ambulatory blood pressure changes after renal sympathetic
TRANSCRIPT
DOI: 10.1161/CIRCULATIONAHA.112.000949
1
Ambulatory Blood Pressure Changes after Renal Sympathetic Denervation in
Patients with Resistant Hypertension
Running title: Mahfoud et al.; ABPM after renal denervation
Felix Mahfoud, MD1*; Christian Ukena, MD1*; Roland E. Schmieder, MD2; Bodo Cremers, MD1; Lars C. Rump, MD3; Oliver Vonend, MD3; Joachim Weil, MD4; Martin Schmidt, MD5;
Uta C. Hoppe, MD6; Thomas Zeller, MD7; Axel Bauer, MD8; Christian Ott, MD2; Erwin Blessing, MD9; Paul A. Sobotka, MD10; Henry Krum, MBBS, PhD11; Markus Schlaich, MD12;
Murray Esler, MBBS, PhD, FRACP12; Michael Böhm, MD1
1Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar; 2Medizinische Klinik IV, Universitätsklinikum
Erlangen, Erlangen; 3Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Düsseldorf; 4Medizinische Klinik 2, Universitätsklinikum Schleswig-Holstein, Lübeck, Lübeck; 5Klinik für Kardiologie, Klinikum
München-Bogenhausen, München-Bogenhausen, Germany; 6Dept für Innere Medizin II, Paracelsus Medical University Salzburg, Salzburg, Austria; 7Klinik für Angiologie, Universitäts-Herzzentrum Bad
Krozingen-Freiburg, Bad Krozingen-Freiburg, Germany; 8Innere Medizin III, Universitätsklinikum Tübingen, Tübingen; 9Medizinische Klinik III, Universitätsklinikum Heidelberg, Heidelberg, Germany; 10The Ohio State University, Columbus, OH & Ardian, Inc, Palo Alto, CA; 11Centre of Cardiovascular
Research and Education in Therapeutics, Dept of Epidemiology and Preventive Medicine, Monash University, Melbourne; 12Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia
*Both first authors contributed equally
Address for Correspondence:
Felix Mahfoud, MD
Klinik für Innere Medizin III
Kardiologie, Angiologie und Internistische Intensivmedizin
Universitätsklinikum des Saarlandes
Kirrberger Str., Geb. 40
66421 Homburg/Saar, Germany
Tel: +49 6841 16 21346
Fax: +49 6841 16 13211
E-mail: [email protected]
Journal Subject Code: Hypertension:[14] Other hypertension
g g gUniversitätsklinikum des Saarlandes, Homburg/Saar; 2Medizinische Klinik IV, Univererrsisisitätätätstst klklklinininikikikumumum
Erlangen, Erlangen; 3Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Düsselddoororf;f;f; 4MeMeMedididizizizininniscschehKlinik 2, Universitätsklinikum Schleswig-Holstein, Lübeck, Lübeck; 5Klinik für Kardiiollogiei , KlKliinikikum
München-Bogenhausen, München-Bogenhausen, Germany; 6Dept für Innere Medizin II, Paracelsus Medid cal Unnivversisityty Salzburg, Salzburg, Austria; 7KlK inik für Angiologie, Uninivev rsitäts-Herzzentrum Bad
KrKrKrozozozininingegegen-n-n-Freieieibbuburgr , Bad Krozingen-Freiburg, GeGeGermrmrmany; 8Innere MMedee izininn IIIIIIII , Universitätsklinikum TTüTübbibingn en, TüTüTübingnggenen;; 9MeMedidiziziniiscschehe KKlilininik k IIIII,I, UUniniveveerrssitättsksklilinnikikummm HHHeeidedelblberere g, HHeieidedelblbererg,g, GGerermamanyn ; 10TTThe Ohio SStataatetete UUUniniivvev rsrsrsititityy,y, CCColoolumummbbubuss,, OOHOH &&& AAArdiiannn, Innnc,, PaPaalooo AAltltl o,o CCA;A;A; 111Ceentntntrrere oof f f CCaCardrdrdioiovavavasccsculullar
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Abstract:
Background—Catheter-based renal sympathetic denervation (RDN) reduces office blood
pressure (BP) in patients with resistant hypertension according to office BP. Less is known about
the effect of RDN on 24-hour BP measured by ambulatory blood pressure monitoring (ABPM)
and correlates of response in individuals with true or pseudo-resistant hypertension.
Methods and Results—A total of 346 uncontrolled hypertensive patients, separated according to
daytime ABPM into 303 with true resistant (office SBP 172.2 ± 22 mmHg; 24-hour SBP 154 ±
16.2 mmHg) and 43 with pseudo-resistant hypertension (office SBP 161.2 ± 20.3 mmHg; 24-
hour SBP 121.1 ± 19.6 mmHg), from 10 centers were studied. At 3, 6 and 12 months follow-up
office SBP was reduced by 21.5/23.7/27.3 mmHg, office DBP by 8.9/9.5/11.7 mmHg, and pulse
pressure by 13.4/14.2/14.9 mmHg (n=245/236/90; p for all <0.001), respectively. In patients
with true treatment resistance there was a significant reduction with RDN in 24-hour SBP (-
10.1/-10.2/-11.7 mmHg, p<0.001), DBP (-4.8/-4.9/-7.4 mmHg, p<0.001), maximum SBP (-
11.7/-10.0/-6.1 mmHg, p<0.001) and minimum SBP (-6.0/-9.4/-13.1 mmHg, p<0.001) at 3, 6 and
12 months, respectively. There was no effect on ABPM in pseudo-resistant patients, while office
BP was reduced to a similar extent. RDN was equally effective in reducing BP in different
subgroups of patients. OSBP at baseline was the only independent correlate of BP response.
Conclusions—RDN reduced office BP and improved relevant aspects of ABPM, commonly
linked to high cardiovascular risk, in patients with true-treatment resistant hypertension while it
only affected office BP in pseudo-resistant hypertension.
Clinical Trial Registration Information—http://www.clinicaltrials.gov. Identifiers:
NCT00664638 and NCT00888433
Key words: hypertension, clinical trial, hypertension, renal, renal denervation
pressure by 13.4/14.2/14.9 mmHg (n=245/236/90; p for all <0.001), respectivelyy... InInIn pppatatatieieientntntss s
with true treatment resistance there was a significant reduction with RDN in 24-hohooururur SSBPBPBP ((--
10.1/-10.2/-11.7 mmHg, p<0.001), DBP (-4.8/-4.9/-7.4 mmHg, p<0.001), maximum SBP (-
111.7.77/-/-/-101010 0.0.0/-/-/-6.6.6 1 mmmmmmHgH , p<0.001) and minimum SSSBPBP (-6.0/-9.4/-13133.1 mmmmmHmHg, p<0.001) at 3, 6 and
12122 mmmonths, rresespepepectcttivvvelelely.y. TTTheheh rerere wwwasass nnnoo o efefe fefeectctc ooon n ABABABPMMM iiinn n pspspseueuudodod r-r-resesesisisistatantt pppatatatieieientntnts,s,s wwwhihihilelele oooffffffici e
BBPBP wwwas reducuced ttooo a ssiimmmilaarr r exexxteentn .. RDRDRDNNN waass equuaualllly y efefeffefefectcc iivve iinin reduuuciiningg BBPBP in didiffffeeereent
uubgbggrororoupupupsss ofoof ppatatatieieienntnts.ss. OOOSBSBS P P atatat bbbaasaselelinine ee wwawasss thththe ee onononlylyly iiindndndepepepenenenddedentntnt cccorororrererelalalatete oooff f BPBPBP rresesspopoponsnsnse.ee
Conclusionss——RDRDRDN N N rereedudd ceceed d d ofofffifificecec BBBP P P ananand d d imimimprprprovovovededed reeelelel vavavantntnt aaaspsps ececectststs ooof f f ABABABPMPMPM,, cococommmm only
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DOI: 10.1161/CIRCULATIONAHA.112.000949
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Ambulatory blood pressure monitoring (ABPM) is important for the management of patients
with hypertension as it allows more sensitive and specific cardiovascular risk stratification
compared to office blood pressure (BP) measurement.1-3 International guidelines recommend
ABPM in patients with resistant hypertension to exclude pseudo-resistance and to more
accurately assess BP control by treatment.4 ABPM with 24-hour, day and night average BP
values correlate more closely to hypertensive or diabetic end-organ damage than office BP
values.5-7 Nighttime BP is more closely related to cardiovascular morbidity and mortality than
daytime BP.3, 8 High nighttime BP and non-dipping patterns have been associated with increased
sympathetic activity in hypertensives.9
Catheter-based renal denervation (RDN) offers a new approach to interrupt renal
sympathetic innervation and has been shown to reduce renal and total body norepinephrine
spillover.10-12 RDN significantly reduced office systolic and diastolic BP in patients with
resistant hypertension,13, 14 reduced left ventricular mass and improved diastolic function15 and
glucose metabolism16 without negatively affecting renal function17 or causing chronotropic
incompetence during exercise.18 However, only limited information about the impact of RDN on
daytime, nighttime and average BP from the Symplicity HTN-2 trial is available.13 Furthermore,
information about the effectiveness of RDN according to patients’ baseline characteristics and
predictors of response are lacking. This study aimed to investigate the effects of RDN on out-of-
office BP by 24-hour ABPM and assessed the potential correlates of response to treatment in the
largest cohort of patients with true resistant and pseudo-resistant hypertension analyzed so far.
Methods
Local ethic committees approved the study. All patients gave written informed consent and were
Catheter-based renal denervation (RDN) offers a new approach to interruuptppt rrrennnalala ff
ympathetic innervation and has been shown to reduce renal and total body norepinephrine
ppililllololoveveverr.10-10-10-121212 RDNDNDN significantly reduced office sysysyssttolic and diasttoloo ic BBBPPP in patients with
eesiiststant hypeertrteennsssionon,,13,3,, 141414 rredededucucededed llefefft vventttriicculaaar mamasssss anannd d imimpprprovovededed ddiaiaststtolololicic fffunununctctc ioioi nnn151515 aaanddd
glglucucucosososee e memeetatatabbobolliismmm1616 wwitithoh uutut nnnegegegatatativiveeely yy aaaffffffeccctitit ngngng rrrenennalall fffuununctctctioioi nnn177 ooor r ccacauususininng g g chchc rororonnnotrtrropppicic
ncompetencecee dddurururinining gg exexexercicicisesese.181818 HHHowowowevevevererer,,, onononlylyly lllimimimitititeded iiinfnfnfororormamamatitit onnn aaaboboboututut tttheheh iimpmpmpacacactt t of RDN onnn
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treated between March 2009 and December 2011 with subsequent follow-up to 12 months.
Eligible patients were 18 years and had an office systolic blood pressure (SBP) 160 mmHg
( 150 mmHg for type 2 diabetic patients), despite being treated with 3 antihypertensive drugs
(including one diuretic) at maximum or maximum tolerated doses, with no changes in
medication for a minimum of two weeks prior to enrolment. Optimization of antihypertensive
therapy was considered in all patients prior to RDN. A total of 346 patients from 9 centers in
Germany and 1 center in Australia were enrolled following protocols of ongoing therapeutic
renal denervation trials. 71 patients were included in the Symplicity HTN-1 or HTN-2 trial. In all
other patients the measurements were performed as an extension to the Symplicity protocol
(NCT00664638 and NCT00888433), using the same inclusion and exclusion criteria. Patients
were excluded if they had an estimated glomerular filtration rate (eGFR) of <45 mL/min per 1.73
m2 or a known secondary cause of hypertension other than sleep apnea or chronic kidney disease.
All patients underwent a complete history and physical examination, assessment of vital signs,
and review of medication. Patients were interviewed whether they had taken their complete
medication at defined doses. Treating physicians and patients were instructed not to change
medications except when medically required.
Office SBP, DBP and PP as well as ABPM readings were obtained at entry, and 3, 6, and
12 months following treatment. Office BP readings were taken in a seated position with an
automatic oscillometric Omron HEM-705 monitor (Omron Healthcare, Vernon Hills, IL, USA)
after 5 minutes of rest according to the Standard Joint National Committee VII Guidelines.19 At
baseline, BP was measured at each arm and the arm with the higher BP was used for all
subsequent readings. Averages of the triplicate measures were calculated and used for analysis.
ABPM was performed using an oscillometric Spacelabs 90207 monitor (Spacelabs Healthcare,
NCT00664638 and NCT00888433), using the same inclusion and exclusion crititeeriaiai . PaPaPatititienenentsts
were excluded if they had an estimated glomerular filtration rate (eGFR) of <45 mL/min per 1.73
mm2 ooor r aaa knknknowowownn seseeccocondn ary cause of hypertensionn ooothhher than sleep apapa neaeaa ooorr chronic kidney disease
AAAll pap tients undnddeeerwwewentnnt aaa cccomomomplppletetee e hhihistttorry annnddd physysysicaalal eeexaxaammiminanatioonon, aassseesssssmemem ntnt ooof ff vivivitttal l sissigngnnss,s,
anndd d rereeviviv eweww ooofff mmeeddidicacatttioonon.. PaPaatitienenentststs wwwererre e ininintetetervvvieiei wwewedd whwhwhetetethhher rr ththt eeyey hhhadadd taakakenenn tttheheh irirr cccomommpllletete e
medication aat t dededefifiinenened d dododoseees.s.s TTTrereeatata ininng g phphphysysysiciciciaiaiansnsn ananandd d paaatitit enenentstst wwwerere e e inininstststruruructctctedede nnnototot ttto oo chcc ange
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Issaqua, WA, USA) with readings taken every 15 minutes in daytime and every 30 minutes at
nighttime. ABP readings were averaged for 24 hours, day (7 AM to 10 PM), and night (10 PM to
7 AM). Patients were assessed while adhering to their usual diurnal activity and nocturnal sleep
routine. Pseudo-resistance was prospectively defined as mean ambulatory 24-hour SBP <130
mmHg (n=43), despite elevated office SBP readings.20 Patients were graded according to their
baseline-dipping pattern into 4 groups: extreme dippers (nighttime BP fall >20%, n=42), dippers
(nighttime BP fall >10% and <20%, n=92), non-dippers (nighttime BP fall <10% and >0%,
n=125), and reverse-dippers (nighttime BP > daytime BP, n=40). Data on baseline dipping
pattern was missing in 47 patients due to missing nighttime average values. The BP was
considered at target when daytime and nighttime values were <135/85 and <120/70 mmHg,
respectively. The RDN procedure was performed as previously described.13
Statistical analysis
Data are presented as mean ± standard deviation (SD) unless otherwise specified. Comparisons
between groups were performed using the Pearson chi-square test for categorical variables and
the Wilcoxon rank sum test or a paired t-test for continuous variables where appropriate. Linear
mixed-effects models were used to assess changes within groups over follow-up time. A two-
tailed p value of <0.05 was regarded as statistically significant. Multivariable unconditional
logistic regression analysis was performed for risk analyses with response (reduction of office
SBP 10 mmHg and reduction of SBP on ABPM 5mmHg at 6 months) as outcome variable.
All statistical analyses were performed with SPSS statistical software (version 15.0, SPSS Inc.,
Chicago, Illinois).
Results
Patient characteristics of the entire patient population (true resistant and pseudo-resistant) are
considered at target when daytime and nighttime values were <135/85 and <1200/7/7/7000 mmmmmHgHgHg, ,
espectively. The RDN procedure was performed as previously described.13
Sttatatatisisistititicacaalll anananalysysysiisis
DDattata are preseentntededed aass memeeananan ±±± ssstatandndndaararddd dddeviaaatiion ((S(SDD) uunnlnleesss otothhherrwrwisiseee ssppececcifififieied.d. CCComomompaaaririsosonnns
beetwtwtweeeeeenn grgrgrouououpsps wweerere e pepeerfrfoormmemeddd usususiniing g thhhee e PPPearararsososonn cchii-i sqsqsquuauareee tttesesst fofoforr cccattetegogooririicacac l l vavavariaabablleless aaanddd
he Wilcoxonn rrranana k k k susus m m m tet ststst ooor r a a a papap iririrededd ttt-t-ttesesest t t fofofor r cococontntntininuououoususus vvvararariaiaiabllleseses wwwhhhererere ee apappprprpropopopriririata e. Linear
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depicted in Table 1. Patients mean age was 62.7 ± 10.8 years, 64% were male, with a mean body
mass index of 30.4 ± 5.6 kg/m2. Type 2 diabetes was diagnosed in 135 patients (39%). Diagnosis
was confirmed as recommended by the American Diabetes Association.21 Coronary artery
disease was prevalent in 83 patients (24%). Patients were treated with 5.2 ± 1.6 antihypertensive
drugs on average (Table 1). True resistant hypertensive patients were less often treated with
beta-blockers compared to pseudo-resistant (75% vs. 93%; p=0.008). Despite antihypertensive
drug treatment, baseline SBP, DBP and PP was 170.7 ± 22.1 mmHg, 91.3 ± 15.2 mmHg and
79.3 ± 18.7 mmHg, respectively, with a heart rate of 70.2 ± 13.6 beats per minute (bpm). Office
and 24-hour mean SBP at baseline was 172.2 ± 22 and 154 ± 16.2 mmHg in true resistant
hypertension and 161.2 ± 20.3 and 121.1 ± 19.6 mmHg in pseudo-resistant hypertension,
respectively. Except for the use of beta-blockers, SBP and APBM values, the baseline
characteristics between true treatment-resistant and pseudo-resistant patients were well matched
regarding their baseline characteristics (Table 1 and 2).
Office-based BP at 3, 6 and 12 months were significantly reduced in the overall cohort:
SBP by 21.5/23.7/27.3 mmHg, DBP by 8.9/9.5/11.7 mmHg, and PP by 13.4/14.2/14.9 mmHg
(n=245/236/90; p for all <0.001), respectively. At 3, 6 and 12 month follow-up 24-hour SBP
decreased by 8.4/8.7/9.9 mmHg and DBP by 4.2/4.3/6.6 mmHg (n=245/236/90; p for all
<0.001), respectively. Changes in office SBP and DBP were significantly more pronounced than
changes in 24-hour SBP and DBP (p<0.0001 for SBP and DBP at each time point). While office
BP reduction were comparable between treatment resistant and pseudo-resistant hypertensive
patients (Figure 1), only in patients with true treatment resistance were 24-hour mean SBP and
DBP significantly reduced 3, 6 and 12 months after treatment (SBP: -10.1/-10.2/-11.7 mmHg,
p<0.001 vs. +2.7/+1.2/-4.4 mmHg, p=0.362/0.465/ 0.386; DBP: -4.8/-4.9/-7.4 mmHg, p<0.001
hypertension and 161.2 ± 20.3 and 121.1 ± 19.6 mmHg in pseudo-resistant hypererrtetensnn ioioion,n,n,
espectively. Except for the use of beta-blockers, SBP and APBM values, the baseline
chharararacaccteteteririristststiicics bebeetwtwtween true treatment-resistant ananandd pseudo-resisttanana t papaatititieents were well matched
eegaaardr ing theiir r bbab ssseliliinnne ccchahaharraracctctererisisi ttiticscss ((TTabbbleee 1 aanandd 222).).)
OfOffifificecec -b-baaaseeded BBBP P atat 33, 6 6 ananand d d 1212 mmmononontthths ss wewewereee siiigngngnififificicicananntltlt yyy rereedudud ccceddd ininn tthhehe oooveveveraallll cccohohooortt:t:
SBP by 21.5/5/232323.7.7/2/2/27.77 3 3 3 mmmmmmHgHgHg, DBDBDBP P P bybyy 888.9.99/9/9/9.5.5.5/1/1/ 1.1..777 mmmmmHgHgHg, , ananand d d PPPP bbby y y 131313.4.4.4/1/114.4.4.2/2/2/141414.9.9. mmHg
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vs. +0.3/-0.3/-0.2, p=0.757/0.991/0.906). In those patients changes of office SBP correlated
poorly with changes of 24-hour mean SBP, even if this limited correlation achieved statistical
significance (3 months: r=0.198, p<0.001). Even in the subgroup of patients treated with an
aldosterone antagonist (n=78), specifically recommended in patients with resistant hypertension,
RDN significantly lowered office SBP/DBP/PP (-29.0/-11.4/-15.2 mmHg, p for all <0.001) and
24-hour SBP/DBP (-11.9/-7.1 mmHg, p for both <0.001) 6 month after RDN. At 3, 6 and 12
months maximum and minimum 24-hour SBP (-11.7/-10.0/-6.1 mmHg and -6.0/-9.4/-13.1
mmHg, p<0.001 compared to baseline) as well as minimum 24-hour DBP (-3.8/-3.9/-7.6 mmHg,
p<0.001 compared to baseline; n=175/153/48) declined. In patients with true resistance daytime
and nighttime ABPM were similarly reduced (Figure 2). In the overall cohort the percentage of
non-dippers and reverse dippers was not altered after RDN (baseline: 43.2%/14.7%; 3 months:
43.3%/20.1%, p=0.201; 6 months: 45.4%/12.6%, p=0.105; 12 months: 37.9%/17.2%, p=0.233).
Patients with a SBP reduction of 10 mmHg in office-based measurements and 5
mmHg in ABPM average were subsequently defined as responders to RDN. Although, these
thresholds were not provided by guidelines they represent clinical relevant BP reductions and
were used in the Symplicity trials. Figure 3 depicts rates of responders according to office and
24-hour BP at 3, 6 and 12 months follow-up. Odds ratios (OR) for response at 6 months
according to gender, age >75 years, per 1 kg/m2 increase in body mass index (BMI), diabetes
type 2, GFR >60 ml/min/1.73 m2, number of antihypertensive >median, treatment with
aldosterone antagonists, treatment with central sympatholytics, office SBP >median, office DBP
>median, office PP >median, ABPM average >median, and dipping pattern are shown in Table
3, indicating that RDN was equally effective in terms of blood pressure lowering in all of the
analyzed subgroups. After adjusting for covariates as age, sex, body mass index, diabetes, and
and nighttime ABPM were similarly reduced (Figure 2). In the overall cohort thehee pppere cececentntntagagage e e oof
non-dippers and reverse dippers was not altered after RDN (baseline: 43.2%/14.7%; 3 months:
433.3.33%/%/%/202020.1.11%,%% pp=0=0=0.2.201; 6 months: 45.4%/12.6%,%,% pp==0.105; 12 mooontn hss:: 33737.9%/17.2%, p=0.233).
Patientsts wwwiitth h aa a SBSBBPPP rreredduductcttioioionn ofof 1000 mmmmHHHggg innn oooffffiiccee-e-babaaseeed d memeeaassururremememenentststs aaandndnd 555
mmmmmHgHgHg iinn ABABABPMPMM aaaveverrraggege wweerere e sususubsbsbseqeqqueueentntntlylyly dddeeefifiinenened d aasa rrresesespopopondndnderersss totot RRDNDNDN.. AAlAlththhouououghghh,, ththheseseee
hresholds wwererere e e nonoot t t prprprovovvidddededed by y y gugug idididelllinini esese ttthehehey y y rerereprprprese enenent t t clclclinininicicicalaa rrreleleleeevavavantntnt BBBPPP rerereduduductctctioi ns and
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GFR, office SBP at baseline was identified as a correlate of response at 6 months follow-up (as
continuous variable (per 1 mmHg): OR 1.026, 95% confidence interval (CI) 1.005-1.048,
p=0.017; office SBP >170 mmHg: OR 2.32, 95%-CI 1.09-4.85, p=0.029).
Patients and physicians were instructed not to change antihypertensive medication during
the study period. However, antihypertensive drug regimen was reduced during follow-up in 118
patients (34%), due to confirmed BP levels below respective target BP or the development of
symptoms of hypotension and confirmed low BP. Antihypertensive treatment was increased in
23 patients (7%) who remained above target BP. When excluding those 23 patients, BP effects
remained unchanged: reduction of office SBP by 21.9/23.8/26.9 mmHg and 24-hour SBP by
8.6/8.6/9.7 mmHg at 3, 6, and 12 months, respectively (p<0.001 for all). No differences existed
concerning medication reductions (p=0.524) or increases (p=0.399) between true-resistant and
pseudo-resistant patients. Figure 4 illustrates the distribution of office and daytime BP levels at
baseline pre-procedure and at 3, 6, and 12 months post-procedure.
Discussion
Renal denervation offers a novel and well-tolerated approach to selectively interrupt sympathetic
fibers and effectively reduce systolic and diastolic office BP.11, 12 Recently, concerns have been
raised that RDN might not reduce ABP equally effective.22 The results of the present multi-
center study in more than 300 patients now confirm that RDN significantly reduces office and
24-hour average, daytime and nighttime BP in patients with true-resistant hypertension and
increases the rate of patients controlled to target BP values, both according to office BP and
ABPM. Of note, office BP also declined in pseudo-resistant patients.
Blood pressure varies throughout the circadian period with a prolonged decrease during
8.6/8.6/9.7 mmHg at 3, 6, and 12 months, respectively (p<0.001 for all). No difffefeereencnn esese eeexixixiststs eed
concerning medication reductions (p=0.524) or increases (p=0.399) between true-resistant and
psseueuudododo-r-resesesisisistattantt pppaatatients. Figure 4 illustrates thehee ddiistribution of ofofofficee aaannnd daytime BP levels at
bbaaseeelil ne pre-pprorocecec dudurree aaandndnd aaatt 33,3, 6,6,6, aaandndd 1112 mmomonnthsss pppostt-t-pprproocceededururre..
Discussion
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nocturnal sleep.1 Daytime BP is more variable than nighttime BP in terms of different physical
and mental activity and nighttime BP is closely related to sympathetic outflow to the heart and
the muscle vasculature.23 Sympathetic activation has been shown to be a major contributor in the
development and progression of hypertension and represents a potential mechanism for the day-
night BP difference.24 Recently, a close inverse relationship between the degree of sympathetic
activation and the magnitude of the nighttime drop in SBP and DBP has been reported.9 The day-
night BP differences correlated inversely with sympathetic nerve activity (r = -0.76, p<0.0001)
with the highest sympathetic activity observed in patients with reverse dipping.9 The Dublin
Outcome Study included 5292 hypertensive patients and demonstrated that nocturnal BP was an
independent predictor of cardiovascular mortality.25 A 10-mmHg increase in mean nighttime
SBP corresponded to a 21% increase in cardiovascular mortality. The Anglo-Scandinavian
Cardiac Outcome Trial (ASCOT) ABPM substudy has demonstrated that nighttime SBP is
superior compared to office SBP in predicting stroke.26 Herein, RDN significantly reduced both
nighttime SBP by 11.9 mmHg, 10.9 mmHg and 12.6 mmHg (p<0.0001) and daytime SBP by
13.6 mmHg, 10.7 mmHg, and 11.6 mmHg (p<0.0001) at 3, 6 and 12 months, respectively.
However, no clear improvement in dipping status was found after RDN, which might be related
i) to the poor reproducibility of the classification of patients into dippers and non-dippers over
time 27, 28 and ii) to the fact that ABPM was performed as usually done in clinical practice with
fixed time intervals for day and night time periods, which might affect the calculation of
nocturnal dipping.
The office BP reductions were more pronounced than the reduction in ABPM, a plausible
finding which has been consistently demonstrated in antihypertensive drug treatment trial.29 In a
meta-analysis including 44 studies with >5800 patients, the averaged weighted reductions in 24-
ndependent predictor of cardiovascular mortality.25 A 10-mmHg increase in meaeaan nnin ghghghttttttimimime e e
SBP corresponded to a 21% increase in cardiovascular mortality. The Anglo-Scandinavian
CaCardrdrdiaiaiaccc OuOuOutcttcomomeee TTrTrial (ASCOT) ABPM substudududy y hhas demonstratata ed tthahahatt nighttime SBP is
uupeeperir or compaparreeddd too oofffffficicicee e SBSBSBPP ininin pprreedddictininnggg strookkke.26266 HHHererreieiin,n RRRDDNDN sssiggninififificacantntlylyly rrredededuucucededed bbboototh
ninighghghttttttimimimee SBSBSBPP bbyby 111.1.999 mmmmmHgHgHg, 101010.9.9.9 mmmmHmHmHggg annnd d d 1112.66. mmmmHmHmHg g (p(p(p<<<0.0000000011) anand dd dadadaytytytimimime SBSBSBP P bbyby
13.6 mmHg,g,, 1110.0.0 77 mmmmmmHgHgH , ananand dd 111111.6.6. mmmmHmHmHg g g (p(p(p<0<0<0.0.000000001)1 atatat 333,,, 6 66 ananand dd 121212 mmmonononththths,s rrresesespepepectctctivi ely.
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hour SBP or DBP were 36.5% and 36.8% less than the reduction in the office based values.29
The differences between office BP and 24-hour BP reductions found herein might be partially
influenced by other factors, including a possible regression to the mean of office BP readings
over repeated visits, a phenomenon which by definition cannot affect mean ABP. Furthermore, it
can be hypothesized that the disparity might be partially mediated by a suppression of the white-
coat effect, frequently encountered in resistant hypertension and associated with increased
sympathetic activity.30 However, the differences between the entire population and the group of
patients with true resistant hypertension were comparable, indicating that this cannot only be
attributed to the inclusion of patients with pseudo-resistant hypertension whose ABPM values
after RDN remain unchanged.
The ASPIRANT (Addition of Spironolactone in Patients With Resistant Arterial
Hypertension) trial 31 demonstrated in patients treated with a mean of 4.5 antihypertensive drugs
a reduction of daytime BP by 5.4 mmHg (p=0.024), nighttime by 8.6 mmHg (p=0.011) and 24-h
SBP by 9.8 mmHg (p=0.004) without significantly influencing DBP by addition of 25 mg
spironolactone once daily. However, the different effects of spironolactone on BP in the
ASPIRANT trial and RDN herein has to be interpreted in view of the different baseline BP
values (office BP: 154/92 vs. 171/91 mmHg, 24-hour ABP: 141/80 vs. 150/85 mmHg, day-time
ABP: 142/82 vs. 154/88, and night-time ABP: 136/77 vs. 141/78 mmHg). Despite the fact that
the patients analyzed herein were intensively treated (mean 5.2 ± 1.6 antihypertensive drugs),
RDN was more effective in lowering 24-hour BP on top of concomitant antihypertensive
medication, even in the subgroup of patients (n=78) who were already treated with
spironolactone (mean 24-hour BP changes 6 months after RDN: -11.9/-7.1 mmHg, p for both
<0.001). Maximum daytime SBP has been shown to predict risk of stroke and coronary events,
after RDN remain unchanged.
The ASPIRANT (Addition of Spironolactone in Patients With Resistant Arterial
HyHyypepepertrtrtenensisisiononon) trriaiaialll 331 demonstrated in patients trrreaee tted with a meaan nn off 444 5.5.5 antihypertensive drugs
a reeedduction off dddaaaytttimemee BBBPPP bybyby 555.4.4 mmmmHmHmHggg (p=0=0=0.02444)),, niiighghghttttimimime e bbyy 88.66 mmmmHmHmHgg g ((p(p=0=00.00011111)) anananddd 24244-h
SBSBBPPP bybyby 99.8.88 mmmmHmHHg g g (p(pp=0=0=0.0.004044))) wiwiwithththouoout t sisigngngnififificcananantltlly ini ffflueueuenncncinnng gg DBDBDBP P P bybyby aaadddddititi ioioion n ofofof 2255 mmgmg
pironolactonenee oooncncnce e e dadadailili y.y. HHHowowowevevevererr,, thhheee didid ffffffererereeentntnt eeeffffffecectststs ooof f f spspspiririronono olololacacactototonenene oon n n BPBPBP iiin n n tht e
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particularly after adjustment for mean daytime SBP.32 At 3, 6, and 12 months follow-up, RDN
significantly reduced maximum SBP. Both the office and 24-hour BP reductions and the
improvement in control rates after RDN found herein, may have relevant implications for
cardiovascular morbidity and mortality in patients at risk.
Although it was not mandatory to exclude pseudo-resistant hypertension according to the
Symplicity protocol,13, 14 the percentage was rather small (approx. 12%). Not surprisingly, in
patients with pseudo-resistant hypertension office BP was significantly reduced, while ABPM
was not influenced following RDN. Our findings are in line with recent recommendation of
several national 33 and international societies (including the European Society of Cardiology 34
and the European Society of Hypertension 35), aimed at avoiding to treat patients with RDN if
only office BP but not ABP is elevated. However, it has been shown that pseudo-resistant
hypertension is a risk indicator of sustained hypertension and is associated with an increased risk
for cardiovascular endpoints, including cardiovascular death, stroke and hypertensive organ
damage.36, 37 Therefore, further investigations are deserved to assess the effects of office BP
reductions by RDN on cardiovascular morbidity, mortality and the development of sustained
hypertension in patients with elevated clinic and normal 24-hour BP.
Response to RDN has been defined as a reduction in office SBP 10 mmHg six months
after treatment. In order to avoid invasive treatment by RDN in patients with low probability of
BP lowering afterwards, identification of correlates of response are essential. In different
subgroups, according to patients’ baseline characteristics, RDN was similarly effective in terms
of blood pressure reductions. Office SBP at baseline was the only correlate of response identified
herein (per 1 mmHg OR 1.026, 95%-CI 1.005-1.048, p=0.017). Of note, current medication with
spironolactone or central sympathetic agents were no correlates.
and the European Society of Hypertension 35), aimed at avoiding to treat patientsts wwititi hh h RDRDRDN N N ifiif
only office BP but not ABP is elevated. However, it has been shown that pseudo-resistant
hyhypepepertrtrteenensisisionono is aa a rririsks indicator of sustained hypepeerrtr eeension and is asasssociciatatateeed with an increased risk
ffoor cac rdiovascculullarara endndndpoooininintststs, iininclcludududiningg ccardddiooovassccuuularr r ddedeatatth,, sstrtrrokokkee anannd hyhyypepepertrtenennsisisivveve ooorgrgganan
dadamamamagegege..36,6, 37377 TTheheereeefoforrere, fufurtr hheher r inininveveveststigiggatatatioioionsnsn aaarere ddeeseeervvvededed to oo asasa sesessssss tthhhe eefffffeecectststs ooff f oofoffiiccece BBPPP
eductions by y y RDRDR N N N ononon cccarrdidid ovovo asasascucuc lalalar momomorbrbrbidididititity,y,y, momomortr alallititi y y y ananand d d thththe dededevevevelololopmpmpmenenent t t ofofof sssusuu tained
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DOI: 10.1161/CIRCULATIONAHA.112.000949
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Our study might have some limitations. Despite the advantages of ABPM, it is not
generally used in prospective trials investigating cardiovascular protection by antihypertensive
treatments. Actually there is not a single prospective study relating BP changes by ABPM to
future cardiovascular outcome, which might be due to difficulties of the procedure (time
consumption, repeated device checking, data heterogeneity, costs, etc.).29 It can be speculated
that such a profound reduction of BP after RDN might have increased patient’s exercise capacity
and daily physical workload and thereby also increased ABP, especially during daytime, which
might explain the similar BP reductions during daytime and nighttime. Although, preliminary
data suggest that RDN reduces BP variability,38 assessment of BP variability was not part of the
study protocol. As the study was mainly focused on the BP changes after 3 or 6 months, the
number of patients completing 12-month follow-up is lower compared to the other time points.
Therefore, the group of patients with 12-month follow-up should be regarded as a subgroup,
illustrating that the effects of RDN on BP are sustained over a longer time period. Changes in
antihypertensive drug treatment might also have influenced ABP measurements. During the
study period antihypertensive treatment was reduced in 24.6% (85 patients), due to symptomatic
hypotension with SBP <120 mmHg, and increased in 4.6% (16 patients, all non-responders).
Even after censoring for post-procedural medication changes, no significant differences were
found, making a relevant influence of treatment intensification unlikely.
Conclusions
Renal denervation reduces office, 24-hour, daytime, nighttime, maximum and minimum BP in
patients with true-treatment resistant hypertension on top of background antihypertensive
medication. In the largest cohort of patients analyzed so far, RDN was equally effective in terms
tudy protocol. As the study was mainly focused on the BP changes after 3 or 6 mmmononnthhhs,s,s, ttthehehe
number of patients completing 12-month follow-up is lower compared to the other time points.
Thherererefefefoorore,ee, tttheheh ggrororouupup of patients with 12-month fofofollloow-up shouldd bbbe reregagagardr ed as a subgroup,
lllluusststrating thaatt ththt eee efefffeff ctctctss s ofofof RRRDNDNN ooonn BBPP arrre sustttaaiineddd ovoveeer aa lloonongeger titit mmeme pppererrioiod.d.d CCChahah ngnggeses iiin n
anntititihyhyhypepepertrtenenensissiveve ddrurur g gg trreaeae tmtmmenene ttt mimimighgght t alallsososo hhhaaavevev iiinfffluluenenencececeddd ABABABPPP mememeasassurrrememmenenentstst .. DuDuDurinngng tthehee
tudy periodd aaantntntihihhypypypererrteteenssivivive e e trrreaeaeatmtmmenenntt t wawawass s rereredududuceceed d d inin 2224.4.4.6%6%6% (((8588 pppaaatitit enenentststs),),) dddueueue tttooo sysysymptomaticcc
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of BP reduction in different subgroups. Additional trials with longer-term follow-up are needed
to investigate the impact of these alterations on cardiovascular outcome in patients with resistant
hypertension.
Funding Sources: The Symplicity HTN1 and HTN2 were sponsored by Medtronic/Ardian Inc.
Conflict of Interest Disclosures: FM, CU, and MB are supported by the Ministry of Science
and Economy of the Saarland. FM is supported by the Deutsche Hochdruckliga and Deutsche
Gesellschaft für Kardiologie. FM, CU and MB are supported by the Deutsche
Forschungsgemeinschaft (KFO 196). MS is supported by an NHMRC Senior Research
Fellowship. PAS was an employee of Medtronic Ardian Inc. All authors received scientific
support and speaker honorarium from Medtronic Ardian Inc.
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35. Schmieder RE, Redon J, Grassi G, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G, Ruilope L, van de Borne P, Tsioufis C. Esh position paper: Renal denervation - an interventional therapy of resistant hypertension. J Hypertens. 2012;30:837-841. 36. Verdecchia P, Reboldi GP, Angeli F, Schillaci G, Schwartz JE, Pickering TG, Imai Y, Ohkubo T, Kario K. Short- and long-term incidence of stroke in white-coat hypertension. Hypertension. 2005;45:203-208. 37. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Polo Friz H, Grassi G, Sega R. Long-term risk of sustained hypertension in white-coat or masked hypertension. Hypertension. 2009;54:226-232.
2011;57:1069-1075.
32. Rothwell PM, Howard SC, Dolan E, O'Brien E, Dobson JE, Dahlof B, Severr PPPSSS, PPououo ltltlterrer NNNRRRPrognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hyppertension. Lancet. 2010;375:895-905.
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201111;1;13636:2:2414 8.8.
3434 MaMahfhfououdd FF LLüsüschcherer TTFF AAndndererssssonon BB BaBaumumgagartrtnenerr II CCififkokovava RR DiDimamaririoo CC DDoeoevevendndananss PPP
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38. Zuern CS, Rizas KD, Eick C, Stoleriu C, Bunk L, Barthel P, Balletshofer B, Gawaz M, Bauer A. Effects of renal sympathetic denervation on 24-hour blood pressure variability. Front Physiol. 2012;3:134.
Table 1. Patient characteristics
All patients n = 346
True resistant n = 303
Pseudo-resistantn = 43
P*
Demographics Age (years) 62.7 ± 10.8 62.6 ± 10.8 63.3 ± 11 0.641 Male gender 223 (64%) 194 (64%) 29 (67%) 0.661 Body mass index (kg/m²) 30.4 ± 5.6 30.5 ± 5.8 29.6 ± 4.3 0.381 Risk factors and target organ damage Type II diabetes 135 (39%) 124 (41%) 11 (26%) 0.054 CAD 83 (24%) 70 (23%) 13 (30%) 0.305 Cystatin C GFR (mL/min) 79.8 ± 29.2 80.3 ± 30.3 76.4 ± 20.6 0.419 Office blood pressure and heart rate measurements SBP (mmHg) 170.8 ± 22.1 172.2 ± 22 161.2 ± 20.3 0.013 DBP (mmHg) 91.3 ± 15.2 92.1 ± 15.2 87.2 ± 14.4 0.128 PP (mmHg) 79.3 ± 18.7 80.1 ± 18.9 74 ± 16.6 0.057 Heart rate (bpm) 70.2 ± 13.6 70 ± 13.4 71.7 ± 17.2 0.758 Antihypertensive treatment No. of antihypertensive drugs 5.2 ± 1.6 5.2 ± 1.6 5.3 ± 1.3 0.867 ACE-I/ARB 304 (88%) 264 (87%) 40 (93%) 0.268 Beta-blockers 267 (77%) 227 (75%) 40 (93%) 0.008 Calcium channel blockers 261 (75%) 224 (74%) 37 (86%) 0.084 Diuretics 318 (92%) 239 (79%) 38 (88%) 0.145 Aldosterone antagonists 88 (25%) 78 (25%) 10 (24%) 0.726 Central sympatholytics 190 (55%) 167 (55%) 23 (54%) 0.841 Direct vasodilators 100 (29%) 88 (29%) 12 (28%) 0.876 CAD: coronary artery disease. GFR: glomerular filtration rate. SBP: systolic blood pressure. DBP: diastolic blood pressure. PP: pulse pressure (mmHg). ACE-I: Angiotensin-converting enzyme inhibitors. ARB: Angiotensin receptor blockers. *P-values for comparison between true resistant and pseudo-resistant.
Type II diabetes 135 (39%) 124 (41%) 11 (26%)%) 00.0.054 CAD 83 (24%) 70 (23%) 13 (300%%)%) 000.3.3005 Cystatin C GFR (mL/min) 79.8 ± 29.2 80.3 ± 30.3 76.4 ± 20200 66.6 000 44.4191919
Office blood pressure and heart rate measurements SBPP (((mmm HgHg) 170.8 ± 22.1 172.2 ± 22 161 1.2 ± 20.3 0.013DDDBPBPBP ((mmmmmHHHg) ) 91.3 ± 15.2 92.1 ± 15.2 878 .2 ± 14.4 0.128PPPPP (mmHHg)g)g) 797979.3.3.3 ±±± 1118.8.8.77 7 80800.1.1.1 ±±± 118.8.999 744 ±±± 1116.6.6.6 6 6 00.0.0500 7HHHeae rt rate (bbpmmm)) 77070.222 ±±± 133.66 707070 ±±± 133.3.44 7171.7.7 ±± 11777.222 000.77758
AnAnAntitiihyhyh pepertrtenenensisivveve ttrereatattmem nntnt NNo.o. ooofff ananantitihyhypepepertrtrtenenensisisiveveve ddruugggsss 5.5 22 ±±± 111.6 6 6 555.222 ±±± 11.1.66 5.5 333 ±±± 1.11 333 0.00 86868677AAACECECE II-I/A/A/ARBRBRB 303030444 (8(8(88%8%8%))) 26262644 4 (8(8(87%7%7%) ) ) 404040 (((939393%)%)%) 000 22.2686868BBeteta-a-blblocockekersrs 262677 (7(77%7%)) 222277 (7(75%5%)) 4040 ((9393%)%) 00 0.008088
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Table 2. ABPM parameters
All patients True resistant Pseudo-resistant P*Baseline n = 346 n = 303 n = 43 Mean SBP 149.9 ± 19.9 154 ± 16.2 121.1 ± 19.6 <0.0001 Mean DBP 84.9 ± 13.1 86.5 ± 12.8 73.6 ± 8.6 <0.0001 Daytime SBP 153.9 ± 18.7 157.7 ± 16.9 129.9 ± 8.7 <0.0001 Daytime DBP 87.8 ± 13.7 89.5 ± 13.6 76.9 ± 8.7 <0.0001 Nighttime SBP 141.3 ± 22.9 145.6 ± 21.2 113.9 ± 11.4 <0.0001 Nighttime DBP 77.6 ± 14.3 79.7 ± 14.1 64.6 ± 7 <0.0001 Non-dippers 165 (55%) 150 (58%) 15 (38%) 0.0072 Maximum SBP 191.3 ± 29.1 195.3 ± 28.4 166.7 ± 20.3 <0.0001 Maximum DBP 113.6 ± 23.4 115.7 ± 24 101.1 ± 14.4 <0.0001 Minimum SBP 111.3 ± 20 115 ± 18.8 89.3 ± 11.8 <0.0001 Minimum DBP 57.6 ± 12.4 59.2 ± 12.3 48.5 ± 8.7 <0.0001 3 months n = 245 n = 213 n = 32 Mean SBP 141.9 ± 19.2 144.3 ± 18.8 126.2 ± 13.5 <0.0001 Mean DBP 80 ± 13.2 81 ± 13.3 73.3 ± 10.2 <0.0001 Daytime SBP 141.8 ± 23.8 144.1 ± 24.3 127.3 ± 13.6 <0.0001 Daytime DBP 85.6 ± 19.1 86.7 ± 19.6 78.2 ± 13.4 <0.0001 Nighttime SBP 132 ± 24 134.5 ± 24.1 116.1 ± 15.1 <0.0001 Nighttime DBP 73.5 ± 13.4 74.7 ± 13.5 65.8 ± 10.1 <0.0001 6 months n = 236 n = 206 n = 30 Mean SBP 141.9 ± 17.4 144.2 ± 17 125.9 ± 10.3 <0.0001 Mean DBP 80.6 ± 12.8 81.6 ± 12.9 73.1 ± 9.1 <0.0001 Daytime SBP 144.6 ± 17.8 146.9 ± 17.5 130.1 ± 11.7 <0.0001 Daytime DBP 82.4 ± 13.7 83.4 ± 13.8 76.3 ± 11 <0.0001 Nighttime SBP 133.5 ± 19.9 135.5 ± 19.8 121.2 ± 15.8 <0.0001 Nighttime DBP 73 ± 13.5 73.9 ± 13.9 67.6 ± 9.9 <0.0001 12 months n = 90 n = 80 n = 10 Mean SBP 140.8 ± 16.3 142 ± 16.1 130.8 ± 15.2 <0.0001 Mean DBP 79.4 ± 10.5 80 ± 10.6 74.5 ± 7.6 <0.0001 Daytime SBP 143.7 ± 15.7 145.2 ± 15.2 134.2 ± 16.1 <0.0001 Daytime DBP 82 ± 10.3 82.8 ± 10.4 77.4 ± 9 <0.0001 Nighttime SBP 130.2 ± 16.8 131.6 ± 16.8 121.6 ± 15.3 <0.0001 Nighttime DBP 71.1 ± 10.5 72 ± 10.9 65.7 ± 5.8 <0.0001 SBP: systolic blood pressure. DBP: diastolic blood pressure. *P-values for comparison of true resistant and pseudo-resistant.
n-dippers 165 (55%) 150 (58%) 15 (38%) 0.0.000 72ximum SBP 191.3 ± 29.1 195.3 ± 28.4 166.7 ± 20.3 <0<0<0.0.000ximum DBP 113.6 ± 23.4 115.7 ± 24 101.1 ± 14.4 <0<0<0.0.00000imum SBP 111.3 ± 20 115 ± 18.8 89.3 ± 11.8 <0<0 0.00000imum DBP 57.6 ± 12.4 59.2 ± 12.3 48.5 ± 8.7 <0.000
nths n = 245 n = 213 n = 32 an SBP P 141.9 ± 19.2 14144.4.3 ± 18.8 12126.6 2 ± 13.5 <0.000an n DBDBDBP P 80 ± 13.2 181 ± 13.3 37373.3. ± 10.2 <0.000titimemm SSSBPBP 141.88 ± ± 232 .88 4141 .4.4 1 ± 2424.3.3 12127.7 3 ± 1313.6.6 <00.0.000ititi eeme DDBP 8585.66.6 ±±± 11199.9.111 8688 7.7. ± 1199.9.6 6 6 78878.2 ±± 1113.3.3.4 4 4 <0<0<0.0.000
hth timemem SBP 1313322 ± ± 42424 331 .4.4 5 ± 242424.1.1 1116.6 11 ± ±± 15151 .1.1 <0<< 00. 00hthh timemem DBP 7377 5.5. ± 113.44 7477 7.7. ± 113.3.3.55 5 5565.8 ±±± 110.0 11 <0<< 00. 00tntnthshh n === 232 6 n n = 020206 6 n === 030
aan n BSBSBPP 4141.1.1 9 ±± 17177.4.4 141 4.4.4 22 ±± ± 7717 2125.5.5 9 9 ±± 1010.3.3.3 <0<< 00.0000an DBDBP P 800.6.6 ±± 112.2.88 818 .6 ±± 112.2.99 733.1.1 ±± 99.1.1 <0< .000000tititimeme SSSBPBPBP 141414444.666 ±±± 171717 88.8 141414666.999 ±±± 171717 55.5 131313000.111 ±±± 111111 77.7 0<0<0 00.0000000time DBP 828282.4 ±±± 1133.3 777 838383.44.4 ±±± 13.3.3 8 88 767676.33.3 ±± 11111 <0.0 0000hthttitime SSBPBP 131333 55 ±± 1919 99 131355 55 ±± 1919 88 121211 22 ±± 1515 88 <0<0 00 00000
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Table 3. Correlate of response
Univariable analysis Multivariable analysis* Variable Wald OR 95% CI p Wald OR 95% CI p All patients Male Gender 0.74 1.33 0.-70-2.54 0.388 Age >75 years 0.43 1.47 0.47-4.64 0.51 Per 1 kg/m² increase in BMI 0.66 1.03 0.96-1.09 0.418 Diabetes 0.63 1.30 0.68-2.48 0.428 GFR >60 ml/min/1.73m² 0.31 0.82 0.41-1.65 0.58 >5 antihypertensive drugs (m) 0.69 1.32 0.69-2.51 0.406 Use of an aldosterone antagonist 1.39 1.6 0.73-3.5 0.238 Use of a central sympatholytic 0.98 1.38 0.73-2.61 0.322 Office SBP >170 mmHg (m) 6.62 2.33 1.22-4.44 0.01 7.2 2.59 1.29-5.18 0.007 Office DBP >91 mmHg (m) 0.01 0.98 0.53-1.82 0.943 Office PP >79 mmHg (m) 2.71 1.67 0.90-3.19 0.101 ABPM >151 mmHg (m) 0.33 0.83 0.45-1.55 0.833 Non-/reverse-dipping 0.01 1.03 0.54-1.96 0.934
True resistant hypertension Male Gender 0.01 1.03 0.51-2.09 0.936 Age >75 years 0.57 1.65 0.45-6.07 0.452 Per 1 kg/m² increase in BMI 0.1 1.01 0.95-1.08 0.75 Diabetes 0.01 1.0 0.5-1.99 0.997 GFR >60 ml/min/1.73m² 0.09 0.89 0.43-1.86 0.761 >5 antihypertensive drugs (m) 0.95 1.42 0.7-2.86 0.33 Use of an aldosterone antagonist 1.57 1.73 0.73-4.11 0.211 Use of a central sympatholytic 3.3 1.9 095-3.79 0.07 2.2 1.77 0.83-3.74 0.138 Office SBP >170 mmHg (m) 4.2 2.7 1.03-4.13 0.041 4.79 2.3 1.09-4.85 0.029 Office DBP >91 mmHg (m) 0.88 0.72 0.37-1.42 0.347 Office PP >79 mmHg (m) 0.22 0.70 0.23-2.51 0.64 ABPM >151 mmHg (m) 0.72 0.75 0.38-1.47 0.396 Non-/reverse-dipping 0.75 1.36 0.68-2.75 0.386
Odds ratios for response (office SBP 10 mmHg) at 6 months in all patients and in patients with true resistant hypertension. OR: odds ratio; CI: confidence interval; m: variable was dichotomized according to the median; BMI: body mass index; GFR: glomerular filtration rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; PP: pulse pressure; ABPM: ambulatory blood pressure 24-h average. *Variables entered the multivariate analysis were age, gender, BMI, GFR, diabetes, and variables with p<0.1 in the univariable analysis
>60 ml/min/1.73m 0.31 0.82 0.41 1.65 0.58 ntihypertensive drugs (m) 0.69 1.32 0.69-2.51 0.406 of an aldosterone antagonist 1.39 1.6 0.73-3.5 0.238 of a central sympatholytic 0.98 1.38 0.73-2.61 0.322 ce SBP >170 mmHg (m) 6.62 2.33 1.22-4.44 0.01 7.2 2.59 1.29-5.18 0.0ce DBP >91 mmHg (m) 0.01 0.98 0.53-1.82 0.943 ce PP >7>79 mmm HgHg ((m)) 2.71 1.67 0.0 9090-3.19 0.101 MM >>>151515111 mmmmmmHgHgHg ((m)mm 0.33 0.83 0.00 5454 -1.55 0.833 --/r/rrevee erere sese-dippipi gngng 0.0.0101 11.0.033 0.00 4545 -1.966 0.934 4 rrres ssistatant hyperrtetensnsioioionn
e G nene ded r 0.0 1101 1.03 0.00 1515 -2 00.0999 .00 93936 6 >7>> 5 yey ars 0.575 1.655 0.00 5454 -6.00777 .00 452 2
11 kgkgkg mm/m²² inncrc eaasesee iiin n n MBMBMI 0.0.11 1.1.01011 000 9.95-5 .1.0808 000.7755 etetess 000.0.00111 1.1.1.00 0 00.0.5-5-5-1.1.1 99999 00.0.99999 7 7
6>600 mll/min/1/1.73mm² 0.0 099 00 8.899 0.43-11.886 0.0 767 1 ntihypertensive drdrugugugs s s (m(mm) ) ) 0.0.0.959595 111.4.4.4222 0.0..7-7 2.2.2 8686 00.3.33333 of an aldosterone antagog ini tst 11.57577 11 7.733 00.7373-444.111 0.0 212111
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Figure Legends:
Figure 1. Office and 24-hour BP changes 3, 6 and 12 months after renal denervation. SBP:
systolic blood pressure; DBP: diastolic blood pressure. Whiskers indicate 5 and 95 percentile. P-
values are for comparison with baseline values. *p-value are comparison of within group
changes over time using linear mixed-effects models.
Figure 2. Daytime and nighttime BP changes in patients with true-treatment resistant
hypertension at 3-, 6- and 12-months follow-up. SBP: systolic blood pressure; DBP: diastolic
blood pressure. Whiskers indicate 5 and 95 percentile. P-values are for comparison with baseline
values. *p-value are comparison of within group changes over time using linear mixed-effects
models.
Figure 3. Rates of responders in patients with true-treatment resistant hypertension, defined as a
SBP reduction of 10 mmHg in office-based measurements or 5 mmHg in ABPM average at 3
months, 6 months and 12 months follow-up.
Figure 4. Distribution of office and BP levels at baseline pre-procedure and at 3, 6, and 12
months post-procedure in patients with true resistant hypertension.
blood pressure. Whiskers indicate 5 and 95 percentile. P-values are for comparissonoon wwititith h h bababaseses liline
values. *p-value are comparison of within group changes over time using linear mixed-effects
momodededelslsls.
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SBP reductioon n n ofofo 10101 mmmmHmHHg g g innn oooffffficicice---bababasesesed d d memem asasasurururememmenenentstst oor r r 55 mmmmmmHgHgHg iiin nn ABABABPMPMPM aaavev rage at 33
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20
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SBP p<0.0001* DBP p<0.0001*
SBP p<0.0001* DBP p=0.015*
SBP p<0.0001* DBP p<0.0001*
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SBP p=0.218* DBP p=0.977*
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3M (n=183)
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Figure 2
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Reduction of ABP 5 mm Hg Reduction of office SBP 10 mm Hg
0
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100
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Figure 3
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n (%
)
Office BP
24h-BP
27
73
33
39
28
27
36
37
31
45
24
56
44
36
46
18
36
46
20
30
49
21
Figure 4
Baseline 3M 6M 12M0
SBP 140-160 mm Hg
SBP >160 mm Hg
BSBPPP <1<1404 mm Hg
6060
80
1000 0
onon((%
)
222444hhh--BBBPPP
27 28 37 24
565656 363 3636 3030
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Erwin Blessing, Paul A. Sobotka, Henry Krum, Markus Schlaich, Murray Esler and Michael BöhmVonend, Joachim Weil, Martin Schmidt, Uta C. Hoppe, Thomas Zeller, Axel Bauer, Christian Ott,
Felix Mahfoud, Christian Ukena, Roland E. Schmieder, Bodo Cremers, Lars C. Rump, OliverResistant Hypertension
Ambulatory Blood Pressure Changes after Renal Sympathetic Denervation in Patients with
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