Skip main navigation
×

First Report of the Global SYMPLICITY Registry on the Effect of Renal Artery Denervation in Patients With Uncontrolled Hypertension

and on behalf of the GSR Investigators
Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.114.05010Hypertension. 2015;65:766–774

Abstract

This study aimed to assess the safety and effectiveness of renal denervation using the Symplicity system in real-world patients with uncontrolled hypertension (NCT01534299). The Global SYMPLICITY Registry is a prospective, open-label, multicenter registry. Office and 24-hour ambulatory blood pressures (BPs) were measured. Change from baseline to 6 months was analyzed for all patients and for subgroups based on baseline office systolic BP, diabetic status, and renal function; a cohort with severe hypertension (office systolic pressure, ≥160 mm Hg; 24-hour systolic pressure, ≥135 mm Hg; and ≥3 antihypertensive medication classes) was also included. The analysis included protocol-defined safety events. Six-month outcomes for 998 patients, including 323 in the severe hypertension cohort, are reported. Mean baseline office systolic BP was 163.5±24.0 mm Hg for all patients and 179.3±16.5 mm Hg for the severe cohort; the corresponding baseline 24-hour mean systolic BPs were 151.5±17.0 and 159.0±15.6 mm Hg. At 6 months, the changes in office and 24-hour systolic BPs were −11.6±25.3 and −6.6±18.0 mm Hg for all patients (P<0.001 for both) and −20.3±22.8 and −8.9±16.9 mm Hg for those with severe hypertension (P<0.001 for both). Renal denervation was associated with low rates of adverse events. After the procedure through 6 months, there was 1 new renal artery stenosis >70% and 5 cases of hospitalization for a hypertensive emergency. In clinical practice, renal denervation resulted in significant reductions in office and 24-hour BPs with a favorable safety profile. Greater BP-lowering effects occurred in patients with higher baseline pressures.

Clinical Trial Registration—

URL: www.clinicaltrials.gov. Unique identifier: NCT01534299

Introduction

Despite intensive medical treatment, hypertension often remains uncontrolled in general practice, accounting for 40% of deaths from ischemic heart disease and 51% of all stroke deaths worldwide.1,2 Sympathetic nerve activation plays an important role in the development and maintenance of hypertension and may contribute to treatment resistance and cardiovascular end-organ damage.35 Percutaneous catheter-based renal denervation (RDN) represents a treatment option for hypertension6 and has been shown to significantly reduce blood pressure (BP) in patients with resistant hypertension in the SYMPLICITY HTN-1 study7 and the SYMPLICITY HTN-2 randomized controlled trial.8 Follow-up of patients in these studies demonstrated sustained antihypertensive effects >36 months in patients with severe, treatment-resistant hypertension.9,10 In contrast, the SYMPLICITY HTN-3 trial randomized 535 patients to RDN or a sham control procedure and applied strict control criteria for blinding.11 The primary efficacy end point of this trial (defined as a superiority margin of 5 mm Hg for the difference in office systolic BP [SBP] change from baseline to 6 months in the RDN group as compared with the sham control group) was not achieved, whereas the primary safety end point was met. However, the results of this trial are inconsistent with clinical and preclinical experience, indicating the need to more clearly understand the reasons for these disparate observations.9,12,13 Further data are also needed to confirm the reported favorable effects of RDN on organ damage and other conditions often associated with hypertension (left ventricular hypertrophy,14,15 increased urinary albumin excretion,16,17 and atrial fibrillation18) in which sympathetic hyperactivity may play a role in addition to and independently of the BP increase.5

Because RDN is an interventional procedure that may expose patients to some risks and could increase costs, large databases on safety and efficacy in clinical practice settings, without the strict inclusion and exclusion criteria and site selection used in clinical trials, are needed. The Global SYMPLICITY registry (GSR)19 will provide data on periprocedural and renal safety as well as the effectiveness of BP reduction in such a real-world population of patients undergoing RDN. Herein, the GSR investigators report on the 6-month follow-up of the largest group of hypertensive patients to undergo RDN in an uncontrolled global clinical setting.

Methods

Design

This analysis is based on 998 patients with complete safety and office BP data at baseline and 6 months of follow-up, who underwent RDN from February 1, 2012, to September 9, 2013. One-hundred thirty-four centers in Canada, Western Europe, Latin America, Eastern Europe, South Africa, Middle East, Asia, Australia, and New Zealand were involved (see online-only Data Supplement).

The study design of the prospective, open-label, multicenter GSR has been published previously.19 In brief, the registry will include ≤5000 patients with hypertension (and some with other conditions associated with sympathetic nervous system activation) undergoing RDN in a real-world setting with the recommendation for follow-up to 5 years. GSR will document current clinical practice with this new technology in participating countries. The only inclusion criteria are age ≥18 years and eligibility for RDN as defined by local regulations for use of the Symplicity RDN system (Medtronic, Inc, Santa Rosa, CA). National regulatory authorities and ethics committees of the participating centers approved the registry. Patients or their legally authorized representatives provided written informed consent. The GSR is registered at ClinicalTrials.gov (NCT01534299).

RDN Treatment and Follow-Up Assessments

RDN procedures were performed with the Symplicity RDN system at the discretion of the treating physician, and patients were recommended to be followed according to the usual care standards of the respective hospitals. Instructions on when to use the Symplicity RDN system were not specified in the registry protocol. Procedural data were recorded in electronic case report forms. Before treatment and at every follow-up visit, investigators confirmed hypertension medication intake by direct questioning and documented any medication changes. The GSR recommended that 3 BP measurements be taken according to standard practice at each office visit and 24-hour ambulatory BP be measured in compliance with published guidelines.20 Before the RDN procedure, the most recently available office and ambulatory BP measurements were taken as baseline BP values and reported in the case report forms. Angiography, MRI, computed tomography, or duplex ultrasounds were recommended for all patients to detect renal artery abnormalities and to determine anatomic eligibility before the denervation procedure was performed. There was no mandatory renal artery imaging follow-up.

Safety Monitoring and Adjudication of Events

An independent clinical events committee (Cardiovascular Research Foundation, New York, NY) adjudicated all protocol-defined safety events potentially related to RDN. In particular, periprocedural complications including vascular complications, such as hematomas, bleeding, pseudoaneurysms, renal artery perforations, or dissections, renal artery reintervention, renal artery–related postindex procedures, new renal artery stenosis >70% within 6 months after procedure, contrast nephropathy (acute glomerular filtration rate [GFR] loss >25%) or new renal failure, need for dialysis, and new onset end-stage renal disease were adjudicated. GFR was estimated according to the modified diet in renal disease formula.21 Forty percent of the data were monitored to ensure the quality of the data.

Statistical Analysis

All data were entered into an electronic data capture form using the Oracle clinical database management system (Oracle, Redwood City, CA). An independent contract research organization (Institut für Herzinfarktforschung, Ludwigshafen, Germany) was responsible for data analysis. All analyses were performed according to the intention-to-treat principle. Patients were stratified according to baseline office SBP (<140, 140–159, and ≥160 mm Hg) for these analyses. To more directly compare the GSR data with those reported in other trials, patients with an office SBP ≥160 mm Hg plus 24-hour mean SBP ≥135 mm Hg while taking ≥3 antihypertensive medications were identified and analyzed as a severe hypertension cohort. Office and ambulatory BP change in patients with and without diabetes mellitus and according to baseline estimated GFR (eGFR) was analyzed to assess the effect of these parameters on RDN outcomes. For between-group comparisons, the Kruskal–Wallis test was used for continuous variables, and the χ2 test was used for categorical variables. Changes between baseline and follow-up BP measurements were analyzed using paired t tests. Changes among baseline and 3- and 6-month follow-up medications were analyzed using the Friedman test. All analyses were done using the SAS statistical package (version 9.3). Data are shown as mean±SD or 95% confidence interval.

Results

Patient Population

Safety and office BP data were available for 998 patients at baseline and 6 months of follow-up. Patients had a high proportion of comorbidities, including diabetes mellitus (41.4%), chronic kidney disease (22.3%), and heart failure (10.7%). Table 1 summarizes baseline characteristics of all enrolled patients and subgroups based on diabetes mellitus or renal function status. Overall, mean age was ≈61 years, and 60% of the patients were men. A small proportion of patients had a baseline office SBP <140 mm Hg (n=146; 14.6%), whereas 574 (57.5%) patients had a SBP ≥160 mm Hg. The severe hypertension cohort comprised 323 of these patients who also had an ambulatory SBP ≥135 mm Hg and ≥3 antihypertensive drugs prescribed. Baseline characteristics of this population, as well as the diabetic and renal function subgroups within this severe hypertension cohort are displayed in Table S1 in the online-only Data Supplement.

Table 1. Baseline Characteristics for All Patients and All Patient Subgroups According to Diabetes Mellitus or Renal Function Status

Baseline CharacteristicAll Patients (n=998)With DM (n=413)Without DM (n=584)P ValueDM vs No DMeGFR <30 (n=22)eGFR 30–59 (n=207)eGFR ≥60 (n=715)P Value Across eGFR Subgroups
Sex male59.9%62.2%58.4%0.2240.9%56.5%61.4%0.08
Age, y61.0±11.963.8±10.359.0±12.5<0.000156.2±16.965.2±10.759.8±11.6<0.0001
BMI, kg/m230.6±5.531.7±5.529.8±5.4<0.000127.6±5.230.8±5.330.8±5.5<0.05
Current smoking10.0%8.0%9.6%0.389.1%9.7%9.0%0.95
Heart rate69.3±13.169.1±12.769.4±13.20.9768.9±17.066.7±12.369.9±12.9<0.01
History of cardiac disease50.1% (495/989)60.5% (248/410)42.7% (247/579)<0.000150.0% (11/22)59.6% (121/203)48.6% (346/712)<0.05
Sleep apnea (AHI≥5)4.9% (46/931)5.3% (20/378)4.7% (26/553)0.684.8% (1/21)3.1% (6/194)5.7% (38/666)0.35
Diabetes mellitus41.4% (413/997)100.0%0.0%36.4%53.6%38.7%<0.001
 Type 13.1% (31/997)7.5% (31/413)0.0%9.1% (2/22)7.2% (15/207)1.8% (13/714)<0.001
 Type 238.2% (381/997)92.3% (381/413)0.0%27.3% (6/22)46.4% (96/207)36.7% (262/714)<0.05
History of chronic kidney disease22.3% (222/995)28.6% (118/412)17.9% (104/582)<0.000190.9% (20/22)76.2% (157/206)5.3% (38/714)<0.0001
Atrial fibrillation12.8% (127/995)12.4% (51/410)13.0% (76/584)0.799.1% (2/22)16.5% (34/206)11.6% (83/713)0.16
Heart failure10.7% (106/989)16.1% (66/410)6.9% (40/579)<0.000122.7% (5/22)12.3% (25/203)10.4% (74/712)0.16
Left ventricular hypertrophy17.1% (169/989)16.3% (67/410)17.6% (102/579)0.6027.3% (6/22)19.2% (39/203)16.7% (119/712)0.34
Comorbidities
 137.7% (376/998)0.0% (0/413)64.2% (375/584)<0.00019.1% (2/22)7.2% (15/207)46.3% (331/715)<0.0001
 238.2% (381/998)51.6% (213/413)28.8% (168/584)<0.000136.4% (8/22)41.1% (85/207)37.9% (271/715)0.70
 3+24.0% (240/998)48.4% (200/413)6.8% (40/584)<0.000154.5% (12/22)51.7% (107/207)15.7% (112/715)<0.0001
No. of renal arteries2.2±0.52.2±0.52.2±0.50.822.2±0.62.2±0.52.1±0.50.45
Renal artery length, mm42.0±13.543.5±13.140.9±13.8<0.0140.8±18.141.0±12.342.6±13.80.75
Right renal artery diameter, mm5.8±3.25.8±3.85.8±2.80.644.6±1.36.2±6.65.7±1.1<0.01
Left renal artery diameter, mm5.8±3.05.9±3.75.7±2.40.334.7±1.66.1±6.05.7±1.1<0.01
Total no. of ablations13.8±4.113.5±3.814.0±4.30.1011.0±3.913.6±4.113.9±4.1<0.001
Total no. of 120-s ablations11.5±3.411.5±3.311.4±3.40.598.6±3.711.5±3.311.5±3.4<0.01
No. of antihypertensive medication classes4.5±1.34.7±1.24.4±1.3<0.055.2±1.14.8±1.24.4±1.3<0.0001
Medication use by class, %
 β-Blockers76.9%79.6%75.0%0.0981.8%78.6%77.1%0.79
 ACE inhibitor33.8%32.5%34.8%0.4640.9%38.3%33.4%0.35
 Angiotensin receptor blocker67.4%70.9%64.9%<0.0554.5%67.0%67.1%0.47
 Calcium channel blocker79.2%81.6%77.4%0.1181.8%82.0%78.6%0.54
 Diuretic80.1%83.7%77.6%<0.0595.5%86.9%77.2%<0.01
 Aldosterone antagonists22.4%22.3%22.4%0.979.1%23.3%21.5%0.30
  Spironolactone20.1%20.9%19.7%0.649.1%21.8%19.1%0.32
 α-Adrenergic blocker33.0%34.7%31.8%0.3468.2%37.4%31.2%<0.001
 Direct-acting vasodilator14.0%15.0%13.2%0.4140.9%18.0%12.0%<0.001
 Centrally acting sympatholytics39.8%40.8%39.1%0.6045.5%45.1%38.8%0.23
 Direct renin inhibitor6.2%4.1%7.7%<0.050.0%4.4%6.9%0.19

Values are % (n/N) or mean±SD. ACE indicates angiotensin-converting enzyme; AHI, apnea-hypopnea index; BMI, body mass index; DM, diabetes mellitus; and eGFR, estimated glomerular filtration rate.

Of the 146 patients with a baseline office SBP <140 mm Hg, 96 patients had masked hypertension (24-hour SBP ≥130 mm Hg or daytime SBP ≥135 mm Hg), and 48 patients had a documented history of severe hypertension and ≥1 other comorbidity (heart failure, obstructive sleep apnea, diabetes mellitus, chronic kidney disease, or atrial fibrillation) possibly associated with sympathetic overdrive. Two patients who did not have hypertension had heart failure with an ejection fraction <35%. Baseline characteristics of this subgroup were notable for a 31% rate of chronic kidney disease, 9.5% with obstructive sleep apnea, 12.5% with a history of heart failure, and 15.1% with a history of atrial fibrillation.

Patients with diabetes mellitus were older and had more comorbidities (48.4% versus 6.8% with ≥3 comorbidities; P<0.0001) than those without diabetes mellitus. Additional comorbidities included cardiac disease, chronic kidney disease, and heart failure (Table 1). Patients with impaired renal function (n=22; eGFR<30 mL/min per 1.73 m2) were younger, with a lower body mass index. This group also had smaller diameter renal arteries and was taking more antihypertensive medications at baseline (Table 1). The mean number of complete 120-second ablations delivered to all patients was 11.5±3.4.

Effect of RDN on Office and Ambulatory BP

In the group as a whole, baseline office SBP was 163.5±24.0 mm Hg, and baseline 24-hour mean SBP was 151.5±17.0 mm Hg (n=506; Table 2). Office SBP was reduced by 11.6±25.3 mm Hg (95% confidence interval, −13.2 to −10.0; P<0.001) at 6 months after RDN; the corresponding reduction of 24-hour mean SBP was 6.6±18.0 mm Hg (95% confidence interval, −8.2 to −5.1; P<0.001). For both office and 24-hour SBP the 6-month reduction was greater in patients with higher baseline SBP values (Figure 1). There was a significant reduction in 24-hour mean SBP in the patients with baseline office SBP <140 mm Hg, which reflects the high proportion of patients with masked hypertension in this subgroup.

Table 2. Office and Ambulatory Blood Pressure at Baseline and 6 Months After Renal Denervation

BP, mm HgAll PatientsSevere HTN Cohort
Office BPn=998n=323
 Baseline
  SBP163.5±24.0179.3±16.5
  DBP89.0±16.694.7±15.9
 6 mo
  SBP151.9±21.9159.0±21.5
  DBP84.7±15.187.4±15.4
24-h ambulatory BPn=506n=221
 Baseline
  SBP151.5±17.0159.0±15.6
  DBP85.3±13.088.9±13.1
 6 mo
  SBP144.6±17.4150.0±18.0
  DBP81.4±12.984.0±13.0

Values are mean±SD. BP indicates blood pressure; DBP, diastolic BP; HTN, hypertension; and SBP, systolic BP.

Figure 1.

Figure 1. Change from baseline in systolic blood pressure (SBP). The 6-month change in office and 24-hour ambulatory SBP is displayed for all patients and for subgroups according to baseline office SBP. The severe hypertension (HTN) cohort comprises patients taking ≥3 antihypertensive medication classes with an office SBP ≥160 mm Hg and a 24-hour ambulatory SBP ≥135 mm Hg. *P<0.0001, †P=0.009, and ‡P=0.001.

Figure 1 also shows the results obtained in the severe hypertension cohort. Baseline office and 24-hour mean SBP were 179.3±16.5 and 159.0±15.6 mm Hg, respectively. At 6 months after RDN, office SBP was reduced by 20.3±22.8 mm Hg and 24-hour mean SBP by 8.9±16.9 mm Hg. Nearly one fifth (18.6%) of patients in the severe hypertension cohort had an office SBP <140 mm Hg at 6 months after RDN, and 11.8% of patients achieved a24-hour ambulatory SBP <130 mm Hg (Figure 2).

Figure 2.

Figure 2. Distribution of systolic blood pressure (SBP) in the severe hypertension cohort of the Global SYMPLICITY Registry. Based on office SBP, 52.6% of the severe hypertension cohort had an SBP <160 mm Hg at 6 months and 18.6% had a SBP <140 mm Hg at this time point. Based on 24-hour SBP, 53.4% had an SBP <150 mm Hg and 11.8% were <130 mm Hg at 6 months.

Response rates based on a reduction in office SBP of 20, 10, or 5 mm Hg ranged from 50% (>20 mm Hg reduction) to 76% (>5 mm Hg reduction) for the severe hypertension cohort (Figure S1). In this same cohort, response rates based on 24-hour ambulatory SBP changes of 8, 5, and 2 mm Hg ranged from 48% (>8 mm Hg reduction) to 68% (>2 mm Hg reduction; Figure S1).

Office and 24-hour ambulatory SBP changes at 6 months were similar between diabetic and nondiabetic patients (Figure 3). Baseline and 6-month hemoglobin A1c were similar between baseline and 6 months for both diabetic and nondiabetic patients; however, fasting glucose levels were significantly lower at 6 months in both groups (Table S2). In the severe hypertension cohort, the SBP changes were also similar in diabetic and nondiabetic patients. There was also no significant difference between the office and 24-hour ambulatory SBP changes among the 3 renal function subgroups although the office SBP drop in the small group of patients with eGFR <30 mL/min per 1.73 m2 was roughly twice that of the drop in the other 2 eGFR subgroups. Fewer patients had ambulatory BP measurements and in these patients there seemed to be a greater drop in the normal renal function subgroup although this is not statistically significant (Figure 3).

Figure 3.

Figure 3. Change from baseline in systolic blood pressure (SBP) for the diabetic and renal dysfunction subgroups. In the overall population there was no difference between mean office SBP change or 24-hour SBP change in patients with diabetes mellitus compared with patients without diabetes mellitus. The drop in 24-hour SBP was significantly greater in the patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min per 1.73 m2 compared with the patients with an eGFR of 30 to 50 mL/min per 1.73 m2 (P<0.05). All other comparisons were nonsignificant.

Medication Analysis

Patients were prescribed intensive treatment with multiple antihypertensive medications (average 4.5±1.3), with the overall number of antihypertensive medications being slightly greater in the severe HTN cohort (4.7±1.1) although with a similar distribution of drugs prescribed (Table 1). After RDN there was a small, albeit statistically significant, reduction in the number of antihypertensive medications (4.4±1.4; P=0.0009). A similar reduction in antihypertensive medication use also occurred in the subgroup with baseline office SBP <140 mm Hg (4.7±1.2 at baseline, 4.4±1.4 at 6 months; P=0.0005). At baseline, 47% of patients in this group were prescribed centrally acting sympatholytics, which was lower at 6 months (40.4%; P=0.0075). Changes in antihypertensive therapy were primarily related to a reduction in the use of α-adrenergic blockers, centrally acting sympatholytics, β-blockers, angiotensin-converting enzyme inhibitors, and direct renin inhibitors (Table 3). At 6 months of follow-up after RDN, the proportion of all patients who had a decrease in the number of prescribed drugs (19.5%) was greater than the proportion of patients who had an increase in them (15.7%; P=0.025).

Table 3. Medication Use Over Time

Medication ClassBaseline3 mo6 moP Value
No. of antihypertensive medication classes4.5±1.34.5±1.44.4±1.40.001
Drug classes
 β-Blocker76.9%75.0%75.3%0.100
 ACE inhibitor33.8%32.1%31.4%<0.0001
 Angiotensin-receptor blocker67.4%66.8%66.9%0.613
 Calcium channel blocker79.2%78.7%77.6%0.318
 Diuretic80.1%79.0%78.7%0.442
 Aldosterone antagonist22.4%24.4%25.1%0.001
  Spironolactone20.1%21.6%22.2%0.015
 α-Adrenergic blocker33.0%31.5%30.7%0.051
 Direct-acting vasodilator14.0%13.9%13.8%0.978
 Centrally acting sympatholytic39.8%38.0%36.6%<0.0001
 Direct renin inhibitor6.2%6.3%5.1%0.012

Values are % or mean±SD. ACE indicates angiotensin-converting enzyme.

Safety Analysis

The RDN procedure was associated with minimal complications (Table 4). Periprocedurally, there were 2 (0.2%) renal artery reinterventions after dissection, 3 pseudoaneurysms (0.3%), and 1 hematoma (0.1%). After the procedure through 6 months, there was 1 new renal artery stenosis >70% and 5 cases of hospitalization for a hypertensive emergency (Table 4). All events to 6 months occurred at a frequency of <1%.

Table 4. Safety at 1 and 6 Months

All PatientsSevere HTN Cohort
Adverse Event1 mo (n=998)6 mo (n=997)1 mo (n=323)6 mo (n=322)
Major adverse events*0.8% (8)0.9% (3)
Cardiovascular events
 Cardiovascular death0.0% (0)0.0% (0)0.0% (0)0.0% (0)
 Stroke0.2% (2)0.7% (7)0.3% (1)0.6% (2)
 Hospitalization for new-onset heart failure0.1% (1)0.4% (4)0.3% (1)0.9% (3)
 Hospitalization for atrial fibrillation0.2% (2)0.6% (6)0.0% (0)0.6% (2)
 Hospitalization for hypertensive crisis/hypertensive emergency0.0% (0)0.5% (5)0.0% (0)0.6% (2)
 Spontaneous MI0.1% (1)0.7% (7)0.3% (1)0.9% (3)
Renal events
 New-onset end-stage renal disease0.1% (1)0.2% (2)0.0% (0)0.3% (1)
 Serum creatinine elevation >50%0.1% (1)0.3% (3)0.3% (1)0.6% (2)
 New renal artery stenosis >70%0.1 (1)0.0% (0)
Postprocedural events
 Noncardiovascular death0.0% (0)0.0% (0)0.0% (0)0.0% (0)
 Renal artery reintervention0.2% (2)0.2% (2)0.3% (1)0.3% (1)
 Vascular complication0.4% (4)0.4% (3)0.6% (2)0.6% (2)

Values are % (n). HTN indicates hypertension; and MI, myocardial infarction.

*Based on 1-month rates of death, new-onset renal disease, renal artery reintervention, vascular complications, hospitalization for hypertensive crisis/emergency, and new renal artery stenosis at 6 mo.

Renal Function

From baseline to 6 months of follow-up, eGFR and serum creatinine levels remained stable in the normal range (Table S3). Two patients developed end-stage renal disease; 1 case occurred after a suicide attempt (ingestion of insecticide) and the other patient was treated with RDN despite a baseline estimated GFR of 19 mL/min per 1.73 m2. Three patients had a >50% elevation of serum creatinine from baseline: the first is the patient with new end-stage renal disease described above; the second is a patient with no history of renal disease who had an elevated serum creatinine noted the day of the denervation procedure; and the third case occurred in an elderly patient after hospitalization for a hypertensive crisis, syncope, and end-organ damage who died shortly thereafter from her underlying disease. Otherwise, there was no evidence of renal injury related to the denervation procedure.

Discussion

The GSR in a real-world population provides the following major findings. First, RDN was safe with low rates of cardiovascular, renal, and periprocedural complications when used in clinical practice. Second, the procedure was followed by a significant reduction in office SBP at 6 months, which was proportional to the baseline office BP values, that is, the reduction was greater in patients with a higher baseline office SBP. The reduction of ambulatory BP was less pronounced than that of the office SBP but was also related to baseline SBP values. The SBP reduction was accompanied by a significant, albeit small, reduction in antihypertensive medication use.

The purpose of the GSR is to document the safety and effectiveness of RDN to lower BP when RDN procedures are performed at the discretion of hypertension and cardiology centers around the world. The inclusion and exclusion criteria of the GSR were minimal to enable assessment of real-world clinical practice and thus differ from the criteria of previous SYMPLICITY trials. As a result, baseline office SBP was lower in the GSR (164 mm Hg) than in the SYMPLICITY HTN-1 (175 mm Hg)9 and SYMPLICITY HTN-2 (178 mm Hg) trials8; this contributes to the smaller BP reduction that was observed in the GSR (SBP, −12 mm Hg) at 6 months compared with patients in SYMPLICITY HTN-1 (−22 mm Hg)9 and SYMPLICITY HTN-2 (−32 mm Hg).8 This explanation is supported by the finding that in the GSR patients with a baseline office SBP similar to that of SYMPLICITY HTN-1 trial, the SBP reductions that followed RDN were comparable (−20 and −22 mm Hg, respectively). This extends to the office SBP reductions reported in other studies in which RDN was performed in patients with entry office SBP values of the same order of magnitude.2224 There is, however, a clear difference between the smaller office SBP reduction observed with RDN in the SYMPLICITY HTN-3 trial (−14.1 mm Hg for original blinded RDN group) and the larger one seen in patients with similar baseline BP values (severe hypertension cohort) of the GSR (−20.3 mm Hg; Figure 4). After the 6-month primary end point was reached, the patients in SYMPLICITY HTN-3 were unblinded to their treatment assignment and those in the sham control group were allowed to crossover and receive the RDN procedure if they still met the eligibility requirements. The effect of RDN in this unblinded crossover group (−17.1 mm Hg at 6 months) is similar to the BP reduction in the original blinded RDN group (Figure 4). Differences in the extent to which antihypertensive drug treatment was modified after RDN may be a possible reason for these discordant results, although medication changes were only moderately less frequent in the GSR compared with the SYMPLICITY HTN-3 trial (34% versus 39%). The possibility also exists that post-RDN adherence to drug treatment was different in SYMPLICITY HTN-3, although unfortunately no objective measure of this factor is available. Finally, differences in operative experience and performance may have played a role, whereas 59% of the GSR operators had performed >15 RDN procedures (Figure 5) even before the GSR started, 50% of those involved in the SYMPLICITY HTN-3 trial performed ≤2 RDN procedures during the study. The procedural experience was different in the 2 studies as, for example, the average number of complete 120 second ablations was 9.2 in SYMPLICITY HTN-3 but 13.7 in the severe hypertension cohort of GSR. Because there was no difference in BP drop between blinded and unblinded interventions in SYMPLICITY HTN-3, the difference between results in the GSR and SYMPLICITY HTN-3 may be related to differences in treatment intensity. A recently published analysis of factors that may account for the unexpected results of SYMPLICITY HTN-3 highlights the importance of delivering an adequate number of renal nerve ablations in a four-quadrant or helical pattern.25 There was a trend for greater SBP reduction with increasing numbers of ablation attempts with a significantly greater drop in RDN versus matched sham patients when patients received ≥14 ablations. Furthermore, SBP reduction correlated with RDN treatment in a four-quadrant pattern (1 superior, 1 inferior, and 2 anterior/posterior); the proportion of patients receiving this pattern of ablations in both renal arteries was small (n=19), yet their office SBP fell by 24.3 mm Hg. Nevertheless, the possibility that regression to the mean, a statistical observation that large or small measurements in repeated data tend to be followed by measures closer to the mean,26 may account for some of the BP change observed in these trials cannot be ruled out.27

Figure 4.

Figure 4. Change in office and 24-hour ambulatory systolic blood pressure (SBP) at 6 months for the severe hypertension (HTN) cohort in Global SYMPLICITY registry (GSR) and SYMPLICITY HTN-3 patients treated under blinded (original renal denervation [RDN] group) and unblinded (crossover RDN group) conditions. The mean±SD number of antihypertensive medications used at baseline is shown below the bars.

Figure 5.

Figure 5. Global SYMPLICITY registry (GSR) operator experience. The majority of operators performing renal denervation in the GSR have done >10 procedures.

Ambulatory BP captures and averages many values >24 hours, thereby providing a more accurate assessment of a patient’s real BP than office measurements with less influence by regression to the mean.20,28 Furthermore, 24-hour mean BP is more closely related to end-organ damage29 and is a more sensitive predictor of morbidity and mortality than office BP.3032 This makes the ambulatory SBP reductions seen after RDN of special interest. Although also related to the baseline office SBP values (and thus greater when baseline values were higher), these reductions were smaller than the office SBP reductions, which is in line with previous observations on the BP effects of the RDN procedure.33 It is also in line with the data provided by the majority of the studies on antihypertensive drug treatment,34 including those in patients recruited for morbidity and mortality trials.35 The likely explanation is that as an average of a large number of values, 24-hour BP has a narrower distribution of the population, which means that smaller changes in response to external interventions have to be expected.36 However, an attenuation of the alerting response to the physician’s visit may also contribute because this phenomenon (known as the white-coat effect) has been shown to raise office BP but not to affect ambulatory BP.37 In this context, it is interesting to note that a reduction of office but not of ambulatory BP has recently been reported in patients with pseudoresistant hypertension, that is, individuals under multiple drug treatment with persistently high office but normal ambulatory BP values.33

In a controlled clinical trial, periprocedural complications were uncommon (<1%).8 Interestingly, a similar low periprocedural complication rate, including dissections, spasms, and perforations (all <1%), was observed in the GSR. Therefore, despite a less strict selection of study centers and investigators, there was no indication of an elevation of periprocedural adverse events. Furthermore, during follow-up of 1 year, renal function remained stable. Similar results were obtained in previous trials.9,12,17

Limitations

We recognize that registry-based studies have limitations. One, the specific indications for RDN could not be assessed because of the nature of the registry, which left patient selection to the decision of the investigators. The lack of defined enrollment criteria exclusively related to high BP led to 2 patients with heart failure being treated who did have documented hypertension although enrollment of patients with other conditions associated with sympathetic nervous system activation was permitted by the protocol. Two, a registry cannot standardize follow-up procedures, which may limit reporting of safety events. Under-reporting of adverse events may have been possible because follow-up renal vascular imaging was performed at the discretion of the investigator. Finally, and most importantly, interventional procedures of this kind have the potential for a placebo/Hawthorne effect with no control group being part of the current analysis; however, this seems less likely given the similar BP reduction with and without blinding in HTN-3. It is possible that office BP reductions at follow-up are partly related to regression to the mean although this is less likely with repeated ambulatory BP measures.

Perspectives

RDN has provided BP-reducing effects in multiple clinical studies. This is the first large scale study to demonstrate that in ≈1000 patients from around the world the procedure is safe and significantly reduces office and ambulatory BP in a real life setting. RDN provides additional BP reduction on top of intensive pharmacological therapies in patients with uncontrolled hypertension with a great level of short-term safety. The BP-lowering effect directly related to the height of BP at baseline. The Global SYMPLICITY registry provides further evidence that radiofrequency RDN safely reduces BP in patients with uncontrolled hypertension requiring complex multidrug antihypertensive therapy. Potential roles for RDN are not yet clearly defined but the procedure might provide an add-on technique to improve BP control in a broad population of hypertensive patients. Further studies to better define appropriate patient populations and clarify the optimal procedural technology and technique for RDN are warranted.

Acknowledgments

We thank Marianne Wanten, MSc, for excellent study management; Tobias Limbourg, PhD, from IHF, and Min Lai, MS, Martin Fahy, MS, and Minglei Liu, PhD, from Medtronic for statistical support; Colleen Gilbert, PharmD, for editorial support; and Sandeep Brar, MD, Sidney A. Cohen, MD, PhD, and Frank van Leeuwen, MD, for study support and expert review.

Footnotes

This paper was sent to David A. Calhoun, Guest Editor, for review by expert referees, editorial decision, and final disposition.

The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.114.05010/-/DC1.

Correspondence to Michael Böhm, Universitätsklinikum des Saarlandes, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Kirrberger Str 1, DE 66424 Homburg/Saar, Germany. E-mail

References

  • 1. Staessen JA, Kuznetsova T, Stolarz K. Hypertension prevalence and stroke mortality across populations.JAMA. 2003; 289:2420–2422. doi: 10.1001/jama.289.18.2420.CrossrefMedlineGoogle Scholar
  • 2. Mancia G, Fagard R, Narkiewicz K, et al.. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).Eur Heart J. 2013; 34:2159–2219. doi: 10.1093/eurheartj/eht151.CrossrefMedlineGoogle Scholar
  • 3. Sobotka PA, Mahfoud F, Schlaich MP, Hoppe UC, Böhm M, Krum H. Sympatho-renal axis in chronic disease.Clin Res Cardiol. 2011; 100:1049–1057. doi: 10.1007/s00392-011-0335-y.CrossrefMedlineGoogle Scholar
  • 4. Hering D, Esler MD, Krum H, Mahfoud F, Böhm M, Sobotka PA, Schlaich MP. Recent advances in the treatment of hypertension.Expert Rev Cardiovasc Ther. 2011; 9:729–744. doi: 10.1586/erc.11.71.CrossrefMedlineGoogle Scholar
  • 5. Mancia G, Grassi G. The autonomic nervous system and hypertension.Circ Res. 2014; 114:1804–1814. doi: 10.1161/CIRCRESAHA.114.302524.LinkGoogle Scholar
  • 6. Krum H, Sobotka P, Mahfoud F, Böhm M, Esler M, Schlaich M. Device-based antihypertensive therapy: therapeutic modulation of the autonomic nervous system.Circulation. 2011; 123:209–215. doi: 10.1161/CIRCULATIONAHA.110.971580.LinkGoogle Scholar
  • 7. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.Lancet. 2009; 373:1275–1281. doi: 10.1016/S0140-6736(09)60566-3.CrossrefMedlineGoogle Scholar
  • 8. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.Lancet. 2010; 376:1903–1909.CrossrefMedlineGoogle Scholar
  • 9. Krum H, Schlaich MP, Sobotka PA, Böhm M, Mahfoud F, Rocha-Singh K, Katholi R, Esler MD. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study.Lancet. 2014; 383:622–629. doi: 10.1016/S0140-6736(13)62192-3.CrossrefMedlineGoogle Scholar
  • 10. Esler MD, Böhm M, Sievert H, Rump CL, Schmieder RE, Krum H, Mahfoud F, Schlaich MP. Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension: 36 month results from the SYMPLICITY HTN-2 randomized clinical trial.Eur Heart J. 2014; 35:1752–1759. doi: 10.1093/eurheartj/ehu209.CrossrefMedlineGoogle Scholar
  • 11. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension.N Engl J Med. 2014; 370:1393–1401. doi: 10.1056/NEJMoa1402670.CrossrefMedlineGoogle Scholar
  • 12. Esler MD, Krum H, Schlaich M, Schmieder RE, Böhm M, Sobotka PA; Symplicity HTN-2 Investigators. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial.Circulation. 2012; 126:2976–2982. doi: 10.1161/CIRCULATIONAHA.112.130880.LinkGoogle Scholar
  • 13. Hering D, Lambert EA, Marusic P, Ika-Sari C, Walton AS, Krum H, Sobotka PA, Mahfoud F, Böhm M, Lambert GW, Esler MD, Schlaich MP. Renal nerve ablation reduces augmentation index in patients with resistant hypertension.J Hypertens. 2013; 31:1893–1900. doi: 10.1097/HJH.0b013e3283622e58.CrossrefMedlineGoogle Scholar
  • 14. Brandt MC, Mahfoud F, Reda S, Schirmer SH, Erdmann E, Böhm M, Hoppe UC. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension.J Am Coll Cardiol. 2012; 59:901–909. doi: 10.1016/j.jacc.2011.11.034.CrossrefMedlineGoogle Scholar
  • 15. Mahfoud F, Urban D, Teller D, et al.. Effect of renal denervation on left ventricular mass and function in patients with resistant hypertension: data from a multi-centre cardiovascular magnetic resonance imaging trial.Eur Heart J. 2014; 35:2224–231b. doi: 10.1093/eurheartj/ehu093.CrossrefMedlineGoogle Scholar
  • 16. Ott C, Mahfoud F, Schmid A, Ditting T, Veelken R, Ewen S, Ukena C, Uder M, Böhm M, Schmieder RE. Improvement of albuminuria after renal denervation.Int J Cardiol. 2014; 173:311–315. doi: 10.1016/j.ijcard.2014.03.017.CrossrefMedlineGoogle Scholar
  • 17. Mahfoud F, Cremers B, Janker J, et al.. Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension.Hypertension. 2012; 60:419–424. doi: 10.1161/HYPERTENSIONAHA.112.193870.LinkGoogle Scholar
  • 18. Linz D, Mahfoud F, Schotten U, Ukena C, Neuberger HR, Wirth K, Böhm M. Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea.Hypertension. 2012; 60:172–178. doi: 10.1161/HYPERTENSIONAHA.112.191965.LinkGoogle Scholar
  • 19. Böhm M, Mahfoud F, Ukena C, et al.. Rationale and design of a large registry on renal denervation: the Global SYMPLICITY registry.EuroIntervention. 2013; 9:484–492. doi: 10.4244/EIJV9I4A78.CrossrefMedlineGoogle Scholar
  • 20. O’Brien E, Parati G, Stergiou G, et al.; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring.J Hypertens. 2013; 31:1731–1768. doi: 10.1097/HJH.0b013e328363e964.CrossrefMedlineGoogle Scholar
  • 21. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.Ann Intern Med. 1999; 130:461–470.CrossrefMedlineGoogle Scholar
  • 22. Ukena C, Mahfoud F, Spies A, Kindermann I, Linz D, Cremers B, Laufs U, Neuberger HR, Böhm M. Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension.Int J Cardiol. 2013; 167:2846–2851. doi: 10.1016/j.ijcard.2012.07.027.CrossrefMedlineGoogle Scholar
  • 23. Hering D, Marusic P, Walton AS, Lambert EA, Krum H, Narkiewicz K, Lambert GW, Esler MD, Schlaich MP. Sustained sympathetic and blood pressure reduction 1 year after renal denervation in patients with resistant hypertension.Hypertension. 2014; 64:118–124. doi: 10.1161/HYPERTENSIONAHA.113.03098.LinkGoogle Scholar
  • 24. Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, Hoppe UC, Vonend O, Rump LC, Sobotka PA, Krum H, Esler M, Böhm M. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study.Circulation. 2011; 123:1940–1946. doi: 10.1161/CIRCULATIONAHA.110.991869.LinkGoogle Scholar
  • 25. Kandzari DE, Bhatt DL, Brar S, Devireddy CM, Esler M, Fahy M, Flack JM, Katzen BT, Lea J, Lee DP, Leon MB, Ma A, Massaro J, Mauri L, Oparil S. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial.Eur Heart J. 2015; 36:219–227. doi:10.1093/eurheartj/ehu441.CrossrefMedlineGoogle Scholar
  • 26. Barnett AG, van der Pols JC, Dobson AJ. Regression to the mean: what it is and how to deal with it.Int J Epidemiol. 2005; 34:215–220. doi: 10.1093/ije/dyh299.CrossrefMedlineGoogle Scholar
  • 27. Persu A, Jin Y, Azizi M, et al.; European Network COordinating research on Renal Denervation (ENCOReD). Blood pressure changes after renal denervation at 10 European expert centers.J Hum Hypertens. 2014; 28:150–156. doi: 10.1038/jhh.2013.88.CrossrefMedlineGoogle Scholar
  • 28. Warren RE, Marshall T, Padfield PL, Chrubasik S. Variability of office, 24-hour ambulatory, and self-monitored blood pressure measurements.Br J Gen Pract. 2010; 60:675–680. doi: 10.3399/bjgp10X515403.CrossrefMedlineGoogle Scholar
  • 29. Mancia G, Zanchetti A, Agabiti-Rosei E, Benemio G, De Cesaris R, Fogari R, Pessina A, Porcellati C, Rappelli A, Salvetti A, Trimarco B, Agebiti-Rosei E, Pessino A. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. SAMPLE Study Group. Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation.Circulation. 1997; 95:1464–1470.LinkGoogle Scholar
  • 30. Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study.Circulation. 2005; 111:1777–1783. doi: 10.1161/01.CIR.0000160923.04524.5B.LinkGoogle Scholar
  • 31. Fagard RH, Celis H, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension.Hypertension. 2008; 51:55–61. doi: 10.1161/HYPERTENSIONAHA.107.100727.LinkGoogle Scholar
  • 32. Metoki H, Ohkubo T, Kikuya M, Asayama K, Obara T, Hashimoto J, Totsune K, Hoshi H, Satoh H, Imai Y. Prognostic significance for stroke of a morning pressor surge and a nocturnal blood pressure decline: the Ohasama study.Hypertension. 2006; 47:149–154. doi: 10.1161/01.HYP.0000198541.12640.0f.LinkGoogle Scholar
  • 33. Mahfoud F, Ukena C, Schmieder RE, et al.. Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension.Circulation. 2013; 128:132–140. doi: 10.1161/CIRCULATIONAHA.112.000949.LinkGoogle Scholar
  • 34. Mancia G, Parati G. Office compared with ambulatory blood pressure in assessing response to antihypertensive treatment: a meta-analysis.J Hypertens. 2004; 22:435–445.CrossrefMedlineGoogle Scholar
  • 35. Mancia G, Parati G, Bilo G, et al.. Ambulatory blood pressure values in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).Hypertension. 2012; 60:1400–1406. doi: 10.1161/HYPERTENSIONAHA.112.199562.LinkGoogle Scholar
  • 36. Mancia G, Sega R, Grassi G, Cesana G, Zanchetti A. Defining ambulatory and home blood pressure normality: further considerations based on data from the PAMELA study.J Hypertens. 2001; 19:995–999.CrossrefMedlineGoogle Scholar
  • 37. Parati G, Pomidossi G, Casadei R, Mancia G. Lack of alerting reactions to intermittent cuff inflations during noninvasive blood pressure monitoring.Hypertension. 1985; 7:597–601.LinkGoogle Scholar

Novelty and Significance

What Is New?

  • This first report of the Global SYMPLICITY Registry shows that in a large number of hypertensive patients treated in routine clinical practice the procedure is safe and significantly reduces office and ambulatory blood pressure.

What Is Relevant?

  • Renal denervation provides additional blood pressure reduction on top of intensive pharmacological therapies with minimal procedure-related complications.

  • The effect is dependent on the height of blood pressure at baseline.

Summary

The Global SYMPLICITY registry provides further evidence that radiofrequency renal denervation safely reduces blood pressure in patients with uncontrolled hypertension receiving a high load of medications. The procedure may provide an add-on technique to improve blood pressure control in hypertensive patients.