is lacking in the literature. PP, an important cardiovascular risk stratification tool [15, 16], has not been evaluated systematically in RD trials. Hence, via this systematic review and meta-analysis we have pooled data from

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available controlled trials published so far to assess the effect of RD when compared to MMT, on systolic BP, diastolic BP and PP change at 6 months follow-up.

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Methods

The Preferred Reporting Items for Systemic Reviews and Meta-analysis

(PRISMA) method was followed for planning, conducting, and reporting of this systematic review and meta-analysis [17]. We searched Medline, Embase, CINAHL, OVID, Cochrane library database, 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

ACCEPTED MANUSCRIPT 4 are detailed in Supplemental methods. 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

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patients who presented with RH; defined as uncontrolled HTN (SBP ≥ 160 mmHg)

despite treatment with 3 maximally dosed anti-hypertensive medications from 3 different classes that include a diuretic, 2) one of the intervention groups received RD, 3) The

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other group (control group) should have received maximal medical therapy for RH, 4) reported systolic BP and diastolic BP, 4) reported BP change at 6 months follow-up;

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rationale being that important RCTs [6, 12] had used 6 months follow-up BP change as their primary outcome. 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

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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 were abstracted: the

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last name of the first author, publication year, country where the study was performed, study design [RCTs or CT], total participants in the study, number of participants who

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received RD, number of participants in the control group, baseline mean systolic BP/diastolic BP (office and/or ambulatory measurement), details regarding antihypertensives 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/diastolic BP at 6 months follow-up in the RD and the MMT group.

ACCEPTED MANUSCRIPT 5 Since we included only RCTs and CTs in our review we used Cochrane collaboration risk of bias assessment tool to determine the quality of included studies. Two investigators

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individually assessed the study quality and differences were resolved by consensus. Abstracted data from the included studies were entered into RevMan 5.1 (Nordic Cochrane Center, Kobenhavn, Denmark) statistical software program [18]. Weighted

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mean differences (WMD) in systolic BP, diastolic BP and PP change at 6 months followup in the RD group was compared to the MMT group pooling all included studies (RCTs

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and CTs). Considering the clinical and statistical heterogeneity between studies, data was combined using DerSimonian and Laird random effects model with inverse variance weighting [19]. Estimates were reported as WMD comparing RD group to MMT group, with 95% CIs. Differences were considered significant at 2-sided P < 0.05. Then, we performed 2 sensitivity analyses; 1) assessing WMD in systolic BP, diastolic BP and PP

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at 6 months follow-up comparing RD group with MMT group using data restricted to RCTs, 2) removing on study at a time and assessing the effect on the WMD. Heterogeneity was assessed with the Cochran’s Q statistic (χ2) with a P < 0.10 for

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significance, and with the I2 test [20]. An I2 value of 50% was considered substantial heterogeneity. Considering the significant statistical heterogeneity, we performed metaregression 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, DM prevalence, and CAD prevalence. These variables were chosen because of their potential to affect BP outcomes. Publication bias was assessed using Egger’s linear regression test [21], visual inspection of funnel plots and

ACCEPTED MANUSCRIPT 6 Begg-Mazumdar’s test. These analyses were performed using STATA version 11 statistical software. P < 0.05 was considered statistically significant.

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Results Study selection details are described in Figure 1. From a total of 1409 citations

identified, 5 studies [6, 7, 12, 13, 14] were included for the meta-analysis. The study by

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Fadl et. al. [22], although an RCT, used European society of hypertension guidelines

definition for RH (systolic BP ≥ 140 mmHg), whereas other included studies uniformly

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used standard criteria systolic BP ≥ 160 mmhg) 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 mentioned in Tables 1, 2 and Supplemental Tables 1 and 2.

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Pooled analysis involving all 5 included studies showed that patients who underwent RD (n = 534) experienced significant reductions in systolic BP (WMD: - 24.7 mmHg, 95% CI: -32.5 to -16.8 mmHg, P = 0.001, I2: 90%), diastolic BP (WMD: -8.4

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mmHg, 95% CI: -10.6 to –6.4 mmHg, P = 0.001, I2: 22%) and PP (WMD: -15.7 mmHg, 95% CI: -22.1 to -9.2 mmHg, P = 0.001, I2: 80%) at 6 months follow-up. The MMT

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group (n = 266) also experienced significant reductions in systolic BP (WMD: - 6.1 mmHg, 95% CI: -11.3 to -0.8 mmHg, P = 0.02, I2: 68%), diastolic BP (WMD: -3.1 mmHg, 95% CI: -5.2 to -0.9 mmHg, P = 0.005, I2: 0%) and PP (WMD: -3.8 mmHg, 95% CI: -7.0 to -0.5 mmHg, P = 0.02, I2: 0%) at 6 months follow-up. Significant reductions in systolic BP (WMD: -19.4 mmHg, 95% CI: -32.8 to -5.9 mmHg, P = 0.005, I2 = 93%), diastolic BP (WMD: -6.4 mmHg, 95% CI: -10.7 to -2.0 mmHg, P = 0.004, I2 = 67%] and PP (WMD: -12.7 mmHg, 95% CI: -22.3 to – 3.1

ACCEPTED MANUSCRIPT 7 mmHg, P = 0.009, I2 = 76%) were reported in the RD group compared to MMT at 6 months follow-up (Figures 2A, 2B and 2C). When data was restricted to RCTs, a borderline significant difference in systolic

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BP lowering (WMD: -18.9 mmHg, 95% CI: -37.9 to -0.1 mmHg, P = 0.049), a

significant difference in diastolic BP lowering (WMD: -7.1 mmHg, 95% CI: -13.3 to -0.9 mmHg, P = 0.02, I2 = 82%), and no significant difference in PP lowering (WMD: -12.2

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mmHg, 95% CI: -26.5 to 2.2 mmHg, P = 0.1) was observed at 6 month follow-up, comparing RD to MMT. Further, when 1 study was removed at a time, there was

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consistent systolic BP lowering (range 16 – 25 mmHg, all P < 0.05), diastolic BP lowering (range 4 – 8 mmHg, all P < 0.05) and PP lowering (range 11 – 18 mmHg, all P < 0.05) in the RD group compared to the MMT group.

Data from 2 RCTs that reported ambulatory blood pressure measurements [6, 12],

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showed no difference in systolic BP lowering (WMD: -16.4 mmHg, 95% CI: -44.5 to 11.7 mmHg, P = 0.25, I2 = 97%), diastolic BP lowering (WMD: -7.1 mmHg, 95% CI: 16.8 to 2.6 mmHg, P = 0.15, I2 = 91%) and PP lowering (WMD: -8.2 mmHg, 95% CI: -

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25.6 to 9.2 mmHg, P = 0.35, I2 = 83%) between the 2 groups. In general, adverse events were rare and included few cases of pseudoaneurysms

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[n = 4 (0.7%)] and hematomas [8 (1.6%)] at the femoral sites. The commonest adverse event was intra-procedural bradycardia (n = 19) (Supplemental Table 3), which uniformly resolved with atropine treatment. No significant publication bias was observed and study quality was rated as "good" (details in supplemental results).

ACCEPTED MANUSCRIPT 8 Discussion: Our meta-analysis using data from 5 CTs, reporting the difference in BP lowering effect of RD versus MMT, has shown that patients treated with RD experienced

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significantly greater systolic BP, diastolic BP and PP reductions at 6 months follow-up. However, when the analysis was restricted to RCTs, RD’s association with systolic BP lowering became weaker although significant and association with PP change

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disappeared compared to MMT, but the association with diastolic BP change at 6 months remained significant. Adverse events associated with RD were rare in the pooled sample.

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Among our included studies, Simplicity 2 [6], Pokushalov et. al. [7] and Ewen et. al. [13] supported the superiority of BP lowering effect of RD, while Mahfoud et. al. [14] and Simplicity 3 [12] refuted the superiority of RD compared to MMT with BP lowering. Potential influence due to ‘Hawthorne effect’ in the RD arm of controlled

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studies where the control group did not receive an invasive intervention, and the phenomenon of ‘regression to mean’, may have been the possible reasons for the reported unprecedented superior BP lowering effect of RD compared to MMT in studies that

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supported RD [6, 7, 13]. The Hawthorne effect argument is less likely to be a valid explanation, as in the study by Pokushalov et al [7], both groups received a procedure, as

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the non-RDN group underwent atrial fibrillation ablation, and despite this “sham” controlled non-RDN group, RDN cohort showed a significant reduction in BP. Among the studies that refuted RD, Mahfoud et. al [14], may have had significant selection bias as 55 patients in their study received RD, while only 17 received MMT. Simplicity HTN3 [12], although had advantages of a large sample, and adequately powered randomized experiment with ‘Sham’ treatment in the control group possibly annulling ‘Hawthorne’

ACCEPTED MANUSCRIPT 9 effect, had limitations such as: increased spiranolactone use, an anti-hypertensive medication that acts mechanistically similar to RD [23], in the MMT group, multiple participating sites with heterogeneous center and operator characteristics, and lack of

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objective method to document effective denervation. Also, differences in RD catheter

prototypes used in US (Flex catheter) versus non-US (Arch catheter) trials with inherent differences in contact force and other characteristics translating differing degrees of renal

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denervation in these two cohorts may have also contributed to the diverse findings. The uniformity of positive findings across different RD radiofrequency catheters, and non-

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radiofrequency based RD device platforms in the non-US experience, indirectly refute the non-biologic theories attempting to explain BP lowering in patients receiving RD in nonUS trials, and raises important concerns regarding the extent of denervation and its effect on findings of Symplicity 3 trial. Further, BP change reported in the RD group of

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Simplicity 3 had wide variance [12]. This raises the possibility of variable efficacy of RD in specific subgroups, as rightly pointed out by Masserli et. al [24], and the possibility of variability in the time to respond to RD. Identifying and sampling these specific

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RD.

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subgroups in future trials will shed better light on the efficacy and clinical applicability of

Though, prior pooled-analyses have assessed the association of RD and BP

change [8, 9, 10], our study is unique in having included data from 3 new RCTs [12, 13, 14], compared 5 controlled trials (RD versus MMT); while prior meta-analyses included only 2 controlled trials in their pooled analyses [9, 10], and having assessed the effect of RD on PP. Our included studies reported short-term follow-up (6 months) as longer follow-up details of recent RCTs [12] were not available. Also, all 5 included studies

ACCEPTED MANUSCRIPT 10 used catheters delivering radiofrequency energy. Hence, we could not perform subgroup analysis based on catheters using other modalities of catheter-based RD. A sensitivity analysis evaluating comparative effect of MMT and RD on ambulatory SBP, DBP and PP

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showed no significant difference, although the fact that only 2 studies were included in this analysis, and a large discrepancy in sample size of the 2 included studies leading to disproportionate weight of the findings of the larger trial driving the point estimate

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despite using random-effects model, limits the ability to derive relevant inferences from

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this sensitivity analysis.

ACCEPTED MANUSCRIPT 11 References: 1. Peet MM. Hypertension and its surgical treatment by bilateral supradiaphragmatic

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splanchnicectomy. Am J Surg 1948;75: 48–68 . 2. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev 1997;77:175197.

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3. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal

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sympathetic denervation for resistant hypertension: a multicentre safety and proof-ofprinciple cohort study. Lancet 2009;373:1275-1281.

4. Hering D, Mahfoud F, Walton AS, Krum H, Lambert GW, Lambert EA, Sobotka PA, Böhm M, Cremers B, Esler MD, Schlaich MP. Renal denervation in moderate to severe CKD. J Am Soc Nephrol 2012;23:1250–1257.

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5. Ahmed H, Neuzil P, Skoda J, Petru J, Sediva L, Schejbalova M, Reddy VY. Renal sympathetic denervation using an irrigated radiofrequency ablation catheter for the management of drug-resistant hypertension. J Am Coll Cardiol Intv 2012;5:758–765.

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6. Symplicity HTN-2 Investigators, Esler MD, Krum H, Sobotka PA, Schmieder RE,

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Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903-1909. 7. Pokushalov E, Romanov A, Corbucci G, Artyomenko S, Baranova V, Turov A, Shirokova N, Karaskov A, Mittal S, Steinberg JS. A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. J

ACCEPTED MANUSCRIPT 12 Am Coll Cardiol 2012;60:1163-1170. 8. Davis MI, Filion KB, Zhang D, Eisenberg MJ, Afilalo J, Schiffrin EL, Joyal D.

review and meta-analysis. J Am Coll Cardiol 2013;62:231-241.

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Effectiveness of renal denervation therapy for resistant hypertension: a systematic

9. Gosain P, Garimella PS, Hart PD, Agarwal R. Renal sympathetic denervation for treatment of resistant hypertension: a systematic review. J Clin Hypertens

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(Greenwich) 2013;15:75-84.

10. Liu M, Chen J, Liu C, Huang D, Ke J, Tang W, Huang S, Wu W. Catheter-based

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renal sympathetic denervation is effective in reducing office and ambulatory blood pressure in patients with resistant hypertension. Int J Cardiol 2014;172:259-260. 11. Medtronic I. Symplicity. RDN System Clinical Trial Data. Mountain View, CA: Medtronic, Inc, 2012: 461

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12. Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL; SYMPLICITY HTN-3 Investigators. A controlled trial of renal

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denervation for resistant hypertension. N Engl J Med 2014;370:1393-1401. 13. Ewen S, Mahfoud F, Linz D, Pöss J, Cremers B, Kindermann I, Laufs U, Ukena C,

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Böhm M. Effects of renal sympathetic denervation on exercise blood pressure, heart rate, and capacity in patients with resistant hypertension. Hypertension 2014;63:839845.

14. Mahfoud F, Urban D, Teller D, Linz D, Stawowy P, Hassel JH, Fries P, Dreysse S, Wellnhofer E, Schneider G, Buecker A, Schneeweis C, Doltra A, Schlaich MP, Esler MD, Fleck E, Böhm M, Kelle S. Effect of renal denervation on left ventricular mass

ACCEPTED MANUSCRIPT 13 and function in patients with resistant hypertension: data from a multi-centre cardiovascular magnetic resonance imaging trial. Eur Heart J 2014. 15. Franklin SS, Larson MG, Khan SA, Wong ND, Leip EP, Kannel WB, Levy D. Does

Framingham Heart Study. Circulation 2001;103:1245–1249.

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the relation of blood pressure to coronary heart disease risk change with aging? The

16. Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, Christiaens T,

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Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM,

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Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J

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Hypertens 2013;31:1281–1357.

17. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med

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2009;6(7):e1000097.

18. Deeks JJ, Higgins JPT, Altman DG. Chapter 9. Analysing data and undertaking meta-

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analyses. In: Higgins JPT, Green S, ed. Cochrane handbook for systematic reviews of interventions. Chichester, UK: John Wiley & Sons, 2008: 79. 19. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trial 1986;7:177e88.

20. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003;327:557–560.

ACCEPTED MANUSCRIPT 14 21. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315:629-634. 22. Fadl EFE, Hoffmann P, Larstorp AC, Larstorp AC, Fossum E, Brekke M, Kjeldsen

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SE, Gjønnæss E, Hjørnholm U, Kjær VN, Rostrup M, Os I, Stenehjem A, Høieggen A. Adjusted Drug Treatment Is Superior to Renal Sympathetic Denervation in

Patients With True Treatment-Resistant Hypertension. Hypertension 2014;63:991-

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999.

23. Gaddam K, Pimenta E, Thomas SJ, Cofield SS, Oparil S, Harding SM, Calhoun DA.

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Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: a preliminary report. J Hum Hypertens 2010;24:532–537. 24. Messerli FH, Bangalore S. Renal Denervation for Resistant Hypertension? N Engl J

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Med 2014;370:1454-1457.

ACCEPTED MANUSCRIPT 15 Figure legends Figure: 1: Flow diagram explaining study inclusion Description: Flow diagram detailing the citations identified, number excluded and

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reasons for exclusion and the number of included studies

Figure 2A: Systolic blood pressure change at 6 months, RD Vs MMT

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Description: Forest plots representing systolic blood pressure change at 6 months in

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renal denervation group compared to the maximal medical therapy group

Figure 2B: Diastolic blood pressure change at 6 months, RD Vs MMT Description: Forest plots representing diastolic blood pressure change at 6 months in the

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renal denervation group compared to the maximal medical therapy group

Fugure 2C: Pulse pressure change at 6 months, RD Vs MMT Description: Forest plots representing pulse pressure change at 6 months in renal

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denervation group compared to the maximal medical therapy group

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Table 1: Characteristics of included studies Year

Esler (Simplicity 2)

2010

d

Ewen

2014

Germany

c

CT

Mahfoud

2014

Germany, bAust

c

CT

Pokusholav

2012

Russia

h

RCT

g

Bhatt (Simplicity 3)

2014

i

h

RCT

g

USA

BP assessment

h

g

Catheter type

RD (n)

Controls (n)

Non-responders

O and aA

Simplicity catheter

52

53

16%

g

O

Simplicity catheter

50

10

14%

g

Simplicity Flex system

55

17

f

Navistar ThermoCool

13

14

0%

Simplicity catheter

364

171

f

RCT

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Er, bAust, eNZ

Design

O O

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Region

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First Author

O and aA

A: ambulatory BP, bAust: Australia cCT: controlled trials, dEr: Europe, eNZ: New Zealand, fNR: not reported,gO: office BP measurement, hRCT: randomized controlled trials, iUSA: United States of America

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a

NR

NR

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Table 2: Baseline characteristics of study participants from included studies

2010

31 ± 5

40%

19%

77 ± 19

MMT

58 ± 12

50%

31 ± 5

28%

7%

86 ± 20

g

RD

64.7 ± 7

78%

30.7 ± 4

50%

24%

f

NR

MMT

68.4 ± 8

80%

28.6 ± 4

30%

40%

f

NR

g

RD

65 ± 10

71%

29.2 ± 4.3

47%

g

f

NR

MMT

70 ± 9

59%

28.6 ± 5.3

41%

g

f

NR

g

RD

57 ± 8

85%

28 ± 6

8%

15%

78 ± 6.1

MMT

56 ± 9

71%

28 ± 5

14%

14%

80 ± 4.2

57 ± 10

59%

34.2 ± 6.5

47%

28%

72 ± 15.7

56 ± 11

64%

33.9 ± 6.4

41%

25%

74 ± 18.7

2012

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e

Pokusholav

g

2014

RD

e

a

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MMT

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e

Bhatt (Simplicity 3)

GFR (ml/min/1.73 m2)

65%

2014

CAD

d

58 ± 12

2014

DM

b

RD

e

Mahfoud

c

g

e

Ewen

BMI (Kg/m2)

Males

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Esler (Simplicity 2)

Treatment group

a

Age (yrs)

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Year

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First Author

NR NR

e

BMI: body mass index (Kg/m2), bCAD: coronary artery disease, cDM: diabetes mellitus, dGFR: glomerular filtration rate, MMT: maximal medical therapy, fNR: not reported, gRD: renal denervation,

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Figure 1

1295 citations identified through database searching Medline: 464 EMBASE: 610 Cinahl, Cochrane, Web of science, Google Scholar, Ovid: 221

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114 citations identified through searching conference abstracts

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691 citations after removal of duplicates

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691 records screened for eligibility

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107 full-text articles assessed for eligibility

5 studies included in qualitative synthesis

5 studies included in quantitative synthesis (meta-analysis)

584 records excluded

102 full text articles excluded due to: 1. 23 studies with no control group 2. 62 review articles, editorials 3. 15 case reports. 4. 1 study with untreated control Group 5. 1 study with different definition for RH

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Figure 2A

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Figure 2B

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Figure 2C

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Search Terms: The search terms included were “renal denervation”, “sympathetic nervous system”, “hypertension”, “systolic blood pressure”, “diastolic blood pressure”, “pulse pressure”,

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“controlled studies”, “randomized controlled trials”, “outcomes”, “resistant hypertension”, “drug resistant hypertension”, “treatment resistant hypertension”, “Trials”, “randomized trials” and

search strategy. Date of search: April 28, 2014

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Search strategy:

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“follow-up study”. For searching randomized studies we used the highly sensitive Cochrane

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Our final combined Pubmed Search strategy will be as follows: 1) ("randomized controlled trials as topic"[MeSH Terms] OR ((randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR "drug therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab]) NOT ("animals"[MeSH Terms] NOT "humans"[MeSH Terms]))) - Highly sensitive cochrane search strategy for RCTs AND

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2) ("Renal nerves"[Mesh] OR "Renal denervation"[All Fields] OR "renal sympathetic denervation"[All Fields] OR “sympathetic nerves”[all fields] OR “sympathetic tone”[all fields] OR "sympathetic tone"[All Fields] OR "systemic sympathetic sctivity"[All Fields] OR "autonomic nervous system"[All Fields] OR "Autonomic nerves"[Mesh] OR "sympathetic autonomic nerves"[All Fields] OR "catheter based denervation"[MESH] OR “renal nerve abalation”[all fields] OR “sympathectomy”[all fields] OR “renal sympathectomy”[all fields] OR “sympathetic ablation”[all fields] OR “sympathetic nerve ablation”[all fields] OR “catheter treatment”[all fields] OR “Medtronic”[all fields] OR “Medtronic catheter”[all fields] OR “Medtronic Adrian catheter”[all fields] OR “catheter based sympathectomy”[all fields] Search Strategy for renal denervation. AND 3) ("Medical therapy"[all fields] OR "treatment resistant hypertension"[MeSH] OR "drug resistant hypertension"[all fields] OR "uncontrolled hypertension"[all fields] OR "resistant hypertension"[all fields] OR "drug refractory hypertension"[all fields]. Search strategy for resistant hypertension. Final Search: #1 AND #2 AND # 3 Cochrane CENTRAL Search: Our Cochrane search strategy will be as follows:

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#1 MeSH descriptor renal denervation explode all trees #2 MeSH descriptor resistant hypertension explode all trees #3 MeSH descriptor medical therapy #4 (renal denervation) OR renal nerves OR (renal sympathetic denervation) OR (renal sympathectomy) OR (sympathectomy) OR (renal nerve ablation) OR (sympathetic tone) OR (systemic sympathetic activity) OR (systemic autonomic tone) OR (sympathetic nerve ablation) OR (sympathetic nerve lysis) OR (sympathetic nervous system) OR (autonomic nerves) OR (catheter based ablation #5 MeSH descriptor Medtronic explode all trees #6 MeSH descriptor trials explode all trees.

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#7 MeSH descriptor randomized controlled trials, Home explode all trees #8 ((#1 OR #2 OR #3 OR #4 OR #5) AND (#6)): will be the final combined search strategy for Cochrane central.

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EMBASE Search: #1 Renal denervation part ‘renal nerves’/exp OR ‘renal denervation’/exp OR ‘renal sympathetic denervation’/exp OR ‘autonomic nerves’ OR ‘sympathetic nerves’ OR ‘sympathetic nervous system’ OR ‘sympathetic nerve ablation’ OR ‘renal nerve ablation’ OR ‘sympathetic tone’ OR ‘systemic sympathetic tone’ OR ‘sympathetic nerve activity’ OR ‘sympathectomy’ OR ‘renal sympathectomy’ OR ‘renal afferents’ OR ‘renal efferents’ OR ‘catheter based ablation’ OR ‘catheter used ablation’ OR ‘catheter based sympathectomy’

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#2 Resistant hypertension part ‘resistant hypertension’/exp OR ‘drug resistant hypertension’/exp OR treatment resistant hypertension OR ‘poor control hypertension’/exp OR ‘drug resistant hypertension’/exp OR ‘medical therapy’/exp OR ‘optimal medical therapy’/exp OR ‘anti-hypertensives’/exp OR ‘maximal anti-hypertensives’/exp OR blood pressure lowering OR ‘blood pressure reduction’/exp #3 RCT part We combined (using OR) the ideas of the most sensitive and middle sensitive approaches from the Wong paper on EMBASE searching strategies for RCTs random*:de,lnk,ab,ti,au OR random:de,lnk,ab,ti,au OR 'clinical trial':de,lnk,ab,ti,au OR 'clinical trials':de,lnk,ab,ti,au OR 'health care quality'/exp OR 'health care quality' OR 'treatment outcome'/exp OR ‘treatment outcome' FINAL COMBO #1 and #2 and #3 = final Embase search.

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Supplemental results Characteristics of included studies: Of the 3 included RCTs [9, 10, 14], study by Esler et. al. (SYMPLICITY HTN-2) [9]

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randomized 106 patients with RH to RDN group (n = 52) and MMT group (n = 54). They used the standard definition for RH. RDN was performed using SYMPLICITY catheter (Arch catheter in the first half of the cohort) (Medtronic Inc, Santa Clara, CA, USA). Both groups were

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followed at 1 month, 3 months and 6 months after enrollment, and their primary endpoint was to assess difference in office-based SBP and DBP between RDN and MMT group at 6 months

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follow-up. They concluded that RDN performed significantly better than MMT at 1 month, 3 months and 6 months with greater SBP and DBP reduction when compared to the control group. Pokushalov et. al [10] involved 27 patients with RH (standard criteria) and symptomatic paroxysmal and persistent atrial fibrillation and randomized them to pulmonary vein isolation

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only group (control group) (n = 14) or pulmonary vein isolation combined with RDN intervention group (n = 13) performed in the same setting, in a double blind fashion and studied their primary endpoint; recurrence of > 30 seconds of atrial tachyarrhythmias’ at 12 months

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follow-up. RDN significantly decreased atrial tachyarrythmia recurrence when compared their control group. As a secondary end point they reported significant reductions in SBP and DBP at

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3 months, 6 months, 9 months and 12 months in RDN group compared to their control group. The control group in this trial, having undergone pulmonary vein isolation, underwent a “sham procedure”. Ewen et. al. [15] performed a controlled trial, with 50 patients assigned to the RDN group and 10 patients assigned to the MMT group (control group) and assessed their primary endpoint of exercise SBP, DBP and heart rate change at 6 and 12 months follow-up. Secondarily they reported office SBP and DBP change at 6 months and 12 months follow-up. They

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concluded that RDN significantly decreased exercise and office SBP, DBP and heart rate at 6 months and 12 months follow-up. Mahfoud et. al. [16] assigned 55 patients to undergo RDN and 17 patients to MMT group (control group) in a prospective non-randomized fashion and assessed

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anatomic and functional parameters such as left ventricular mass index, left ventricular ejection fraction and left ventricular circumferential strain at 6 months follow-up as their primary

outcome and BP change as their secondary outcome. They concluded that RDN significantly

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reduced SBP, DBP and left ventricular mass index and improved ejection fraction and

circumferential strain in patients with RH. Symplicity HTN-3 trial, reported by Bhatt et al [14],

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evaluated 2 primary end points; 1) efficacy end point of change in SBP and DBP in the RDN group compared to the MMT group at 6 months follow-up, 2) safety end point of adverse events associated with RDN compared to MMT group at 6 months follow-up. This large sample, well powered randomized controlled double blind study used ‘Sham” treatment’ in their control arm.

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With a 2:1 randomization design, 364 patients were randomized to RDN group (performed using “Flex” catheter) and 171 patients to MMT + Sham group. They concluded that, though safety end point was similar in RDN and MMT groups, RDN did not fare better with SBP and DBP

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reductions at 6 months when compared to MMT group. Comparison between RDN and MMT group at 6 months follow-up

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Significantly lower mean SBP (WMD: - 14.17 mmHg, 95% CI: -26.51 to -1.82 mmHg, P = 0.02, I2: 94%), borderline significantly lower mean DBP (WMD: - 5.13 mmHg, 95% CI: -10.19 to 0.06 mmHg, P = 0.05, I2: 84%) and significantly lower mean PP (WMD: - 9.59 mmHg, 95% CI: -18.38 to -0.8 mmHg, P = 0.03, I2: 87%) were reported in the RDN group compared to the MMT group. In the analysis restricted to the 3 included RCTs (n = 668) [9, 10, 14], significantly lower mean SBP (WMD: -19.00 mmHg, 95% CI: -37.23 to -0.76 mmHg, P = 0.04, I2 = 97%) and DBP

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(WMD: -8.1 mmHg, 95% CI: -13.86 to -2.34 mmHg, P = 0.006) were reported in the RDN group compared to MMT group at 6 months follow-up. Whereas, there was no difference in PP (WMD: -10.76 mmHg, 95% CI: -25.28 to 3.76 mmHg, P = 0.15) between the two groups.

assessment of risk of bias is mentioned in the supplemental figures.

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Study quality: risk of bias was generally low in all the 6 included studies and the detailed

Heterogeneity and publication bias: Though visual inspection of funnel plots showed evidence

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for possible publication bias with under-representation of large sample studies and negative studies for SBP, DBP and PP analyses (supplemental tables), Egger’s and Begg’s coefficients for

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SBP (P = 0.487, P = 0.911), DBP (P = 0.322, P = 0.624) and PP (P = 0.895, P = 0.327) did not confirm these findings. Further, meta-regression analysis using age, gender, BMI, DM prevalence and CAD prevalence as operator variables found no significant association between these operator variables and differences in reduction in SBP, DBP or PP (all P > 0.05), and could

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not explain the heterogeneity between study populations. (Supplemental figures).

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Supplemental Table 1: Inclusion criteria and exclusion criteria followed in included studies

2014 2014

Pokusholav

2012

Bhatt et. al. Simplicity 3

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Exclusion criteria 1) Renal artery stenosis, 2) Previous renal intervention, 3) Renal artery anatomy that precluded treatment (defined as 50% 1.4, embolic event: 0.3, renal artery intervention: 0, hypertensive crisis: 2.6%, stroke 1.1, new onset heart failure: 2.6, new renal artery stenosis >70%: 0.3

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Year 2010

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Author Esler et. al. (Simplicity 2)

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Supplemental figures

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Funnel plot for SBP change 6 months RDN Vs MT

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Standard error of SMD 6 4 2

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Funnel plot with pseudo 95% confidence limits

0 2 4 6 8 SMD for SBP change

Begg’s: 0.911, Eggers: 0.487

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Funnel plot for DBP change at 6 months RDN Vs MT

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Standard error of SMD 6 4 2

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Funnel plot with pseudo 95% confidence limits

0 2 4 SMD for DBP change

Begg’s: 0.624, Egger’s: 0.322

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Funnel plot for Pulse pressure change at 6 months RDN Vs MT

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Standard error of SMD 6 4 2

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Funnel plot with pseudo 95% confidence limits

0 SMD for PP change

Begg’s: 0.327, Eggers: 0.895

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-2 0 Age difference (Yrs) RDN Vs MT

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P = 0.276

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Meta-regression for SBP change at 6 months (RDN Vs MT)

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-10 0 10 Difference in % of Males (RDN Vs MT)

P = 0.130

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0 1 Difference in BMI (Kg/m2) RDN Vs MT

P = 0.356

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Meta-regression for SBP change at 6 months (RDN Vs MT)

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P = 0.345

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Meta-regression for SBP change at 6 months (RDN Vs MT)

P = 0.104

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-2 0 Age difference (Yrs) RDN Vs MT

P = 0.313

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Meta-regression for DBP change at 6 months (RDN Vs MT)

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-10 0 10 Difference in % of Males (RDN Vs MT)

P = 0.168

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0 1 Difference in BMI (Kg/m2) RDN Vs MT

P = 0.597

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Meta-regression for DBP change at 6 months (RDN Vs MT)

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0 10 Difference in DM prevalence (RDN Vs MT)

P = 0.465

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Meta-regression for DBP change at 6 months (RDN Vs MT)

-40 -20 0 Difference in CAD prevalence (%) (RDN Vs MT)

P = 0.112

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-2 0 Age difference (Yrs) RDN Vs MT

P = 0.269

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Meta-regression for Pulse Pressure change at 6 months (RDN Vs MT)

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-10 0 10 Difference in % of Males (RDN Vs MT)

P = 0.173

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0 1 Difference in BMI (Kg/m2) RDN Vs MT

P = 0.472

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Meta-regression for Pulse Pressure change at 6 months (RDN Vs MT)

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Meta-regression for Pulse Pressure change at 6 months (RDN Vs MT)

P = 0.183

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Mean SBP at 6 months, RDN Vs MMT

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Mean DBP at 6 months, RDN Vs MMT

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Pulse pressure at 6 months, RDN Vs MMT

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SBP at 6 months, RDN Vs MMT (Only RCTs)

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DBP at 6 months, RDN Vs MMT (only RCTs)

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Mean pulse pressure at 6 months, RDN Vs MMT (Only RCTs)

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Meta-analysis using data from controlled trials show that renal denervation decreases systolic blood pressure, diastolic blood pressure and pulse pressure at 6 months follow-up

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Data restricted to randomized controlled trials, though confirm the association of renal

association with systolic blood pressure and pulse pressure.

Methodological and procedural limitations in the included studies allude to a need for

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further exploration, via studies with superior methodology and standardized procedural techniques, to accurately determine the association of renal denervation and blood

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pressure.

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denervation with improvement in diastolic blood pressure, report an attenuated