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. 2016 Feb 9;18(6):585–592. doi: 10.1111/jch.12789

Controversies Surrounding Renal Denervation: Lessons Learned From Real‐World Experience in Two United Kingdom Centers

Amy E Burchell 1,2,†, Kenneth Chan 3,4,†, Laura EK Ratcliffe 1,5, Emma C Hart 1,5, Manish Saxena 3,4, David J Collier 3, Ajay K Jain 3,6, Anthony Mathur 3,6, Charles J Knight 3,6, Mark J Caulfield 3,4, Julian FR Paton 1,5, Angus K Nightingale 1, Melvin D Lobo 3,4,‡,✉, Andreas Baumbach 1,2,‡,✉
PMCID: PMC8031946  PMID: 26857092

Abstract

Renal denervation (RDN) is a therapy that targets treatment‐resistant hypertension (TRH). The Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity) HTN‐1 and Symplicity HTN‐2 trials reported response rates of >80%; however, sham‐controlled Symplicity HTN‐3 failed to reach its primary blood pressure (BP) outcome. The authors address the current controversies surrounding RDN, illustrated with real‐world data from two centers in the United Kingdom. In this cohort, 52% of patients responded to RDN, with a 13±32 mm Hg reduction in office systolic BP (SBP) at 6 months (n=29, P=.03). Baseline office SBP and number of ablations correlated with office SBP reduction (R=−0.47, P=.01; R=−0.56, P=.002). RDN appears to be an effective treatment for some patients with TRH; however, individual responses are highly variable. Selecting patients for RDN is challenging, with only 10% (33 of 321) of the screened patients eligible for the study. Medication alterations and nonadherence confound outcomes. Adequate ablation is critical and should impact future catheter design/training. Markers of procedural success and improved patient selection parameters remain key research aims.

Renal denervation (RDN) was developed as an endovascular ablation technique for patients with treatment‐resistant hypertension (TRH; blood pressure [BP] ≥140/90 mm Hg despite the use of ≥3 antihypertensive medications). The procedure uses various energy modalities such as radiofrequency (RF), ultrasound, and cryotherapy to disrupt the nerves innervating the kidney including both sympathetic efferent and sensory afferent nerves1 When activated, the latter can trigger reflex increases in sympathetic activity and arterial pressure.2 Initial proof‐of‐concept and safety studies (the Renal Denervation in Patients With Uncontrolled Hypertension [Symplicity] HTN‐1 and the Safety and Efficacy Study of Renal Artery Ablation in Resistant Hypertension Patients [EnligHTN I] trials) and a subsequent randomized controlled trial (Symplicity HTN‐2) reported response (≥10 mm Hg drop in office systolic BP [SBP]) rates of ≥80% at 6 months post‐RDN.3, 4, 5 Significant reductions in office BP were maintained out to at least 24 months post‐denervation in all three of these studies (−29/−14 mm Hg, −29/−13 mm Hg, and −30/−11 mm Hg, respectively).6, 7, 8 However, most recently, the American randomized sham‐controlled trial (Symplicity HTN‐3) failed to meet its primary outcome of a reduction in office BP at 6 months, prompting renewed discussion into the efficacy of RDN.9 In this review we will address the current controversies surrounding RDN and consider how real‐world RDN outcomes can be put into perspective in light of the data from these large‐scale studies.

We will support this review with data from two United Kingdom centers, St Bartholomew's Hospital in London (Bart's) and the Bristol Heart Institute (BHI). These data illustrate the real‐world clinical experience of RDN and highlight the variability in BP response, as well as some of the challenges involved in implementing a novel, invasive, irreversible, and expensive therapy, in rigorously selected patients with TRH. The key findings from the cohort of our first 29 patients treated with RDN for TRH are described in Box 1; these lessons, which predict some of the problems that led to the failure of the large‐scale trial Symplicity HTN‐3, will form the basis of our discussion.

Box 1. Findings from the Bart's/BHI renal denervation cohort.

Following rigorous screening, 29 patients underwent renal denervation using a Symplicity Flex catheter with baseline and outcome measures of office and ambulatory blood pressure. SBP, systolic blood pressure; RDN, renal denervation; BP, blood pressure; TRH, treatment resistant hypertension.

  • Despite rigorous patient selection, using similar inclusion criteria, we could not reproduce the response rate of >80% seen in the first two Symplicity studies; the response rate in our cohort was only 52% at 6 months (n=29).4, 5

  • Baseline office SBP predicts an individual patient's response (≥10 mm Hg reduction in office SBP) to RDN, with patients with an office SBP of >177 mm Hg most likely to respond.

  • Previous studies have reported outcome data as a mean reduction in office BP, but this does not tell the full story. The individual patient response to RDN is highly variable and responders, nonresponders, and even reverse responders (with an increase in office BP after RDN) can be identified. Reverse responders had fewer ablation points than both responders and nonresponders in our cohort, a finding that highlights the importance of operator experience and has significant implications for the development of novel RDN catheters.

  • Identifying appropriate patients for RDN is a challenge. From our specialist hypertension clinics, 321 patients were screened to identify only 33 (10 %) individuals with TRH who were eligible for RDN. A total of 20% of these patients (36 of 184) were anatomically ineligible for RDN, including eight cases of renal artery stenosis.

  • Despite our aim to keep medications unchanged during the first 6 months of follow‐up, 17 of 29 patients (59%) had changes to their drug regimens during this period. Challenges in controlling medications and confirming medication adherence in real‐world clinical situations make BP outcome data more difficult to interpret.

Methods

A total of 321 patients were screened in order to recruit 29 patients with TRH from two British Hypertension Society–accredited Specialist Hypertension Clinics (Bart's: 11 patients, BHI: 18 patients) for RDN (Figure 1). The patients were enrolled between December 2009 and January 2011 in the Bart's cohort, and between March 2012 and January 2013 in the BHI cohort. Prior to RDN, our patients were investigated for secondary causes of hypertension, assessed for white‐coat hypertension (home and/or ambulatory BP monitoring [ABPM]), and questioned about drug adherence (with observed tablet‐taking and subsequent ABPM at Bart's). Renal anatomy was determined prior to RDN using magnetic resonance or computerized tomography angiography and deemed suitable for ablation according to Joint British Society guidelines.10 RDN was performed via a 6 French femoral arterial sheath, under fluoroscopic guidance, using a Symplicity‐Flex catheter (Medtronic, Inc, Santa Rosa, CA). Four to seven discrete 8‐watt RF ablations of 2 minutes’ duration each were administered within both renal arteries in a helical distribution. Patients were followed up for measures of office BP and ABPM at baseline and at 1, 3, 6, and 12 months. The primary intent was to keep medications unchanged during follow‐up; however, medications could be changed at the discretion of the treating physician if clinically indicated. The study was approved by the local ethics committees, and all patients provided written informed consent.

Figure 1.

Figure 1

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Patient screening pathway prior to renal denervation. All patients identified via Specialist Hypertension Clinic. BP indicates blood pressure; eGFR, estimated glomerular filtration rate (mL/min/1.73m2).

Statistical Analysis

Our data are presented as mean±standard deviation. Changes in physiological parameters were assessed for significance using Student t test or one‐way analysis of variance (with Bonferroni multiple comparison test) for continuous data with equal variances, Kruskal‐Wallis test for continuous data with unequal variances, and Pearson chi‐square test for categorical data. Relationships between these parameters were evaluated using Pearson's correlation coefficient and linear regression (GraphPad Prism; GraphPad Software, Inc, La Jolla, CA). A two‐tailed P value of <.05 was considered statistically significant.

Results and Discussion

BP Outcomes

The response rate in our cohort was only 52% (15 of 29) at 6 months and 62% (13 of 21) at 12 months post‐RDN. While there was a significant 13±32 mm Hg reduction in mean office SBP in our study cohort at 6 months following the procedure (n=29, P=.03), this change was not of the magnitude seen in Symplicity HTN‐1 and HTN‐2 (−22±22 mm Hg and −32±23mm Hg, respectively).3, 5 Baseline patient characteristics for our cohort are summarized in Table 1 and mean office BP outcome data are shown in Figure 2. The BP responses were highly variable, with some patients developing a clinically significant (≥10 mm Hg, n=15) reduction in office SBP 6 months post‐RDN, while, in others, little BP effect (n=7) or an increase (n=7) was observed. Among the 15 patients who did respond to RDN, the office SBP reduction at 6 months was robust (−38±23 mm Hg, P<.05) and similar to that observed in Symplicity HTN‐1 and HTN‐23, 5; furthermore, by 12 months, four patients had an office SBP reduction of >50 mm Hg. These individual data are shown in Figure 3.

Table 1.

Patient Baseline Characteristics

Baseline (n=29)
Demographics
Age, y 55.4±12.9
Male sex, No. (%) 14 (48)
Body mass index, kg/m² 30.2±4.3
Risk factors and target organ damage
eGFR, mL/min/1.73m2 74±18
Type II diabetes, No. (%) 5 (17)
Hypercholesterolemia, No. (%) 7 (24)
Rheumatoid arthritis, No. (%) 2 (7)
Coronary artery disease, No. (%) 8 (28)
Cerebrovascular disease, No. (%) 9 (31)
Antihypertensive treatment
Antihypertensive drugs, No. 5.2±1.7
ACE inhibitors/ARBs, No. (%) 23 (79)
Calcium channel blockers, No. (%) 21 (72)
Diuretics, No. (%) 22 (76)
Aldosterone antagonists, No. (%) 13 (45)
Beta‐Blockers, No. (%) 18 (62)
Alpha‐Blockers, No. (%) 18 (62)
Direct renin inhibitors, No. (%) 6 (21)
Centrally acting agents, No. (%) 12 (41)
Direct vasodilators, No. (%) 4 (14)
Office blood pressure and heart rate measurements
SBP, mm Hg 188±20
DBP, mm Hg 104±21
PP, mm Hg 84±20
Heart rate, beats per min 82±18
ABPM data
Daytime SBP, mm Hg (n=18) 171±19
Daytime DBP, mm Hg (n=18) 101±18
Nighttime SBP, mm Hg (n=16) 157±23
Nighttime DBP, mm Hg (n=16) 89±21
24‐h SBP, mm Hg (n=16) 168±19
24‐h DBP, mm Hg (n=16) 99±20
24‐h heart rate, beats per min (n=16) 76±12
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Abbreviations: ACE, angiotensin‐converting enzyme; ARBs, angiotensin receptor blockers; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; PP, pulse pressure; SBP, systolic blood pressure. Baseline demographic data are presented for our cohort, including ambulatory blood pressure monitoring (ABPM) data excluding white‐coat hypertension for 18 of 29 patients. The remaining 11 patients were assessed for pseudoresistant hypertension using home blood pressure monitoring or ABPM assessment in primary care prior to enrollment in our study. Data are expressed as mean±standard deviation.

Figure 2.

Figure 2

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Change in mean office systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 1, 3, 6, and 12 months post–renal denervation (RDN). oBP indicates office blood pressure. *P=.03. **P=.002.

Figure 3.

Figure 3

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Change in office systolic blood pressure (oSBP) for individual patients at 1, 3, 6, and 12 months post–renal denervation (RDN). Patients grouped by oSBP outcome at 6 months post‐RDN: (A) responders (reduction in oSBP ≥10 mm Hg), (B) nonresponders (change in oSBP between −9 and +10 mm Hg), and (C) reverse responders (increase in oSBP >10 mm Hg).

Our real‐world data cannot replicate the findings of the Symplicity studies and are more reflective of the success rates seen in other European studies.11, 12, 13 The UK Renal Denervation Affiliation14 reported an office BP reduction of 22/9 mm Hg, with a 65% response rate, in a cohort of 253 patients from 18 centers. The ALSTER and Heidelberg registries also reported real‐world data, with better response rates of 76% (n=93) and 73% (n=63), respectively.15, 16 Persu and colleagues17 reported a response rate of 59.6% in their meta‐analysis of 10 European expert RDN centers, and the Global Symplicity Register18 of 998 patients showed a response rate of 67%. These findings are more consistent with our 52% response rate and corroborate our clinical impression that while RDN is effective in some patients, it is not a panacea for all patients with poorly controlled hypertension.

Thirteen patients in our cohort had ABPM data available at 6 months. There was a change in mean 24‐hour BP of −12±21/−7±14 mm Hg (P=.07/.10). Mean daytime BP changed by −14±21/−8±14 mm Hg (P=.04/.07) and mean nighttime BP by −9±23/−6±15 mm Hg (P=.23/.53) (Figure 4). The lack of ABPM data for all patients in our cohort is a clear limitation of the study. Our access to ABPM devices has improved; however, some patients (particularly those with the highest BP) continue to find high‐pressure cuff inflations during ABPM intolerable.

Figure 4.

Figure 4

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Change in blood pressure (BP) parameters for the 13 patients with ambulatory BP data at baseline and 6 months post–renal denervation. DBP indicates diastolic blood pressure; SBP, systolic blood pressure. *P=.04.

Mahfoud and colleagues19 compared the reduction in office and ambulatory BP in patients with resistant and pseudoresistant hypertension following RDN. While both groups demonstrated a reduction in office BP, only those with true resistant hypertension demonstrated a significant reduction in 24‐hour ABPM of −10.2/−4.9 mm Hg. The use of 24‐hour ABPM data as an outcome measure may also prove to better reflect the regression of end organ damage in these significantly hypertensive patients, since nocturnal hypertension in particular strongly correlates with cardiovascular morbidity and mortality.20, 21 Ultimately, BP is only a surrogate marker for the physical and economic burden inflicted by conditions such as stroke, myocardial infarction, and chronic kidney disease.19, 22

Predictors of BP Response to RDN

The strongest positive predictor for a reduction in office SBP in the Symplicity HTN‐3 study was a baseline office SBP of ≥180 mm Hg,9, 23 a criterion that has previously been shown to correlate with BP reduction post‐RDN, as highlighted in the UK Renal Denervation Affiliation, Global Symplicity, and Heidelberg registry data.14, 16, 18 We confirmed this significant correlation between baseline office SBP and the change in office SBP at 6 months in our patients (R=−0.47, P=.01; Figure 5a).

Figure 5.

Figure 5

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(A) Correlation between baseline office systolic blood pressure (oSBP) and the change in office SBP (primary outcome measure) at 6 months post–renal denervation. In the 13 patients with available ambulatory blood pressure (BP) data: (B) correlation between baseline office diastolic BP (oDBP) and the change in mean 24‐hour SBP at 6 months post–renal denervation, and (C) correlation between baseline daytime DBP and the change in mean 24‐hour SBP at 6 months post–renal denervation. R indicates Pearson's correlation coefficient.

Recent findings by Ewen and colleagues24 indicate that patients with isolated systolic hypertension (ISH) and therefore lower diastolic BP have a restricted response to RDN. This finding is supported by our data with respect to baseline office and ambulatory diastolic BP and ABPM outcomes (Figure 5b and c).

Conventionally, a BP response to RDN has been arbitrarily defined as a reduction in office SBP of ≥10 mm Hg.3 If our cohort is divided into RDN BP responders (n=15, office SBP reduction ≥10 mm Hg), nonresponders (n=7, change in BP −9 mm Hg to +10 mm Hg) and reverse responders (n=7, increase in office SBP >10 mm Hg), the key significant differences in baseline characteristics between these groups relate to the number of ablations the participants received (Table 2). Our data demonstrate a significant correlation between both the number of ablations per artery and the total number of ablations for any given patient and the reduction in office SBP at 6 months (R=−0.56 [P=.002] and R=−0.55 [P=.002], respectively).

Table 2.

Difference in Office BP Outcomes and Baseline Parameters Between BP Responders, Nonresponders, and Reverse Responders

Responders (n=15) Nonresponders (n=7) Reverse Responders (n=7) P Value
Response to RDN at 6 months
∆ Office SBP −38±23 [−49 to −26]a , b 1±4.4 [−4.2 to 2.2]a 26±10 [18–34]b <.0001
∆ Office DBP −11±19 [−20 to −1] −3±12 [−12 to 5] 5 ±16 [−6 to 17] .12
Baseline parameters
Age, y 59.9±12.1 49.6±9.0 51.4±15.5 .14
Men, No. (%) 9 (60) 3 (43) 2 (29) .37
Body mass index, kg/m² 29.7±2.6 32.1±5.1 29.8±6.5 .52
eGFR, mL/min/1.73m2 77±13 72.4±17.8 68.6±25.9 .55
Antihypertensives, No. 4.9±1.6 5.9±2.0 5.0±1.8 .49
Ablations per artery, No. 5.6±0.6b 5.5±0.8c 4.4±0.8b , c .003
Total ablations, No. 11.0±1.2b 11.0±1.5c 8.9±1.7b , c .008
Office SBP, mm Hg 192±17 186±14 180±30 .41
Office DBP, mm Hg 101±21 105±21 109±24 .69
Heart rate, beats per min 79±18 86±17 90±20 .49
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Abbreviations: ∆, change; BP, blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; RDN, renal denervation; SBP, systolic blood pressure. Significant differences between subgroups for each parameter as indicated (P<.05): aresponders (reduction in office SBP ≥10 mm Hg) vs nonresponders (change in office SBP between −9 and +10 mm Hg), bresponders vs reverse responders (increase in office SBP >10 mm Hg), and cnonresponders vs reverse responders. Data are expressed as mean±standard deviation [confidence interval]. P values from one‐way analysis of variance with Bonferroni multiple comparison test for continuous data and Pearson chi‐square test for categorical data.

RDN Technique

One of the main critiques of Symplicity HTN‐3 has been inadequate denervation as a result of operator inexperience/inadequate proctoring. There were 111 operators across 88 sites, of whom 31% performed only one procedure and 23% performed five or more procedures.9 This contrasts with the greater BP reductions seen in the Global Symplicity Registry in which 59% of operators performed more than 15 procedures.18 Only 19 of 364 patients received per‐protocol RDN in Symplicity HTN‐3 and this, along with the confounding effects caused by medication changes in 39% of the population, renders the trial difficult to interpret.9, 23

In our cohort, reverse responders had significantly fewer ablations than responders and nonresponders (Table 2). It is possible that patients who receive only partial RDN may have an increase in BP as a result of unopposed action of the (usually inhibitory) reno‐renal reflexes.25 Alternatively, partial denervation could cause sensitization of those nerves that remain, inflammation of the nerves, or growth of new nerves, which could exacerbate the degree of hypertension.26, 27

So, how much denervation is required? In Symplicity HTN‐1, a subset of patients underwent assessment with norepinephrine spillover, a validated technique for assessing regional sympathetic tone28 A 47% reduction in sympathetic nerve activity appeared sufficient to achieve a reduction in BP.3, 29 Further analyses by Esler and colleagues29, 30 have shown that denervation following renal nerve ablation is highly variable between individuals and it is clear that the procedure is far more technically challenging than previously considered. When the Symplicity catheter was first launched, operators were advised to prioritize ablation of the proximal superior aspect of the renal artery in order to target the highest density of renal nerves. However, review of novel anatomical human data indicates that the renal nerves accessible to intraluminal RF energy lie more distally in the renal artery adventitia31; therefore, operators following the earlier guidance device may have been targeting the wrong part of the artery, resulting in inadequate denervation.32

If the “completeness” of denervation relates to procedural success, then a method for assessing the degree of renal nerve disruption achieved would be of significant clinical benefit and guide development of evolving catheter technologies. Techniques including direct electrical renal nerve stimulation, urinalysis for breakdown products of renal sympathetic nerve degradation (eg, tyrosine hydroxylase), and measurement of reflex responses to afferent renal nerve stimulation with agents such as adenosine or bradykinin are under evaluation.33, 34, 35

Patient Selection for RDN

In Symplicity HTN‐2, 109 of 190 (56%) patients screened were eligible for RDN. With tighter screening in Symplicity HTN‐3 (including ABPM), of the 1441 patients assessed across 88 sites in the United States, 561 (39%) were eligible for enrollment.5, 9 In our experience, meticulous screening of 321 patients referred to our Specialist Hypertension Clinics identified only 33 individuals (10%) with true TRH and suitable renal artery anatomy and without significant excluding comorbidities (including estimated glomerular filtration rate <45mL/min/1.73m2 as per Symplicity HTN‐25) who were eligible for RDN (Figure 1 and Table 1). This is consistent with estimates that 10% to 15% of patients with hypertension are genuinely treatment‐resistant once secondary causes of hypertension, pseudoresistant hypertension, and poor medication adherence are excluded.36, 37

From our clinics, 184 of the 321 patients screened underwent renal magnetic resonance or computerized tomography (CT) angiography as part of their assessment for secondary hypertension; 20% of these patients (36 of 184) were anatomically ineligible for RDN, including eight cases of renal artery stenosis. This is a slightly higher anatomical exclusion rate than the 16% (30 of 190) of patients with ineligible anatomy in Symplicity HTN‐2, but of a similar magnitude to the 20% (179 of 880) anatomical exclusion rate in Symplicity HTN‐3.5, 9

Medication Alteration and Adherence

There are important limitations with both our cohort and the Symplicity HTN studies surrounding the confirmation of adherence to medications and also changes in antihypertensive medication during the follow‐up period.3, 5, 9

In Symplicity HTN‐2 and HTN‐3 there were medication changes in 23% and 39% of patients prior to 6‐month follow‐up, respectively; however, the primary study outcomes were unaltered if patients with medication changes were removed from analyses.5, 9, 23 In our cohort, medications were changed in 59% of patients (17 of 29); however, there were no medication increases in patients who responded to RDN, and so these drug changes would have blunted, rather than supplemented, any BP effect seen. The standardized stepped‐care antihypertensive medication regimen used in the Renal Denervation in Hypertension (DENER‐HTN) study38 demonstrates that this issue can be well managed, although adequate patient support and infrastructure are required.

The run‐in period prior to RDN should also be considered. In Symplicity HTN‐3, patients were only required to be on a stable drug regimen for 2 weeks prior to baseline assessments and it is therefore possible that medication changes could have influenced the data if there was an inadequate wash‐in/wash‐out period. An 8‐week period on stable medication should be required to ensure that any intervention is not confounded by a time‐dependent drug effect.39

Symplicity HTN‐3 did not simply show a failure to alter BP, it demonstrated a significant reduction in office SBP in both the RDN and sham groups (−14.13±23.93 mm Hg and −11.74±25.94 mm Hg, respectively [both P<.001]).9 Of note, in Symplicity HTN‐2, 35% of control patients had a ≥10 mm Hg reduction in office SBP 6 months post‐RDN.5 This decrease in BP may be explained by an improvement in medication adherence. The phenomenon of a “placebo” effect attributable to enrollment in a clinical study (also known as the Hawthorne effect) is well‐established40 and it is likely that the eight study contact points between screening and 6‐month follow‐up in Symplicity HTN‐3 provided greater patient support than standard medical care.23

Kandazari and colleagues23 highlight the significant reduction in office SBP in RDN vs sham patients among non–African American patients in Symplicity HTN‐3 (−15.2 mm Hg vs −8.6 mm Hg, P=.01). In fact, African American and non–African American patients had similar office SBP responses 6 months after RDN (−15.5 mm Hg and −15.2 mm Hg, respectively), and the difference in the office SBP outcomes lies in the sham arm of the study.23 Among the sham group, African American participants demonstrated a borderline significant greater reduction in office SBP than non–African American patients (−17.8 mm Hg vs −8.6 mm Hg, P=.057).23, 41 Flack and colleagues41 recent multivariate analysis of Symplicity HTN‐3 demonstrated that African American race did not independently predict SBP outcomes in either the RDN or the sham group; however, in the sham group, the interaction between African American race and being prescribed at least one antihypertensive medication three times per day was associated with a greater reduction in office SBP at 6 months. In the sham group there was also a trend towards a greater reduction in office SBP for patients living in the south/southeastern regions of the United States41—areas that have previously been associated with lower rates of medication adherence.42

In Symplicity HTN‐3, African American participants were taking a greater number of antihypertensive medications and had more complex medication regimens than non–African Americans.41 Individuals with complex drug regimens or who are prescribed a greater number of medications may be particularly likely to be nonadherent and hence more vulnerable to a Hawthorne effect if enrolled in a clinical trial.43, 44 Hameed and colleagues12 addressed this issue by using directly observed medication administration with subsequent BP monitoring to confirm adherence prior to RDN. Their cohort achieved a response rate of 51%, with an office BP reduction of −15/−6 mm Hg (P=.01/0.2) at 6 months, which is unlikely attributable to improved medication adherence. Given that at least 50% of patients with TRH are known to be nonadherent with their medications,45 more thorough assessment of medication adherence at screening, and during follow‐up, should be mandatory in order to assess true drug resistance and establish any unreported changes in medication. Unfortunately, the best technique for assessing adherence, be it urine drug testing or observed tablet‐taking and ABPM, has yet to be established.

Conclusions

The failure of Symplicity HTN‐3 to meet its primary BP outcome could condemn RDN to the history books. However, while individual responses vary considerably and real‐world data cannot replicate the high success rates of earlier trials,18 and a Hawthorne effect among study participants must be considered, there does appear to be a subpopulation of patients with TRH who respond to RDN. Whether this variability in outcome is the result of inappropriate patient selection (including those with pseudoresistant or nonsympathetically mediated hypertension), confounding drug titrations and adherence issues, or technical issues related to incomplete denervation has yet to be clarified.46 Many of the controversies that now surround RDN could have been predicted from preexisting real‐world experience. The lessons detailed in Box 2 may help to identify those most likely to respond to RDN and evaluate the mechanisms underlying this intervention.

Box 2. Clinical implications for future studies of renal denervation.

RDN, renal denervation; SBP, systolic blood pressure; BP, blood pressure; ABPM, ambulatory blood pressure monitoring.

  • The magnitude and rate of response to RDN in the real world is not as high as in Symplicity HTN‐1 and HTN‐2, and future trials should be powered accordingly.

  • ABPM at baseline and study endpoints should be mandatory, and the relationship between white‐coat effect and response to RDN should be further addressed.

  • BP is a marker for hypertensive disease and data for hard endpoints based on target organ damage (eg, left ventricular hypertrophy, excretory renal function, albuminuria, stroke, myocardial infarction) are required to support the efficacy of RDN.

  • RDN is consistently most effective in patients with severe treatment‐resistant hypertension (office SBP >160 mm Hg). A greater understanding of the mechanisms underlying RDN should be established before this therapy is offered to the broader hypertensive population.

  • Hypertension is an umbrella term and may cover a range of pathologies. Patients with white‐coat effect or isolated systolic hypertension represent subgroups with different underlying physiology and therefore potentially different susceptibility to RDN.

  • Adequate ablation is critical and should impact operator training and catheter design. BP outcomes can only be interpreted if we know that adequate denervation has been achieved. On‐table markers of procedural success are required.

  • The extent of renal denervation required to reduce BP has yet to be established, and the possibility that inadequate denervation could exacerbate hypertension must be considered.

  • Medication changes and adherence issues confound BP outcomes. Every attempt should be made to standardize and monitor adherence to concurrent pharmacotherapy during RDN trials.

Conflicts of Interest and Source of Funding

Dr Burchell is funded by a University Hospitals Bristol NHS Foundation Trust Clinical Research Fellowship. Dr Lobo is supported by the Bart's Charity. The Bristol NIHR Biomedical Research Unit for Cardiovascular Disease and Above and Beyond charity supported the renal denervation procedures performed in Bristol. Medtronic is supporting ongoing renal denervation research at the Bristol Heart Institute. Funding for renal denervation procedures at St Bartholomew's was provided by Medtronic as sponsor of Symplicity HTN‐2 and also as provider of ablation catheters for use outside Symplicity HTN‐2. Dr Lobo is a member of the advisory board and speakers’ bureau for Medtronic 2010 to 2012 and the advisory board and speakers’ bureau for St Jude Medical (2012–2015).

Acknowledgments

We would like to thank the Barts Charity, the Bristol NIHR Cardiovascular Research Unit, and the Bristol Above and Beyond charity for supporting this research.

J Clin Hypertens (Greenwich). 2016;18 585–592. DOI: 10.1111/jch.12789. © 2016. Wiley Periodicals, Inc.

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