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IMR Press / RCM / Volume 23 / Issue 2 / DOI: 10.31083/j.rcm2302065
Open Access Original Research
Preprocedural features of patients under antihypertensive drugs may help identify responders to renal denervation: a hypothesis-generating study
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1 Cardiovascular Center, MacKay Memorial Hospital, 104217 Taipei, Taiwan
2 Department of Medicine, Mackay Medical College, 252 New Taipei, Taiwan
3 Department of Healthcare Administration, College of Medicine, I-Shou University, 84001 Kaohsiung, Taiwan
4 Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, 112 Taipei, Taiwan
5 Department of Cardiology, Hsinchu MacKay Memorial Hospital, 300 Hsinchu, Taiwan
6 Department of Cardiology, Taitung MacKay Memorial Hospital, 950 Taitung, Taiwan
7 Department of Artificial intelligence and Medical Application, MacKay Junior College of Medicine, Nursing, and Management, 11260 Taipei, Taiwan
8 Department of Internal Medicine, National Taiwan University Hospital, 100 Taipei, Taiwan
*Correspondence: speakerlee@gmail.com (Ying-Hsiang Lee)
Academic Editors: Stefano Omboni, Brian Tomlinson and Takatoshi Kasai
Rev. Cardiovasc. Med. 2022, 23(2), 65; https://doi.org/10.31083/j.rcm2302065
Submitted: 1 December 2021 | Revised: 12 January 2022 | Accepted: 19 January 2022 | Published: 16 February 2022
(This article belongs to the Special Issue State-of-the-Art Cardiovascular Medicine in Asia 2021)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Background: Renal denervation (RDN) is effective to lower systolic blood pressure (SBP) in essential hypertension. However, patient selection under medications remains an important unmet clinical need. Methods: This multicenter study aimed at observing whether preprocedural features associated with increased renin-angiotensin-aldosterone activity influence RDN response. This study enrolled the patients who underwent RDN for uncontrolled hypertension. Medical records were reviewd and patients were divided into 2 groups depending by meeting any of the following conditions prior to RDN: (1) $>$10 mmHg of office SBP reduction after aldosterone inhibition, (2) aldosterone-renin ratio $>$30 or (3) slow flow on the renal angiogram. RDN responders were defined by a reduction in 24-hour mean $\geq$6 mmHg or by $\geq$1 class of antihypertensive drug withdraw. Results: A total of 46 patients were enrolled, of which 27 (59%) were in control group A and 19 (41%) in group B. The baseline age, gender, office and 24-hour SBP (mean 140.0 $\pm{}$ 12.8 mmHg vs. 144.0 $\pm{}$ 16.5 mmHg, p = 0.577) were comparable, while the number of prescribed drug classes was fewer in group A (4.0 $\pm{}$ 1.3 vs. 4.9 $\pm{}$ 0.9, p = 0.014). The proportion patients with prescribed aldosterone antagonist or high aldosterone-renin ratios were higher in group B. At 12 months post RDN, the results were significantly better in group B in terms of mean change in office SBP (12.4 $\pm{}$ 23.5 mmHg vs. 29.9 $\pm{}$ 25.5 mmHg, p = 0.046) and the proportion of RDN responders (51.9% vs. 89.5%, p $<$ 0.001). Conclusion: RDN was more effective in patients with any of 3 clinical indices.

Keywords
aldosteronism
hypertension
patient selection
renal denervation
1. Introduction

Several prospective randomized sham-controlled trials have demonstrated that percutaneous renal denervation (RDN) lowers office and 24-hour blood pressure (BP) in patients with uncontrolled hypertension in both the presence and absence of antihypertensive drug therapy [1, 2, 3]. This procedure provides an opportunity to achieve BP goals with lower tablet burden [4]. Current clinical interest fucusses on further increasing the RDN response rate. However, the latest evidence focusing on heart rate and renin-angiotensin-aldosterone system (RAAS) were all derived from a drug-free population [5, 6, 7]. Thus, distinguishing those hypertensive patients on medication who are best suited to the renal denervation procedure remains an unmet need.

A post-hoc analysis of the randomized sham-controlled Symplicity HTN-3 trial indicated that the use of an aldosterone antagonist at baseline was an independent predictor of the blood pressure response to RDN [8, 9]. However, patients with primary aldosteronism were excluded from the Symplicity HTN-3 trial. It is, therefore, possible that RDN is more effective in patients who tend to continue using an aldosterone antagonist for the underlying overactivity of RAAS [10]. In a pilot proof of concept study, several preprocedural characteristics featuring overactive RAAS on medical treatment were associated with RDN response [11]. The present analysis was aimed at increasing the sample size to compare blood pressure response among RDN recipients with vs. without the three features of overactive RAAS in a multi-center database.

2. Methods
2.1 Patient population and study design

We reviewed medical records of consecutive patients who received catheter-based radiofrequency RDN (Symplicity Flex™ or Spyral™, Medtronic, Minneapolis, MN, USA) for uncontrolled hypertension in three medical centers between September 2013 and August 2019 under approval of Institutional Review Boards, MacKay Memorial Hospital (IRB No. 20MMHIS087e), which waived the requirement for informed consent in this retrospective study. As of August 2019, patients meeting inclusion criteria were consecutively identified by the same inclusion and exclusion criteria from three hospitals, including the first 18 patients in the prior single-center pilot study [11]. Patient records were de-identified to preserve patient privacy and the study was performed in accordance with the guidelines of ICH-GCP (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use–Good clinical practice). Patients had no previous diagnosis of secondary hypertension, such as primary aldosteronism, although some had a reported history of obstructive sleep apnea and chronic kidney disease (CKD, defined as eGFR [estimated glomerular filtration rate] $<$60 mL/min/1.73 m${}^{2}$). Diabetes was usually diagnosed as HbA1c (Glycated Hemoglobin) $>$6.5%, fasting sugar $>$126 mg/dL on at least 2 separate measurements, or taking anti-diabetic agents. The stroke diagnosis was according to brain imaging studies and the neurologists’ documentation. All classifications were determined by an independent review of the patients’ medical record. Patients with primary aldosteronism identified by confirmatory tests, imaging studies, and/or NP-59 scintigraphy consistent with recommendations of the Taiwan Society of Aldosteronism [12] were excluded, as were patients with treatable proclaimed secondary causes, stage 5 CKD and patients on hemodialysis. We reviewed the patients’ baseline characteristics, prescribed antihypertensive medications, and pre-/post-procedural changes in BP via the electronic medical records of three hospitals around Taipei.

2.2 Predictive triad at baseline

Patients were divided into two groups, including control patients (group A) and those meeting at least one criteria in the predictive triad (group B). This preprocedural triad consisted of the following characteristics prior to RDN: (1) more than 10 mmHg of BP reduction after at least 14-day use of aldosterone antagonist, (2) ratio of serum aldosterone concentration to plasma renin activity (ARR) $>$30, or (3) the presence of slow flow on the renal angiogram. Slow flow refers to TIMI-2 flow, which is defined as delayed or sluggish antegrade flow with complete filling of the distal territory [13]. The ARR was calculated at the time of baseline 24-hour ambulatory BP measurement (ABPM) on contemporary antihypertensive medications.

2.3 Blood pressure and antihypertensive medications

Most patients had office BP measurement at 0, 1, 3, 6 and 12 months and 24-hour ABPM at 0, 1, 3–6 and 12 months after RDN. The medication was adjusted by the physicians’ decision for clinical needs. The number of medications prescribed was recorded at 0, 1, 3, 6, and 12 months by reviewing the electronic medical records.

2.4 Definition of RDN responder

Consistent with previous studies, RDN responders were defined by any of the following criteria: (1) 24-hour systolic BP reduction $\geq$6 mmHg without increasing antihypertensive medication, or (2) withdrawal of $\geq$1 class of antihypertensive medication [1, 2, 14]. Otherwise, the patient was labeled a non-responder.

2.5 Statistical analyses

All data were analyzed using SPSS version 24.0 for Windows (IBM Corp., Chicago, IL, USA). Comparison of the baseline characteristics and blood pressure during times of follow-up between group A and B were examined using the Mann-Whitney U test for continuous variables, the Fisher’s exact test for categorical variables and analysis of covariance (ANCOVA) for baseline difference adjustment.

3. Results
3.1 Patient characteristics

After excluding 3 cases with stage 5 CKD, 46 consecutive patients were enrolled in the study, of which 27 (59%) were in group A and 19 (41%) in group B. Five of 46 patients (11%) had two features of the triad and none had all three. The regimen of aldosterone antagonist was spironolactone 25 mg once daily. No significant differences between the groups in baseline patient demographics, BP, comorbidities, or neurohormones were observed. However, group A patients had a numerically higher mean 24-hour heart rate (70.7 bpm vs. 65.3 bpm, p = 0.071) and comparable 24-hour systolic (140.0 mmHg vs. 144.0 mmHg, p = 0.577) and diastolic BP (77.5 bpm vs. 76.6 bpm, p = 0.928). Group A subjects were prescribed fewer antihypertensive agents (4.0 vs. 4.9, p = 0.014) and fewer aldosterone antagonist (3.7% vs. 47.4%, p = 0.001). The proportion of CKD (55.6% vs. 80%, p = 0.350) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (66.7% vs. 89.5%, p = 0.092) was lower in group A, but without statistical significance (Table 1). The baseline ARR was 8.5 and 93.5 in group A and B (p = 0.012), respectively. Aldosterone antagonist was associated with a systolic BP reduction of 11 mmHg in those prescribed the drug. There were no procedure-related complications.

Table 1.Baseline characteristics.
 Characteristic Group A (n = 27) Group B (n = 19) p Age (y) 57.4 $\pm$ 13.4 62.3 $\pm$ 13.2 0.220 Men 66.7% 52.6% 0.373 Blood pressure Office SBP (mmHg) 154.4 $\pm$ 22.8 164.3 $\pm$ 27.7 0.190 Office DBP (mmHg) 82.8 $\pm$ 17.4 87.4 $\pm$ 16.9 0.382 Office pulse pressure (mmHg) 71.6 $\pm$ 16.5 77.0 $\pm$ 19.5 0.316 Mean 24-hour SBP (mmHg) 140.0 $\pm$ 12.8 144.0 $\pm$ 16.5 0.577 Mean 24-hour DBP (mmHg) 77.5 $\pm$ 11.2 76.6 $\pm$ 9.9 0.928 Mean 24-hour pulse pressure (mmHg) 62.5 $\pm$ 12.0 67.4 $\pm$ 19.5 0.386 Mean 24-hour HR (beat per min) 70.7 $\pm$ 8.7 65.3 $\pm$ 7.2 0.067 Comorbidity eGFR (mL/min/1.73 m${}^{2}$) 65.2 $\pm$ 25.1 48.7 $\pm$ 28.5 0.712 Chronic Kidney Disease 55.6% 80% 0.350 Diabetes 77.8% 50.0% 0.350 Previous stroke 22.2% 20.0% 1.000 Medication Number of medication class 4.0 $\pm$ 1.3 4.9 $\pm$ 0.9 0.011 ACEi or ARB 66.7% 89.5% 0.092 Calcium-channel blocker 88.9% 100.0% 1.000 Beta blocker 77.8% 73.7% 0.588 Alpha blocker 37.0% 57.9% 0.231 Central alpha2 agonist 14.8% 5.3% 0.387 Direct-acting vasodilator 51.9% 63.2% 0.551 Loop diuretics or thiazide 55.6% 52.6% 1.000 Aldosterone antagonist 3.7% 47.4% 0.001 Neurohormone Aldosterone (ng/dL) 51.5 $\pm$ 52.2 61.0 $\pm$ 68.1 0.654 Renin activity (ng/mL/hr) 16.6 $\pm$ 25.0 7.0 $\pm$ 11.1 0.160 ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HR, heart rate; SBP, systolic blood pressure. Values are presented as the mean $\pm{}$ standard deviation or percentage. Group A: triad (–); Group B: triad (+).
3.2 Office and ambulatory blood pressure

On average, office systolic BP was 154.4 $\pm$ 22.8 mmHg in group A and 164.3 $\pm$ 27.7 mmHg in group B (p = 0.310) at baseline. At 3- and 6-months post RDN, mean office systolic BP was 137.9 mmHg vs. 133.2 mmHg, respectively. Among the groups, the average reduction in office systolic BP was similar (–18.5 $\pm$ 22.8 mmHg vs. –19.3 $\pm$ 27.6 mmHg, p = 0.916) at 1 month. However, the difference between group A and B became greater at 3 months (–14.3 $\pm$ 23.2 mmHg vs. –30.7 $\pm$ 29.8 mmHg, p = 0.057) and 12 months (–12.4 $\pm$ 23.5 mmHg vs. –29.9 $\pm$ 25.5 mmHg, p = 0.046) (Table 2). The difference at 12 months remained significant after adjusting the baseline BP (p for model 1 = 0.048) and other confounding factors (p for model 2 = 0.025) (Table 2). Observed differences at 6- and 12-months post RDN might have been attenuated due to drug withdraw, especially in the group B. Mean 24-hour systolic BP at baseline was 140.0 $\pm$ 12.8 mmHg vs. 144.0 $\pm$ 16.5 mmHg (p = 0.577). At 1-month post RDN, the 24-hour systolic BP decreased from 132.5 $\pm$ 17.7 mmHg to 136.3 $\pm$ 14.0 mmHg. Numerically, the decline in 24-hour systolic BP was greater in group B at 3–6 months (–9.4 $\pm$ 19.6 mmHg vs. –18.3 $\pm$ 12.3, p = 0.330) and 12 months (–8.9 $\pm$ 17.0 mmHg vs. –12.5 $\pm$ 5.3, p = 0.693), respectively (Table 2).

Table 2.Office and 24-hour systolic blood pressure at times of follow-up.
 Office SBP (mmHg) 24-hour SBP (mmHg) Baseline 1 month 3 months 6 months 12 months Baseline 1 month 3–6 months 12 months Patient number 27 vs. 19 25 vs. 17 22 vs. 18 20 vs. 15 19 vs. 15 19 vs. 14 13 vs. 11 12 vs. 9 7 vs. 4 Group A vs. B Group A 154.4 $\pm$ 22.8 137.4 $\pm$ 17.0 137.9 $\pm$ 15.6 137.9 $\pm$ 17.9 144.9 $\pm$ 18.9 140.0 $\pm$ 12.8 132.5 $\pm$ 17.7 129.9 $\pm$ 11.5 133.4 $\pm$ 12.6 Group B 164.3 $\pm$ 27.7 142.7 $\pm$ 19.9 133.2 $\pm$ 23.3 133.2 $\pm$ 20.6 131.0 $\pm$ 19.0 144.0 $\pm$ 16.5 136.3 $\pm$ 14.0 134.2 $\pm$ 16.3 131.2 $\pm$ 4.1 ∆ Office SBP (mmHg) ∆ 24-hour SBP (mmHg) 1 month 3 months 6 months 12 months 1 month 3–6 months 12 months Group A –18.5 $\pm$ 22.8 –14.3 $\pm$ 23.2 –13.4 $\pm$ 27.2 –12.4 $\pm$ 23.5 –7.7 $\pm$ 16.0 –9.4 $\pm$ 19.6 –8.9 $\pm$ 17.0 Group B –19.3 $\pm$ 27.6 –30.7 $\pm$ 29.8 –26.9 $\pm$ 34.5 –29.9 $\pm$ 25.5 –7.3 $\pm$ 12.9 –18.3 $\pm$ 12.3 –12.5 $\pm$ 5.3 p 0.916 0.057 0.748 0.046 0.398 0.330 0.693 p for model 1 0.465 0.256 0.495 0.048 0.373 0.961 0.707 p for model 2 0.421 0.052 0.459 0.025 0.900 0.629 0.430 SBP, systolic blood pressure. Group A: triad (–); Group B: triad (+). $\Delta{}$, change in blood pressure after renal denervation. p for model 1: adjusting for baseline SBP, age and gender by analysis of covariance (ANCOVA). p for model 2: adjusting for baseline office SBP, DBP, age, gender, number of medication class, aldosterone, and renin activity by analysis of covariance (ANCOVA).
3.3 Response to renal denervation

The percentage of drug classes in use by each group is depicted in Fig. 1; the proportion of patients in group B prescribed at least four classes of drug decreased from 95% to 73% within three months and to 62% at 12 months. Compared to group A, the number of drug classes continued to decrease to 12 months in group B.

Fig. 1.

Percentage of drug class number distribution. Group A: triad (–); Group B: triad (+). The percentage of drug classes in use is depicted at baseline and 1, 3, 6, 12 months. The percentage of patients taking less than four classes of drug increases till 12 months only in group B.

Overall, nineteen patients (41%) had response to RDN in the first month. Thirty (65%) and thirty-one (67%) of all patients responded to the RDN procedure in six months and twelve months, respectively. The response rate was significantly greater in group B at 3 months (48.1% vs. 84.2%, p = 0.016); and (48.1% vs. 89.5%, p = 0.005) at 6 months. The proportion and timeline of response in two groups are depicted in Fig. 2.

Fig. 2.

Response rate to renal denervation (RDN) by groups. Group A: triad (–); Group B: triad (+). The change in proportion of responders in both groups during 12 months after RDN.

4. Discussion

Sympathetic nerveous system activity is associated with RAAS overdrive in neurogenic hypertension [15]. The RAAS may have a critical role in the activation of the sympathetic nervous system. Accumulated basic and clinical evidence supports the use of inhibitors of the RAAS, including aldosterone antagonists. These findings are consistent with the result that RDN significantly reduces the level of renin and aldosterone [5]. This study demonstrated that RDN was associated with a greater response in group B patients, who had predictive features suggesting occult aldosterone overactivity. RDN may further inhibit pre-existing sympathetic activity in patients with relatively active RAAS, which was inadequately suppressed by concomitant antihypertensive medications.

Due to its complexity, the concept of aldosteronism remains incompletely understood, and its true prevalence remains uncertain. Usually, the differential diagnosis would be initiated when ARR $>$30, suggestive of the presence of aldosteronism [16, 17]. Compared to the well-established criteria for primary aldosteronism, the secondary type depends on a diagnosis of exclusion [12, 18]. Several studies have reported that higher baseline heart rate and plasma renin activity predict better RDN response in drug-naive patients [5, 19]. However, its influence in patients on treatment remains unclear. The on-treatment ARR in this study helps identify residual aldosterone overactivity. Also, patients with occult RAAS overactivity could be present when having greater BP response to aldosterone inhibition than expected, i.e., more than 10 mmHg. The present results indicate that a patients’ prior response to an aldosterone antagonist might be an important predictor of RDN response.

Impaired renal blood flow secondary to systemic disorders is a common etiology of RAAS overactivity [10, 20]. Therefore, decreased renal blood flow (TIMI-2) on the renal angiogram was another feature we chose to identify patients with overactive RAAS. Notably, the effect of BP lowering by angioplasty alone is disappointing [21]. However, RDN has been shown to increase renal blood flow in animals [22], and investigating its impact on BP control is worthy of prospective investigation.

The patients in group B showed comparable BP effects at 1 month and more delayed response from 3 to 6 months. These findings might suggest a possible mechanism for to explain continuous BP decline for months in randomized control trials [1, 23]. Decreased spillover of norepinephrine could happen soon after RDN, but the process to modulate RAAS could last much longer. Notably, the SPYRAL HTN-ON MED trial also showed an apparent time effect of gradually decreasing systolic BP in the RDN treated group compared to the sham control group [1]. However, the present 24-hour BP measurements at 1 month also seem to indicate that RDN could help to lower BP immediately within one month in nearly half of all RDN recipients.

This multi-center, retrospective post-hoc analysis has several limitations, including the relatively small sample size and imbalanced medication choices. The imbalanced RAAS inhibitors could also reflect the discriminative power of predictive triad. BP change may be attenuated by medication adjustment in the late period of follow-up; however, we still observed significant reduction of office BP at 12 months in group B compared with group A. Because our study cohort was not drug-naïve, the determinant ARR could be influenced by multiple drug interactions, leading to nonspecific diagnosis in both groups. So, the predictive triad should not be interpreted as criteria of diagnosis. It is possible that a small proportion of patients in group A may have unknowingly met one of the triad criteria due to missing data. However, the difference in proportion still led to a lower response rate in group A.

5. Conclusions

Patient selection under medications remains an important unmet clinical need. We observed a superior response rate following RDN in the group with the predictive triad at baseline. Our results warrant further investigation on its application and causality.

Author contributions

SIL and YHL contributed to the conception and design of the study. SIL, SHS, LYML, PLL, WRL, CLC, WRC, CTT, YJW, TDW, YHL collected the data. CCH and YHL performed and supervised statistical analysis. SIL drafted the manuscript. SIL, CCH, YHL critically reviewed the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

This study was approved by the Institutional Review Boards of MacKay Memorial Hospital (approval number: 20MMHIS087e), which waived the requirement for informed consent in this retrospective study.

Acknowledgment

We would like to express our gratitude to all those who have supported our work. Thanks to all the peer-reviewers for their opinions and suggestions.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest. Tzung-Dau Wang is serving as one of the Editorial Board members of this journal. We declare that Tzung-Dau Wang had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Stefano Omboni, Brian Tomlinson and Takatoshi Kasai.

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