Scholarly article on topic 'Impact of renal sympathetic denervation on home blood pressure monitoring in well defined patients with resistant hypertension'

Impact of renal sympathetic denervation on home blood pressure monitoring in well defined patients with resistant hypertension Academic research paper on "Health sciences"

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Academic research paper on topic "Impact of renal sympathetic denervation on home blood pressure monitoring in well defined patients with resistant hypertension"

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Impact of renal sympathetic denervation on home blood pressure monitoring in well defined patients with resistant hypertension

K.F. Franzen a1 M. Reppeld1 M. Neuwirth b, J. Köster b, T. Grafb, F. Bode b, J. Weilc, K. Mortensen b'*

a Medizinische Klinik III, Campus Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany b Medizinische Klinik II, Campus Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany c Sana Kliniken Lübeck, Lübeck, Germany d Cardiology Landsberg, Landsberg, Germany



Article history:

Received 24 September 2015 Accepted 28 September 2015 Available online 9 October 2015

Keywords: Renal denervation Home blood pressure

Background: Catheter-based percutaneous renal denervation therapy (RDN) is a controversially discussed treatment-strategy for patients with resistant arterial hypertension. Home blood pressure monitoring (HBPM) is superior to office blood pressure (OBP) measurements documenting effects of drug or interventional therapy and for predicting cardiovascular morbidity and mortality. We therefore aimed at comparing effects of RDN on OBP and HBPM.

Methods: 28 patients with resistant hypertension were studied; 21 patients (29-85 years, median 67 years, 5.4 ± 1.3 antihypertensive drugs) were included into the treatment arm and 7 patients (37-70 years, median 68 years, 5.1 ± 2.2 antihypertensive drugs) served as controls. RDN was performed with a Medtronic™ radiofrequency catheter-ablation-system. For OBP and HBPM measurements patients were followed up to 6 months. For controls, a mean of approximately 378 measurements in 167 ± 13.5 days was included into analysis. In RDN patients follow-up was 157.7 ± 61.8 days with a mean of approximately 323 ambulatory measurements. A mean for each week was calculated.

Results: In controls, no significant change of OBP was observed (baseline: systolic 162.2 ± 11.6 mm Hg vs. 6 months: systolic 162.8 ± 22.9 mm Hg; p > 0.05). Accordingly, HBPM values didn't change (baseline: systolic 161.2 ± 15.1 mmHgvs.6months: systolic 155.8 ± 24.6mmHg,p > 0.05). In RDN patients a significant reduction of OBP (baseline: systolic 169 ± 12.5 mm Hg vs. 6 months: systolic 150.6 ± 19.2 mmHg,p < 0.01) and HBPM (baseline: systolic 156.2 ± 12.9 mm Hg vs. 6 months: systolic 139.7 ± 10.2 mm Hg, p < 0.001) was observed. Conclusion: In patients with resistant hypertension RDN significantly reduced HBPM and OBP already one week after treatment.

© 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license


1. Introduction

Arterial hypertension is a widespread disease and an important cardiovascular risk factor [1 -2]. [3-5]. Approximately 10% of hypertensive patients are suffering from resistant arterial hypertension where therapeutic targets are not met [6-7]. Therefore resistant arterial hypertension was defined as a remaining systolic blood pressure (SBP) > 140 mm Hg despite an antihypertensive treatment with at least three different drugs including one diuretic [8]. The pathophysiology is complex and remains, at least in part, unclear. It is known that the central nervous system is linked and communicates with efferent and

* Corresponding author at: Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Medizinische Klinik II, D-23538 Lübeck, Germany.

E-mail address: (K. Mortensen). 1 Contributed equally.

afferent renal sympathetic nerve fibers that contribute to the development and perpetuation of hypertension.

Several interventional approaches to control resistant hypertension exist. RDN is one of these approaches reducing central sympathetic activity [9]. RDN uses radiofrequency energy intercepting afferent and efferent renal sympathetic nerves. In treated patients, RDN showed a significant reduction of OBP up to 36 months [10-12] as well as 24 hour ambulatory blood pressure measurements (ABPM) up to 24 months [13]. Furthermore, RDN improved central pressures and arterial stiffness [14-15]. In contrast to previously published promising data [9, 12,16] the Symplicity HTN-3 study [17] - which was the first multicenter, randomized trial - didn't show a significant reduction of systolic blood pressure in the 24 hour ABPM compared to a control group treated with a sham procedure [18].

HBPM is recommended in the management of hypertension since it e.g. excludes the white coat effect and might help improve hypertension control [19]. Furthermore out of office measurements are stronger 016/j.ctrsc.2015.09.005

2405-5875/© 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (

related to hypertension-induced organ damage than OBP [3,20-29]. However, the already published Symplicity HTN-3 focused only on OBP and as a secondary endpoint on 24 h-ABPM [17-18]. Taken together, it is of great importance to demonstrate the effects of RDN on HBPM. For this reason, we addressed the question whether RDN with its known reduction of peripheral blood pressures and improvement of central blood pressures [14,30] might also affect HBPM measurements.

Finally since now it remained unclear, when effects after the RDN procedure might start independently of the OBP or 24 h-ABPM. In the present study, we therefore determined the beginning of a significant blood pressure reduction by using HBPM besides the effects on office blood pressure.

2. Methods

2.1. Study design and patients

All patients had to fulfill the following inclusion criteria [31-32]: I) age over 18 years; II) peripheral office SBP of at least 150 mm Hg at screening; III) stable treatment with three or more antihypertensive drugs in maximum tolerable doses of different classes, including diuretics. Exclusion criteria were the following: I) an estimated glomeru-lar filtration rate (GFR) of less than 45 mL/min per 1.73 m2; II) substantial valvular heart disease, III) pregnancy or planned pregnancy during the study, IV) history of myocardial infarction, unstable angina, or cerebral vascular event in the previous six months, or V) significant renal artery stenosis and/or previous renal artery intervention. Additionally, secondary hypertension including e.g. obstructive sleep apnea and pseudo-resistance were extensively ruled out. During the screening process, each patient was asked to start with a blood pressure logbook for documentation. The screening visit was two weeks before RDN. 35 patients fulfilled the inclusion criteria. 21 patients were treated with RDN while 7 served as controls. The other 7 patients were not included, because 2 documented HBPM insufficiently, 1 didn't appear to the date of treatment and 4 patients withdrew the written consent. At baseline visit, blood pressure was measured two days before treatment and documented as baseline, which was taken for statistical reference of blood pressure follow-ups. Routine follow-up visits were scheduled as per protocol at one month ( + 30 days), three months ( + 90 days) and six months ( + 180 days) after inclusion. The study was approved by the local ethic committee (AZ 10-211). Before enrollment each patient provided written informed consent.

2.2. Procedure and follow-up

All ablations were performed by two experienced operators. After preparing the access a standard endovascular technique was selected via the right femoral artery. Thereafter the interventionalist probed the renal artery with the ablation catheter, advanced it into the vessel and connected the catheter system to a radiofrequency generator (Medtronic). Applying a maximum of six ablation points per renal artery using a maximum power of 8 W at each single point the procedure was performed by retracting the catheter from the distal to the proximal part of the artery. The second artery was treated accordingly. Unfractionated heparin was applied with an activated clotting time of >250 s. Patients were asked to avoid any change of baseline doses of anti-hypertensive treatment unless judged medically urgent. This was described as any relevant changes in blood pressure associated with signs or even symptoms of severe hypo- or hypertension. As defined by protocol all patients were asked for follow-up visits at one, three and six months after the procedure. These follow-up visits included assessment of adverse events and current medication, measurements of OBP as well as collecting data of the blood pressure pass. Measurements of OBP were done according to protocol-specified guidelines based on Standard Joint National Committee VII, European Society of Cardiology, and European Society of Hypertension recommendations [3] and with

an automatic oscillometric Omron HEM-705 monitor (Omron Healthcare, Vernon Hills, IL, USA).

2.3. Endpoints

1. Changes of HBPM from baseline to follow-up. 2. Changes of OBP. According to the relevant studies in the field response was defined as a reduction of office SBP of > 10 mm Hg [12,32].

2.4. HBPM and blood pressure logbook

All patients used fully automated oscillometric upper arm devices that were approved by the German Hypertension League (DHL e.V.). For a detailed documentation patients were asked to measure and report the blood pressure values on a daily basis, i.e. at least twice per day under the same standard conditions. Patients were trained according to the guidelines for blood pressure measurement of the ESH/Ger-man, Hochdruckliga [3,33] and the practice guidelines for home blood pressure monitoring of the ESH [19]. Measurements were performed in the morning within 1 h after waking up, after urinating, before morning antihypertensives, before breakfast and after at least 5 min of rest in a sitting position as well as at bedtime after at least 5 min of rest in a sitting position. A patient specific logbook contained also a detailed guideline-based manual. The logbooks were copied at each follow-up visit and immediately entered in our database manually.

2.5. Statistical analysis

The week prior to the ablation served as reference point. "Baseline" was used as the reference point for the OBP. The HBPM as well as the OBP were compared by a paired t-test during the follow-up. ANOVA on ranks (RANOVA) was applied where applicable comparing both groups. All data are shown as mean ± standard deviation (SD) if not stated otherwise. A p-value of < 0.05 was defined as statistically significant. All statistical analyses were performed with SPSS statistical software (SPSS 19 Inc., Chicago, USA). Figures as well as tables were created by SigmaPlot 8.0 (Systat Software Inc., San Jose, USA) and edited by CorelDraw 11.0 (Corel Inc., Mountain View, USA).

3. Results

3.1. Baseline characteristics

After screening 35 patients fulfilled the inclusion criteria and 28 of them were finally included (flow-chart Fig. 1). Baseline characteristics for the RDN (TG) as well as control group (CG) are shown in Table 1. One patient of the TG refused to complete the follow-up at 6 months. This patient's data were excluded from statistical analysis for this time point. Furthermore data of the blood pressure logbook that were missing at any follow-up were excluded from analysis for this time point.

There were no statistical differences for number of measurements, number of days or weeks between TG and CG (analyzed weeks of TG included into statistics: 22.5 ± 8.8 vs. CG23.8 ± 1.9, p~ 0.754; analyzed days: TG 157.7 ± 61.8 vs. CG 166.6 ± 13.5, p ~ 0.754; blood pressure measurements: TG 322.9 ± 158.5 vs. CG 377.8 ± 71.8 single measurements, p ~ 0.462).

3.2. RDN improves systolic and diastolic blood pressures in the OBP

3.2.1. OBP measurements — lowering of systolic as well as diastolic blood pressure

In the TG, office SBP was reduced significantly from 169 ± 12.5 mm Hg by approximately 6.3% after one month (p < 0.05) and by 11.9% and 10.9% after three and six months, respectively (p < 0.01, Table 2, Fig. 2A). Office SBP didn't change in the CG. Peripheral diastolic blood pressure (DBP) showed a trend to improvement at one month

Fig. l. Flowchart of the study.

(p = 0.053) in the TG. However, DBP was significantly decreased by 8.7% after three months (p < 0.05) and by 8.7% after six months (p < 0.05) (Table 2, Fig. 2A).

3.3. RDN improves SBP in the HBPM

SBP of the TG improved significantly (1 month: 5.8%, p < 0.01; 3 months 7.2%, p < 0.01; 6 months 10.6%, p < 0.01) ( Fig. 3A). Detailed analysis showed that the SBP improved already after the first week (reduction by 7.5%, p < 0.01, Fig. 3A). HBPM of the CG didn't change at any time point significantly (Fig. 3A). In addition, TG and CG didn't differ significantly at baseline (TG 156.2 ± 12.9 mm Hg vs. CG 161.2 ± 15.1 mmHg, p ~ 0.717). During follow-up TG showed significantly lower SBP than CG at one month (p < 0.05) and three months (p < 0.05). At six months, however, the difference was not significant (p ~ 0216).

Table 1

Baseline characteristics. Data are expressed as mean ± SD.

Therapy Control

group group

(n = 21) (n = 7) p-Value

Gender [percentage of men] 62% 40% N 0.05

Age [years] 67.4 ± 12.3 67.8 ± 10.0 N 0.05

Hypercholesterolemia 57% 60% N 0.05

Diabetes mellitus 24% 60% N 0.05

Adipositas 48% 100% .034

Smoking 29% 60% N 0.05

pAVD 24% 20% N 0.05

Pulmonary disease 19% 40% N 0.05

Height at baseline [m] 1.76 ± .11 1.72 ± .07 N 0.05

Weight at baseline [kg] 86.8 ± 19.0 102.9 ± 12.7 N 0.05

BMI at baseline [kg/m2] 27.9 ± 4.1 34.8 ± 2.8 .002

Number of drugs 7.3 ± 2.5 7.9 ± 2.4 N 0.05

Number of antihypertensive drugs 5.4 ± 1.3 5.1 ± 2.2 N 0.05

Number of ablation points of the 4.6 ± 1

left renal artery

Number of ablation points of the 4.6 ± 1.1

right renal artery

Analyzed weeks 22.5 ± 8.8 23.8 ± 1.9 N 0.05

Analyzed days 157.7 ±61.8 166.6 ± 13.5 N 0.05

Analyzed measurements 322.9 ± 158.5 377.8 ± 71.8 N 0.05

3.4. RDN improves DBP in the HBPM

DBP of the TG improved significantly after one month (reduction by 5.7%, p < 0.01), after three months (reduction by 6.8%, p < 0.001) and after six months (reduction by 5.1.%, p < 0.001) (Fig. 3B). Comparable with the effect of RDN on SBP, DBP declined significantly after the first week and remained afterwards at this level (p < 0.01). The diastolic blood pressure of the CG didn't change significantly during follow-up (Fig. 3B). In the ANOVA no differences could be shown between TG and CG.

3.5. No differences occurred between OBP measurements and HBPM

Office and HBPM showed no significant difference for the mean of SBP as well as DBP for the TG and CG. SBP of the HBPM of the TG lay in a range of 92% and 95% and DBP of the HBPM lay between 101% and 103% compared to the OBP (p > 0.05). The CG achieved systolic values between 96% and 99% and diastolic values between 95% and 101% in the HBPM compared to the OBP (p > 0.05).

4. Discussion

After Symplicity HTN-3 RDN is controversially discussed [17,34]. Joint UK societies' 2014 consensus statement on RDN recommended no clinical practice but further research [35]. Guidelines are in favor of HBPM besides 24 h-ABPM compared to OBP measurements in the management of hypertension. Both methods have proved to overcome the limitations of OBP measurements [3,36-38]. Consequently, the ESH and ESC guidelines recommend HBPM and ABPM besides OBP measurements [3,20-22]. Although a great number of reported trials, e.g. Symplicity HTN 1 and 2 trials, as well as various other trials, proved a significant RDN-induced reduction of OBPs [32,39] only a very limited number of trials are based on out of office measurements with ABPM. The recently published Symplicity HTN-3 showed no significant reduction of ABPM [17-18] in contrast to the data of Lambert [13], who demonstrated a reproducible and significant blood pressure reduction in the ABPM despite a great variation of the OBP. Detailed data of HBPM in the follow-up after RDN were up to now lacking. Different studies as well as meta-analyses had shown that HBPM could predict cardiovascular morbidity and mortality more precisely than OBP measurements.

Statistical analysis of the OBP as well as of the HBPM during follow-up. Data are expressed as mean ± SD.

SBP of therapy group SBP of control group p-Value TG vs. CG DBP of therapy group DBP of control group p-Value TG vs. CG

p-Value FU vs. baseline p-Value FU vs. baseline p-value FU vs. Baseline p-Value FU vs.


Office Baseline

1 month follow-up 3 months follow-up 6 months follow-up

Out of office/HBPM One week before RDN Week of RDN One week after RDN Two weeks after RDN Four weeks after RDN 13 weeks after RDN 26 weeks after RDN

168.8 ±3.3 163.3 ± 3.6 92.8 ± 2.5 92.5 ± 4.6 p > 0.05

156.5 ±4.5 p < 0.05 166.5 ± 12.4 p > 0.05 88.5 ± 2.5 p = 0.053 88.4 ±3.7 p> 0.05 p > 0.05

149.0 ±4.6 p < 0.01 164.8 ± 9.8 p > 0.05 84.7 ±3.1 p < 0.05 91.6 ± 4.4 p> 0.05 p > 0.05

150.6 ±4.2 p < 0.01 159.4 ± 6.0 p > 0.05 84.9 ± 2.4 p < 0.05 90.9 ± 4.8 p> 0.05 p > 0.05

156.2 ±3.0 161.2 ± 6.8 p > 0.05 p > 0.05 92.1 ± 2.4 p < 0.01 90.5 ± 7.0 p > 0.05

144.5 ± 4.0 86.7 ± 2.7

144.0 ± 3.6 p < 0.01 85.8 ± 2.5 p < 0.01

144.4 ± 3.2 p < 0.01 85.5 ± 2.2 p < 0.01

146.2 ± 3.3 p < 0.01 167.1 ± 7.1 p > 0.05 p < 0.05 86.8 ± 2.6 p < 0.01 92.9 ± 7.1 p > 0.05

141.5 ± 3.6 p < 0.01 168.3 ± 10.0 p > 0.05 p < 0.05 83.8 ± 2.6 p < 0.01 93.7 ± 9.2 p > 0.05

139.7 ± 3.2 p < 0.01 155.8 ± 11.0 p > 0.05 p > 0.05 82.1 ± 2.9 p < 0.01 90.0 ± 6.9 p > 0.05

Fig. 2. RDN improves OBP (Omron™ device). Effects of RDN on office systolic blood pressure (SBP, A) and on office diastolic blood pressure (DBP, B). Measurements were performed with an Omron™ device with the patient in sitting position. Asterisks indicate significant reduction of blood pressure values as compared to baseline. Data are expressed as mean ± sem.

Fig. 3. RDN improves HBPM. Effects of RDN on out of office systolic blood pressure (SBP, A) and on out of office diastolic blood pressure (DBP, B). Measurements were performed with patients' device in a sitting position. Asterisks indicate significant reduction of blood pressure values as compared to baseline. Data are expressed as mean ± sem.

Our current findings are in line with previous reports [13,40] that (a) RDN improves peripheral OBP and (b) out of office measurements like 24-h ABPM [40]. In addition we describe for the first time that 1. RDN has favorable effects on HBPM also compared to a CG and 2. significant blood pressure effects of RDN commence already one week after index ablation. During follow-up it seemed that there was a trend to an increase of the systolic blood pressure after six months. These findings are in line with the latest publication of the working group of Booth with the postulation of a reinnervation which led to an increase of the systolic blood pressure over the time [41]. Therefore a long-term analysis of HBPM based on blood pressure logbooks is urgently needed.

4.1. Limitations

Limitations of our study were (a) the relatively small number of patients, (b) the short follow-up period of 6 months and (c) a missing shame ablation. Especially the missing shame ablation might be of importance, since some criticism may occur that the described blood pressure effects are based on a potential better compliance of included patients. The data of the control group showed no decline in systolic blood pressure and even these patients had higher systolic blood pressures during follow-up. Further analysis with a longer follow-up time as well as a shame ablation is needed in future studies to investigate the effects on blood pressure after RDN. Furthermore a strict medication surveillance should be implemented in these studies to ensure the patients' compliance.

Conflict of interests


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