Reports detailing the response of hypertensive patients to renal denervation (RDN) in Asian patients are limited. We evaluated 6- and 12-month outcomes after RDN in an Asian population and compared outcomes to a primarily Caucasian population. The Global SYMPLICITY Registry (GSR) is a prospective, all-comer, worldwide registry that evaluates the safety and effectiveness of RDN and includes the Korean registry substudy (GSR Korea) and a Caucasian subset (GSR Caucasian). Given differences in baseline characteristics among GSR Korea (n=93) as compared with GSR Caucasian (n=169) patients, including lower baseline office systolic blood pressure (SBP), lower body mass index and differences in medications, propensity score adjustment was performed when comparing the change in SBP between subsets. The 6- and 12-month change in SBP in GSR Korea was −19.4±17.2 and −27.2±18.1 mm Hg, respectively (P<0.001 for both vs baseline). GSR Caucasian had a SBP change similar to GSR Korea at 6 months (−20.9±21.4 mm Hg, unadjusted P=0.547, adjusted P=0.998), whereas at 12 months the change was significantly less pronounced (−20.1±23.9 mm Hg, unadjusted P=0.004, adjusted P=0.002). There were no protocol-defined procedure-related adverse events and no chronic adverse events associated with the device in an Asian population. RDN provided a significant reduction in 6- and 12-month office SBP among Asian patients, with a favorable safety profile. The 12-month SBP reduction was larger than that observed in Caucasian patients.
Increasing awareness of the importance of sympathetic nervous system activation in the pathogenesis of hypertension has led to the development of a novel, minimally invasive procedure to reduce sympathetic activity and lower blood pressure (BP) in patients with uncontrolled hypertension.1, 2 Catheter-based renal denervation (RDN) by radiofrequency ablation of the renal artery nerves has been associated with substantial reductions in BP in certain trials. SYMPLICITY HTN-1 and SYMPLICITY HTN-2 demonstrated a significant and sustained reduction in systolic BP (SBP) on the order of 25 mm Hg at 12 months that was sustained out to 36 months in patients with severe, uncontrolled hypertension using the Symplicity RDN system (Medtronic Inc., Santa Rosa, CA, USA).3, 4, 5, 6, 7, 8 The SYMPLICITY HTN-3 multicenter, single-blind, randomized controlled trial of RDN vs sham, however, failed its primary efficacy end point, defined as 6-month change in office SBP (−14.1 mm Hg) compared with sham (−11.7 mm Hg), P=0.26 for superiority.9 Potential explanations for the different results in SYMPLICITY HTN-3 compared with previous RDN trials include study design, patient selection, medication adherence, ethnicity, and procedural issues.10 SYMPLICITY HTN-1, SYMPLICITY HTN-2 and SYMPLICITY HTN-3 were conducted in primarily Caucasian populations (95–98% in SYMPLICITY HTN-1 and SYMPLICITY HTN-2; 72% Caucasian, 26% African American and 0.4% Asian (2 patients) in SYMPLICITY HTN-3). Reports detailing the response of hypertensive patients to RDN in Asian patients (who on average have a smaller body habitus, a lower body mass index (BMI) and different associations between BMI, body fat percentage and health risks compared with Caucasian populations) are limited.11, 12, 13 In addition, it is unclear whether the pathophysiology of uncontrolled hypertension could be different in Asian patients and whether any differences might affect the role of sympathetic tone and consequently RDN results in these patients. The aim of the present study was to analyze outcomes of RDN in patients from the Korea substudy treated in the Global SYMPLICITY Registry (GSR) and to compare them with Caucasian patients who met similar inclusion and exclusion criteria in GSR.
Subjects and methods
The GSR is a prospective, open-label, single-arm, all-comer registry that is enrolling up to 5000 patients worldwide, including Asia, to evaluate the safety and effectiveness of treatment with the Symplicity RDN system in ‘real world’ uncontrolled hypertensive patients. The trial design and interim results were recently published.14, 15 The GSR is enrolling patients with uncontrolled hypertension or other conditions characterized by increased sympathetic activity. All treatment decisions are left to the discretion of the treating physician according to best local practices and in accordance with the product instructions for use. 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).
The GSR includes the Korean registry substudy (GSR Korea), which limits enrollment to patients who met similar inclusion and exclusion criteria with previous SYMPLICITY studies. Specifically, patients were eligible if they had an office SBP ⩾160 mm Hg (or ⩾150 mm Hg if they had type 2 diabetes mellitus) while receiving three or more antihypertensive medications without changes for 2 weeks before enrollment. Exclusion criteria included prior renal artery intervention, main renal arteries <4 mm in diameter or <20 mm in length and hemodynamically or anatomically significant renal artery abnormalities, such as renal artery stenosis; GSR Korea also allowed for RDN treatment in patients with multiple renal arteries on one or both sides. The baseline estimated glomerular filtration rate (eGFR) was recommended to be >45 ml min−1 per 1.73 m2, as calculated by the Modification of Diet in Renal Disease formula.16 Patients with type 1 diabetes mellitus, stenotic valvular heart disease, myocardial infarction, unstable angina or cerebrovascular accident within 6 months of enrollment were also excluded, as were individuals with possible secondary hypertension. Ambulatory BP monitoring was not mandated in GSR Korea.
Before treatment and at every follow-up visit, investigators interviewed patients and documented any changes to antihypertensive medications. GSR, including GSR Korea, recommended that three BP and heart rate measurements be taken at each visit, with the patient sitting quietly for at least 1 min between each reading, and according to standard practice. To allow comparisons of outcomes in GSR with a Caucasian population (GSR Caucasian), patients enrolled in Asian countries were excluded from the analysis, as were patients of African descent (information on African descent was collected as required for the calculation of eGFR by the Modification of Diet in Renal Disease formula); other than African descent, race information was not directly collected. GSR Caucasian patients resided in Western Europe (in particular Germany), Australia, Eastern Europe/Greece, the Middle East (in particular Israel), Canada and Russia. In addition, similar inclusion/exclusion criteria were applied as used in GSR Korea. However, although GSR Caucasian also limited patients to those on three or more antihypertensive medication classes at the time of enrollment, it did not require no medication changes for 2 weeks before enrollment or explicitly exclude patients with possible secondary hypertension (as this information was not recorded). In addition, few patients in GSR Caucasian had length and diameter of renal arteries recorded; therefore, patients without this information recorded were still included in this analysis.
Denervation time was defined as the interval between RDN catheter insertion and guide catheter removal. Procedure time was defined as the interval between arterial access site puncture to discharge from the catheterization laboratory.
Analysis included only patients with matched baseline, 6-month and 12-month office SBP measurements. Continuous data were reported as mean±standard deviation (normally distributed data) and compared using t-tests. Categorical data were presented as frequencies or percentages and compared using χ2 or Fisher’s exact test, as appropriate.
To take into consideration differences in baseline characteristics between GSR Korea and GSR Caucasian, propensity score adjustment was performed using a Cox regression model when comparing the change in office BP in these two cohorts with the following baseline covariates: baseline office SBP, male gender, diabetes mellitus, age, number of RDN ablation attempts, eGFR <60 ml min−1 per 1.73 m2, combined hypertension (baseline office SBP ⩾140 mm Hg and baseline office diastolic BP ⩾90 mm Hg) vs isolated systolic hypertension (baseline office SBP ⩾140 mm Hg and baseline office diastolic BP <90 mm Hg), as well as the following baseline antihypertensive medication classes: angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, calcium channel blocker, aldosterone antagonist, β-blocker, α-adrenergic blocker and direct-acting vasodilators.
Furthermore, multivariate stepwise regression analysis was conducted to assess independent correlates of 6- and 12-month change in office SBP. A simple univariate linear regression was performed on 6- and 12-month change in office SBP using the following baseline characteristics: Korean (vs Caucasian), baseline office SBP, baseline office diastolic BP, age, gender, diabetes mellitus, baseline heart rate, BMI, renal insufficiency (eGFR <60 ml min−1 per 1.73 m2), history of cardiac disease, heart failure, left ventricular hypertrophy, current smoker, total number of ablation attempts, number of 120-s ablation attempts, total number of antihypertensive medication classes and types of antihypertensive medications. Then, a multiple linear regression was performed, including only covariates with P<0.2 from the univariate analysis; Korean (vs Caucasian) was included in the final multivariate model regardless of the P-values in univariate regression. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA).
The ongoing Global SYMPLICTY Registry has enrolled 1000 patients with 12-month follow-up, and includes 102 patients from Korea, among whom 93 patients had matched baseline, 6- and 12-month BP measurements recorded and also 432 patients estimated to be Caucasian who met inclusion/exclusion criteria similar to GSR Korea, and among whom 169 had matched baseline, 6- and 12-month measurements (Figure 1).
Baseline characteristics and RDN procedure
The baseline characteristics of GSR Korean and GSR Caucasian patients are shown in Table 1. In GSR Korea, patients were 55.9±13.4 years old, mostly male (72%), and the prevalence of type 2 diabetes mellitus was high (46.2%). As compared with GSR Caucasian, GSR Korea patients were younger, had a lower BMI and a lower baseline SBP, were more likely to have had a previous stroke, myocardial infarction or suffer from angina pectoris, but were less likely to be obese or have renal insufficiency. GSR Korea patients also had higher baseline eGFR and faster heart rate.
Table 2 summarizes baseline antihypertensive medication prescriptions in GSR Korea and GSR Caucasian. At baseline, GSR Korea patients were prescribed 3.7±0.9 classes of antihypertensive medication classes. The majority of these medication classes prescribed were an angiotensin receptor antagonist, a calcium channel blocker, a diuretic and a β-blocker. As compared with GSR Caucasian, patients in GSR Korea were prescribed a lower mean number of antihypertensive medication classes, and differences existed in baseline medication classes prescribed.
There was no difference between GSR Korea and GSR Caucasian in average number of RDN ablation attempts (14±6 vs 14±4, P=0.690), denervation time (57±52 vs 52±26 min, P=0.624) or procedure time (84±42 vs 81±38, P=0.360).
Table 2 summarizes antihypertensive medication prescriptions at 6 and 12 months in GSR Korea and GSR Caucasian. Consistent with that observed at baseline, GSR Korea patients as compared with GSR Caucasian patients at 12 months were prescribed a lower mean number of antihypertensive medication classes, and differences existed in 12-month medication classes. In addition, there was no significant change in the number of antihypertensive medication classes in either the GSR Korea substudy (P=0.460) or the GSR Caucasian (P=0.676) between baseline and 12 months. Although there were also no significant changes in specific medication classes with patients in GSR Korea between baseline and 12 months, patients in GSR Caucasian had a decrease in prescriptions of angiotensin-converting enzyme inhibitors, but an increase in prescription of aldosterone antagonists at 12 months as compared with baseline.
Baseline office SBP in GSR Korea was 168.3±13.9 mm Hg, which was significantly lower than SBP in GSR Caucasian (176.1±15.6 mm Hg, P<0.001). Baseline diastolic BP in GSR Korea was 95.5±12.8 mm Hg, which was no different than that in GSR Caucasian (94.5±14.5 mm Hg, P=0.403).
In GSR Korea, office SBP was significantly reduced from 168.3±13.9 mm Hg at baseline to 148.8±18.4 mm Hg at 6 months (P<0.001) and 141.0±17.2 mm Hg at 12 months (P<0.001). At 6 months, the change in SBP in GSR Korea was similar to that in GSR Caucasian (−19.4±17.2 vs −20.9±21.4 mm Hg, respectively, unadjusted P=0.547, adjusted P=0.998), but at 12 months the SBP continued to decrease in GSR Korea (27.2±18.1 mm Hg, P<0.0001 vs 6 months) and was a larger reduction than that observed in GSR Caucasian (−20.1±23.9 mm Hg, unadjusted P=0.004, adjusted P=0.002; Figure 2). The change in diastolic BP in GSR Korea was larger than that observed in GSR Caucasian at both 6 and 12 months (Figure 2).
At 6 months, 69.9% of GSR Korea patients and 68.6% of GSR Caucasian patients experienced ⩾10 mm Hg reduction in SBP (P=0.834); however, at 12 months, GSR Korea patients showed a significantly higher proportion of patients with ⩾10 mm Hg reduction (87.1% vs 65.7%, respectively, P<0.001; Figure 3). Furthermore, 55% of patients in GSR Korea and 19% in GSR Caucasian had SBP <140 mm Hg at 12 months (P<0.001). The percentage of patients with SBP ⩾180 mm Hg decreased from 19% at baseline to 4% at 12 months, P<0.001 in GSR Korea and from 35% at baseline to 13% at 12 months in GSR Caucasian, P<0.001 (Figure 4). SBP decreased to <90 mm Hg in only one patient in GSR Korea (SBP was 87 mm Hg at the 12-month visit); the patient was asymptomatic and did not experience a hypotensive crisis or require hospitalization.
Univariate and multivariate analyses were conducted to assess baseline characteristics and medication classes associated with a greater change in 6- and 12-month office SBP. Variables with P<0.2 in the univariate analysis that were associated with a SBP change and therefore introduced into the multivariate model were: at 6 months, both baseline systolic and diastolic BP, heart failure, absence of left ventricular hypertrophy and not being prescribed aldosterone antagonists or calcium channel blockers; at 12 months, Korean (as compared with Caucasian) patients, both baseline systolic and diastolic BP, lower BMI, absence of diabetes, heart failure, more RDN ablation attempts, lower number of antihypertensive medication classes and not being prescribed aldosterone antagonists, calcium channel blockers or α-adrenergic blocker.
In multivariate analysis (Table 3), a higher baseline office SBP was also associated with a larger reduction in SBP at both 6 and 12 months. Korea patients also had a larger reduction in SBP at 12 months independent of baseline office SBP. In addition, left ventricular hypertrophy and calcium channel blockers were associated with a smaller 6-month reduction in office SBP, whereas α-adrenergic blockers was associated with a smaller 12-month reduction in SBP.
In the GSR Korea, no device-, procedure- or therapy-related adverse events and no chronic adverse events associated with the device were reported out to 12 months. One patient developed renal failure (due to attempted suicide by ingestion of insect poison), two patients were hospitalized due to atrial fibrillation, two experienced strokes, and one patient had a hypertensive crisis requiring hospitalization. These safety results are consistent with those observed in the GSR Caucasian subset, where the only safety events were two access-site-related hematomas (Table 4).
Estimated GFR was available only in a subgroup of GSR Korea patients that had follow-up laboratory testing and decreased from 88.9±25.3 ml min−1 per 1.73 m2 (n=87) at baseline to 78.1±24.7 ml min−1 per 1.73 m2 (n=43) at 12 months (a change of −9.3±13.8 ml min−1 per 1.73 m2 in 38 matched patients, P<0.001). Estimated GFR in GSR Caucasian also decreased from 80.9±18.2 ml min−1 per 1.73 m2 (N=169) at baseline vs 76.2±20.7 ml min−1 per 1.73 m2 (N=144) at 12 months (a change of −4.1±12.7 ml min−1 per 1.73 m2 in 144 matched patients, P<0.001).
The main finding of our study is that Asian hypertensive patients participating in the GSR Korea substudy had a substantial reduction in office SBP at 6 and 12 months. This reduction in SBP was similar to that observed in the GSR Caucasian subset at 6 months, but significantly greater at 12 months, despite differences in baseline characteristics between the two groups and even after propensity score adjustment. This larger reduction in SBP was achieved in Korean patients despite a lower baseline SBP (168.3 vs 176.1 mm Hg). This finding is notable as previous analyses have consistently shown an association between a higher baseline office SBP and a greater reduction in SBP after RDN,10, 17, 18, 19 and the progressive decrease in BP could imply an early as well as a progressive or later effect of RDN on SBP.
Differences in baseline clinical characteristics between GSR Korea patients and GSR Caucasian included lower BMI, prevalence of obesity, age, faster heart rate and less antihypertensive medication classes prescribed. Upon multivariate analysis that adjusted for all baseline characteristics and baseline medication classes, Korean (as compared with Caucasian) patients remained more likely to have a larger reduction in 12-month SBP.
The reduction in BP following RDN is not immediate, but the time course of response to RDN may differ by race. In the GSR Korea substudy, mean SBP continued to decrease between 6 months (−19.4 mm Hg) and 12 months (−27.2 mm Hg). In the GSR Caucasian subset, however, the reduction in SBP was similar between 6 months (−20.9 mm Hg) and 12 months (−20.1 mm Hg). This similarity in the BP change in GSR Caucasian at 6 and 12 months is consistent with that observed in other studies of RDN in a primarily Caucasian population, including SYMPLICITY HTN-1 (−26 mm Hg, n=88, at 6 months and −27 mm Hg, n=85, at 12 months)4 and SYMPLICITY HTN-2 (−28 mm Hg at 6 months, n=84 and −26 mm Hg at 12 months, n=80).6 However, the absolute 12-month change in SBP in GSR Korea was no different than that reported in SYMPLICITY HTN-1 or SYMPLICITY HTN-2.
At 12 months in GSR Korea as compared with GSR Caucasian, not only was the average reduction in SBP larger (−27.2 vs −20.1 mm Hg) but also the distribution was tighter: the standard deviation on the 12-month change in SBP was 18.1 mm Hg in GSR Korea vs 23.9 mm Hg in GSR Caucasian. Both factors help explain the significantly greater number of patients with a ⩾10 mm Hg reduction in SBP (87.1% vs 65.7%, respectively, P<0.001). Ethnic differences, differences in baseline characteristics, differences in medication adherence and differences in BP assessment technique could have led to the difference in standard deviation. GSR Korea had a more homogenous patient population, including a lower BMI, compared with GSR Caucasian patients. Furthermore, only 10 sites participated in GSR Korea, which might have helped limit end-point variability.
In addition, although both GSR Korea and GSR Caucasian patients were treated with a similar number of RDN ablation attempts (14.4±5.5 vs 13.7±4.1, P=0.690), it is unknown whether the ablations in GSR Korea more often targeted all four quadrants of the renal artery wall. An analysis conducted in SYMPLICITY HTN-3 found a trend toward a greater reduction in SBP after RDN when delivery of ablations is applied in a four-quadrant pattern.10
The RDN procedure was safe in GSR Korea: no adverse renal vascular effects were reported. Although a significant reduction in eGFR was observed, this comparison is limited because only 38 patients of the 93 patients had matched baseline and 12-month eGFR estimates. In addition, eGFR using Modification of Diet in Renal Disease is known to have increased variability within the normal range as compared with low range and the calculation used has been validated only in Caucasian and African American populations20 and thus may be less applicable in Asian populations.21, 22, 23
Our findings in GSR Korea have important implications since the study population was different from those of previous RDN studies, which were primarily comprised of Caucasian patients. The SYMPLICITY HTN-3 trial failed its primary efficacy end point; however, the difference in the reduction in office SBP with RDN compared with sham in non-African American patients (but not African American patients) was statistically significant, albeit only when the superiority margin was not applied.9, 10 Although racial differences may alter the response to RDN, the findings of GSR Korea support that RDN is effective in Asian populations and might be more effective in Asians than in Caucasians. The concurrence of clinical outcomes in SYMPLICITY HTN-14 and SYMPLICITY HTN-26 is supportive of a persistence of SBP reduction to 3 years, whereas post hoc analysis of the SYMPLICITY HTN-3 trial suggests multiple other factors may have negatively impacted the efficacy end point.10 The disparate findings of Asian and Caucasian patients are informative in this context.
Hypertension has a more important role in the development of heart disease and stroke in Asia than in Western countries,24 and hemorrhagic strokes are more common in Asia.25 The prevalence of obesity in Asia has been increasing as a consequence of economic development in the past two to three decades, as has the prevalence of diabetes mellitus.24 Therefore, the identification of safe and effective antihypertensive treatments for Asian patients, such as RDN, could significantly decrease the cardiovascular morbidity and mortality burden in the Asian hypertensive population.
The present analysis has several limitations. The analysis does not include a control arm and thus cannot account for potential placebo or Hawthorne effects on the outcome measures. However, the main hypothesis is related to comparisons based on ethnicity and geography in treated patients. Also, many baseline demographic characteristics and hypertension drug treatment strategies differed between the two comparison populations (an interesting observation in and of itself). However, after adjusting for these baseline differences, GSR Korea patients still had a significantly greater decrease in office SBP at 1 year. In addition, follow-up of ambulatory BP measurements was not mandatory; the comparison of the changes of 24-h ambulatory BP values between the groups could not be performed. Finally, the GSR Korea protocol required a minimum of 2 weeks on a stable antihypertensive regimen before enrollment; this window may have been two short to ensure all antihypertensive medications reached their maximum effect. However, because maximum tolerable dose was not required, there were likely less medication changes before enrollment than likely required in SYMPLICITY HTN-3.
RDN in the GSR Korea substudy provided a significant reduction in office SBP at 6 and 12 months. As compared with the GSR Caucasian subset, the reduction in SBP in GSR Korea was similar at 6 months but higher at 12 months. This beneficial effect of RDN on BP control in an Asian population was observed despite a lower baseline SBP compared with the Caucasian population, contrary to prior studies that consistently indicated a relationship between baseline SBP and RDN BP-lowering response. Finally, RDN showed favorable safety profiles, suggesting that the procedure could provide significant clinical benefits in both patient populations.
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We thank JiSun Yun and Marianne Wanten for study management, Nicole Brilakis, Colleen Gilbert and Sidney A Cohen for editorial assistance, and Martin Fahy and Minglei Liu for statistical analysis oversight (all from Medtronic, Inc.). This study was sponsored by Medtronic, Inc. Trial Registration: clinicaltrials.gov Identifier: NCT01534299.
M Böhm received research support and speaker fees from Medtronic, Inc., and St Jude Medical. F Mahfoud received speaker honoraria from Medtronic, Inc., St Jude Medical and Boston Scientific, and is supported by the Deutsche Hochdruckliga and Deutsche Gesellschaft für Kardiologie. G Mancia is a consultant for Medtronic, Inc. M Esler received research support, honoraria and travel support from Medtronic, Inc. All other authors have no conflict of interest to declare.
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Kim, BK., Böhm, M., Mahfoud, F. et al. Renal denervation for treatment of uncontrolled hypertension in an Asian population: results from the Global SYMPLICITY Registry in South Korea (GSR Korea). J Hum Hypertens 30, 315–321 (2016). https://doi.org/10.1038/jhh.2015.77
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