Efficacy of catheter-based ultrasound renal denervation in the treatment of hypertension

Abstract

BACKGROUND

Hypertension (HTN) is a prevalent chronic health condition that significantly increases the risk of cardiovascular diseases-associated mortalities. Despite the use of antihypertensive medications, numerous patients fail to achieve guideline-recommended blood pressure (BP) targets.

AIM

To evaluates the efficacy of catheter-based ultrasound renal denervation (uRDN) for the treatment of HTN.

METHODS

Relevant studies were identified through searches in PubMed, Embase, the Cochrane Library, Web of Science, and China National Knowledge Infrastructure, with a cut-off date at April 1, 2024. A random-effects model was employed in this study to mitigate potential biases. The risk of bias for included studies was assessed using the Cochrane Risk of Bias assessment tool. Statistical analyses were conducted using Review Manager version 5.3. This meta-analysis incorporated four studies encompassing a total of 627 patients. The reporting bias of this study was deemed acceptable.

RESULTS

Compared to the Sham group, the uRDN group demonstrated a significant reduction in daytime ambulatory systolic BP (SBP) [mean difference (MD) -3.87 mmHg, 95% confidence interval (CI): -7.02 to -0.73, P = 0.02], office SBP (MD -4.13 mmHg, 95%CI: -7.15 to -1.12, P = 0.007), and home SBP (MD -5.51 mmHg, 95%CI: -8.47 to -2.55, P < 0.001). However, there was no statistically significant reduction observed in either 24-hour or nighttime ambulatory SBP levels. Subgroup analysis shows that uRDN can significantly reduce the SBP in patients with non-resistant HTN (MD -6.19 mmHg, MD -6.00 mmHg, MD -7.72 mmHg, MD -5.02 mmHg, MD -3.61 mmHg).

CONCLUSION

The current evidence suggests that uRDN may effectively reduce home, office, and daytime SBP in patients with HTN, particularly in those with non-resistant HTN.

Key Words: Hypertension; Renal denervation; Ultrasound; Randomized controlled trial; Meta-analysis

Core Tip: This is the latest meta-analysis to date, and it confirms the clinical significance of ultrasound renal denervation (uRDN) for reducing systolic blood pressure (SBP). uRDN may effectively reduce daytime SBP in patients with hypertension (HTN), particularly in those with non-resistant HTN.

INTRODUCTION

Currently, approximately 1 billion individuals worldwide suffer from hypertension (HTN), contributing to more than 9 million annual fatalities due to various HTN-related complications[1]. Drug therapy remains the standard approach for managing HTN[2]. Nevertheless, poor medical compliance and drug tolerance can significantly impact patients’ ability to control blood pressure (BP)[3]. Therefore, exploring novel strategies for BP management is crucial. The renal sympathetic nerves play a key role in the persistence of HTN[4]. Inhibiting their activity has been shown to effectively reduce BP in patients with HTN. Although several interventions targeting renal sympathetic nerve activity have been explored[5], one of the most prominent methods is renal sympathetic denervation (RDN). Since the initial positive outcomes of renal nerve surgery were published, RDN has demonstrated significant promise in the treatment of HTN[6]. The more established technique involves the ablation of renal artery sympathetic nerves using high-focused radiofrequency energy. Meanwhile, clinical research is ongoing to investigate alternative ablation methods such as absolute ethanol ablation and ultrasound ablation. In recent years, ultrasound renal denervation (uRDN), a novel technique for treating HTN, has garnered increasing global attention. Unlike traditional radiofrequency-based approaches, uRDN employs ultrasound as the ablation energy source. Ultrasound is a superior energy source option, as it allows for deeper penetration, a larger ablation area, and minimal damage to the vascular intima[7]. Additionally, the hypotensive effects of uRDN are sustained over time. In recent years, two multi-center clinical trials have reported that uRDN is effective in treating HTN, despite some controversies arising from earlier studies. This article presents a comprehensive meta-analysis of the latest clinical trials to evaluate the efficacy of uRDN therapy for HTN.

MATERIALS AND METHODS

This meta-analysis was conducted in accordance with the PRISMA 2020 guidelines for systematic reviews and meta-analyses[8]. This study was not registered.

Study design

Relevant literature on the effect of uRDN was queried from PubMed, Embase, the Cochrane Library, Web of Science, and China National Knowledge Infrastructure from their inception to April 1, 2024. The main search terms included: HTN, high BP, refractory HTN, resistant HTN, renal denervation, renal sympathetic, and sympathetic denervation.

All candidate articles were screened and extracted by two independent authors (Liu M and Ou YC). In case of discrepancies regarding data extraction, a third investigator (Peng XY) was consulted. The following information was extracted from each study: The first author’s name, country or region, sample size, gender, type of HTN in patients, uRDN system used, primary outcomes, number of anti-HTN medications, and follow-up duration.

Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) Randomized controlled trial (RCT) design; (2) Studies involving patients with HTN or resistant HTN; and (3) Interventions including renal denervation (uRDN group) vs a sham procedure (Sham group). For a series of related studies, the article with the longest follow-up period was selected. Exclusion criteria included: (1) Abstracts, letters, case reports, reviews, or non-clinical studies; (2) Studies with incomplete or unusable data; and (3) Studies with duplicate data.

Risk of bias assessment

The risk of bias for the included studies was evaluated using the Cochrane Risk of bias assessment tool[9].

Statistical analysis

Statistical analyses were performed using Review Manager version 5.3 (The Cochrane Collaboration, Copenhagen, Denmark). The heterogeneity among the included RCTs was assessed using the I² test and the Q test. Heterogeneity was considered insignificant if the I² value was < 50% and P > 0.10. A random-effects model was employed in this study to minimize the potential bias. Subgroup analyses were performed to explore sources of heterogeneity.

Ethical statement

As this is a meta-analysis, ethical approval was not required.

RESULTS

Characteristics of included studies

A total of 1587 studies were identified in the preliminary literature search. After reviewing the abstracts and full texts, only four studies were finally included[10-13] (Figure 1). One RCT involving the Kona Medical Surround Sound System was excluded to avoid systemic errors. The primary outcome was the change in daytime ambulatory systolic BP (SBP), with secondary outcomes including mean changes in 24-hour ambulatory, home, and office SBPs. Baseline characteristics were comparable between the uRDN and Sham groups in this meta-analysis (Table 1). According to the risk of bias graph (Figure 2), the reporting biases in this study was deemed acceptable.

Figure 1 PRISMA flow diagram. uRDN: Ultrasound renal denervation.

Figure 2  Bias risk assessment of the included studies.

Table 1 Basic characteristics of the included studies.

Ref.	Country or region	Sample	Mean age, years uRDN/sham	Female, % uRDN/sham	Diabetes, % uRDN/sham	eGFR, mL/min/1.73 m2 uRDN/sham	Type of HTN patients	uRDN system	Primary outcome	Number of AHT drugs uRDN/sham	Follow-up, months
Azizi et al[10]	United States, Europe	146	54.4/53.8	37.8/45.8	2.7/6.9	84.7/83.2	Aged 18-75 years; ABPM systolic BP/diastolic BP >/= 135/85 mmHg and < 170/105 mm Hg	ParadiseTM	Change in daytime ambulatory systolic BP at 2 months	1.2/1.2	2
Azizi et al[11]	United States, Europe	129	51.9/53.0	18.5/20.3	29.2/26.6	86.8/82.5	Aged 18-75 years; resistant hypertension; office systolic and diastolic BP >/= 140/90 mmHg, despite 3 or more AHT drugs including a diuretic	ParadiseTM	Changes in ambulatory, home, and systolic SBP	4.0/3.9	6
Kario et al[12]	Japan, South Korea	143	50.5/55.6	30.4/20.9	26.1/29.9	74.2/69.6	Aged 20-75 years; resistant hypertension; office BP >/= 150/90 mmHg and ABPM systolic BP > /= 140 mmHg; despite maximum tolerated dosages of at least three AHT drugs from different classes including a diuretic	ParadiseTM	Change in 24-hour ambulatory systolic BP from baseline at 3 months	4.1/3.9	3
Azizi et al[13]	United States, Europe	224	55.1/54.9	31.3/23.0	6.0/6.8	81.4/82.3	Aged 18-75 years; ABPM systolic BP/diastolic BP >/= 135/85 mmHg and < 170/105 mmHg	ParadiseTM	Mean change in daytime ambulatory systolic BP at 2 months	0.9/1.0	2

uRDN: Ultrasound renal denervation; BP: Blood pressure; SBP: Systolic blood pressure; eGFR: Estimated glomerular filtration rate; HTN: Hypertension; AHT: Anti-hypertensive treatment; NA: Not available.

Effectiveness of uRDN

Compared to the Sham group, the uRDN group had an effective reduction in daytime ambulatory SBP [mean difference (MD) -3.87 mmHg, 95% confidence interval (CI) -7.02 to -0.73, P = 0.02], office SBP (MD -4.13 mmHg, 95%CI: -7.15 to -1.12, P = 0.007), and home SBP (MD -5.51 mmHg, 95%CI: -8.47 to -2.55, P < 0.001) (Figure 3A-C). However, no statistically significant reductions were observed in the 24-hour ambulatory SBP (MD -2.95 mmHg, 95%CI: -5.94 to 0.04, P = 0.05) or nighttime ambulatory SBP reduction (MD -2.10 mmHg, 95%CI: -5.14 to 0.94, P = 0.18) (Figure 3D). The uRDN groups comprised 345, 345, 336, 352, and 351 participants, respectively, whereas the corresponding control groups comprised 275, 273, 264, 275, and 274 participants, respectively.

Figure 3 Forest plot for mean changes of blood pressure in ultrasound renal denervation and sham group. A: Comparison of daytime ambulatory systolic blood pressure (SBP) between the two groups; B: Comparison of office SBP between the two groups; C: Comparison of home SBP between the two groups; D: Comparison of 24-hour ambulatory SBP and nighttime SBP between the two groups. BP: Blood pressure; uRDN: Ultrasound renal denervation; CI: Confidence interval; SBP: Systolic blood pressure.

Subgroup analysis

Subgroup analysis further revealed that uRDN exhibited particular effectiveness in reducing SBP among patients with non-resistant HTN. There are significant reductions in home SBP (MD -7.72 mmHg, 95%CI: -9.68 to -5.75, P < 0.00001), office SBP (MD -6.00 mmHg, 95%CI: -9.02 to -2.98, P < 0.0001), 24-hour ambulatory SBP (MD -5.02 mmHg, 95%CI: -7.08 to -2.97, P < 0.00001), nighttime ambulatory SBP (MD -3.61 mmHg, 95%CI: -7.13 to -0.09, P = 0.04), and daytime ambulatory SBP (MD -6.19 mmHg, 95%CI: -8.31 to -4.07, P < 0.00001). The only subgroups with low heterogeneity were the 24-hour ambulatory SBP subgroup (I² = 2%) and the nighttime ambulatory SBP subgroup (I² = 49%) (Supplementary Figures 1-5).

No statistical significant reductions were observed in home SBP (MD -2.20 mmHg, 95%CI: -5.73 to 1.33, P = 0.22), office SBP (MD -0.84 mmHg, 95%CI: -5.28 to 3.61, P = 0.71), 24-hour ambulatory SBP (MD 0.33 mmHg, 95%CI: -3.28 to 3.93, P = 0.86), nighttime ambulatory SBP(MD 0.93 mmHg, 95%CI: -3.57 to 5.44, P = 0.69), and daytime ambulatory SBP (MD -0.27 mmHg, 95%CI: -3.90 to 3.36, P = 0.88) of patients with resistant HTN (Supplementary Figures 1-5).

DISCUSSION

This meta-analysis included 627 patients from four randomized, sham-controlled trials. Our comprehensive review of the current clinical research, based on the latest and largest meta-analysis to date, confirms the clinical significance of uRDN in reducing SBP.

Increased activity of renal sympathetic nerves contributes to the development of HTN by excessively activating the renin-angiotensin-aldosterone system. This activation may lead to water and sodium retention, as well as the production of various vasoactive substances that elevate BP[14]. The sympathetic nervous system plays a crucial role in regulating perfusion and renal function by connecting afferent and efferent fibers from the aorta to the kidney via fibers located in the adventitia of the renal artery[15]. Renal denervation has been shown to effectively reduce renal artery overactivity, thereby blocking undesirable signals that contribute to high BP. A study published in the New England Journal of Medicine reported that RDN can reduce BP in patients with HTN through several mechanisms such as reducing renal norepinephrine overflow, halving renin activity, increasing renal plasma flow, and reducing central sympathetic drive. Additionally, it can reduce ventricular remodeling and the risk of adverse events[16].

Following the use of radiofrequency and chemical ablation, RDN has advanced with the introduction of ultrasound ablation technology. The uRDN procedure employs a balloon ablation catheter to generate ultrasound energy, which penetrates the renal artery at depths of 1 to 6 mm. This intervention effectively reduces renal sympathetic nerve activity, interrupting signals associated with HTN. The results of the RADIOSOUND-HTN trial demonstrated that the antihypertensive effect of ultrasonic RDN is superior to that of radiofrequency RDN[17]. Additionally, ultrasound ablation can achieve longer distances and more complete ablation[7]. These findings suggest that uRDN offers significant advantages. We conducted a comprehensive analysis of all current clinical RCTs using the ReCor Medical Paradise System to provide reliable evidence-based medical assessments for the future clinical application of uRDN.

Our study’s findings demonstrate that uRDN effectively reduces daytime ambulatory, office, and home SBPs (MD -3.87 mmHg, MD -4.13 mmHg, MD -5.51 mmHg, respectively). For patients with HTN, particularly those with resistant HTN, it effectively lowers SBP (MD -6.19 mmHg, MD -6.00 mmHg, MD -7.72 mmHg, repectively). This outcome aligns with previous meta-analyses exploring the variations in the efficacy of RDN in reducing SBP across different HTN patient profiles[18,19].

Patients with non-resistant HTN may be more influenced by sympathetic nervous system activity than those with resistant HTN. Evidence suggests that sympathetic nervous system activity is less pronounced in patients with resistant HTN than in patients with non-resistant HTN[20], potentially resulting in a less responsive reaction to renal denervation treatment. Additionally, the degree of vascular wall remodeling may influence the effectiveness of renal denervation. Patients with non-resistant HTN tend to be younger and have well-controlled BP, meaning vascular remodeling may still be reversible. In contrast, patients with resistant HTN often exhibit target organ damage such as renal fibrosis and vascular sclerosis, which are more challenging to reverse. Certain studies suggest that patients with abnormal endothelial function, inflammation, and extreme vascular stiffness may not be candidates for renal denervation for BP control[21,22]. Despite these concerns, our analysis found no significant difference in BP reduction between the groups. However, more patients in the uRDN group achieved controlled BP without additional antihypertensive medication compared to those in the Sham group. This indicates that uRDN can reduce the need for additional medications in patients with resistant HTN, which may improve medication adherence and reduce adverse reactions. This finding suggest that uRDN may serve as an adjunctive treatment to reduce BP for resistant HTN.

Our findings also suggest that the lack of significant disparities in BP reduction between the 24-hour ambulatory and nighttime SBP groups may be attributed to nocturnal vagal excitation and sympathetic inhibition, which help maintain relatively lower SBP levels during sleep, thus attenuating the antihypertensive effects of uRDN. Consequently, the observed differences between the groups were not pronounced. Although the variance between the 24-hour ambulatory and nighttime SBP did not reach statistical significance, prioritizing the reduction of daytime ambulatory SBP assumes paramount importance, as most adverse events in patients with HTN occur during this period. Our subgroup analysis also indicated that uRDN may be less effective in reducing refractory HTN, whereas it showed a positive antihypertensive effect on 24-hour ambulatory and nighttime SBP in patients with non-resistant HTN (MD -5.02 mmHg, and MD -3.61 mmHg, respectively).

Current guidelines recommend the addition of multiple antihypertensive medications, including spironolactone, for patients with resistant HTN, increasing the risk of side effects and poor medication adherence[23] -a major factor contributing to uncontrolled HTN management[24]. The continuous antihypertensive effect of uRDN eliminates concerns regarding medication adherence. Furthermore, our study determined that uRDN is safe and does not increase the risk of adverse events, which is consistent with other studies.

Study limitations

The limited scale of current clinical trials may reduce statistical power attributed to the novelty of uRDN technology. Despite utilizing a random-effects model in our analysis to minimize potential bias, the small sample size remains a constraint. Moreover, none of the included studies employed a double-blind design due to the nature of the intervention. Although uRDN had a positive effect in lowering BP in patients with non-resistant HTN, its development is limited by the invasive nature of the technique, its inability to achieve significant reduction of BP and its high cost, which present barriers to widespread application.

CONCLUSION

In summary, the available evidence suggests that uRDN can effectively lower home, office, and daytime SBP in patients with HTN and has a more pronounced effect on reduction of SBP in patients with non-resistant HTN. Larger sample sizes, higher-quality studies with longer follow-up periods are needed to further confirm these findings.