Effectiveness of Renal Denervation Therapy for Resistant Hypertension meta

Objectives This study sought to determine the current effectiveness and safety of sympathetic renal denervation (RDN)for resistant hypertension.

Background RDN is a novel approach that has been evaluated in multiple small studies.

Methods

We performed a systematic review and meta-analysis of published studies evaluating the effect of RDN in patients with resistant hypertension.Studies were strati ?ed according to controlled versus uncontrolled design and analyzed using random-effects meta-analysis models.

Results

We identi ?ed 2randomized controlled trials,1observational study with a control group,and 9observational studies without a control group.In controlled studies,there was a reduction in mean systolic and diastolic blood pressure (BP)at 6months of –28.9mm Hg (95%con ?dence interval [CI]:–37.2to –20.6mm Hg)and –11.0mm Hg (95%CI:–16.4to –5.7mm Hg),respectively,compared with medically treated patients (for both,p <0.0001).In uncontrolled studies,there was a reduction in mean systolic and diastolic BP at 6months of –25.0mm Hg (95%CI:–29.9to –20.1mm Hg)and –10.0mm Hg (95%CI:–12.5to –7.5mm Hg),respectively,compared with pre-RDN values (for both,p <0.00001).There was no difference in the effect of RDN according to the 5catheters employed.Reported procedural complications included 1renal artery dissection and 4femoral pseudoaneurysms.

Conclusions

RDN resulted in a substantial reduction in mean BP at 6months in patients with resistant hypertension.The

decrease in BP was similar irrespective of study design and type of catheter https://www.wendangku.net/doc/4c1261521.html,rge randomized controlled trials with long-term follow-up are needed to con ?rm the sustained ef ?cacy and safety of RDN.(J Am Coll Cardiol 2013;62:231–41)a2013by the American College of Cardiology Foundation

Resistant hypertension (RH)is de ?ned as uncontrolled systolic blood pressures (BP)despite therapy with !3anti-hypertensive agents from at least 3different classes including a diuretic.In most studies,10%to 15%of hypertensive subjects (1,2),but up to 20%of the hypertensive population in some publications (3),have RH,particularly those with advanced age,obesity,diabetes mellitus,sleep apnea,and chronic kidney disease (4–6).In patients with RH,phar-macological options are limited.Historically,a surgical option,namely sympathectomy,led to a signi ?cant reduc-tion in BP but was associated with high surgical morbidity

(7–9).Although surgical sympathectomy was largely aban-doned in clinical practice,there has been a renewed interest in the concept as animal models (10,11)have shown that renal sympathectomy leads to signi ?cant reduction in BP and improvement in end organ function (12–15).

Percutaneous renal sympathectomy has emerged as a safer,although invasive approach using radiofrequency probes to ablate the sympathetic ?bers along the renal artery.The proof of concept study (16)demonstrated surprisingly good results and was subsequently followed by a series of studies using different catheters.These studies have generated great enthusiasm such that percutaneous renal denervation therapy (RDN)has been adopted at a rate rarely seen in the hyper-tension ?eld.RDN for RH is currently approved in Europe and Canada and is pending approval in the United States.One RDN catheter system (Medtronic Ardian Inc.,Palo Alto,California)has been used to treat over 4,000patients worldwide thus far (17).Despite the enthusiasm and rapid uptake,there has yet to be a comprehensive review of the available evidence to support the practice of RDN.

From the *Department of Internal Medicine,Jewish General Hospital,McGill University,Montreal,Canada;y Division of Clinical Epidemiology,Jewish General Hospital,McGill University,Montreal,Canada;z Division of Cardiology,Jewish General Hospital,McGill University,Montreal,Canada;and the x Lady Davis Institute for Medical Research,Jewish General Hospital,McGill University,Mon-treal,Canada.The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received January 10,2013;revised manuscript received March 18,2013,accepted April 7,2013.

Journal of the American College of Cardiology

Vol.62,No.3,2013ó2013by the American College of Cardiology Foundation ISSN 0735-1097/$36.00

Published by Elsevier Inc.https://www.wendangku.net/doc/4c1261521.html,/10.1016/j.jacc.2013.04.010

We have systematically re-viewed the current body of evi-dence for RDN and quanti ?ed its BP-lowering effect in patients with RH using a random effects meta-analysis model.Methods

Data sources and search

strategy.We performed a sys-tematic review and meta-analysis in accordance with the standards

set forth by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)statement (18,19).We searched PubMed,EMBASE,and the Cochrane Collaboration database using the key words “renal dener-vation,”“blood pressure,”and “hypertension.”The search was limited to English language articles published in the last 5years (this technology was only developed in that time frame).In addition,we hand-searched references of retrieved articles and used PubMed ’s related articles feature to identify studies not captured by our primary search strategy.The ?nal search was run on December 1,2012.

Study selection.We included randomized and observa-tional studies comparing BP response in patients treated with RDN versus patients treated with standard medical therapy (controlled studies)and observational studies comparing BP in a single group of patients before and after RDN (uncontrolled studies).Inclusion criteria were:1)RDN per-formed using contemporary percutaneous catheters and radiofrequency probes;2)patient population with RH (not meeting BP target despite therapy with 3or more antihy-pertensive agents from at least 3different classes);3)at least 10study participants;and 4)at least 3months of follow-up for BP response.BP measurements could include manual,automated,or invasive BP recordings,as long as the same method was used before and after RDN.Reviews,editorials,letters,animal studies,case reports,and conference abstracts were excluded.Once full articles were retrieved,studies were further excluded if there was an overlap in patients with another study within the same analysis (in which case,the larger sample size of the 2studies was selected).Thus,whereas some patients could possibly have been included in both the controlled and uncontrolled study analyses,they were only included once in any given analysis.Consequently,there was no overlap in patients included in our meta-analyses.Data extraction.Data was extracted in duplicate by 2inde-pendent reviewers (M.D.,D.Z.).Disagreements were resolved by consensus.We extracted data pertaining to baseline char-acteristics of study subjects (number of subjects,age,sex,comorbidities,antihypertensive agents),trial inclusion and exclusion criteria,method of BP measurement,type of catheter used,BP response to RDN (including BP before and after RDN),nonresponder rate,procedural complications,maximal length of follow-up,and mortality.

Outcomes.The primary outcome measure was mean systolic and diastolic BP reduction following RDN between 3and 6months of follow-up.Secondary outcome measures included:1)nonresponder rate,de ?ned as an achieved decrease in systolic BP of <10mm Hg;2)mean BP reduction strati ?ed by catheter type;and 3)reported procedural complications and averse outcomes including death from any cause.

Methodological quality.To determine the quality of the included studies,we used the Cochrane Collaboration Risk of Bias Tool (Online Appendix 1)for the 2randomized control trials and the Newcastle-Ottawa scale for the observational studies.We set a follow-up rate of >70%at 6months as a limit to determine high risks of bias at follow-up for studies evaluated with the Newcastle-Ottawa scale in the outcome section of this scale (Online Appendix 2).

Data synthesis and statistical analysis.For controlled stud-ies,the difference in BP change with RDN versus medical therapy was pooled across studies and analyzed using random-effects meta-analysis models with inverse variance weighting.Separate models were constructed for 3and 6months of follow-up.For uncontrolled studies,the BP change before versus after RDN was pooled and analyzed using the same meta-analysis models.The magnitude of heterogeneity present was estimated using the I 2statistic,an estimate of the proportion of the total observed variance that is attributed to between-study variance.To compare the magnitude of BP reduction based on the type of RDN catheter used,we constructed a separate meta-analysis strati ?ed by catheter type using a random-effects generic inverse variance-weighting model to compare heterogeneity using the I 2statistic.

Certain studies reported measures of variability other than SD.In these cases,95%con ?dence intervals or standard error of the mean were converted to SD to maintain consistency of the reported results.In a study by Witkowski et al.(20),the only measure of variability reported was interquartile range.By including this study in the meta-analysis models,we are assuming a normal distribution of change in BP.In the study by Prochnau et al.(21),no estimate of variance was reported,thus we assumed a SD equal to the mean of other reported SD.Sensitivity analyses were performed excluding these 2studies.We considered p <0.05signi ?cant.Throughout,values are presented as mean ?SD unless otherwise stated.Analyses were performed using the Cochrane Collaboration Review Manager (version 5.1.7,Cochrane Collaboration,Copenhagen,Denmark)and the GraphPad Prism (version 6.0,GraphPad Software,La Jolla,California)software packages.Results

Study selection and characteristics.Our literature search identi ?ed 294potentially relevant studies as shown in the ?ow diagram (Fig.1).Of these,18studies met the inclusion criteria.Six additional studies were excluded due to

overlap

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of patients (22–27).All six of these studies were con-trolled studies with overlap of patients with the Symplicity HTN-2(Renal Sympathetic Denervation in Patients With Treatment-Resistant Hypertension)study and could not be included in the controlled study meta-analysis.On the other hand,the Ukena et al.study (28),which is an uncontrolled study,is included in the uncontrolled study meta-analysis even though 18(of 136)patients overlap with Symplicity HTN-2,because these 2studies are included in separate meta-analyses.Thus,12studies were included in our sys-tematic review,encompassing 561patients treated between 2008and 2012.The 12-month follow-up data for a study was published in a separate article and the follow-up data was extracted (29,30).The follow-up duration varied between 1and 24months with a median follow-up of 6months.Table 1summarizes the design and methods of the included studies.There were 2randomized controlled trials (n ?133)and 1observational study with a control group (n ?50)(i.e.,controlled studies),and 9observational studies without a control group (n ?396)(i.e.,uncontrolled studies).The inclusion and exclusion criteria were in large part similar,although 1study included patients at the lower end of the RH spectrum (31),and another study included only patients with moderate to severe chronic kidney disease (32).Ambulatory BP monitors were employed to measure the primary outcome of BP response (and used for the meta-analysis)in 2studies (21,33),with these measurements being relatively lower than of ?ce measurements,which were used as the primary outcome measure (and used for the meta-analysis)in the other 10studies (16,20,28,30–32,34–37).The risk of bias was low in the majority of studies,with a detailed assessment available in Online Appendixes 1and 2.

Tables 2and 3summarize the patient characteristics and concomitant therapies,respectively.Sixty percent of patients were male and the average age was 60years.Thirty-?ve percent of patients had type 2diabetes mellitus and 18%had coronary artery disease.Patients with RH were receiving an average of 5different antihypertensive medications.Effectiveness of RDN.In controlled studies,there was a reduction in mean systolic and diastolic BP at 6months of –28.9mm Hg (95%con ?dence interval [CI]:–37.2to

Diagram for Study Selection

3-stage exclusion process.Studies were ?rst screened based on abstract.Following selection of appropriate studies,participants and length of follow-up.Finally,6further studies were excluded due to an overlap in patient populations.

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–20.6mm Hg)and –11.0mm Hg (95%CI:–16.4to –5.7mm Hg),respectively,with RDN versus medical therapy (for both,p <0.0001)(Fig.2).At 3months,there were reductions of –20.8mm Hg systolic (95%CI:–26.4to –15.2mm Hg)and –7.6mm Hg diastolic BP (95%CI:–11.0to –4.2mm Hg).At 12months,there were reductions of –25.4mm Hg systolic (95%CI:–27.8to –23.0mm Hg)and –10.0mm Hg diastolic (95%CI:–11.0to –9.0mm Hg).There was a modest amount of heterogeneity (I 2?0at 3months and 50%to 60%at 6months)between these studies.

In uncontrolled studies,there was a reduction in mean systolic and diastolic BP at 6months of –25.0mm Hg (95%CI:–29.9to –20.1mm Hg)and –10.0mm Hg (95%CI:–12.5to –7.5mm Hg),respectively,before compared with after RDN (for both,p <0.00001)(Fig.3).At 3months,there were reductions of –22.8mm Hg systolic blood pressure (SBP)(95%CI:–26.3to –18.5mm Hg)and –9.1mm Hg diastolic blood pressure (DBP)(95%CI:–12.1to –6.1mm Hg).At 12months,there were reductions of –22.8mm Hg SBP (95%CI:–29.6to –16.0)and –10.6mm Hg DBP (95%CI:–15.0to –6.0mm Hg).There was a signif-icant amount of heterogeneity at the 3-month (I 2?66%and 80%for SBP and DBP,respectively)and 6-month (I 2?70%and 50%for SBP and DBP,respectively)time points.However,sensitivity analysis excluding the Kaltenbach study (which included patients with lower baseline BP)indicated that the heterogeneity was no longer apparent (I 2?0),whereas the BP change was maintained (–24/–10and –27/–11mm Hg at 3and 6months,respectively).Only 6studies (21,30–33,37)had adequate 6-month follow-up of ambulatory BP following RDN.The overall BP response was smaller than that seen in studies solely evaluating of ?ce BP.For these 6studies,there was a reduction in mean SBP and DBP at 6months of –13.2mm Hg (95%CI:–19.4to –7.0mm Hg)and –7.3mm Hg (95%CI:–10.2to –4.5mm Hg),respectively,before compared with after RDN (p <0.0001for SBP and p <0.00001for DBP).Statistical heterogeneity was present for the SBP response only (I 2?76%for SBP and 0%for DBP).

Catheter comparison.A total of 5different catheters were employed among the 12studies:the Symplicity/Flex catheter (Medtronic,Minneapolis,Minnesota)is a radio-frequency ablation catheter designed for RDN,the Celsius ThermoCool and Navistar ThermoCool (Biosense Webster Diamond Bar,California)are irrigated radiofrequency ab-lation catheters,the Marinr (Medtronic,Minneapolis,Minnesota)is a standard steerable radiofrequency ablation catheter,and the PARADISE (ReCor Medical,Ronkon-koma,New York)is an ultrasound ablation catheter.Given the overlap of 18patients between 2studies with separate

Figure 2Meta-Analysis of Controlled Studies

Forest plot demonstrating the changes in systolic and diastolic blood pressures (BP)strati ?ed by follow-up time among controlled studies following renal sympathetic

denervation (RDN).CI ?con ?dence interval(s);IV ?inverse variance;Symplicity HTN-2?Renal Sympathetic Denervation in Patients With Treatment-Resistant Hypertension study.

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study designs,we excluded the Symplicity HTN-2study (30)from the comparison of catheter meta-analysis and included the Ukena et al.study (28),given the larger amount of included patients treated with RDN.With all 95%CI overlapping,there is no evidence of difference in the ach-ieved BP response after RDN among the different catheters used (Fig.4).Procedural safety.The pooled nonresponder rate was 13.3%.The Kaltenbach et al.(31)study had the highest nonresponder rate,and excluding this study from the pooled estimate decreased the nonresponder rate to 11.7%.No deaths were reported during the stipulated follow-up periods.A total of 5procedural complications were reported (<1%).These included 1renal artery dissection (remote from where

Figure 3Meta-Analysis of Uncontrolled Studies

Forest plot demonstrating the changes in systolic and diastolic blood pressures strati ?ed by follow-up time among uncontrolled studies following RDN.Symplicity HTN-1catheter-based renal sympathetic denervation for resistant hypertension:durability of blood pressure reduction out to 24months;other abbreviations as in Figure 2.

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RDN was performed)(16)and 4pseudoaneurysms at the site of arterial puncture (16,30,34).Discussion

We have conducted the ?rst systematic review and meta-analysis of the published body of literature pertaining to RDN in patients with RH.Our study was designed to evaluate the effect of RDN on BP reduction in a RH population.We found that there was a substantial reduction in BP after RDN at 6months,which was apparent as early as 3months and sustained up to 12months.Importantly,the rate of procedural complications was quite low.

We chose to pool the results of the studies based on the study design.Hence,the 2randomized controlled trials were pooled with the only controlled cohort study,and the uncontrolled observational studies were pooled together.Observational studies tend to overestimate treatment effects by confounding by indication.In our analysis,however,all studies have demonstrated a consistent BP reduction regardless of study design.

The current study population is composed of only 561patients,which is a small number for a meta-analysis.It represents,however,most of the published experience of RDN in patients with RH.In a meta-analysis,more important than the number of patients is the number of included studies,especially when the outcome is continuous.As RDN is now used for clinical care in Europe,Canada,and parts of Asia,knowledge of the current extent of effec-tiveness of the procedure,and the source of the evidence,is of utmost importance.Before large studies are completed and reported,the quality of the evidence and effectiveness and safety of the procedure must be based on current data.

The short-to-intermediate term data suggests that RDN is safe and well-tolerated,with the most common periprocedural complaint being abdominal pain that responds to sedatives

Figure 4Catheters Used for RDN

Forest plot,strati ?ed by catheter type,demonstrating the change in systolic blood pressure at 3-month follow-up after RDN.Testing for heterogeneity between catheter and blood pressure –lowering effect is represented at the bottom of the ?gure using the I 2statistic.Three-month follow-up time was used for comparison of catheters as all

catheters employed had this minimal length of follow-up.Note,Symplicity HTN-2is not included in this analysis as 18patients overlapped with the Ukena et al.(30)study,and this study had a greater number of patients treated with RDN.Abbreviations as in Figures 2and 3.

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and/or narcotics(16,38).Serial vascular imaging follow-up up to6months in the Symplicity HTN-1(catheter-based renal sympathetic denervation for resistant hypertension:durability of blood pressure reduction out to24months)trial(34)did not reveal renal artery abnormalities secondary to RDN(based on renal duplex,magnetic resonance imaging or computed tomography angiography).Serial biochemical follow-up did not demonstrate deterioration in renal function(30,34).The only complications identi?ed in our review were pseudoa-neurysms at the vascular access site in4subjects,and1case of renal artery dissection on initial placement of the catheter prior to delivery of the radiofrequency signal.Hence,the renal artery dissection was the only non-access-related complication re-ported.Among the12studies included in the meta-analysis, 8studies presented data on follow-up imaging of the renal arteries via ultrasound duplex,computed tomography angiography or magnetic resonance imaging angiography (16,20,21,30,31,33,34,36).Of the191patients with follow-up imaging,there were no documented cases of renal artery stenosis,and only2patients had progression of previously visualized renal artery atherosclerosis.To date,2case reports (39,40)have been published of individual patients whose blood pressure initially responded to RDN but subsequently had an increase in blood pressure on follow-up visits.In both instances,renal Doppler and angiography demonstrated renal artery stenoses,which were treated by renal artery stenting.It is still unclear what proportion of patients develops renovascular abnormalities following RDN.Further studies are needed to evaluate long-term changes in renal artery anatomy after RDN as well as to determine the appropriate imaging follow-up. The average nonresponder rate,de?ned as a reduction in BP of<10mm Hg after RDN,was13%.Careful exami-nation of the studies shows that patients who had a lower baseline sBP(<150mm Hg)were less likely to respond to RDN.The Kaltenbach et al.(31)study included patients with sBP between140and160mm Hg and had the highest nonresponder rate of nearly50%.Therefore,it appears that patients with severe elevations of BP may derive the greatest relative bene?t from RDN.It remains unclear if the response persists in this patient population at long-term follow-up or if a rebound phenomenon may occur.

In addition to the primary BP-lowering effect,secondary effects of RDN have been documented.Brant et al.(22) showed that RDN led to a decrease in left ventricular hypertrophy,a decrease in end-systolic volume,and an increase in left ventricular ejection fraction.Mahfoud et al.

(24)showed that RDN led to a signi?cant reduction in fasting blood glucose as well as a reduction in insulin and C-peptide levels.Additionally,Mahfoud et al.(23)showed that RDN reduced albuminuria.A recent double-blind study(36)showed that RDN prevented a recurrence of atrial?brillation after pulmonary vein isolation.Another study(28)showed RDN led to a reduction in heart rate and prolongation of the PR interval.

We did not identify any studies directly comparing the effectiveness of different catheters.Based on the studies included in this meta-analysis,the magnitude of the ach-ieved BP reduction was consistent with all of the different catheters employed.Although RDN-speci?c catheters with multiple electrodes are being evaluated,it remains to be seen whether they are more effective at lowering BP.

Current studies.A number of RDN trials are currently underway.The Symplicity-HTN3(Renal Denervation in Patients With Uncontrolled Hypertension)trial(41) (NCT01418261)is a single-blind clinical trial that is randomizing530patients in a2:1fashion to RDN or control with a follow-up period of6months.The INSPiRED(Renal Denervation for Management of Drug-Resistant Hyperten-sion)study(NCT01505010)is a randomized clinical trial with a longer follow-up period of36months.The DEPART(Study of Catheter Based Renal Denervation Therapy in Hyperten-sion)(NCT01522430)is a double-blind clinical trial that is randomizing patients to RDN or sham procedure with a follow-up period of6months.The SymplicityHF(Renal Denervation in Patients With Chronic Heart Failure and Renal Impairment Clinical Trial)(NCT01392196)is evalu-ating the effect of RDN in patients with heart failure,and contrary to the aforementioned studies that will be focusing on BP response,this study will focus on procedural safety and renal and cardiac function.The DREAMS(Denervation of the Renal Artery in Metabolic Syndrome)study(NCT01465724) is evaluating the effect of RDN in patients with metabolic syndrome,with the primary outcome being a change in insulin-resistance parameters after12months of follow-up.

Study limitations.First,most of the included studies were observational in nature and thus may be affected by con-founding by indication and/or selection bias.Whereas the BP reduction was modestly greater in the observational controlled study than in either of the randomized controlled studies, large clinically important treatment effects were reported in all controlled studies.Second,with the use of published aggre-gate data,we were unable to examine the effect of RDN in patient subgroups.Third,inclusion was restricted to pub-lished studies and may therefore be affected by publication bias.Fourth,the follow-up rate was quite limited in many of the included studies,resulting in less than70%6-month follow-up.Fifth,although we conducted secondary analyses that were strati?ed by catheter type,there were5different catheters used in the12included studies and studies of catheters other than the Symplicity catheter were of modest size.Consequently,there were insuf?cient data to draw meaningful conclusions regarding the comparative ef?cacy of the different https://www.wendangku.net/doc/4c1261521.html,stly,given the recent evolution of RDN,the pooled person-time remains modest. Conclusions

The current available data suggest that RDN results in a substantial BP reduction at6-month follow-up in patients with RH.With few adverse events reported,avail-able data also suggest that RDN has a favorable safety pro?le.Nonetheless,large randomized controlled trials with

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long-term follow-up are needed to con?rm the sustained ef?cacy and safety of RDN in this patient population. Reprint requests and correspondence:Dr.Dominique Joyal, Division of Cardiology,Jewish General Hospital,McGill Univer-sity,3755Cote Ste-Catherine Road,Montreal,Quebec H3T 1W3,Canada.E-mail:djoyal@jgh.mcgill.ca.

REFERENCES

1.Persell SD.Prevalence of resistant hypertension in the United States,

2003–2008.Hypertension2011;57:1076–80.

2.de la Sierra A,Segura J,Banegas JR,et al.Clinical features of8,295

patients with resistant hypertension classi?ed on the basis of ambula-tory blood pressure monitoring.Hypertension2011;57:898–902.

3.Roberie DR,Elliott WJ.What is the prevalence of resistant hyper-

tension in the United States?Curr Opin Cardiol2012;27:386–91. 4.Sara?dis PA,Bakris GL.Resistant hypertension:an overview of eval-

uation and treatment.J Am Coll Cardiol2008;52:1749–57.

5.Sander GE,Giles TD.Resistant hypertension:concepts and approach

to management.Curr Hypertens Rep2011;13:347–55.

6.Calhoun DA,Jones D,Textor S,et al.Resistant hypertension:diagnosis,

evaluation,and treatment.A scienti?c statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.Hypertension2008;51:1403–19.

7.Evelyn KA,Singh MM,Chapman WP,Perera GA,Thaler H.Effect

of thoracolumbar sympathectomy on the clinical course of primary (essential)hypertension:a ten-year study of100sympathectomized patients compared with individually matched,symptomatically treated control subjects.Am J Med1960;28:188–221.

8.Hoobler SW,Manning JT,Paine WG,et al.The effects of splanch-

nicectomy on the blood pressure in hypertension.Circulation1951;4: 173–83.

9.Smithwick RH,Thompson JE.Splanchnicectomy for essential hyper-

tension:results in1,266cases.J Am Med Assoc1953;152:1501–4. 10.DiBona GF.Sympathetic nervous system and the kidney in hyper-

tension.Curr Opin Nephrol Hypertens2002;11:197–200.

11.DiBona GF,Kopp UC.Neural control of renal function.Physiol Rev

1997;77:75–197.

12.Joles JA,Koomans HA.Causes and consequences of increased

sympathetic activity in renal disease.Hypertension2004;43:699–706.

13.Recordati G,Zorzoli F,Zanchetti A.Effects of a reversible

‘nephrectomy’on renal sympathetic activity and blood pressure in the rat:evidence for an acute angiotensin-mediated hypertension.

J Hypertens2000;18:1277–87.

14.Id D,Bertog SC,Wunderlich N,Sievert H.Catheter-based renal

sympathectomy.J Cardiovasc Surg(Torino)2010;51:721–39.

15.Rippy MK,Zarins D,Barman NC,Wu A,Duncan KL,Zarins CK.

Catheter-based renal sympathetic denervation:chronic preclinical evidence for renal artery safety.Clin Res Cardiol2011;100:1095–101.

16.Krum H,Schlaich M,Whitbourn R,et al.Catheter-based renal

sympathetic denervation for resistant hypertension:a multicentre safety and proof-of-principle cohort https://www.wendangku.net/doc/4c1261521.html,ncet2009;373:1275–81. 17.Medtronic I.Symplicity?RDN System Clinical Trial Data.Mountain

View,CA:Medtronic,Inc,2012.

18.Liberati A,Altman DG,Tetzlaff J,et al.The PRISMA statement for

reporting systematic reviews and meta-analyses of studies that evaluate health care interventions:explanation and elaboration.PLoS Med 2009;6:e1000100.

19.Moher D,Liberati A,Tetzlaff J,Altman DG,PRISMA Group.

Preferred reporting items for systematic reviews and meta-analyses:the PRISMA statement.PLoS Med2009;6:e1000097.

20.Witkowski A,Prejbisz A,Florczak E,et al.Effects of renal sympathetic

denervation on blood pressure,sleep apnea course,and glycemic control in patients with resistant hypertension and sleep apnea.Hypertension 2011;58:559–65.

21.Prochnau D,Figulla HR,Surber R.Ef?cacy of renal denervation with

a standard EP catheter in the24-h ambulatory blood pressure

monitoring-long-term follow-up.Int J Cardiol2012;157:447–8.22.Brandt MC,Mahfoud F,Reda S,et al.Renal sympathetic denervation

reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension.J Am Coll Cardiol2012;59:901–9.

23.Mahfoud F,Cremers B,Janker J,et al.Renal hemodynamics and renal

function after catheter-based renal sympathetic denervation in patients with resistant hypertension.Hypertension2012;60:419–24.

24.Mahfoud F,Schlaich M,Kindermann I,et al.Effect of renal sympa-

thetic denervation on glucose metabolism in patients with resistant hypertension:a pilot study.Circulation2011;123:1940–6.

https://www.wendangku.net/doc/4c1261521.html,ena C,Mahfoud F,Kindermann I,et al.Cardiorespiratory response

to exercise after renal sympathetic denervation in patients with resistant hypertension.J Am Coll Cardiol2011;58:1176–82.

26.Prochnau D,Lucas N,Kuehnert H,Figulla HR,Surber R.Catheter-

based renal denervation for drug-resistant hypertension by using a standard electrophysiology catheter.EuroIntervention2012;7:1077–80.

27.Brandt MC,Reda S,Mahfoud F,Lenski M,B?hm M,Hoppe UC.

Effects of renal sympathetic denervation on arterial stiffness and central hemodynamics in patients with resistant hypertension.J Am Coll Cardiol2012;60:1956–65.

https://www.wendangku.net/doc/4c1261521.html,ena C,Mahfoud F,Spies A,et al.Effects of renal sympathetic

denervation on heart rate and atrioventricular conduction in patients with resistant hypertension.Int J Cardiol2012Aug20[E-pub ahead of print].

29.Esler MD,Krum H,Schlaich M,Schmieder RE,Bohm M,

Sobotka PA,the Symplicity HTN-2Investigators.Renal sympathetic denervation for treatment of drug-resistant hypertension:one-year results from the Symplicity HTN-2randomized,controlled trial.

Circulation2012;126:2976–82.

30.Esler MD,Krum H,Sobotka PA,et al.,for the Symplicity HTN-2

Investigators.Renal sympathetic denervation in patients with treatment-resistant hypertension(The Symplicity HTN-2Trial):

a randomised controlled https://www.wendangku.net/doc/4c1261521.html,ncet2010;376:1903–9.

31.Kaltenbach B,Franke J,Bertog SC,Steinberg DH,Hofmann I,

Sievert H.Renal sympathetic denervation as second-line therapy in mild resistant hypertension:a pilot study.Catheter Cardiovasc Interv 2013;81:335–9.

32.Hering D,Mahfoud F,Walton AS,et al.Renal denervation in

moderate to severe CKD.J Am Soc Nephrol2012;23:1250–7.

33.Ahmed H,Neuzil P,Skoda J,et al.Renal sympathetic denervation

using an irrigated radiofrequency ablation catheter for the management of drug-resistant hypertension.J Am Coll Cardiol Intv2012;5:758–65.

34.Symplicity HTN-1Investigators.Catheter-based renal sympathetic

denervation for resistant hypertension:durability of blood pressure reduction out to24months.Hypertension2011;57:911–7.

35.Mabin T,Sapoval M,Cabane V,Stemmett J,Iyer M.First experience

with endovascular ultrasound renal denervation for the treatment of resistant hypertension.EuroIntervention2012;8:57–61.

36.Pokushalov E,Romanov A,Corbucci G,et al.A randomized com-

parison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial ?brillation and resistant hypertension.J Am Coll Cardiol2012;60: 1163–70.

37.Zuern CS,Rizas KD,Eick C,et al.Effects of renal sympathetic

denervation on24-hour blood pressure variability.Front Physiol2012;

3:134.

38.Sapoval M,Azizi M,Bobrie G,Cholley B,Pagny JY,Plouin PF.

Endovascular renal artery denervation:why,when,and how?Car-diovasc Intervent Radiol2012;35:463–71.

39.Kaltenbach B,Id D,Franke JC,et al.Renal artery stenosis after renal

sympathetic denervation.J Am Coll Cardiol2012;60:2694–5.

40.Vonend O,Antoch G,Rump LC,Blondin D.Secondary rise in blood

pressure after renal https://www.wendangku.net/doc/4c1261521.html,ncet2012;380:778.

41.Kandzari DE,Bhatt DL,Sobotka PA,et al.Catheter-based renal

denervation for resistant hypertension:rationale and design of the SYMPLICITY HTN-3Trial.Clin Cardiol2012;35:528–35.

Key Words:meta-analysis-renal denervation-resistant hypertension.

APPENDIX

For bias analysis information,please see the online version of this article.

JACC Vol.62,No.3,2013Davis et al.

July16,2013:231–41Renal Denervation for Resistant Hypertension

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