Blood Pressure, 2014; 23: 228–232

ORIGINAL ARTICLE

Effect of catheter-based renal sympathetic denervation on 24-h ambulatory blood pressure in patients with resistant hypertension

SEBASTIAN VÖLZ1, BERT ANDERSSON1, KARIN MANHEM2, INGER HARALDSSON1 & BENGT RUNDQVIST1 1Department 2Department

of Cardiology, Sahlgrenska University Hospital, 4 Bruna stråket, 41345 Gothenburg, Sweden, and of Medicine, Sahlgrenska University Hospital, 6 Blå Stråket, 41345 Gothenburg, Sweden

Abstract We investigated the effect of renal denervation on office blood pressure (OBP) and 24-h ambulatory blood pressure (BP) measurement (ABPM) at baseline and 6 months after intervention in 25 consecutive patients with resistant hypertension. Mean baseline 24-h ABPM and OBP were 158/88 mmHg and 169/96 mmHg, respectively. Patients were treated with an average of 4 ⫾ 1 antihypertensive drugs. Among the 22 patients included in data analysis, mean ambulatory systolic and diastolic BP were reduced by 6 mmHg from 158 ⫾ 17 to 152 ⫾ 20 mmHg (p ⬍ 0.05) and by 3 mmHg from 88 ⫾ 12 to 85 ⫾ 14 mmHg (p ⫽ ns) after 6 months follow-up, respectively. Blood pressure reduction was most pronounced during daytime with a decrease of 9 mmHg from 164 ⫾ 17 to 155 ⫾ 19 (p ⬍ 0.05) in systolic (SBP) and 6 mmHg from 94 ⫾ 14 to 88 ⫾ 14 mmHg in diastolic BP (DBP) (p ⬍ 0.05). Night-time SBP mmHg and DBP were similar at baseline compared with follow-up. Systolic and diastolic OBP during follow-up were significantly reduced by 17 mmHg from 169 ⫾ 20 to 152 ⫾ 21 (p ⬍ 0.05) and by 9 mmHg from 96 ⫾ 16 to 87 ⫾ 13 mmHg (p ⬍ 0.05), respectively. These results provide new insight into the effect of renal denervation on ABPM day- and night-time blood pressure profile in comparison with OBP. The decrease in ABPM was identified during daytime registration and was less pronounced compared with reduction of OBP. Key Words: 24-h ambulatory blood pressure, renal sympathetic denervation, resistant hypertension

Introduction Arterial hypertension remains a major global health challenge and is the leading risk factor for cardiovascular mortality (1). Despite a variety of available antihypertensive pharmacological agents, a significant number of patients with hypertension do not reach target blood pressure (BP) level. In a recent report, the prevalence of drug resistant hypertension was 3–9% in a large cohort of patients with primary arterial hypertension (2). The kidneys and renal sympathetic nerve activity are crucial in the etiology of arterial hypertension. Animal studies have demonstrated that renal sympathetic denervation reduces BP in various models of hypertension (3). Subsequently performed human studies showed increased renal sympathetic nerve activity in patients with primary hypertension (4). Recently a catheter-based

endovascular method has been developed to selectively decrease renal sympathetic nerve activity (5). This technique is based on radiofrequency ablation of sympathetic nerve fibers located within the renal arteries’ vessel wall. The first randomized controlled study showed a marked decrease in office BP (OBP) in patients with drug-resistant hypertension 6 months after catheter ablation of the renal nerves (6). However, OBP has several limitations and thus 24-h ambulatory BP measurement (24-h ABPM) has become an essential part in the diagnostic work up and treatment follow-up in resistant hypertension (7). Importantly, 24-h ABPM identifies pseudoresistant hypertension and has also been shown to add prognostic information independent of OBP (8). In spite of this, data on the effect of renal denervation on 24-h ABPM is scarce. The aim of this study was

Correspondence: Sebastian Völz, Department of Cardiology, Sahlgrenska University Hospital, Institute of Medicine, and Department of Molecular and Clinical Medicine, Sahlgrenska Academy at University of Gothenburg, 4 Bruna straket, 41345 Gothenburg, Sweden. Tel: ⫹ 46-(0)31-34200. E-mail: sebastian.volz@ vgregion.se (Received 12 April 2013 ; accepted 17 October 2013) ISSN 0803-7051 print/ISSN 1651-1999 online © 2014 Scandinavian Foundation for Cardiovascular Research DOI: 10.3109/08037051.2013.867663

Effect of renal sympathetic denervation on 24-h ABPM to examine the effect of renal denervation on 24-h ABPM at 6 months after renal denervation in 25 consecutive patients with true resistant hypertension at our center.

Materials and methods The study population comprised 25 consecutive patients with drug-resistant hypertension (n ⫽ 25) who underwent renal denervation during the period April 2011–June 2012 at Sahlgrenska University Hospital, Gothenburg, Sweden. The patients were recruited from a population of 60 individuals with suspected treatment resistant hypertension who were referred to our institution. Renal denervation was performed in 38/60 patients and the study population consisted of 25 individuals who completed follow-up 24-h ABPM. Patients were referred from the Department of Internal Medicine (Hypertension Unit), Sahlgrenska University Hospital, general practitioners, the Department of Cardiology, Sahlgrenska University Hospital and other hospitals in the region. Inclusion criteria were OBP ⱖ 140/90 mmHg in the sitting position and mean daytime ABPM ⬎ 135/ 85 mmHg during treatment with three or more antihypertensive drugs. All patients underwent a thorough investigation of possible secondary causes of hypertension before being accepted for renal denervation. Exclusion criteria were secondary forms of hypertension, hemodynamically significant valve disease, significant renal dysfunction (eGFR ⬍ 45 ml/min/ 1.73 m2), lack of drug-compliance, diabetes mellitus type 1 and previously being subject to renal artery or abdominal aortic stenting. Details of renal denervation have been described in previous publications (5,6). Via femoral artery access, a guiding catheter was introduced into the renal artery and a selective angiography was performed. The ablation catheter (Simplicity©, Medtronic, Mountain View, USA) was then introduced and 4-6 RF-ablations were delivered bilaterally in all patients. Due to the painful nature of the procedure, patients were sedated using shortacting morphine derivates. During renal denervation, heparin was administered intravenously with a target active clotting time of (ACT) ⬎ 250 s. A follow-up 24-h ABPM was performed 6 months after renal denervation. After a 3-month clinical follow-up at our center, patients were referred back to the referring physician for subsequent follow-up including the 24-h ABPM. All patients were advised to continue and not to change their antihypertensive medication. However, changes in treatment were up to the discretion of the referring physician. Since patients were referred from different institutions, a variety of validated automated BP monitoring devices were used including ABPM 6100© (Welch Allyn, Skaneateles Falls, NY, USA) (n ⫽ 10), Space Labs Ultralite 1434© (Spacelabs Healthcare, Issaquah,

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WA) (n ⫽ 6), Spirare© (Diagnostica AS, Oslo, Norway) (n ⫽ 3), Sun Tech Oscar 2™(Sun Tech Medical, Inc., Morrisville, NC, USA) (n ⫽ 2) and Schiller MT-300© (Schiller AG, Baar, Switzerland) (n ⫽ 1). Only ABPM measurements meeting the quality requirements stated in the NICE (National Institute for Health and Clinical Excellence, London, UK) hypertension guideline of 2011 (7) were included. After having completed 24-h follow-up ABPM, all patients were contacted by a research nurse and interviewed about changes in BP medication after renal denervation. OBP was measured in accordance with NICE-guidelines and documented at 3- and 6-month follow-up. In order to assess the problem with regression towards the mean, we also compared OBP values 3–9 months prior to renal denervation with baseline OBP at entry. Thus subjects who underwent renal denervation included in this study also served as their own control. The study was approved by the ethics committee at the University of Gothenburg and all patients gave their informed consent. Reference group The reference group comprised 22 consecutive patients with conservatively treated resistant hypertension attending the outpatient hypertension unit at Sahlgrenska University Hospital, Gothenburg during the period June 2010–December 2012. During this period, we documented index OBP and one consecutive BP measurement during a follow-up period of 3–9 months. Baseline patient characteristics are described in Table I. Included individuals fulfilled criteria for resistant hypertension as previously described in this study. OBP was measured in accordance with NICE guidelines. All patients had undergone a thorough investigation of possible secondary causes of hypertension. Included patients were not considered for renal denervation by their treating physician, not interested in interventional antihypertensive therapy or under investigation and waiting to be treated with renal denervation. Statistical analysis Results are expressed as means ⫾ SD or means and 95% confidence intervals. The Student t-test was used for paired and unpaired comparisons and a p-value ⬍ 0.05 was considered as statistically significant.

Results Renal denervation was successfully completed in all 25 patients. The mean number of ablations was 6 ⫾ 2 in the right and 6 ⫾ 1 in the left renal artery. Mean procedure time was 98 ⫾ 21 min. Due to insufficient amount of valid measurements (n ⫽ 1) and chronic

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S. Völz et al. Table I. Patient characteristics.

Age (years) Sex (female) BMI Patient history Ischemic heart disease Diabetes mellitus type II Sleep apnea syndrome History of stroke Time since hypertension diagnosis (years) Baseline systolic OBP (mmHg) Baseline diastolic OBP (mmHg) Number of antihypertensive drugs Drug classes ACE inhibitor Angiotensin II receptor inhibitor Beta-blocker Calcium channel blocker Diuretic Other eGFRb (ml/min/1.73 m2) LVEF (%)

RDN group (n ⫽ 22)

Control group (n ⫽ 22)

61 ⫾ 10a 12 (54%) 30 ⫾ 5

63 ⫾ 9 7 (32%) 29 ⫾ 5

4 (18%) 5 (23%) 6 (27%) 2 (9%) 16 ⫾ 11 169 ⫾ 20 96 ⫾ 16 4⫾1

5 (22%) 6 (27%) 4 (18%) 4 (18%) 10 ⫾ 7 161 ⫾ 15 87 ⫾ 12 4⫾1

10 (45%) 16 (73%) 20 (91%) 16 (73%) 13 (59%) 8 (36%) 98 ⫾ 34 60 ⫾ 8

9 (41%) 15 (68%) 13 (59%) 17 (77%) 21 (95%) 10 (45%) 95 ⫾ 32 55 ⫾ 9 (n ⫽ 12)

aMean⫾ standard deviation. bEstimated GFR according to Cockcroft–Gault. RDN, renal denervation; BMI, body mass index; OBP, office blood pressure; ACE, angiotensin-converting enzyme; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction.

atrial fibrillation (n ⫽ 2), three patients were excluded from data analysis. Patient base line-characteristics are shown in Table I. Among the remaining 22 patients included in the study, two patients did not have valid night-time values and therefore only daytime BP was analyzed and presented. Follow-up 24-h ABPM was conducted 6.7 ⫾ 1.6 months after renal denervation. At the time of 24-h ABPM follow-up, eight patients had reduced their antihypertensive medication by one antihypertensive agent, one patient had increased antihypertensive medication and in one patient continuous positive airway pressure (CPAP) therapy was initiated due to new-diagnosed sleep-apnea syndrome. Mean ABPM systolic and diastolic BP were reduced by 6 mmHg from 158 ⫾ 17 to 152 ⫾ 20 mmHg (p ⬍ 0.05) and 3 mmHg from 88 ⫾ 12 to 85 ⫾ 14 mmHg (p ⫽ ns), respectively (Figure 1). The daytime SBP mean 20

SBP DBP

mm Hg

10 0 –10

* –20 24 hour

* * Day

* Night

*

Office

Figure 1. Illustrates mean changes in systolic and diastolic blood pressure at 6-month follow-up. Error bars represent 95% confidence interval. *p ⬍ 0.05.

decrease was 9 mmHg, from 164 ⫾ 17 to 155 ⫾ 19 in systolic BP (SBP) (p ⬍ 0.05) and daytime diastolic BP (DBP) was reduced from 94 ⫾ 14 to 88 ⫾ 14 mmHg (p ⬍ 0.05) (Figure 1). Night-time SBP mmHg and DBP were similar at baseline compared with follow-up, 142 ⫾ 21 vs 142 ⫾ 19 and 76 ⫾ 12 vs 77 ⫾ 13 mmHg. Eleven of twenty-two patients showed a mean reduction of at least 5 mmHg in 24-h mean ambulatory SBP. Systolic and diastolic office OBP at follow-up was reduced by 17 mmHg from 169 ⫾ 20 to 152 ⫾ 21 mmHg (p ⬍ 0.05) and 9 mmHg from 96 ⫾ 16 to 87 ⫾ 13 mmHg (p ⬍ 0.05), respectively. Ten of 22 patients showed a systolic OBP reduction of at least 10 mmHg. The correlation between 24-h ABPM SBP and office SBP was weak (r ⫽ 0.4), at baseline and during follow-up (r ⫽ 0.5). Diastolic OBP showed a moderate correlation with 24-h ambulatory DBP both at baseline and at 6 months (r ⫽ 0.7). No serious adverse events were noted during follow-up or during the procedure. No changes in renal function were detected. Follow-up OBP measurements in the conservatively managed group of patients (reference group) were conducted at 6 ⫾ 2 months. SBP and DBP were similar at baseline compared with follow-up, 161 ⫾ 15 vs 161 ⫾ 16 mmHg (p ⫽ ns) and 87 ⫾ 12 vs 89 ⫾ 13 mmHg (p ⫽ ns). In 9/22 patients, antihypertensive treatment had been increased during the follow-up period. OBP profiles in the renal denervation group were documented 5 ⫾ 2 months prior to intervention (n ⫽ 20) and were similar compared with pre-procedure OBP baseline values (SBP 167 ⫾ 24 vs 169 ⫾ 20

Effect of renal sympathetic denervation on 24-h ABPM (p ⫽ ns); DBP 96 ⫾ 16 vs 94 ⫾ 13 mmHg (p ⫽ ns)). Decreases in OBP regarding both SBP and DBP at follow-up in the intervention group differed significantly compared with changes from first to second time of BP measurement in the reference group (p ⬍ 0.05). Patient selection work-up process prior to renal denervation revealed that 22/60 patients were not eligible for intervention due to the following reasons: 13 patients presented with normal 24-h ABPM, five patients chose not to undergo interventional BP treatment, two patients proved to have a secondary form of hypertension and the remaining two patients did not undergo renal denervation due to unspecified reasons.

Discussion In the present study, we report a significant decrease in 24-h ABPM as well as OBP following renal denervation. In spite of reduced antihypertensive medication in a third of the patients, the mean systolic 24-h ABPM and OBP was significantly reduced after renal denervation at 6-month follow-up. In addition, the reduction in 24-h ABPM differed between dayand night-time measurements. The decrease in 24-h ABPM was evident during daytime, but not nighttime, with a significant reduction of both SBP and DBP. This finding is consistent with the circadian pattern of sympathetic nerve firing, which is more intense during wakening compared with sleep, supporting the concept that renal denervation affects central sympathetic outflow mediated by renal afferent nerve activity (9). In a recent report, muscle sympathetic nerve activity was shown to decrease after renal denervation indicating that renal denervation alters central processing of sympathetic outflow to the cardiovascular system (10). In order to understand the therapeutic potential of renal denervation it is important to measure and verify its effect on 24-h ABPM. ABPM improves BP management by providing a considerable quantity of both day- and night-time measurements, the latter being of superior prognostic value (11). Furthermore, white coat hypertension (12) can be revealed and prognostically relevant parameters such as BP variability and early morning surge can be recorded. Several lines of evidence support that 24-h ABPM correlates closely to the development of end-organ damage (13) and to the risk of cardiovascular events (11). Previous small studies have documented a positive impact of renal denervation on 24-h ABPM. Consistent with our results, a significant decrease of the mean 24-h ABPM at 6 months after renal denervation was observed in a subgroup of the patients in the Simplicity-HTN-2 trial. Yet, no further details on 24-h ABPM day and night pattern, or patient characteristics were specified in this patient population (6). The findings in the present study are also consistent

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with the results in a recent report by Kaltenbach and coworkers (14) who showed a significant reduction of mean 24-h ABPM after renal denervation in 20 patients with milder forms of resistant hypertension. However, in their study, the day- and night-time results were not presented separately. In another small patient series, a significant decrease in 24-h BP variability and a non-significant trend towards BP reduction in both mean and daytime 24-h ABPM was noted 6 months after renal denervation (15). Similar to our results, there was little effect on BP during sleeping hours. In contrast, Hering et al. (16) showed a significant reduction of night-time ABPM in patients with chronic kidney disease and resistant hypertension following renal denervation. However, renal function was preserved in our study population, which together with other differences in patient characteristics makes comparison difficult. In the presented patient population reduction of OBP was more pronounced compared with the observed decrease in mean 24-h ABPM, a finding that is consistent with previous pharmacological studies (17,18). Furthermore, in our study, we found only weak to modest correlations between 24-h ABPM and resting OBP, which underscores that the two methods reflect different aspects of the disease, and with regard to the yet not fully comprehended effects of renal denervation on day- and night BP, clinicians should consider the use of 24-h ABPM in order to evaluate and tailor therapy. In our patient population, we observed patient cases showing reduction in 24-h ABPM without any response in OBP and vice versa. This discrepancy is consistent with previous research in large cohorts of hypertensives (17). In our patient series, the proportion of responders to renal denervation was approximately 50% and similar for both OBP and 24-h ABPM applying the criteria proposed in the HTN-2 study. This is lower than in the Symplicity HTN-2 trial. There is no valid explanation for this inconsistency but we speculate that in a real life clinical setting like our study, results may be effected by changes in medication made by the patient or his physician during follow-up. Furthermore, patient characteristics may have differed since 24-h ABPM was not mandatory at baseline in the Symplicity HTN-2 trial. At our center, 24-h ABPM is used as standard procedure in order to preoperatively exclude patients with pseudoresistant hypertension. The lack of data on the responder rate to renal denervation in clinical practice emphasizes the need for larger registry studies. Study limitations The reduction of antihypertensive medication in eight of 22 patients probably influenced 24-h ABPM results. Previous studies have documented a reduction in BP medication in 20% of all treated patients (6,14). Due to the non-randomized design of this

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study, a possible placebo effect after intervention, however, cannot be entirely ruled out. However, intraindividual comparison of BP profiles 5 ⫾ 2 months prior to and at entry showed no significant changes in OBP suggesting a stable degree of drugcompliance during follow-up period and confirm the severity of disease in the intervention group. Data were obtained in a clinical setting implying certain limitations: 24-h ABPM could not be provided for the reference group. Furthermore, the sample size of our study was relatively small and drug compliance was not monitored in a structured manner. It is well known that drug adherence in arterial hypertension is generally low (19). In line with this, it is emphazised by Savard et al. and coworkers (20) that referrals for resistant hypertension must be carefully selected prior to renal denervation to identify patients with true resistant hypertension. Finally, a limitation of the study is the use of different ABPM devices in nine of 22 patients at baseline and follow-up. However all devices were well established and validated. In summary, the results in this study demonstrate that renal denervation had a significant impact on mean and daytime 24-h ABPM in patients with true resistant hypertension. However, BP changes in 24-h ABPM were not as pronounced as in OBP and responder rate was lower than in previous clinical trials, stressing the need for further randomized controlled studies to assess the method’s clinical significance and its future capacity in preventing cardiovascular morbidity and mortality. Furthermore, our findings underline the importance of a well-structured eligibility work-up program for appropriate patient selection. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References 1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, AdairRohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2224–2260. 2. Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension. 2011;57:1076–1080. 3. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997;77:75–197. 4. Esler M, Lambert G, Jennings G. Increased regional sympathetic nervous activity in human hypertension: Causes and consequences. J Hypertens Suppl. 1990;8:S53–S57. 5. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation

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