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Safety and performance of the second generation EnligHTN™ Renal Denervation System in patients with drug-resistant, uncontrolled hypertension

Open AccessPublished:April 29, 2017DOI:https://doi.org/10.1016/j.atherosclerosis.2017.04.022

      Highlights

      • The second generation EnligHTN™ System permitted simultaneous delivery of radiofrequency therapy.
      • There were no major safety concerns out to 24 months with the second generation EnligHTN™ System.
      • Renal denervation with the second generation EnligHTN™ System was efficacious at reducing blood pressure 24 months post renal denervation.

      Abstract

      Background and aims

      Catheter-based renal denervation for the treatment of drug-resistant hypertension has been intensively investigated in recent years. To date, only limited data have been published using multi-electrode radiofrequency ablation systems that can deliver lesions with a pre-determined pattern. This study was designed to evaluate the safety and performance of the second generation EnligHTN™ Renal Denervation System.

      Methods

      This first-in-human, prospective, multi-center, non-randomized study included 39 patients (62% male, mean age 63 years, and mean baseline office blood pressure 174/93 mmHg) with drug-resistant hypertension. The primary safety and performance objectives were to characterize, from baseline to 6 months post procedure, the rate of serious procedural and device related adverse events, as adjudicated by an independent Clinical Events Committee, and the reduction of office systolic blood pressure.

      Results

      Renal artery denervation, using the second generation EnligHTN multi-electrode system significantly reduced office blood pressure from baseline to 1, 3, 6, 12, 18 and 24 months by 19/7, 26/9, 25/7, 23/7, 25/8 and 27/9 mmHg, respectively (p ≤ 0.0005). No serious device or procedure related adverse events affecting the renal arteries or renal function occurred through 24 months of follow-up.

      Conclusions

      Renal sympathetic denervation using the second generation EnligHTN Renal Denervation System resulted in safe, rapid, and significant mean office blood pressure reduction that was sustained through 24 months. Future studies will need to address the utility of this system against an appropriate sham based comparator.

      Keywords

      1. Introduction

      Hypertension is the leading attributable risk factor for cardiovascular morbidity and mortality around the world [
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      ]. Resistant hypertension, as defined by the inability to achieve target blood pressure despite three or more antihypertensive agents remains a treatment dilemma, with an incidence of between 10 and 12% [
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      ]. Furthermore, this group of patients has a three-fold increased risk of cardiovascular events over the group of patients with hypertension that is treated to target blood pressures [
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      Prospective studies collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies (vol 360, pg 1903, 2002).
      ].
      A number of novel device based therapies are emerging with the potential to improve blood pressure in patients with treatment resistant hypertension [
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      Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.
      ]. The most studied of these remains catheter based radiofrequency renal artery denervation. Initial observational trials showed this therapy to be associated with approximately a 25 mmHg BP reduction at 6 months in resistant hypertension patients and led to a consensus opinion for clinical appropriateness in treatment resistant hypertension [
      • Krum H.
      • Schlaich M.
      • Whitbourn R.
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      Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.
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      Investigators SH
      Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.
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      Expert consensus document from the European Society of Cardiology on catheter-based renal denervation.
      ,
      • Worthley S.G.
      • Tsioufis C.P.
      • Worthley M.I.
      • Sinhal A.
      • Chew D.P.
      • Meredith I.T.
      • Malaiapan Y.
      • Papademetriou V.
      Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial.
      ]. Controversy now exists over the incremental value of this technology with the recent SYMPLICITY HTN-3 trial failing to meet its primary effectiveness endpoint versus sham control [
      • Bhatt D.L.
      • Kandzari D.E.
      • O'Neill W.W.
      • D'Agostino R.
      • Flack J.M.
      • Katzen B.T.
      • Leon M.B.
      • Liu M.
      • Mauri L.
      • Negoita M.
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      • Rocha-Singh K.
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      Investigators SH
      A controlled trial of renal denervation for resistant hypertension.
      ]. However, this technology utilized a first generation single-tip electrode radiofrequency ablation catheter that requires significant operator manipulation with point by point ablation. Therefore, there is a higher risk of producing an inadequate ideal geometric distribution of lesions in the renal artery. Furthermore, fewer lesions were created in trials of the SYMPLICITY™ Renal Denervation System than other systems and this may have a relationship with BP reduction. In fact, a SYMPLICITY HTN-3 subgroup analysis showed that more robust response was related to more lesions and four-quadrant positioning [
      • Kandzari D.E.
      Second deep dive into SYMPLICITY HTN-3: novel mechanistic Insights from the trial.
      ].
      The EnligHTN Renal Denervation System has a multi-electrode platform with a predefined geometric orientation facilitating a more favorable lesion creation pattern for the purpose of interrupting renal artery nerve traffic [
      • Chokka R.G.
      • Delacroix S.
      • Psaltis P.J.
      • Anavekar N.S.
      • Worthley S.G.
      Percutaneous renal denervation and the second generation EnligHTN System.
      ]. The system can be positioned once and deliver four lesions prior to movement. The EnligHTN I study, a multicenter, first-in-human observation safety and performance study utilizing the first generation EnligHTN Renal Denervation System (St Jude Medical, MN, USA), reported a 26 mmHg reduction in office systolic BP at the 6 month primary endpoint [
      • Worthley S.G.
      • Tsioufis C.P.
      • Worthley M.I.
      • Sinhal A.
      • Chew D.P.
      • Meredith I.T.
      • Malaiapan Y.
      • Papademetriou V.
      Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial.
      ]. However, the first generation of this system required each electrode to deliver therapy sequentially, and therefore the procedure was time consuming. Extensive preclinical testing to optimize adequate renal artery lesion resulted in the second generation EnligHTN system that allows for simultaneous delivery of all four electrodes and includes modifications in the temperature, including rate of rise over time and duration. The EnligHTN III trial was designed to allow comparisons to be made with the first generation, and therefore test both the safety and performance of this second generation system. The 6-month results were previously presented [
      • Worthley S.
      • Wilkins G.
      • Webster M.W.
      • Antonis P.
      • Warren R.
      • Whitbourn R.J.
      Safety and performance of the next generation EnligHTN (TM) Renal Denervation System in patients with drug-resistant, uncontrolled hypertension: a first-in-human multicentre study.
      ]. In this report, we present the long term 24-month, safety and performance data from the multicenter, first-in-human EnligHTN III trial.

      2. Patients and methods

      2.1 Study population

      Patients from 18 to 80 years of age, who had been referred for management of resistant HTN by a primary healthcare practitioner or specialist at six participating centers (4 in Australia and 2 in New Zealand), were screened for participation. The protocol was based on the previously published EnligHTN I trial [
      • Worthley S.G.
      • Tsioufis C.P.
      • Worthley M.I.
      • Sinhal A.
      • Chew D.P.
      • Meredith I.T.
      • Malaiapan Y.
      • Papademetriou V.
      Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial.
      ]. In brief, patients needed to have an office systolic BP that remained ≥ 160 mmHg despite the stable use of ≥3 anti-hypertensive medications concurrently at maximally tolerated doses. At least one of the anti-hypertensive medications was required to be a diuretic, unless there was documented intolerance. Patients also had to have a mean daytime systolic ambulatory BP > 135 mmHg. In all participating patients the anti-hypertensive drug regimen was to remain stable for a minimum of 14 days prior to the procedure and through the 6-month follow-up.

      2.2 Study design

      The EnligHTN III study was a first-in-human, prospective, multi-center, non-randomized study to evaluate safety and performance of a new generator and algorithm with the same multi-electrode catheter used in the EnligHTN I trial, allowing simultaneous delivery of therapy from all four electrodes, for the purpose of renal artery sympathetic denervation in patients with drug-resistant hypertension. The primary safety objective was to characterize the rate of serious procedural and device related adverse events from date of procedure through 6 months post procedure, as adjudicated by a Clinical Events Committee (CEC). The primary performance objective was the reduction of office systolic BP at 6 months post procedure as compared to baseline. Additional objectives that were assessed and reported include change in ambulatory BP parameters over time as compared to baseline, renovascular safety as measured by new renal artery stenosis or aneurysm at the site of ablation over time as compared to baseline, and change in renal function as assessed by eGFR over time as compared to baseline. Study patients continued follow-up at 1, 3, 6, 12, 18, and 24 months post denervation procedure.

      2.3 Study procedure

      2.3.1 Baseline

      Following written informed consent, medical history and physical examination including office BP were completed. The office BP was collected according to the Standard Joint National Committee VII Guidelines and ESC/ESH Guidelines [
      • Chobanian A.V.
      • Bakris G.L.
      • Black H.R.
      • Cushman W.C.
      • Green L.A.
      • Izzo J.L.
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      • Materson B.J.
      • Oparil S.
      • Wright J.T.
      • Roccella E.J.
      Prog NHBPE
      The Seventh report of the Joint National committee on prevention, detection, evaluation, and treatment of High blood pressure - the JNC 7 report.
      ,
      • Chobanian A.V.
      • Bakris G.L.
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      • Cushman W.C.
      • Green L.A.
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      • Materson B.J.
      • Oparil S.
      • Wright J.T.
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      Prog NHBPE
      Seventh report of the Joint National committee on prevention, detection, evaluation, and treatment of High blood pressure.
      ,
      • Mancia G.
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      • Redon J.
      • Zanchetti A.
      • Bohm M.
      • Christiaens T.
      • Cifkova R.
      • De Backer G.
      • Dominiczak A.
      • Galderisi M.
      • Grobbee D.E.
      • Jaarsma T.
      • Kirchof P.
      • Kjeldsen S.E.
      • Laurent S.
      • Manolis A.J.
      • Nilsson P.M.
      • Ruilope L.M.
      • Schmieder R.E.
      • Sirnes P.A.
      • Sleight P.
      • Viigimaa M.
      • Waeber B.
      • Zannad F.
      2013 practice guidelines for the management of arterial hypertension of the european Society of hypertension (ESH) and the european Society of cardiology (ESC).
      ]. Each center and each enrolled patient was provided with an automatic BP monitor (Omron Healthcare, Inc. Bannockburn, Illinois USA) for collection of office and home BP values. All patients recorded home BP values for seven days (three readings in the morning and three readings in the evening), anti-hypertensive medication regimen daily for a minimum of 14 days and completed a 24-h ambulatory BP assessment. The 24-h ambulatory BP was obtained by using an ambulatory BP System (Spacelabs Healthcare, Inc. Issaquah, Washington USA).
      After the 14 day screening period, all patients returned to their respective study center to complete the baseline assessment. Blood and urine were collected for Complete Blood Count, Basic Metabolic Profile, Serum Creatinine, Estimated Glomerular Filtration Rate (eGFR), Cystatin C, and Urine Albumin to Creatinine ratio. An auntomatic BP Monitor (Omron Healthcare, Inc., Bannockburn, IL, USA) was used for office BP assessment as per ESC/ESH guidelines [
      • Chobanian A.V.
      • Bakris G.L.
      • Black H.R.
      • Cushman W.C.
      • Green L.A.
      • Izzo J.L.
      • Jones D.W.
      • Materson B.J.
      • Oparil S.
      • Wright J.T.
      • Roccella E.J.
      Prog NHBPE
      The Seventh report of the Joint National committee on prevention, detection, evaluation, and treatment of High blood pressure - the JNC 7 report.
      ,
      • Chobanian A.V.
      • Bakris G.L.
      • Black H.R.
      • Cushman W.C.
      • Green L.A.
      • Izzo J.L.
      • Jones D.W.
      • Materson B.J.
      • Oparil S.
      • Wright J.T.
      • Roccella E.J.
      Prog NHBPE
      Seventh report of the Joint National committee on prevention, detection, evaluation, and treatment of High blood pressure.
      ,
      • Mancia G.
      • Fagard R.
      • Narkiewicz K.
      • Redon J.
      • Zanchetti A.
      • Bohm M.
      • Christiaens T.
      • Cifkova R.
      • De Backer G.
      • Dominiczak A.
      • Galderisi M.
      • Grobbee D.E.
      • Jaarsma T.
      • Kirchof P.
      • Kjeldsen S.E.
      • Laurent S.
      • Manolis A.J.
      • Nilsson P.M.
      • Ruilope L.M.
      • Schmieder R.E.
      • Sirnes P.A.
      • Sleight P.
      • Viigimaa M.
      • Waeber B.
      • Zannad F.
      2013 practice guidelines for the management of arterial hypertension of the european Society of hypertension (ESH) and the european Society of cardiology (ESC).
      ]. Office heart rate, quality of life questionnaire, a renal artery CT scan, and a review of medication logs were also assessed. Qualifying patients were scheduled for the renal denervation procedure within the following 30 days.

      2.3.2 The second generation EnligHTN renal denervation system

      The EnligHTN™ Renal Denervation System (St. Jude Medical, St. Paul, MN, USA) used in this study consists of the second generation EnligHTN radiofrequency generator, the EnligHTN renal artery ablation catheter, and the EnligHTN Renal Artery Guide Catheter and has been described previously [
      • Kandzari D.E.
      Second deep dive into SYMPLICITY HTN-3: novel mechanistic Insights from the trial.
      ]. The generator utilizes a novel algorithm for the delivery of 60 s of radiofrequency energy, optimised for simultaneous delivery of therapy through all 4 electrodes. There is a two-stage rate of temperature rise with an initial rate of 4 °C/sec, reducing to 1 °C/sec between 65 and 70 °C. The second generation generator also uses a proprietary algorithm described as Adaptive Control that modulates the power and temperature to minimize interrupted ablation errors that may have caused electrode shut-offs with the first generation system.
      Importantly, this system utilizes a diagnostic mode, in order to ensure good electrode contact and thus provides a predictor of adequate lesion creation. The generator allows for up to 5 min of continuous delivery of 0.5 W of radiofrequency energy, which has failed to induce any vascular injury in preclinical models, attesting to the safety of this diagnostic mode. The generator with this system comes with an interactive, user interface that simultaneously displays temperature, impedance and power for all four electrodes. Thus the results of temperature rise, impedance change and power modulation can be monitored continuously throughout both the diagnostic phase, as well as during therapy delivery.

      2.3.3 Renal denervation procedure

      Patients were taken to the Catheterization Laboratory to undergo the renal denervation procedure using conscious sedation. Images of the left and right main renal arteries were recorded using non-ionic contrast and the diameter and length of each of the main renal arteries measured. The renal denervation basket size was determined from the renal artery diameter (small basket 4.0–5.5 mm diameter/large basket 5.5–8.0 mm diameter) and the renal denervation catheter was inserted such that the catheter's tip was proximal to the bifurcation of one of the main renal arteries. The basket on the catheter was then opened with the impedance of each electrode on the basket monitored in diagnostic mode.
      Renal artery denervation was commenced and performed simultaneously by all four electrodes with the impedance, temperature and RF energy delivery monitored, as explained earlier. The basket was then collapsed and pulled back proximally approximately 1 cm to avoid lesion overlap. The basket was rotated approximately 45° and then expanded. Placement was confirmed under fluoroscopy and the ablation procedure was repeated. In general, 8 ablations were delivered per renal artery to achieve circumferential ablation. Images of the renal artery were taken using non-ionic contrast and checked for signs of renal artery irregularities (i.e., vasospasm, stenosis or dissection). The renal artery ablation procedure was then repeated for the other renal artery and the catheter was withdrawn. Finally, the sheath was removed and hemostasis achieved according to each center's standard of care. Procedural data were recorded for each patient, including procedure duration and number of ablations delivered.

      2.3.4 Post-procedure and pre-discharge

      Upon completion of the renal denervation procedure, the patient was moved to a recovery area and vital signs were monitored continuously. BP was measured every 15 min during the first 2 h post-procedure and then in 4-h intervals when the subject was awake until discharge. Patients were discharged from the hospital on the following day if medically stable.

      2.3.5 Follow-up

      The following data were collected during the post-discharge visits: office BP assessment, review of medications, blood and urine collection, 24-h ambulatory BP assessment, home BP monitoring and physical assessment. Patients were scheduled for follow-up visits at 1, 3, 6, 12, 18 and 24 months post procedure. Renal artery imaging by CT or duplex ultrasound were completed at the 6-month follow up visit. Renal artery imaging during other follow-up visits was performed if clinically indicated.

      2.4 Study oversight

      An independent Clinical Events Committee (CEC) adjudicated all adverse events for relatedness and severity. The CEC consisted of three physicians (nephrologist, IC and HTN specialist) familiar with hypertension therapies including RF ablation of the renal artery. The corresponding author and Steering Committee members had full access to the study data and final authority on this manuscript. The study was approved by each institution's Human Research Ethics Committee and is registered with Clinical Trials Registry (Registration No. NCT01836146). The trial was sponsored by St. Jude Medical, St. Paul, Minnesota, USA.

      2.5 Statistical analysis

      All continuous variables were summarized using mean, median, standard deviation (SD) and range. All categorical variables were summarized using frequencies and percentages. Normality of data was verified with the use of box plots and Kolmogorov-Smirnov normality test. For normally distributed data, comparisons of primary and secondary outcomes between time points were analyzed using paired t tests. In cases where the data was not normally distributed the non-parametric Wilcoxon Signed-Rank test was used to analyze the data. Blood pressure measurements at follow-up were accessed whether the difference between values at follow up and baseline has a mean value that is significantly different from 0. Statistical analyses were performed using SAS 9.3 (by SAS Institute Inc., Cary, NC, USA). Statistical significance was achieved if a two-sided test obtained a p value < 0.05.

      3. Results

      The study enrollment was conducted from April 2013 until August 2013. A total of 65 patients were consented for enrollment and underwent screening, of which 26 patients were excluded, mainly due to failure to continue to meet the BP enrollment criteria, the presence of renal artery anomalies, or the presence of significant renal artery atherosclerosis as defined in the protocol. Thereafter, 39 patients completed baseline evaluation and were scheduled for the renal denervation procedure.
      Baseline demographic, clinical conditions and medication data for the 39 patients are presented in Supplementary Table 1. All 39 patients successfully underwent renal denervation. The median procedure time from initiation to completion of RF energy delivery was 13 min and the mean ± SD number of ablations delivered was 7.85 ± 0.49 for the right and 8.00 ± 0.69 for the left renal arteries. Thus, the total number of ablations was 15.85 ± 1.01 and this was delivered with a mean of 4.33 ± 0.62 sets of RF applications.

      3.1 Safety results

      All adverse events were collected in the study. A CEC adjudicated the events for seriousness and relevance to the procedure and device. A complete listing of non-serious procedure and/or device related adverse events as adjudicated by the CEC is presented in Table 1. There were no unanticipated adverse device effects reported in the trial. There was one death reported 22 months after the index procedure. This event was due to ischemic heart disease with myocardial infarction and was not related to the device or procedure as determined by the independent CEC.
      Table 1Summary of non-serious adverse events related to procedure and/or device.
      Adverse eventNumber of eventsNumber of patients (%)
      Access site hematoma1010 (25.6%)
      Access site bruise99 (23.1%)
      Access site drainage66 (15.4%)
      Hypotension65 (12.8%)
      Back pain44 (10.3%)
      Vasospasm44 (10.3%)
      Access site pain33 (7.7%)
      Kidney pain/flank pain33 (7.7%)
      Emesis/vomiting22 (5.1%)
      Low back pain22 (5.1%)
      Nausea22 (5.1%)
      Pain22 (5.1%)
      Access site bleeding11 (2.6%)
      Arterial hypertension/hypertension11 (2.6%)
      Fever11 (2.6%)
      Headache11 (2.6%)
      Heartburn11 (2.6%)
      Vaso vagal response11 (2.6%)
      TOTAL5931 (79.5%)
      Through twenty-four months of follow-up, there were no serious device related adverse events during the procedure, including no renal artery damage (i.e. no renal artery dissections, aneurysms, flow limiting renal artery vasospasms, or renal artery stenosis). There was one reported (1/39, 2.6%) serious vascular access site complication (pseudoaneurysm of the femoral artery) which resolved after manual compression and thrombin injection. This event extended hospitalization by 24 h but resolved without further sequelae. A number of minor peri-procedural events were noted without further clinical sequelae (Table 1).
      Furthermore, there were no serious device related adverse events as independently adjudicated throughout the 24 month follow-up.
      Renal artery evaluation was conducted on all patients at 6 months by CT imaging, or by ultrasound if contraindicated for a CT. No patients developed a new hemodynamically significant renal artery stenosis.
      Renal function was evaluated by repeated measurements of eGFR, serum creatinine, and cystatin C from baseline through 24 months of follow-up. No patient experienced a reduction in eGFR >50%, a two-fold increase in serum creatinine, or progressed to end stage renal disease. There were no statistically or clinically significant changes in eGFR or creatinine at 6 months post-procedure versus baseline, attesting to the renal safety of the procedure. Furthermore, there were no clinically significant changes in cystatin C levels (mg/l, a renal injury marker) (Table 2).
      Table 2Renal function.
      VariableBaselineMonth 1Month 3Month 6Month 12Month 18Month 24
      eGFR (mL/min/1.73 m2)73.97 ± 16.78

      (n = 38)
      75.9 ± 15.73

      (n = 39)
      73.74 ± 16.41

      (n = 38)
      73.76 ± 17.44

      (n = 37)
      70.89 ± 17.21

      (n = 37)
      72.76 ± 17.91

      (n = 37)
      74.29 ± 17.12

      (n = 34)
      Serum creatinine (umol/L)88.90 ± 19.39

      (n = 39)
      86.67 ± 21.22 (n = 39)88.24 ± 24.39 (n = 38)88.32 ± 26.15 (n = 37)91.16 ± 23.62 (n = 37)89.32 ± 25.35 (n = 37)85.38 ± 23.81 (n = 34)
      Cystatin C (mg/L)1.03 ± 0.30

      (n = 37)
      1.01 ± 0.28

      (n = 39)
      1.04 ± 0.28

      (n = 35)
      1.09 ± 0.30

      (n = 37)
      1.12 ± 0.29

      (n = 36)
      1.15 ± 0.32

      (n = 37)
      1.07 ± 0.27

      (n = 35)
      Urine Albumin-to-Creatinine Ratio (mg/g)*306.53 ± 841.90

      32.4

      (n = 36)
      230.19 ± 658.96

      27.0

      (n = 36)
      106.01 ± 234.24

      21.2

      (n = 33)
      274.64 ± 613.18

      25.6

      (n = 31)
      242.93 ± 651.83

      19.5

      (n = 35)
      288.26 ± 772.19

      20.8

      (n = 34)
      326.16 ± 928.11

      20.3

      (n = 33)
      Values reported are median ± standard deviation, *median (if applicable), n.

      3.2 Performance results

      Compared to baseline, office and ambulatory systolic BP of the cohort significantly decreased at all time points (p ≤ 0.006). The average office BP (mmHg) at baseline was 174/93 (mmHg). Patients on average had the following changes in office BP from baseline: 1-month −19/−7 mmHg, 3-month −26/−9 mmHg, 6-month −25/−7 mmHg, 12-month −23/−7 mmHg and 24-months −27/−9 mmHg (all p < 0.0001) (Fig. 1). With regards to responder rates using a definition of a reduction in office systolic BP of at least 10 mmHg or greater, rates were as follows 1-month – 67% (n = 26/39), 3-month – 82% (n = 31/38), 6-month – 81% (n = 30/37), 12-month – 78% (n = 29/37) and 24-month – 89%) n = 31/35). In addition, by 24 months, over one-third of patients are now controlled (<140 mmHg systolic) and the majority are <160 mmHg (Fig. 2).
      Fig. 1
      Fig. 1Office blood pressure change from baseline.
      Fig. 2
      Fig. 2Office systolic blood pressure classification by follow-up.
      In addition, in-office resting heart rate was collected at baseline 67.7 ± 15.6 (n = 39) bpm, 1-month 65.0 ± 14.5 (n = 39), 3-months 65.5 ± 15.9 (n = 38), 6-months 66.0 ± 14.8 (n = 37), 12-months 67.0 + 15.3 (n = 37), and 12-months 66.1 + 12.7 (n = 35).
      The average 24-h ambulatory BP at baseline was 155/82 mmHg. The average 24-h ambulatory BP (mmHg) changes from baseline were, 1-month −7/-4 mmHg, 3-months −11/-4 mmHg, 6-months −9/-3 mmHg, 12-months −11/-4 mmHg and 24 months −13/-5 mmHg (p ≤ 0.0024 for systolic changes) (Fig. 3).
      Fig. 3
      Fig. 324-h ambulatory blood pressure change from baseline.
      Fig. 4 shows average office BP, 24-h ABPM, and daytime ABPM measures at baseline and at 1, 3, 6, 12 and 24 months post procedure. Both systolic and diastolic values measured in the office or by ambulatory monitoring were consistent, exhibiting reductions at 1-month and remaining stable through 24-months post procedure.
      Fig. 4
      Fig. 4Change in office, 24-h ambulatory, and daytime ambulatory measurements over time.
      ABPM, ambulatory BP monitoring; D, diastolic; S, systolic.
      Over the 6-month follow-up period, 15/37 subjects (41%) had changes to their anti-hypertension medications: nine patients had a decrease in their number of anti-hypertensive medications or doses and six had an increase in their number of anti-hypertensive medications or doses. For patients that did not have an increase or decrease in their number of anti-hypertensive medications or doses (n = 22), the 6-month office blood pressure change was similar to the entire cohort at −23/−6 mmHg (p ≤ 0.0006) as well as 24-h ABPM change of −8/−3 mmHg (p = 0.0025, 0.0738).

      4. Discussion

      This data demonstrates that the second generation EnligHTN Renal Denervation System is safe and performs as intended in the treatment of patients with drug-resistant hypertension. This is evidenced by the absence of serious device or procedure related adverse events affecting the renal arteries or renal function throughout the primary endpoint of 6 months of follow-up and the presence of a statistically and clinically significant 25/7 mmHg reduction in office BP at 6 months.
      The safety data from this study are excellent and add to the growing body of data regarding the safety of this technique. In the SYMPLICITY HTN-1 trial, one patient had a renal artery dissection and this low frequency has been described in other datasets [
      • Krum H.
      • Schlaich M.
      • Whitbourn R.
      • Sobotka P.A.
      • Sadowski J.
      • Bartus K.
      • Kapelak B.
      • Walton A.
      • Sievert H.
      • Thambar S.
      • Abraham W.T.
      • Esler M.
      Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.
      ]. Furthermore, renal artery stenosis is a described phenomenon occurring in approximately 2% of patients after renal artery denervation in early trials [
      • Krum H.
      • Schlaich M.
      • Whitbourn R.
      • Sobotka P.A.
      • Sadowski J.
      • Bartus K.
      • Kapelak B.
      • Walton A.
      • Sievert H.
      • Thambar S.
      • Abraham W.T.
      • Esler M.
      Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.
      ,
      • Worthley S.G.
      • Tsioufis C.P.
      • Worthley M.I.
      • Sinhal A.
      • Chew D.P.
      • Meredith I.T.
      • Malaiapan Y.
      • Papademetriou V.
      Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial.
      ]. The absence of any of these serious adverse events in this study warrants discussion. Although possible that this is simply by chance given the sample size tested, it is worth noting that this study was performed by experienced operators all of whom had prior renal denervation experience with most having specific experience with the EnligHTN catheter and system. In addition, the EnligHTN catheter requires less manipulation, which may reduce the risk of renal artery injury. Moreover, the fact that all patients enrolled were able to undergo renal denervation in both renal arteries is evidence of both the selection process and the procedural efficacy.
      The performance seen in this study is commensurate with that seen in other published studies, including the EnligHTN I study, and confirms the consistency of this therapy in experienced hands [
      • Esler M.D.
      • Krum H.
      • Sobotka P.A.
      • Schlaich M.P.
      • Schmieder R.E.
      • Boehm M.
      • Mahfoud F.
      • Sievert H.
      • Wunderlich N.
      • Rump L.C.
      • Vonend O.
      • Uder M.
      • Lobo M.
      • Caulfield M.
      • Erglis A.
      • Azizi M.
      • Sapoval M.
      • Thambar S.
      • Persu A.
      • Renkin J.
      • Schunkert H.
      • Weil J.
      • Hoppe U.C.
      • Walton T.
      • Scheinert D.
      • Binder T.
      • Januszewicz A.
      • Witkowski A.
      • Ruilope L.M.
      • Whitbourn R.
      • Bruck H.
      • Downes M.
      • Luscher T.F.
      • Jardine A.G.
      • Webster M.W.
      • Zeller T.
      • Sadowski J.
      • Bartus K.
      • Straley C.A.
      • Barman N.C.
      • Lee D.P.
      • Witteles R.M.
      • Bhalla V.
      • Massaro J.M.
      Investigators SH
      Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.
      ,
      • Worthley S.G.
      • Tsioufis C.P.
      • Worthley M.I.
      • Sinhal A.
      • Chew D.P.
      • Meredith I.T.
      • Malaiapan Y.
      • Papademetriou V.
      Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial.
      ]. The lesser reduction in office systolic BP at 1-month than was seen at 3- and 6-months is consistent with many other studies of renal denervation, although different from what was seen in the EnligHTN I study [
      • Krum H.
      • Schlaich M.
      • Whitbourn R.
      • Sobotka P.A.
      • Sadowski J.
      • Bartus K.
      • Kapelak B.
      • Walton A.
      • Sievert H.
      • Thambar S.
      • Abraham W.T.
      • Esler M.
      Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.
      ,
      • Esler M.D.
      • Krum H.
      • Sobotka P.A.
      • Schlaich M.P.
      • Schmieder R.E.
      • Boehm M.
      • Mahfoud F.
      • Sievert H.
      • Wunderlich N.
      • Rump L.C.
      • Vonend O.
      • Uder M.
      • Lobo M.
      • Caulfield M.
      • Erglis A.
      • Azizi M.
      • Sapoval M.
      • Thambar S.
      • Persu A.
      • Renkin J.
      • Schunkert H.
      • Weil J.
      • Hoppe U.C.
      • Walton T.
      • Scheinert D.
      • Binder T.
      • Januszewicz A.
      • Witkowski A.
      • Ruilope L.M.
      • Whitbourn R.
      • Bruck H.
      • Downes M.
      • Luscher T.F.
      • Jardine A.G.
      • Webster M.W.
      • Zeller T.
      • Sadowski J.
      • Bartus K.
      • Straley C.A.
      • Barman N.C.
      • Lee D.P.
      • Witteles R.M.
      • Bhalla V.
      • Massaro J.M.
      Investigators SH
      Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.
      ,
      • Worthley S.G.
      • Tsioufis C.P.
      • Worthley M.I.
      • Sinhal A.
      • Chew D.P.
      • Meredith I.T.
      • Malaiapan Y.
      • Papademetriou V.
      Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial.
      ]. There is no clear explanation for this difference, however, we should be careful to speculate too broadly given the small sample size. Looking at the datasets of first-in-human trials of renal denervation to date, generally there is a lesser BP reduction at 1-month that appears to be numerically greater at the 6-month time point [
      • Krum H.
      • Schlaich M.
      • Whitbourn R.
      • Sobotka P.A.
      • Sadowski J.
      • Bartus K.
      • Kapelak B.
      • Walton A.
      • Sievert H.
      • Thambar S.
      • Abraham W.T.
      • Esler M.
      Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.
      ,
      • Esler M.D.
      • Krum H.
      • Sobotka P.A.
      • Schlaich M.P.
      • Schmieder R.E.
      • Boehm M.
      • Mahfoud F.
      • Sievert H.
      • Wunderlich N.
      • Rump L.C.
      • Vonend O.
      • Uder M.
      • Lobo M.
      • Caulfield M.
      • Erglis A.
      • Azizi M.
      • Sapoval M.
      • Thambar S.
      • Persu A.
      • Renkin J.
      • Schunkert H.
      • Weil J.
      • Hoppe U.C.
      • Walton T.
      • Scheinert D.
      • Binder T.
      • Januszewicz A.
      • Witkowski A.
      • Ruilope L.M.
      • Whitbourn R.
      • Bruck H.
      • Downes M.
      • Luscher T.F.
      • Jardine A.G.
      • Webster M.W.
      • Zeller T.
      • Sadowski J.
      • Bartus K.
      • Straley C.A.
      • Barman N.C.
      • Lee D.P.
      • Witteles R.M.
      • Bhalla V.
      • Massaro J.M.
      Investigators SH
      Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.
      ].
      The efficiency and speed of the second generation system can be directly compared with the first generation EnligHTN System, and indirectly with those of other systems. Indeed, in this study, the time taken to perform the procedure, the time spent with the renal denervation catheter in situ in the renal arteries, were all less than that for the first generation EnligHTN system. In particular, the median time from initiation to completion of RF energy delivery was reduced by more than half, with the second generation system versus the first system (13 min versus 34 min). This provides evidence for potentially improved work-flows in the cath lab and potentially would impact over all cost-effectiveness. More importantly, it can be hypothesized that shorter procedural times potentially played some role in the excellent safety seen in this study. The marked reduction in the time required for renal artery instrumentation for the entire renal denervation procedure may have been a factor for the absence of serious device related adverse events seen in this study.
      Further issues, such as defining and identifying responders using parameters such as office or ABP index, identifying the time point at which this should be considered, remain to be elucidated. Datasets have shown increased responder rates at the 24-month time-point and beyond [
      • Worthley S.
      • Wilkins G.
      • Webster M.W.
      • Antonis P.
      • Warren R.
      • Whitbourn R.J.
      Safety and performance of the next generation EnligHTN (TM) Renal Denervation System in patients with drug-resistant, uncontrolled hypertension: a first-in-human multicentre study.
      ], however, this may be more reflective of additional therapies or other changes, rather than the result of renal denervation per se. Clearly further data and focused study are required to better understand patient and procedural predictors of response to renal denervation.
      The limitation of the study is that it is a single arm, observational, first-in-human study and, although the performance signal seen is consistent with many other such trials, it is not a randomized placebo controlled trial. The SYMPLICITY HTN-3 trial was a rigorous, randomized sham-controlled trial of 535 patients that failed to show that renal denervation with the SYMPLICITY catheter was superior to sham control for the purpose of reducing office BP at 6 months [
      • Bhatt D.L.
      • Kandzari D.E.
      • O'Neill W.W.
      • D'Agostino R.
      • Flack J.M.
      • Katzen B.T.
      • Leon M.B.
      • Liu M.
      • Mauri L.
      • Negoita M.
      • Cohen S.A.
      • Oparil S.
      • Rocha-Singh K.
      • Townsend R.R.
      • Bakris G.L.
      Investigators SH
      A controlled trial of renal denervation for resistant hypertension.
      ]. Many factors may be suggested to explain this lack of benefit, including the limited number of lesions created, raising the question of the adequacy of the renal denervation procedure. For example, the mean number of lesions in HTN-3 was 9.2 versus 15.9 in this study. There are also some potential concerns around the geographic location of lesions with a single-electrode system that are well addressed with a geometrically pre-specified electrode array of the EnligHTN system. However, further studies are warranted to prove that second generation multielectrode renal denervation systems are superior to appropriate placebo based comparator arms. This study, therefore, is pivotal from a safety and performance perspective since it lays the foundation for such studies using the EnligHTN system.
      Herein, 39 patients successfully underwent renal sympathetic denervation using the second generation EnligHTN system that permits simultaneous radiofrequency delivery from all four electrodes. This study with a 24-month follow up period demonstrates that the new system is both safe and effective in the treatment of patients with resistant hypertension. Additional studies using an appropriate placebo based comparator are needed to address further utility of this system.

      Conflict of interest

      Dr. Whitbourn reports grants from St Jude Medical during the conduct of the study. Dr. Worthley reports grants from St. Jude Medical Inc., during the conduct of the study; grants from Medtronic, outside the submitted work.
      All other authors have nothing to disclose.

      Financial support

      The study was sponsored by St. Jude Medical Inc.

      Author contributions

      S.G.W conceived the study, participated in its design, acquisition of the data, critical review and correction of manuscript. G.T.W participated in acquisition of the data and critical review of manuscript. M.W.W participated in acquisition of the data and critical review of manuscript. J.K.M participated in acquisition of the data and critical review of manuscript. S. D participated in its design, acquisition, analysis and interpretation of the data and drafting of manuscript. R.J.Wh participated in acquisition of the data and critical review of manuscript. R.J.Wa participated in acquisition of the data and critical review of manuscript.

      Acknowledgements

      We thank the following St. Jude Medical personnel: Rita Omega Ella, for statistical analyses.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

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