CLINICAL RESEARCH

Impact of Renal Denervation on24-hour Ambulatory Blood PressureResults From SYMPLICITY HTN-3

Q21 George L. Bakris, MD,* Raymond R. Townsend, MD,y Minglei Liu, PHD,z Sidney A. Cohen, MD, PHD,yzRalph D’Agostino, PHD,x John M. Flack, MD, MPH,k David E. Kandzari, MD,{ Barry T. Katzen, MD,#Martin B. Leon, MD,** Laura Mauri, MD, MSC,yy Manuela Negoita, MD,z William W. O’Neill,zz Suzanne Oparil, MD,xxKrishna Rocha-Singh, MD,kk Deepak L. Bhatt, MD, MPH,{{ for the SYMPLICITY HTN-3 Investigators

ABSTRACT

BACKGROUND Prior studies of catheter-based renal artery denervation have not systematically performed ambulatory

blood pressure monitoring (ABPM) to assess the efficacy of the procedure.

OBJECTIVES SYMPLICITY HTN-3 was a prospective, blinded, randomized, sham-controlled trial. The current analysis

details the effect of renal denervation or a sham procedure on ABPM measurements 6 months post-randomization.

METHODS Patients with resistant hypertension were randomized 2:1 to renal denervation or sham control. Patients

were on a stable antihypertensive regimen including maximally tolerated doses of at least 3 drugs including a diuretic

before randomization. The powered secondary efficacy endpoint was a change in mean 24-h ambulatory systolic blood

pressure (SBP). Nondipper to dipper (nighttime blood pressure [BP] 10%&ndash20% lower than daytime BP) conversion

was calculated at 6 months.

RESULTS The 24-h ambulatory SBP changed �6.8 � 15.1 mm Hg in the denervation group and �4.8 � 17.3 mm Hg in

the sham group: difference of �2.0 mm Hg (95% confidence interval [CI]: �5.0 to 1.1; p ¼ 0.98 with a 2 mm Hg

superiority margin). The daytime ambulatory SBP change difference between groups was �1.1 (95% CI: �4.3 to 2.2;

p ¼ 0.52). The nocturnal ambulatory SBP change difference between groups was �3.3 (95 CI: �6.7 to 0.1; p ¼ 0.06).

The percent of nondippers converted to dippers was 21.2% in the denervation group and 15.0% in the sham group

(95% CI: �3.8% to 16.2%; p ¼ 0.30). Change in 24-h heart rate was �1.4 � 7.4 in the denervation group and �1.3 � 7.3

in the sham group; (95% CI: �1.5 to 1.4; p ¼ 0.94).

CONCLUSIONS This trial did not demonstrate a benefit of renal artery denervation on reduction in ambulatory BP

in either the 24-h or day and night periods compared with sham (SYMPLICITY HTN-3; Renal Denervation in Patients

With Uncontrolled Hypertension NCT01418261). (J Am Coll Cardiol 2014;-:-–-) © 2014 by the American College

of Cardiology Foundation.

From the *University of Chicago Medicine, Chicago, Illinois; yPerelman School of Medicine, University of Pennsylvania, Phila-

delphia, Pennsylvania; zMedtronic CardioVascular, Santa Rosa, California; xHarvard Clinical Research Institute and Boston Uni-

versity School of Public Health, Boston, Massachusetts; kWayne State University and Detroit Medical Center, Detroit, Michigan;

{Piedmont Heart Institute, Atlanta, Georgia; #Baptist Cardiac and Vascular Institute, Miami, Florida; **New York Presbyterian

Hospital, Columbia University Medical Center, and Cardiovascular Research Foundation, New York, New York; yyHarvard Clinical

Research Institute, Brigham and Women’s Hospital Heart and Vascular Center, and Harvard Medical School, Boston, Massachu-

setts; zzDivision of Cardiology, Henry Ford Hospital, Detroit, Michigan; xxUniversity of Alabama at Birmingham, Birmingham,

Alabama; kkPrairie Heart Institute, Springfield, Illinois; {{Brigham and Women’s Hospital Heart and Vascular Center and Harvard

Medical School, Boston, Massachusetts.Q2

This Q4study was funded byQ12

Medtronic. Dr. Bakris has received consultant fees from

J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . - , N O . - , 2 0 1 4

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A mbulatory blood pressure moni-toring (ABPM) is recommended forinitial evaluation of all persons

with newly diagnosed hypertension and forevaluation of antihypertensive drug efficacyin blood pressure (BP) trials (1,2). Its impor-tance is exemplified by positive outcomes

on ABPM in a randomized trial in which office read-ings were not different (3). Early studies of renaldenervation in participants with resistant hyperten-sion did not assess ABPM in all participants studied(4,5). SYMPLICITY HTN-3 (Renal Denervation in Pa-tients With Uncontrolled Hypertension) was a pro-spective, blinded, randomized, sham-controlledtrial. In this trial, ABPM was an inclusion criterion,and all participants were evaluated at baseline andat 6 months; the change in ambulatory systolic bloodpressure (SBP) from baseline to 6 months was a pre-specified, powered secondary endpoint (6,7). The pri-mary results of the trial demonstrated the safety ofthe renal denervation procedure but failed to showa greater reduction in office or ambulatory SBPcompared with the sham procedure at 6 months (7).This paper presents the detailed 24-h ABPM resultsof SYMPLICITY HTN-3.

METHODS

The design of SYMPLICITY HTN-3 was publishedpreviously (6). Briefly, patients 18 to 80 years old withresistant hypertension were randomized 2:1 to eitherrenal artery denervation or a sham procedure andwere followed for 6 months. All patients providedsigned informed consent.

STUDY POPULATION. Patients on a stable antihy-pertensive drug regimen including maximally toler-ated doses of $3 antihypertensive medications of

complementary classes, including an appropriatelydosed diuretic, were required to have seated officeSBP $160 mm Hg (using the average of 3 measure-ments) at their first screening visit. For the 2 weeksbefore the second screening visit, patients recordedtheir home BP and kept a diary recording theiradherence to medical therapy. Antihypertensivemedication changes were not allowed during this2-week period. At the second screening visit, theoffice SBP $160 mm Hg was confirmed, adherencewith medications was documented, and 24-h ABPMwas performed to ensure an ambulatory SBP $135mm Hg. All ABPMs were performed with the SpaceLabs 24 Ambulatory Blood Pressure Monitoring Sys-tem (Space Labs Medical, Issaquah, Washington).Patients were instructed to place the cuff on the samearm as used for office BP measurements, and theimportance of leaving the cuff in place was stressed.The ABPM parameters were preset to measure BPevery 30 min during the day (7:00 AM to 9:59 PM) andfor every 30 min at night (10:00 PM to 6:59 AM). Pa-tients were instructed to engage in their normal dailyactivities and to hold their arm still by their side toavoid strenuous exercise during the device readings.All patients kept a diary that documented time to bedand time waking up, medications taken, and anyother events of significance. On return of the ABPMmachine, the patients’ diaries were collected, and theABPM data were downloaded to a computer. A 24-hABPM was considered adequate if the number ofsuccessful daytime readings captured was at least 21and the number of successful nighttime readingscaptured was at least 12. Only ABPMs with the pre-specified number of readings per protocol were in-cluded in the analysis.

Additional clinical exclusion criteria includedknown secondary causes of hypertension or more

ABBR EV I A T I ON S

AND ACRONYMS

ABPM = ambulatory blood

pressure monitoring

DBP = diastolic blood pressure

SBP = systolic blood pressure

Takeda Pharmaceutical Company, AbbVie, Novartis Pharmaceuticals Corporation, Janssen Pharmaceuticals, Bristol-Myers Squibb

(BMS), Bayer Healthcare, Medtronic, Relypsa, Inc., Orexigen Therapeutics, Merck & Co., Inc., and GlaxoSmithKline and has grant

funding of an investigator-initiated grant from Q13Takeda. He is the Editor of the American Journal of Nephrology and the hyper-

tension section of UpToDate. He is Associate Editor of Diabetes Care and Section Editor of Nephrology Dialysis Transplantation.

Dr. Bhatt is on advisory boards for Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; is on the

board of directors for the Boston Veterans Affairs Research Institute, Society of Cardiovascular Patient Care; is Chair of the

American Heart Association’s Get With The Guidelines Steering Committee; is on Data Monitoring Committees for Duke Clinical

Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute (including for

EnligHTNment) and receives honoraria from the American College of Cardiology (Editor, Clinical Trials, Cardiosource), Belvoir

Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard

Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor-in-Chief, Journal of Invasive Cardi-

ology); Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology

Today’s Intervention), WebMD (CME steering committees); other: Clinical Cardiology (Associate Editor); Journal of the American

College of Cardiology (Section Editor, Pharmacology). Research grants were received from the following companies: Q14Amarin

Corporation, Q15AstraZeneca;

Q16

BMS;

Q17

Eisai, Inc.;Q18

Ethicon Endo-surgery, Inc.; Medtronic; Q19Hoffman-La Roche, Inc.Q5

;

Q20

Sanofi Aventis;

The Medicines Company; unfunded research: FlowCo, Inc.; PLx Pharma; and Takeda Pharmaceutical Company.

Q6Manuscript received XXX, 2014; revised manuscript received XXX, 2014, accepted XXX, 2014.

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than 1 hospitalization for a hypertensive emergency inthe past year. Anatomic exclusion criteria included>50% renal artery stenosis, renal artery aneurysm,prior renal artery intervention, multiple renal arteries,renal artery diameter <4 mm, or treatable seg-ment <20 mm in length.

After undergoing a renal angiogram and anassessment of anatomy, patients were randomized toeither renal artery denervation or the sham controlgroup in a 2:1 ratio. Patients were followed for6 months, at which time the primary and pre-specified powered ambulatory SBP secondary end-points were assessed. Patients in the control groupwere then allowed to cross over to receive renaldenervation treatment, if they still met the inclusioncriteria for the study.

STUDY PROCEDURE. The renal denervation proce-dure used radiofrequency energy delivered by theSymplicity Renal Denervation System (Medtronic,Santa Rosa, California) to ablate the nerves within themain renal arteries. Patients were blinded to whetherthey received renal artery denervation or only renalangiography (sham). Assessors of BP and study per-sonnel also were blinded to the treatment received bypatients. Details of the blinding procedure and con-firmation of adequate blinding have been providedpreviously (7). Antihypertensive medication changeswere not allowed during the 6-month follow-upperiod unless clinically required.

ENDPOINTS. The primary efficacy endpoint was acomparison of office SBP change from baseline to6 months in the renal denervation group comparedwith the SBP change from baseline to 6 months inthe sham control group and required a superioritymargin of 5 mm Hg for success. The secondary effi-cacy endpoint was the change in mean 24-h ambu-latory SBP at 6 months. In addition to 24-h ABPM,daytime and nighttime ambulatory BP differencesfrom baseline to 6 months, as well as differences inthe change between the 2 groups, were assessed.ABPM differences in BP and heart rate variabilityalso were assessed at baseline and at 6 months forboth groups.

The proportion of patients who were extremedippers (decline of >20% in night to day BP), dippers(10%&ndash20% decline in night to day BP), non-dippers (<10% decline in BP at night), and reversedippers (night BP greater than day BP) were calcu-lated at each follow-up visit.

For the current analysis, patients in each groupwere further categorized according to tertiles ofbaseline ambulatory SBP. Baseline and 6-monthABPMmeasurements were determined for each group.

The primary safety endpoint has been previouslydescribed and reported (7). Treated patients willbe followed biannually, and non-crossover controlpatients will be followed annually through 5 yearspost-randomization.

STATISTICAL ANALYSES. The analyses were per-formed based on the intent-to-treat principle. Thedata were collected and analyzed by the sponsor(Medtronic, Minneapolis, Minnesota) and indepen-dently validated by Harvard Clinical Research Insti-tute (Boston, Massachusetts). Means and standarddeviations of continuous variables were presentedby treatment group. Variability of ambulatory BP ineach visit was defined as the standard deviation (SD)or coefficient of variation (%, 100 * Q7SD / mean). Be-tween group differences were compared using con-fidence intervals and evaluated using unpairedStudent Q8t tests. Within group differences frombaseline to follow-up were evaluated using pairedStudent t tests. For categorical variables, the treat-ment group presented the counts and percentages.They were tested using the exact test for binaryvariables and Chi-squared test for multi-level cate-gorical variables. All subgroups shown were pre-specified.

Differences within and between groups of earlymorning slope analysis also were calculated. Baselineambulatory SBP was plotted against early morningtime (3 AM to 8 AM), and the slopes of the regressionlines were calculated for each group at baseline and at6 months. The changes in slopes from baseline to6 months for each group were compared using anal-ysis of covariance.

RESULTS

All randomized patients (n ¼ 535) had an ABPM placedas part of the inclusion criteria for the study (7). Nosignificant differences in baseline characteristics werenoted between the 2 groups with the exception of24-h and daytime diastolic blood pressure (DBP),which was greater in the sham control group (Table 1).Patients were taking an average of 5 antihyperten-sive medications, and on average 4 medications wereat maximally tolerated doses (7). Antihypertensivemedication use remained similar in both groups at6-month follow-up.

The primary efficacy endpoint was the meanchange in office SBP from baseline to 6 months in thedenervation group, as compared with the meanchange in the sham control group, with a superioritymargin of 5 mm Hg. This endpoint was not differentfrom the sham control group (7). The powered sec-ondary efficacy endpoint was the change in mean

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24-h ambulatory SBP at 6 months between groupswith a superiority margin of 2 mm Hg. This endpointwas also not different between groups (�6.75 �15.11 mm Hg in the denervation group and �4.79 �17.25 mm Hg in the sham group, for a difference be-tween groups of �1.96 mm Hg [95% CI: �4.97 to 1.06;p value with a 2 mm Hg superiority margin ¼ 0.98])(Central Illustration). The ambulatory DBPs were

consistent with the trends in ambulatory SBPs (seeCentral Illustration). The mean daytime and nighttimeBPs in both groups also were not different betweengroups at 6 months (Figs. 1 and 2).

The greatest reduction from baseline in mean 24-hSBP occurred in patients who were in the highestbaseline ambulatory SBP tertile (Fig. 3). There was nosignificant change from baseline for the lowest tertilegroup and no difference in any of the ABPM changesbetween the denervation and sham groups. Mean24-h heart rates were similar at baseline and at 6months in the 2 lower tertiles. Details of 24-h, day-time, nighttime, and heart rate measures are reportedin Online Table 1.

The proportion of patients who converted fromnondipper to dipper at 6 months post-randomizationwas 21.2% in the denervation group and 15.0% in thesham control group (difference, 6.2%; 95% CI: �3.8 to16.2%). Early morning (3 AM to 8 AM) SBP increaseswere not significant for either group, with a slopechange of �0.05 at 6 months for the denervationgroup (p ¼ 0.90) and �0.52 in the sham group(p ¼ 0.35).

No change was noted in 24-h, daytime, or night-time BP or heart rate variability assessed by ABPMbetween or within groups (Table 2, Online Table 2).

The differences in ambulatory SBP from baseline to6 months in various subgroups of participants areshown in the Central Illustration. The absolute mag-nitudes of difference were small (<6 mm Hg) and notsignificant in any of the pre-specified subgroups. Nosignificant differences were noted between groups asa function of baseline ambulatory SBP. There was nosignificant difference in 24-h heart rate betweenbaseline and 6 months �1.36 � 7.41 for denervationand �1.30 � 7.25 for sham control (95% CI: �1.45 to1.35; p ¼ 0.94).

The primary safety endpoint and other safetyevents have been described previously (7). Few majoradverse events occurred in the trial: 1 (0.6%) inthe sham control arm and 5 (1.4%) in the treatmentarm, for a difference of 0.8% (95% CI: �0.9%, 2.5%;p ¼ 0.67).

DISCUSSION

This randomized, sham-controlled, blinded trialfailed to show a benefit of renal artery denerva-tion on the powered secondary endpoint of 24-hambulatory SBP. Daytime and nighttime ABPM andheart rate change were also not different betweenthe denervation and sham control groups. Earlierunblinded trials of renal denervation demonstra-ted significant reductions in ABPM measurements

TABLE 1 Baseline Characteristics of the Study Population*

Characteristic

Renal DenervationGroup

(N ¼ 364)

Sham ProcedureGroup

(N ¼ 171)

Age, yrs 57.9 � 10.4 56.2 � 11.2

Male sex, % 215 (59.1%) 110 (64.3%)

BMI, kg/m2 34.2 � 6.5 33.9 � 6.4

Race, %

Black 90 (24.8%) 50 (29.2%)

White 265 (73.0%) 119 (69.6%)

Other 8 (2.3%) 2 (1.2%)

Medical history, %

Renal insufficiency (eGFR<60 ml/min/1.73 m2) 34 (9.3%) 17 (9.9%)

Coronary artery disease 101 (27.7%) 43 (25.1%)

Diabetes, type 2 171 (47.0%) 70 (40.9%)

24-h heart rate, beats/min 71.0 � 13.0 72.4 � 12.3

Ambulatory blood pressure

24-h systolic 159.1 � 13.2 159.5 � 15.3

24-h diastolic 88.0 � 14.0 90.9 � 14.4

Daytime systolic 163.0 � 13.4 164.2 � 15.0

Daytime diastolic 91.3 � 14.5 94.78 � 15.0

Nighttime systolic 152.5 � 16.3 151.4 � 18.7

Nighttime diastolic 82.5 � 14.5 84.3 � 15.1

Dipper status

Extreme dipper, % 12/360 (3.3%) 9/167 (5.4%)

Dipper, % 96/360 (26.7%) 52/167 (31.1%)

Nondipper, % 185/360 (51.4%) 83/167 (49.7%)

Reverse dipper, % 67/360 (18.6%) 23/167 (13.8%)

Conversion of nondipper to dipper at 6 months, % 35/165 (21.2%) 12/80 (15.0%)

Number of BP lowering medications 5.1 � 1.4 5.2 � 1.4

ACE inhibitors 179 (49.2%) 71 (41.5%)

% at max tolerated dose 167 (45.9%) 64 (37.4%)

Angiotensin receptor blockers 182 (50.0%) 91 (53.2%)

% at max tolerated dose 180 (49.5%) 88 (51.5%)

Aldosterone antagonists 82 (22.5%) 49 (28.7%)

Alpha-adrenergic blockers 40 (11.0%) 23 (13.5%)

Beta-blockers 310 (85.2%) 147 (86.0%)

Calcium channel blockers 254 (69.8%) 125 (73.1%)

% at max tolerated dose 208 (57.1%) 109 (63.7%)

Centrally acting sympatholytics 179 (49.2%) 75 (43.9%)

Diuretics 363 (99.7%) 171 (100%)

% at max tolerated dose 351 (96.4%) 167 (97.7%)

Direct renin inhibitors 26 (7.1%) 12 (7.0%)

Direct-acting vasodilators 134 (36.8%) 77 (45.0%)

*All differences in characteristics between groups are nonsignificant. Data are mean � standard deviationor number (%).

ACE ¼ angiotensin-converting enzyme; BMI ¼ body mass index; BP ¼ blood pressure; eGFR, ¼ estimatedglomerular filtration rate.

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6 months post-denervation that were similar inmagnitude to the current trial, but without thebenefit of a blinded control (8,9). Previous renaldenervation studies reported smaller decreases in24-h and daytime ABPM than office BP; this finding is

consistent with our observations (8,9). This BP dif-ference between office and ambulatory settings waspredicted by a meta-analysis of antihypertensivedrug and renal denervation trials that noted thatdifferences in office and ambulatory BP reductions

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CENTRAL ILLUSTRATION Change in Ambulatory Systolic Blood Pressure for All Patients and Pre-specified Subgroups in the

SYMPLICITY HTN-3 Trial

(A) The mean 24-h ambulatory systolic and diastolic blood pressure at baseline and at 6 months are shown from both study groups. (B) The

change in ambulatory systolic blood pressure at 6 months is displayed for pre-specified subgroups. Squares denote blood pressure changes,

and horizontal lines represent 95% confidence intervals.

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disappear in double-blind placebo controlled drugtrials (10,11).

ABPM has the advantage of less bias comparedwith office readings and provides a complete pictureof BP throughout the day. This concept is further

supported by this trial because disappearance ofthe difference between office and ABPM effect in adouble-blind, placebo-controlled trial suggests thatthe placebo effect is stronger for office than ABPMvisits. ABPM Q9is generally believed to be less

200

180

160

140

120

100

80

60

40

20

0

Ambu

lato

ry D

aytim

e BP

(mm

Hg)

Denervation Sham Denervation Sham

SBP DBP

Δ=-1.1 (95% CI, -4.3 to 2.2)p=0.52

p<0.001Δ=-7.2 (95% CI, -8.9 to -5.5)

p<0.001Δ=-6.1 (95% CI, -8.9 to -3.3)

p=0.62Δ=-0.5 (95% CI, -2.5 to 1.5)

p<0.001Δ=-4.4 (95% CI, -5.4 to 3.4)

p<0.001Δ=-3.9 (95% CI, -5.6 to -2.2)

Baseline6 Months

(N=361) (N=334) (N=168) (N=163) (N=360) (N=334) (N=167) (N=163)

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FIGURE 1 Daytime Blood Pressure Readings

Depicted here are the mean ambulatory daytime systolic and diastolic blood pressure at baseline and at 6 months.

20018016014012010080604020

0Ambu

lato

ry N

ight

time

BP (m

m H

g)

Denervation Sham Denervation Sham

SBP DBP

Δ=-3.3 (95% CI, -6.7 to 0.1)p=0.06

p<0.001Δ=-5.6 (95% CI, -7.6 to -3.7)

p=0.10Δ=-2.4 (95% CI, -5.2 to 0.5)

p=0.09Δ=-1.8 (95% CI, -3.9 to 0.3)

p<0.001Δ=-3.3 (95% CI, -4.5 to -2.1)

p=0.08Δ=-1.5 (95% CI, -3.2 to 0.2)

Baseline6 Months

(N=362) (N=337) (N=168) (N=166) (N=362) (N=337) (N=168) (N=166)

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FIGURE 2 Nighttime Blood Pressure Readings

Depicted here are the mean ambulatory nighttime systolic and diastolic blood pressure at baseline and at 6 months.

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vulnerable to placebo-like effects because it isassessed in a patient’s daily life (12). Given that areaunder the curve of the 24-h ABPM is more accuratethan office readings taken at fixed times, differencesin BP may be detected by ABPM when office read-ings fail to show differences (3). In the currenttrial, no such differences were noted, although atrend was noted for a greater nighttime BP reduc-tion in the denervation group compared with thesham control group.

High BP variability correlates with higher cardio-vascular event rates (13,14). In this trial, BP variabilitywas not significantly different between groups at6 months. Additionally, a reduction in early morningBP surge or restoration of dipping status was notaffected by renal denervation (15,16).

Small reductions in office-measured heart rate aswell as glycemic control were observed in previoustrials of renal denervation. In the current trial, 24-hheart rate and glycemic control did not significantlychange from baseline in either group. There are afew possible reasons for this observation. First,

effective denervation may not have occurred in allpatients randomized to denervation because therewas no definitive way to assess denervation. A secondpossibility, however, is that the drug doses affectingheart rate, which also would adversely affect glucosecontrol, may have been maximized in both groups,hence blunting the small previous effect seen onheart reduction and glycemic control. Regardless ofthe possible causes, an effect on heart rate was notseen in this trial.

Several possible explanations exist for the discor-dant findings between the prior renal denervationdata and the present results (5,8,9). Previous re-nal denervation studies described the change inABPM from baseline without a control arm, and thustreatment efficacy was assumed but could not beverified. This trial also observed significant ambula-tory BP reductions from baseline to 6 monthsfollowing renal denervation, but the similar signifi-cant 24-h ambulatory BP drop in the sham controlgroup resulted in a lack of significant differencebetween the 24-h ambulatory BP reductions between

24-h Heart rate

Baseline

6 Months

70.6 (13.5)N=118

69.7 (13.2)N=109

67.0 (13.3)N=57

68.7 (11.8)N=114

70.9 (11.7)N=47

69.8 (12.6)N=102

74.9 (11.5)N=55

67.3 (13.1)N=58

69.6 (11.7)N=125

73.8 (9.9)N=50

72.9 (13.8)N=117

76.3 (11.7)N=59

Δ=-1.6 (95% CI, -6.5 to 3.3)p=0.52

Δ=-3.4 (95% CI, -8.6 to 1.8)p=0.20

Δ=-1.2 (95% CI, -6.9 to 4.5)p=0.69

Baseline 24-h SBP135.1 to <151.8 mm Hg

Baseline 24-h SBP151.8 to 164.4 mm Hg

Baseline 24-h SBP164.5 to 208.5 mm Hg

42

6

0

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ge in

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bula

tory

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m H

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p=0.38 p=0.86 p=0.11p<0.001 p<0.001 p<0.001

RDNControl

print&web4C=FPO

FIGURE 3 Changes in 24-h Ambulatory Systolic Blood Pressure

Depicted here is the change in 24-h ambulatory systolic blood pressure by tertiles of baseline ambulatory 24-h systolic blood pressure.

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the 2 groups. It is intriguing that the nocturnalSBP and DBP dropped significantly from baseline,but the BP reductions in the sham control groupwere less and were not significantly different frombaseline (Fig. 2). The similar overall ambulatory BPreduction seen in the sham control arm may bepartly attributed to participation in a trial that pro-vided a high degree of patient support and oversightthat may have led to improved adherence withmedications and diet, an observation known asthe Hawthorne effect (17,18). These data suggest thatthe prior renal denervation studies overestimatedthe treatment effect of the procedure.

The potential contribution of a placebo effect tothe BP reductions attributed to renal denervation inprior studies cannot be ascertained (19,20). Ouranalysis suggests that a placebo effect, perhapsenhanced by the interventional procedure in thecontrol group, did affect BP change. Alternatively,however, one could hypothesize that the placebo ef-fect could have worsened BP in the interventiongroup because the patient may have been concernedthat he or she received sham treatment. Both thesestatements are speculative at best; however, thisobservation has important implications for future

trial designs of medications and devices for hyper-tension and other diseases.

STUDY LIMITATIONS Q10. There are limitations in inter-preting the data from this trial. There was no valida-tion of medication adherence by assessing urinelevels for metabolites of antihypertensive drugs. It iswell documented that more than 50% of patients withresistant hypertension are nonadherent with medi-cations (21,22). In this trial, however, assessment ofpatient diaries completed before treatment andagain before unblinding at 6 months fails to suggest adifference in medication adherence between thegroups. Moreover, only 5.8% of subjects had medi-cation changes during the 2 weeks before the secondscreening visit. Although that may have affectedbaseline BP, no significant differences in office BPor ABPM were noted between groups at screeningvisits. Medication adherence may have improved as aresult of the intervention, as suggested by changes inABPM at 6 months in the sham control group. Thisfinding further supports the concept of an objectivemeasure of medication adherence in patients en-rolled in trials to treat drug-resistant hypertension.Finally, there was no formal prospective assessmentof generator values of impedance, and this Q11mayaccount for a variable response between centers.

The trial was not powered to detect small differ-ences in ambulatory BP or any potential differencesin pre-specified subgroups. The trend for improvednighttime BP control following renal denervationthat was not detected during the day suggests theneed for further research on the physiologic effectsof renal denervation. A relative lack of operator ex-perience could have affected the outcomes in therenal denervation group, although all procedureswere proctored. However, we found no evidence ofan operator learning curve when results of earlyprocedures were compared with later procedures.The catheter generator system provides confirmationof energy delivery, but no biomarker or easilyapplied test is available to confirm adequate dener-vation at the time of the treatment. Finally, thesetrial results are specific to the Symplicity catheterand may not be generalizable to other renal dener-vation systems.

CONCLUSIONS

The current trial confirms the safety of renal dener-vation with the Symplicity catheter; however, a sig-nificant BP-lowering effect on 24-h ambulatory BPwas not observed. Further clinical research usingrigorous trial design will be required to understand

TABLE 2 Analysis of Ambulatory Blood Pressure and Heart Rate Variability

Renal DenervationGroup

(N ¼ 364)

Sham ProcedureGroup

(N ¼ 171)Difference

(95% confidence interval)

24-h ABPM

Baseline, mm Hg 159.1 � 13.2 159.5 � 15.3 �0.39 [�3.10, 2.31]

6 month, mm Hg 151.8 � 16.0 153.9 � 19.1 �2.05 [�5.48, 1.38]

ABPM variability

SBP

24-h SD, baseline 16.1 � 4.7 16.0 � 4.6 0.08 [�0.78, 0.95]

24-h SD, 6 months 15.5 � 4.0 15.6 � 4.5 �0.07 [�0.90, 0.75]

24-h CV%, baseline 10.2 � 3.1 10.2 � 3.2 0.01 [�0.56, 0.59]

24-h CV%, 6 months 10.3 � 2.7 10.3 � 3.1 0.04 [�0.51, 0.60]

DBP

24-h SD, baseline 11.3 � 3.0 11.3 � 3.4 �0.05 [�0.64, 0.55]

24-h SD, 6 months 11.3 � 3.0 11.3 � 3.4 �0.05 [�0.64, 0.55]

24-h CV%, baseline 13.2 � 3.7 13.2 � 3.8 0.02 [�0.67, 0.70]

24-h CV%, 6 months 13.7 � 3.5 13.1 � 3.9 0.56 [�0.12, 1.24]

24-h heart rate

Baseline 71.0 � 13.0 72.4 � 12.3 �1.41 [�3.77, 0.94]

6 months 69.4 � 12.5 71.0 � 12.6 �1.55 [�3.90, 0.81]

Heart rate variability

24-h SD, baseline 8.2 � 4.2 9.1 � 4.0 �0.85 [�1.61, �0.09]

24-h SD, 6 months 8.0 � 3.7 8.4 � 3.2 �0.47 [�1.11, 0.16]

24-h CV%, baseline 11.5 � 5.1 12.6 � 5.3 �1.07 [�2.01, �0.12]

24-h CV%, 6 months 11.4 � 4.9 12.0 � 4.4 �0.55 [�1.44, 0.34]

ABPM ¼ ambulatory blood pressure monitoring; CV ¼ coefficient of variation; DBP ¼ diastolic blood pressure;SBP ¼ systolic blood pressure; SD ¼ standard deviation.

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whether renal denervation has any role in the treat-ment of resistant hypertension.

ACKNOWLEDGMENT S The authors would liketo thank Xiaohua Chen, MS, and Lanyu Lei, MS,from Harvard Clinical Research Institute for statisticalanalyses funded by Medtronic and Colleen Gilbert,PharmD, from Medtronic for editorial support. Theauthors also would like to thank Sandeep Brar, MD,and Juan Wu, MS, for data analysis support andVanessa DeBruin, MS, Denise Jones, RN, BSN, DanJolivette, MD, and the entire SYMPLICITY HTN-3study team for dedicated research support.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.George L. Bakris, Director, ASH Comprehensive Hyper-tension Center, University of Chicago Medicine, Hyper-tensive Diseases Unit, 5841 South Maryland Avenue, MC1027, Chicago, Illinois 60637Q3 . E-mail: gbakris@medicine.bsd.uchicago.edu.

RE F E RENCE S

1. U.S. Food and Drug Administration. Guidancefor Industry Hypertension Indication: Drug Label-ing for Cardiovascular Outcome Claims. 2011.Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Accessed May 23, 2014.

2. National Clinical Guideline Centre. Hyperten-sion: The Clinical Management of Primary Hyper-tension in Adults. Clinical Guideline 127: Methods,Evidence and Recommendations: National Insti-tute for Health and Clinical Excellence. 2011:328.

3. Bakris GL, Lindholm LH, Black HR, et al. Diver-gent results using clinic and ambulatory bloodpressures: report of a darusentan-resistanthypertension trial. Hypertension 2010;56:824–30.

4. Krum H, Schlaich MP, Sobotka PA, et al.Percutaneous renal denervation in patients withtreatment-resistant hypertension: final 3-yearreport of the Symplicity HTN-1 study. Lancet2014;383:622–9.

5. Esler MD, Krum H, Schlaich M, et al. Renalsympathetic denervation for treatment of drug-resistant hypertension: one-year results from theSymplicity HTN-2 randomized, controlled trial.Circulation 2012;126:2976–82.

6. Bhatt DL, Kandzari DE, O’Neill WW, et al.A controlled trial of renal denervation for resistanthypertension. N Engl J Med 2014;370:1393–401.

7. KandzariDE,BhattDL, SobotkaPA, etal.Catheter-based renal denervation for resistant hypertension:rationale and design of the SYMPLICITY HTN-3 trial.Clin Cardiol 2012;35:528–35.

8. Mahfoud F, Ukena C, Schmieder RE, et al.Ambulatory blood pressure changes after renalsympathetic denervation in patients with resistanthypertension. Circulation 2013;128:132–40.

9. Krum H, Schlaich M, Whitbourn R, et al. Cath-eter-based renal sympathetic denervation forresistant hypertension: a multicentre safety andproof-of-principle cohort study. Lancet 2009;373:1275–81.

10. Howard JP, Nowbar AN, Francis DP. Size ofblood pressure reduction from renal denervation:insights from meta-analysis of antihypertensivedrug trials of 4,121 patients with focus on trialdesign: the CONVERGE report. Heart 2013;99:1579–87.

11. Howard JP, Cole GD, Sievert H, et al. Unin-tentional overestimation of an expected antihy-pertensive effect in drug and device trials:mechanisms and solutions. Int J Cardiol 2014;172:29–35.

12. Pickering TG, Shimbo D, Haas D. Ambulatoryblood-pressure monitoring. N Engl J Med 2006;354:2368–74.

13. Parati G, Ochoa JE, Lombardi C, et al. Assess-ment and management of blood-pressure vari-ability. Nat Rev Cardiol 2014;11:314.

14. Rothwell PM, Howard SC, Dolan E, et al.Prognostic significance of visit-to-visit variability,maximum systolic blood pressure, and episodichypertension. Lancet 2010;375:895–905.

15. Kario K, Pickering TG, Umeda Y, et al. Morningsurge in blood pressure as a predictor of silent andclinical cerebrovascular disease in elderly hyper-tensives: a prospective study. Circulation 2003;107:1401–6.

16. Kario K, Shimada K. Risers and extreme-dippers of nocturnal blood pressure in hyperten-sion: antihypertensive strategy for nocturnalblood pressure. Clin Exp Hypertens 2004;26:177–89.

17. McCambridge J, Witton J, Elbourne DR. Sys-tematic review of the Hawthorne effect: newconcepts are needed to study research participa-tion effects. J Clin Epidemiol 2014;67:267–77.

18. Gale EA, Beattie SD, Hu J, et al. Recruitment toa clinical trial improves glycemic control in pa-tients with diabetes. Diabetes Care 2007;30:2989–92.

19. Vaclavik J, Sedlak R, Plachy M, et al. Additionof Spironolactone in Patients With ResistantArterial Hypertension (ASPIRANT): a randomized,double-blind, placebo-controlled trial. Hyperten-sion 2011;57:1069–75.

20. Weber MA, Black H, Bakris G, et al. A selectiveendothelin-receptor antagonist to reduce bloodpressure in patients with treatment-resistant hy-pertension: a randomised, double-blind, placebo-controlled trial. Lancet 2009;374:1423–31.

21. Tomaszewski M, White C, Patel P, et al.High rates of non-adherence to antihyperten-sive treatment revealed by high-performanceliquid chromatography-tandem mass spectrom-etry (HP LC-MS/MS) urine analysis. Heart 2014;100:855–61.

22. Jung O, Gechter JL, Wunder C, et al. Resistanthypertension? Assessment of adherence by toxi-cological urine analysis. J Hypertens 2013;31:766–74.

KEY WORDS ambulatory blood pressuremonitoring, resistant hypertension, renaldenervation

APPENDIX For the supplemental tables,please see the online version of this paper.

PERSPECTIVES

Competency in medical knowledge: Compared with a sham

procedure, catheter-based renal artery sympathetic denervation

did not reduce BP either during daytime or nighttime periods, as

assessed by systematic ABPM.

Competency in patient care: Renal artery denervation is an

investigational procedure not currently approved for clinical use

in the United States, and it should not be recommended for

patients with resistant hypertension outside the context of

properly designed and regulated clinical trials.

Translational outlook: Additional studies are needed to assess

whether selection of hypertensive patients according to different

criteria, alternative methods, or more complete renal artery

sympathetic denervation could provide more effective BP

control.

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