Single or dual antiplatelet therapy after transcatheter aortic valve implantation. A meta-analysis of randomized controlled trials

INTRODUCTION

Atrial septal defect (ASD) is the congenital heart disease most frequently diagnosed in adulthood, with the ostium secundum type being the most prevalent (80% of cases). Since the first transcatheter closures of atrial septal defects, advances in both experience and devices have made the transcatheter technique the method of choice for most patients. However, some specific cases, such as ASDs with multiple defects or multi-fenestrated ASDs (mASDs), which account for 10% of all patients with ostium secundum type ASD, continue to pose diagnostic and therapeutic challenges. Furthermore, the available scientific evidence in this subgroup is scarce.1-4

The objective of our study was to analyze and compare the results of the transcatheter closure of mASD vs the transcatheter closure of the remaining patients with ostium secundum type ASD.

METHODS

Study design and population

We conducted a retrospective study that included all cases of transcatheter ASD closure performed in adults older than 18 years at our center from October 2014 through October 2024.

The patients’ demographic, echocardiographic, and hemodynamic data were collected, including a 6-month follow-up following the intervention, assessing residual shunt and echocardiographic parameters such as right ventricular remodeling. This is a retrospective study in which the patients’ informed consent was obtained for the use of their interventional procedure for research purposes. The authors confirm that the interventions were performed in full compliance with the regulations of the Clinical and Ethical Research Committee and the Declaration of Helsinki of the World Medical Association.

Endpoints

The primary endpoint of this study is to analyze the clinical and echocardiographic results of the transcatheter closure of mASDs. Similarly, these results are compared with those obtained after the transcatheter closure of simple (non-multi-fenestrated) ostium secundum type ASDs.

Statistical analysis

Qualitative variables are expressed as percentages and the continuous ones as mean and standard deviation, or as median with interquartile range, depending on whether they follow a normal distribution. For inter-group comparison, the chi-square test or Fisher’s exact test was used for qualitative variables, and the Student’s t-test or the Mann-Whitney U test for continuous variables, as appropriate. The threshold for statistical significance was set at P < .05. Analyses were performed with SPSS software (version 21; IBM Corp, Armonk, NY, United States).

RESULTS

During the study period, a total of 67 transcatheter closures of ostium secundum type ASDs were performed in patients older than 18 years. The patients’ baseline characteristics and ASDs, the procedure, and the results are shown in table 1. The mean age of the population was 52 years, with a predominance of women (65%). The most common indication for ASD closure was dilation of the right ventricular dilatation (88%). In most cases (91%), transcatheter closure was performed with a single device; however, due to anatomical complexity, 5 patients required 2 devices and 1, 3 devices. The combination of transthoracic echocardiography (TTE) and fluoroscopy was the advanced imaging modality selected to guide the procedure in 65% of cases. Four out of all patients had perioperative complications. Three of these complications were due to device embolization, and all recovered uneventfully; 1 patient presented paroxysmal atrial flutter that required pharmacological cardioversion with amiodarone. All patients progressed favorably and were discharged at 24 hours without complications. At follow-up, 82% had no residual shunt, and zero cases of grade ≥ II shunt were found.

Table 1. Baseline characteristics of all patients undergoing transcatheter atrial septal defect closure

Twelve out of all the patients with ASD closure (18%) had ≥ 2 atrial septal defects, whose characteristics are shown in table 2. The patients’ mean age was 42 years, with an equitable sex distribution. Right heart dilatation was the most common reason for closure (83%), with 2 patients presenting with strokes. All patients were in New York Heart Association functional class I-II/IV.

Table 2. Baseline characteristics, procedure, and outcomes of patients undergoing transcatheter closure of multi-fenestrated atrial septal defects

Regarding the echocardiographic study of mASDs, all patients underwent a TEE prior to the procedure. Patients had between 2 (66% of cases) and 4 atrial septal defects. The most common location of the largest defect was anterosuperior (10 patients), and most (92%) had an associated atrial septal aneurysm (defined as a displacement > 10 mm). The sizes of the largest defects and the distance between the defects are shown in table 2. No patient had pulmonary hypertension prior to the procedure.

Regarding the procedure, all cases were guided by transesophageal echocardiography (TEE) and fluoroscopy, and 3 of them by intracoronary ultrasound (ICUS). In most cases, a single closure device was used (66% of patients); however, in 4 cases, 2 devices were needed, which were implanted during the same procedure (simultaneous implantation). The most widely used devices were the Amplatzer Septal Occluder (AGA Medical, United States) and the Amplatzer Cribriform (AGA Medical, United States). In one procedure, the Figulla Flex device (FFO, Occlutech GmbH, Germany) was used, and in another, the Occlutech device (Occlutech International AB, Sweden). Figure 1 shows one of the procedures that required 2 devices and was fluoroscopy-, TEE-, and ICUS-guided.

Figure 1. A: fluoroscopic image of the closure of a multi-fenestrated atrial septal defect with 2 devices guided by fluoroscopy, transesophageal echocardiography, and intracoronary ultrasound. B: transesophageal echocardiography, mid-esophageal plane, showing the 2 implanted closure devices.

Transcatheter closure was successful in all patients with mASD, without intraoperative complications. Transthoracic echocardiography (TTE) was performed 24 hours after closure and, then, 6 months later. Acetylsalicylic acid monotherapy was prescribed at discharge and maintained for 3 months, except for the 2 patients who had a stroke.

At 6 months, 75% showed no residual shunt, while the remaining 25% showed a grade 1 shunt (minimal, without hemodynamic consequences). Most patients with right ventricular dilatation, (8 out of 9 patients) showed a reduction in the baseline right ventricular end-diastolic diameter after the procedure. There were no strokes at the follow-up.

Table 3 compares the characteristics and results of transcatheter closure in patients with a single ASD and with mASD. In our cohort, patients with mASD were significantly younger (42 vs 54 years; P = .011), with no statistically significant differences in sex distribution (50% vs 69%; P = .207). The mASD group had smaller defects (8 mm vs 16 mm in the single ASD group) and a higher prevalence of atrial septal aneurysm (91% vs 27%). In both groups, the most frequent indication for closure was right heart dilatation. No differences were observed in the choice of imaging modality during the procedure or in the mean size of the implanted device. However, patients with mASD more frequently required > 1 device (single device in 66% vs 96% in the single ASD group). There were no inter-group differences regarding complications or the presence of residual shunt during follow-up.

Table 3. Comparison of patients with transcatheter closure of single vs multi-fenestrated atrial septal defect

DISCUSSION

Transcatheter closure of ostium secundum ASD has become a safe and effective alternative in adult patients. Our study analyzed the results of transcatheter ASD closure in patients older than 18 years, highlighting the differences between single ASD and mASD.

At our center, transcatheter closure has proven to be safe and effective in patients with mASD. The results obtained indicate a high success rate associated with the procedure, with the absence of significant intraoperative complications and a good short- and mid-term safety profile.

A relevant finding is that patients with mASD were significantly younger than those with a single ASD, which could be explained by the earlier detection of these defects due to more evident symptoms, or by the presence of atrial septal aneurysm, which in our cohort was significantly more frequent in the mASD group. This data is consistent with the literature, which describes a strong association between atrial septal aneurysm and the presence of multiple defects.5

As expected, the use of multiple devices was more common in the mASD group than in the single ASD group. Although most cases were treated with a single device in patients with mASD, a considerable percentage (40%) required additional devices due to greater anatomical complexity. This finding highlights the importance of a thorough preoperative planning and the need to guide the intervention with TEE or ICUS. Although the TEE provides a wider field of view, the ICUS is particularly useful in certain situations, as it allows for a more precise visualization of the posteroinferior border of the atrial septum.6

The described complications associated with transcatheter ASD closure include arrhythmias, atrioventricular block, and device erosion. Device embolization is usually a consequence of inadequate size or incorrect placement, and its incidence rate is < 1%. In our cohort of patients, complications were a rare finding, with only 3 cases of device embolization and 1 of supraventricular arrhythmia being reported. In the literature, there are doubts on whether these complications are more common when implanting multiple devices; however, in our patients with mASD, 40% of whom needed > 1 device, no complications were observed.7

Most patients with mASD showed complete closure of the defect at 6 months (75%), and the remaining 25% had a minimal shunt without hemodynamic consequences. A high percentage of patients with right heart dilatation showed favorable right ventricular remodeling. Furthermore, the absence of strokes during the observation period indicates the effectiveness of the procedure in terms of secondary prevention in this subgroup of patients.

Limitations

Among the limitations of our study, the following stand out: first, those inherent to its observational and retrospective design, in addition to being single-centered. Furthermore, the number of patients with mASD is relatively small (n = 12), which reduces statistical power. The absence of a control group of patients with mASD treated conservatively or with surgical closure prevents direct comparisons on the relative benefits of each strategy. Prospective studies with a larger sample size and prolonged follow-up will be necessary to confirm our findings and optimize the management of these patients.

CONCLUSIONS

Although the transcatheter closure of mASD is a solid therapeutic option in selected patients, with results comparable to those observed in patients with a single ASD, the need for prospective and multicenter studies remains to confirm these findings and optimize the therapeutic strategy in this group of patients.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

Informed consent was obtained from all patients for the use of their interventional procedure for research purposes. The authors confirm that procedures were performed in full compliance of the regulations of the Clinical and Ethical Research Committee, and of the Helsinki Declaration of the World Medical Association. The authors confirm that sex and gender variables have been taken into consideration according to the SAGER guidelines.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Artificial intelligence has not been used for the development of this work.

AUTHORS’ CONTRIBUTIONS

L. Cerdán Ferreira and M. López Ramón contributed to data collection. L. Cerdán Ferreira performed the statistical analysis. G. Fuertes Ferre, J. Sánchez-Rubio Lezcano, and M. López Ramón contributed to result interpretation. L. Cerdán Ferreira and G. Fuertes Ferre wrote the article, which was later reviewed by G. Fuertes Ferre, J. Sánchez-Rubio Lezcano, and M. López Ramón.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

In our setting, transcatheter aortic valve implantation (TAVI) has become the treatment of choice for patients older than 75 years or with high surgical risk.1 Despite the good results documented in various studies, the stay after the procedure remains considerably long. According to data from the Spanish registry2, the mean length of stay is approximately 8 days. Given the increasing volume of patients, it is essential to implement protocols that optimize the length of stay and facilitate early discharge.

Experiences documented to this date on early discharge protocols after TAVI have demonstrated their safety profile.3-13 However, there is no uniform definition of the term “early discharge,” as it can range from 24 to 72 hours after the procedure.3-13

Most studies share common characteristics. On the one hand, they focus on procedures with a minimalist approach that favors faster patient recovery.14,15 On the other hand, many of them exclusively include patients with favorable pre-implant conditions,3-5,10,12 such as absence of frailty, adequate femoral access for transcatheter closure, absence of advanced conduction disorders, low-risk aortic annulus anatomy, body mass index < 35, left ventricular ejection fraction > 30%, and adequate family support. Consequently, these protocols only cover 22-55% of patients treated with TAVI.

A study conducted by a Spanish group has shown that early discharge, combined with artificial intelligence-based follow-up, is a safe strategy comparable to prolonged hospitalization in an unselected population after TAVI.13

Another important aspect is the type of valves used in the studies. Although the safety profile of early discharge after balloon-expandable valve implantation has been demonstrated,6,7 evidence on self-expanding valves is scarcer, due to doubts about the occurrence of conduction disturbances in the following days. However, in recent years, experiences have been published indicating that early discharge after the implantation of this type of valve is also safe.4,5,8,13,14

Finally, another relevant issue in these studies is that they have been conducted in highly experienced centers.3-13 Several analyses show that centers with a higher volume of procedures and more accumulated experience have lower complication rates and better overall results,16,17 which may translate into greater confidence in adopting early discharge practices.

It seems clear that reducing the length of stay through the implementation of early discharge protocols is a strategy that has demonstrated its feasibility in experienced centers. However, its application in those starting TAVI programs requires additional studies that ensure comparable results in terms of safety. Therefore, the objective of our study is to evaluate the length of stay of the first 100 patients treated with TAVI in our hospital (very early discharge: < 24 hours; early discharge: 24-48 hours; late discharge: > 48 hours) and determine the feasibility of establishing an early discharge protocol during the team’s learning curve.

METHODS

Patient selection and follow-up

We conducted a prospective, single-center registry that consecutively included all patients with severe symptomatic aortic stenosis who underwent TAVI in a center without on-site cardiac surgery, from the beginning of the program. The reference cardiac surgery department is located in a different center 2 km away.

The patients’ baseline characteristics, pre- and postoperative electrocardiographic and echocardiographic findings, the procedural characteristics, and the 30-day and 1-year clinical outcomes were recorded. The registry has been approved by Hospital Universitario Nuestra Señora de Candelaria ethics committee. Relevant informed consents were obtained.

Pre- and postoperative care protocol

We developed a pre- and postoperative care protocol to standardize patient management (figure 1), in such a way that during the week prior to implantation, a cardiologist and a nurse specialized in TAVI jointly assess patients in the monographic valvular heart disease clinic. During this visit, additional tests are reviewed, the patient and their family are briefed on the procedure and possible complications, the informed consent form and a leaflet with relevant information are provided (drug management, how to proceed on implantation day, contact telephone number, etc.). Patients receive a call from nursing staff 48 hours prior to the intervention to remind them of the instructions.

Figure 1. Pre- and postoperative care protocol for transcatheter aortic valve implantation. ECG, electrocardiogram.

On the morning of the procedure, patients go to the interventional cardiology unit of our center, where a venous line is established, an electrocardiogram is performed, and prophylactic antibiotics are administered. After implantation, they are admitted to the acute cardiac care unit with electrocardiographic monitoring. The next day, the absence of complications is ruled out, an electrocardiogram and a transthoracic echocardiogram are performed, and the discharge decision is made according to the protocol for the approach and treatment of conduction disorders by Rodés-Cabau J et al.18 adapted to our center (figure 2).

During follow-up, a telephone consultation is conducted 48 hours after discharge to rule out any complications, and a face-to-face consultation with electrocardiogram and transthoracic echocardiogram is performed 10 days later. If progress is adequate, follow-up continues in general cardiology clinics. The care protocol and the algorithm for the treatment of conduction disorders are showin in figure 1 and figure 2, respectively.

Figure 2. Protocol for the management of conduction disorders after transcatheter aortic valve implantation. Very early discharge: < 24 hours; early discharge: 24-48 hours. AVB, atrioventricular block; ECG, electrocardiogram; EPS, electrophysiological study; LBBB: left bundle branch block; RBBB, right bundle branch block.

Procedural characteristics

During the team’s learning curve, a “mixed” approach was selected. Procedures were performed under general anesthesia. Regarding vascular access, transcatheter transfemoral primary access and closure with double Prostyle (Abbott Vascular, United States) and AngioSeal (Terumo) were prioritized; the radial route was used as secondary access. Pacing was performed with a balloon-tipped electrocatheter via jugular venous access. Urinary catheterization was omitted. The self-expanding Evolut R/PRO+ (Medtronic, United States and Ireland) and ACURATE neo2 (Boston Scientific, United States) valve were implanted. Transthoracic echocardiography was used for postoperative monitoring.

Endpoints

The endpoint of this study is to analyze the length of stay of the first 100 patients undergoing TAVI in our center, differentiating between very early (< 24 hours), early (24-48 hours), and late discharge (> 48 hours) and evaluate the possibility of establishing an early discharge protocol during the team’s learning curve.

In addition, we aim to evaluate clinical outcomes according to the VARC-3 standardized definitions,19 including cardiovascular and non-cardiovascular mortality at 30 days and between 30 days and 1 year, procedural or cardiovascular-related rehospitalizations at 30 days, need for pacemaker implantation in the same period, and rate of neurological events, bleeding complications > BARC 3a, major vascular complications, and cardiac structural complications.

Statistical analysis

Qualitative variables are expressed as absolute frequency and percentage, and the continuous ones as mean and standard deviation.

RESULTS

The first 100 patients treated with TAVI in a tertiary referral center without an on-site cardiac surgery department were prospectively included from April 2022 through January 2024.

The patients’ baseline characteristics

The patients’ baseline characteristics are shown in table 1. Of note, 50% were men, with a mean age of 82.4 ± 5.3 years. The STS score was 4.3 ± 5.1% and the EuroSCORE II score, 4.38 ± 5.1%. The main indication for implantation was age older than 75 years in 96% and high surgical risk in patients younger than 75 years in 4%. Regarding baseline conduction disorders, 10% of patients had complete left bundle branch block, 11%, complete right bundle branch block, and 12% a previously implanted pacemaker.

Table 1. Patient characteristics and indication for transcatheter aortic valve implantation

Procedural characteristics and perioperative results

Procedural characteristics and perioperative results are summarized in table 2. Procedures were performed under general anesthesia, and all patients were extubated in the operating room. Access was transcatheter transfemoral in 95% of patients, with closure using double Prostyle (Abbott Vascular, United States) and AngioSeal (Terumo, Japan). A total of 5% of these patients required surgical access by the vascular surgery service (2%, femoral; 3%, axillary). Second access was radial in 98% of cases.

Table 2. Procedural characteristics and perioperative outcomes

A total of 24 proctored cases were performed. Valve implantation was successful in 100% of cases. A total of 98 procedures were performed on native aortic valves (95, trileaflet; 3, bicuspid) and 2 on degenerated surgical bioprostheses using the chimney stent technique. Self-expanding valves were implanted (87%, Evolut R/PRO+; 13%, ACURATE neo2).

The immediate outcome was monitored with transthoracic echocardiography. More than moderate residual aortic regurgitation occurred in only 2 patients. There were no annular ruptures, aortic complications, coronary artery occlusions, device embolizations, or need for conversion to surgery. No patients died during the procedure.

Mortality and complications after TAVI

Mortality and complications after TAVI are shown in table 3. The 30-day cardiovascular mortality rate was 1% (1 patient who died during hospitalization due to heart failure complicated by a respiratory sepsis). In the follow-up after discharge, 2 deaths due to non-cardiovascular causes were recorded: 1 patient died from aspiration pneumonia at 6 months and another due to complications derived from colon cancer 9 months after implantation.

Table 3. Complications and mortality after transcatheter aortic valve implantation

Within the first 30 days, 6 patients required admission for procedural or cardiovascular-related causes. The reason for admission was infection in 3 patients: a wound infection in a patient who underwent surgical femoral access, an early infective endocarditis that had a good outcome with optimal medical therapy, and a pacemaker pocket infection that required device explantation and contralateral implantation. One patient was admitted with heart failure for developing rapid atrial fibrillation. Two patients were admitted for syncope; one had a PR interval of 350 ms and the other complete atrioventricular block. Both underwent permanent pacemaker implantation.

The rate of major vascular complications was 4%: 3 patients presented stenosis or dissection of the common femoral artery requiring stent implantation during the same procedure; furthermore, a femoral pseudoaneurysm was detected in 1 patient and was surgically repaired. One case of BARC > 3a bleeding complication was detected; the patient required transfusion of 2 packed red blood cell concentrates due to lower GI bleeding.

One patient had a stroke at 24 hours. The need for permanent pacemaker implantation was 12.5% within the first 30 days. The delay for permanent pacemaker implantation once the indication was established was < 48 hours.

Length of stay

The pre-specified care protocol was implemented in all patients (figure 1 and figure 2). As a result, the median length of stay was 2 days (range, 1-19) for all patients (table 4). Regarding time to discharge (figure 3), 27 patients (27.27%) were discharged within the first 24 hours (very early discharge), 48 (48.49%) between 24 and 48 hours after implantation (early discharge), while 24 patients (24.24%) had to be hospitalized for more than 48 hours (late discharge). Late discharges corresponded to 8 patients whose TAVI was performed during admission for heart failure or cardiogenic shock, 10 patients who had pre-existing conduction disorders (mainly first-degree atrioventricular block or complete right bundle branch block) or who developed them after implantation and required prolonged electrocardiographic monitoring, 2 patients who underwent surgical femoral access, 2 patients with major vascular complications, 1 patient who had a stroke at 24 hours, and 1 patient who developed bacteremia due to Streptococcus mitis.

Figure 3. Length of stay of the first 100 TAVI patients. TAVI, transcatheter aortic valve implantation.

Table 4. Length of stay

DISCUSSION

The main findings of our study are a) it is feasible to establish a protocol that favors the early discharge of patients during the medical team’s learning curve; b) approximately 75% of patients achieve early discharge (< 48 hours); and c) it is a safe strategy associated with a low rate of adverse events at 30 days.

The progressive increase in the number of patients we will be facing in the coming years makes it essential to establish protocols that optimize the length of stay and allow for efficient use of resources.

Several experiences can be found in the literature confirming that early discharge protocols after TAVI are safe. The main problems they present are the lack of a standardized definition of early discharge, which can vary from 24 to 72 hours,3-13 and that most studies on early discharge agree on including patients with favorable anatomical characteristics,3-5,10,12 such as adequate femoral access for transcatheter closure, absence of advanced conduction disorders, low-risk aortic annulus anatomy, body mass index < 35, and left ventricular ejection fraction > 30%; in addition, they exclude patients with factors that could prolong the length of stay, such as frailty or lack of family support. Following these criteria, only 59% of our patients would have been eligible for an early discharge program, yet we were able to discharge 75% of the patients within the first 48 hours. In our series, the median length of stay for outpatients with the favorable characteristics described above is 2 days (1-10), and that of outpatients who did not meet favorable criteria is 2 days (1-18), while the length of stay of the 8 patients undergoing TAVI during hospitalization for decompensated heart failure or cardiogenic shock is 10.5 days (1-30). In this regard, the experience of Herrero et al.13 is noteworthy, who demonstrated in their study that most patients (73%) in an unselected population can be safely discharged within the first 24-48 hours.

The minimalist approach14,15 is another key aspect that has been shown to favor early discharge. This approach is especially suitable when conducted by experienced teams and applied to collaborative, hemodynamically stable patients without anatomical characteristics involving a higher risk of complications. Its implementation should be progressive, so that the safety profile of the procedure is guaranteed as the fundamental priority. We opted to start the TAVI program with a “mixed” approach with general anesthesia, mainly femoral or radial access, pacing with a transvenous pacemaker, and monitoring with transthoracic echocardiography until the team overcame the learning curve. All patients were successfully extubated in the operating room. Therefore, we believe that this type of approach did not cause any delays in patient discharge. Once the first 100 cases have been completed, we are transitioning towards a fully minimalist procedure due to the benefits this entails for the patient.

The safety profile of early discharge after the implantation of self-expanding valves has been widely discussed4,5,8,13,14, due to the increased risk of developing cardiac conduction disorders. In our study, all patients received a self-expanding valve. The algorithm by Rodés-Cabau et al.18 was applied to determine the duration of electrocardiographic monitoring and manage conduction disorders. The need for permanent pacemaker implantation was confirmed in 12.5% of cases within the first 30 days. Only 2 patients required readmission after discharge due to advanced conduction disorders requiring pacemaker implantation.

In addition, it is important to have a close follow-up system that allows for the early detection of post-discharge complications and ensures continuity of care. To this end, our patients receive a telephone consultation 48 hours after discharge, and a face-to-face consultation with electrocardiograms and echocardiograms being performed at 10 days. They also have a telephone number to contact the team during working hours. Undoubtedly, this is a system that takes human and economic resources. Experiences have been reported in which the implementation of a virtual voice assistant facilitates the detection of complications, thus demonstrating the effectiveness of this system,13 which should be considered the standard we should look for in clinical practice.

Reducing the length of stay after TAVI requires a real commitment from the heart team to the implementation and adherence to an early discharge protocol. The BENCHMARK study20 showed that adherence to an 8-point structured protocol allows for shorter lengths of stay of approximately 2 days. The key aspects identified in this protocol include educating the health care team, a clear definition of discharge criteria, a structured decision algorithm to assess the need for pacemaker implantation, echocardiographic or angiographic follow-up of the puncture site, early patient mobilization, patient and family education, and anticipated discharge planning from admission. In our own experience, the role of a cardiologist coordinating the TAVI program, along with close collaboration with key units and services, such as acute cardiac care, imaging, electrophysiology, anesthesiology, vascular surgery, and radiology, has enabled the effective implementation of these strategies. This approach has facilitated the consolidation of an early discharge protocol from the start of the program.

Limitations

Our study has multiple limitations that may affect result extrapolation. On the one hand, this was a study of observational design conducted in a single center and with a small sample size; additionally, a total of 24 cases were performed under supervision. On the other hand, only self-expanding valves were used, meaning that results cannot be generalized to other types of valves.

CONCLUSIONS

During the team’s learning curve, the application of a standardized care protocol allows for early and safe discharge after TAVI in most patients in an unselected population.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

Approval was obtained from Hospital Universitario Nuestra Señora de Candelaria ethics committee. Informed consents are available. The SAGER guidelines regarding potential sex and gender biases have been followed.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Artificial intelligence has not been used for the development of the study.

AUTHORS’ CONTRIBUTIONS

R. Pimienta González and A. Quijada Fumero participated developing the protocol, collecting data, and drafting the manuscript. All authors participated in the study design, critically reviewed the text, and approved its final version.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

The optimal strategy and timing of complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease remains unclear, and current recommendations are controversial.1 According to 2023 European Society of Cardiology (ESC) guidelines, complete revascularization, based solely on angiographic severity, is recommended in “stable” STEMI patients.2 Conversely, the 2023 Asia-Pacific Expert Consensus Document suggested a treatment strategy of non-culprit lesions (NCL) based on angiographic severity and invasive physiological assessment with fractional flow reserve (FFR) or non-hyperemic pressure ratios for patients with STEMI.3

FFR and non-hyperemic pressure ratios may be inaccurate in acute coronary syndrome (ACS), as hyperemic flow may be reduced due to microcirculatory dysfunction, while the resting flow may be higher due to neurohumoral compensatory mechanisms.4

Angiography-derived indices are additional physiological tools. They need ≥ 1 angiographic projections plus frame count analysis and/or aortic pressure that may also be different in the acute setting.

Furthermore, drugs such as hypolipidemic agents may promote plaque regression, potentially impacting the results of physiological assessment after a few months into therapy.5

Our main objective was to evaluate the changes in invasive physiological measurements of NCL between the acute and staged phases of ACS.

Secondly, we aimed to evaluate the effects of different therapies on physiological measurements.

METHODS

Eligibility criteria

We included studies that evaluated the physiology of NCL during acute and staged interventions for ACS. Studies conducted on assessments following percutaneous coronary interventions of non-culprit vessels, or with patients with chronic coronary syndrome were excluded.

Case reports, conference abstracts, commentaries, editorials, and reviews were excluded as well. An initial protocol was registered in PROSPERO with registration No. CRD42024574683.

Search strategy, and study selection

We conducted the search across ClinicalTrials.gov, Embase (via Ovid), Google Scholar, PubMed, and Web of Science from inception through 26 April 2024 (initial search). We used the “Review articles” filter in Google Scholar and the “Topic” field in Web of Science. No language restrictions were applied.

Duplicates were removed using Deduplicator (SR-Accelerator) software. Title/abstract and full text screening was conducted independently by 2 authors using Rayyan software.

Back in July, 2 authors conducted a backward and forward citation analysis of the included articles using Citationchaser software.

The search strings were repeated in 6 December 2024 (in Embase, sources with invalid date limits were excluded). Simultaneously, we looked into any online conference news on imaging modalities and physiological measurements.6 Additionally, we looked into the “Slide Library” section using the “2024” filter on another web page.7

Finally, we manually reviewed the references of the articles included after the initial search.

All discrepancies were resolved by consensus.

Selection process was recorded in sufficient detail to complete a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram.8

Data extraction

The following data were extracted from each article: a) study characteristics; b) population characteristics; c) type of physiological index(es); d) follow-up duration; e) primary endpoint.

The primary endpoint was the variation between acute and staged indices regarding statistical significance, mean difference (MD), and disagreement on revascularization decision.

One author extracted the data, and another one checked it independently. We contacted the authors of eligible studies when clarifications were needed.

Risk of bias assessment

Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools,9-11 as appropriate.

Two authors independently assessed the risk of bias for each study. We used red for high, yellow for moderate, and green for low risk of bias based on positive answers being ≤ 49%, 50%-69%, or ≥ 70%.

Data synthesis

We conducted a descriptive synthesis of the evidence. Results from data extraction were shown in separate tables based on risk of bias, or bubble charts. Some data were rounded to the nearest integer (age, diameter of stenosis of NCL, and follow-up) or 2 decimal places (MD).

Unless otherwise specified, P values < .05 were considered statistically significant. When MDs were unreported, they were estimated by calculating the difference between staged and acute mean values. When required, a formula for estimating the means was applied.12

In bubble charts, the size of the bubbles represents the number of patients or lesions if the former was not reported. Acute−/staged+ disagreement indicates an acute value above the threshold, with the staged value below the revascularization cut-off. Acute+/staged− disagreement represents the opposite.

RESULTS

Characteristics of the articles, participants, and indices

Results of the search and selection processes are shown in figure 1. Extracted data are shown in table 1 and table 2.

Figure 1. PRISMA flow diagram. PRISMA, preferred reporting items for systematic reviews and meta-analyses.

Table 1. Extracted data of studies with low risk of bias

A total of 20 articles were included13-32 (1 article in the form of a conference presentation).19 Publication years went from 2010 through 2024. The total number of reported patients was 4379.

In every publication, the patients are predominantly men and non-diabetic. The main clinical presentation was STEMI, except for 3 studies.19,29,31

The following methods were assessed: a) angiography-derived: Murray law-based quantitative flow ratio (muQFR), quantitative flow ratio (QFR), vessel FFR (vFFR); b) hyperemic (FFR); and c) non-hyperemic indices: instantaneous wave-free ratio (iFR), resting distal-to-aortic coronary pressure ratio (P_d/P_a). When reported, the FFR was obtained using adenosine.

Reported patients for each index are as follows: 2340 (muQFR), 1187 (QFR), 710 (FFR), 243 (iFR), 92 (vFFR), and 73 (resting P_d/P_a).

Risk of bias

The studies mainly used an observational (cohort) design. Cohort studies on angiography-derived methods were retrospective, except for 1 article on QFR.28 Those on FFR and non-hyperemic indices were prospective, except for 2 substudies.22,26

QFR was also evaluated by 1 quasi-experimental study27 and 1 randomized controlled trial.13

Finally, the FFR was assessed by 2 randomized controlled trials, in samples with predominance of non-ST-segment elevation myocardial infarction (NSTEMI).19,31,33

Results are shown in table 1 of the supplementary data, table 2 of the supplementary data, and table 3 of the supplementary data. There were no studies with high risk of bias.

Table 2. Data drawn from studies with moderate risk of bias

Primary endpoint

Statistical significance

There were no articles on relevant changes in muQFR,16,30 resting P_d/P_a,25 and vFFR17 at the follow-up.

A significant difference in FFR, iFR, and QFR was found in 3, 2, and 1 article(s),14,22-26 respectively. In 1 study, the difference in QFR was non-significant, with a significance threshold of .001.28

These variations were seen in cohorts of STEMI patients.14,22-26 Studies including non-ST-segment elevation acute coronary syndrome (NSTEACS) did not show any relevant differences regarding the QFR15 or the FFR.19,21,29,31

A total of 4 articles20,22,25,26 evaluated > 1 method. The iFR and FFR were both stable in the study by Musto et al.,20 while the iFR was more stable than the FFR in a different article.25 The QFR was compared to both the FFR26 and the iFR.22 Unlike these indices, the QFR did not show any significant changes in staged phases.22,26

Mean differences

The most valued indices showed varying results. muQFR had MD values close to 0 in both studies.16,30

QFR variations were observed at both lower22,26,28 and higher values.14,15,18 Conversely, the FFR and the iFR varied towards smaller and greater values, respectively.22-26,29,31 Their MDs ranged from − 0.02 to + 0.06 (QFR), − 0.03 to 0.00 (FFR), and 0.00 to + 0.03 (iFR).14,19-21,24,25,28 MD values of 0.01 were observed more often.

In STEMI patients, the MDs of the FFR, the iFR, and the QFR were close to 0 only in studies with mean follow-ups of < 1 week.20,32 In studies including NSTEACS, the FFR MDs were close to 0 after longer mean follow-ups (> 1 month).19,21 Furthermore, Ntalianis et al. showed a greater stability of FFR in patients with NSTEMI (MD, 0.00) vs those with STEMI (MD, − 0.02).21

Disagreement

Disagreement in the indication for revascularization is shown in figure 2. MDs of 0.01 resulted in variable disagreements: 5%-18%.15,18,23,25

Figure 2. Disagreement between acute and staged values in the indication for PCI. B, Barauskas; C, Cortés; E, Erbay; FFR, fractional flow reserve; H, Huang; iFR, instantaneous wave-free ratio; K, Kirigaya; L, Li; muQFR, Murray law-based QFR; N, Ntalianis; PCI, percutaneous coronary intervention; QFR, quantitative flow ratio; SE, Sejr-Hansen; SH, Shukla; SP, Spitaleri; T, Thim; V, van der Hoeven; vFFR, vessel fractional flow reserve.

Unlike the QFR, the FFR and the iFR consistently showed a higher frequency of one type of disagreement: acute−/staged+ for FFR,21,23,25 and acute+/staged− for iFR.24,25

Secondary endpoint

A total of 4 studies compared the effects of different drugs on the physiological parameters.13,19,27,31

Ticagrelor (which can increase the levels of adenosine) was compared to clopidogrel and no significant differences were found in the FFR of non-culprit vessels after 6 months of treatment.31

Another 3 studies compared a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (eg, alirocumab or evolocumab) plus high-intensity statin (HIST) (eg, rosuvastatin 20 mg/day) vs statin-only therapy.13,19,27

In a nonrandomized study, the QFR values were significantly higher in the evolucumab group at 12 months.27 However, in 2 randomized studies, no significant differences were observed across the 2 treatment groups in the QFR at 12 months or in the FFR at 3 months, respectively.13,19

DISCUSSION

The main findings of this systematic review are these: firstly, in STEMI patients, the muQFR, resting P_d/P_a, and vFFR indices remained relatively stable in retrospective and/or small studies. The FFR, iFR, and QFR showed variability between acute and staged phases. Secondly, the FFR did not change significantly in prospective cohorts or randomized controlled trials including NSTEACS. Thirdly, the QFR was more stable than both the FFR and the iFR in direct comparisons, although only the FFR and the iFR exhibited consistent directions of change. Fourthly, PCSK9 inhibitors added to HIST did not influence physiological measurements compared with HIST in randomized controlled trials.

The muQFR demonstrated stability in a large sample of patients. This index is based on a single angiographic view, unlike other angiography-based methods that require 2 angiographic projections. This characteristic might reduce observer variability and enhance reliability. Future prospective and comparative studies are needed to confirm the validity of this method.

Although low variations for FFR, iFR, and QFR were observed in cohorts of STEMI patients,20,32 these studies were limited by short-term follow-ups. Thim et al. found a non-significant change in the iFR with 5-day follow-ups, whereas there were significant changes with ≥ 5 day follow-ups.24 Therefore, physiological disarrangements initiated at the acute moment of STEMI might still exist if a staged procedure is conducted close to the index event.24,25

Angiographic, hemodynamic, and microcirculatory variables may alter acute physiologic assessment and account for the higher reliability of the FFR in NSTEACS vs STEMI.

In patients with microvascular dysfunction, epicardial blood flow cannot increase sufficiently during maximal hyperemia, thus causing a reduced pressure gradient across the stenotic lesion,29 and higher FFR values.

In STEMI patients, microcirculatory indices (coronary flow reserve and index of microcirculatory resistance) were significantly worse during the acute phase, along with a higher FFR.25 Conversely, studies including NSTEACS did not show any significant differences in the coronary flow reserve and/or index of microcirculatory resistance at the follow-up.21,29,31

Furthermore, STEMI patients showed greater acute angiographic severity, along with lower QFR or iFR values,14,22 which may be attributed to vasoconstriction typically occurring during the acute phase.

Consequently, the FFR seems more reliable in NSTEACS vs STEMI due to reduced acute microcirculatory impairment and/or vasoconstriction.

Literature trials support the use of the FFR in NCL of NSTEMI during the acute phase (eg, within the index hospitalization).34,35 In contrast, acute FFR-guided complete revascularization did not show any significant benefits in terms of death or myocardial infarction in STEMI patients.36-39

The higher stability of QFR when directly compared to the FFR or the iFR was limited to a small number of patients in post-hoc substudies.22,26 A MD of 0.01 sometimes led to non-trivial disagreement on revascularization decision,25 likely due to baseline values being near the cut-off. Therefore, it is essential to have an index which remains stable or demonstrates consistent changes, such as the FFR and the iFR. Similarly, these indices demonstrated a greater frequency of a specific type of disagreement (methodological variations–wire positioning–may explain the less frequent cases of disagreement).24

Therefore, the FFR and the iFR could be considered in the acute STEMI as an alternative to delayed assessments,25 considering that the FFR tends to decrease and the iFR tends to increase. The FFR could guide the revascularization of positive lesions (FFR ≤ 0.80).25 In patients with a FFR > 0.80, acute iFR assessment can be used to delay the revascularization of negative NCL (iFR > 0.89).24 In the remaining cases (iFR ≤ 0.89), some authors suggested a staged reevaluation.24 At least 5 days after the index procedure should go by. This was the minimum time needed to observe the initial resolution of acute physiological disturbances.24

Finally, when plaques are correctly identified as functionally negative, they may still be vulnerable and associated with adverse events. NCL exhibiting thin-cap fibroatheromas as defined by optical coherence tomography, and having a muQFR ≤ 0.80, showed the highest event rate,40 which suggests that imaging can offer additional prognostic information.

PCSK9 inhibitors have shown minimal impact on coronary physiology, despite greatly reducing low-density lipoprotein-cholesterol (LDL-C) levels. A large treatment effect on HIST only,19 minor flow limitation at baseline, and microvascular compensation may account for this finding.13

However, combining alirocumab with HIST resulted in a greater increase in cap thickness of fibroatheromas vs statin monotherapy as assessed by optical coherence tomography.41 Moreover, lower LDL-C levels after an ACS are associated with the occurrence of fewer cardiovascular events.2 Therefore, PCSK9 inhibitor treatment is recommended in patients who do not reach their LDL-C target despite maximum tolerated statin and ezetimibe therapy.2

Limitations

The wide variety of indices to assess coronary physiology has led to a lack of evidence on some of them; similarly, few studies made direct comparisons among such indices.

Our evaluations are mainly based on observational studies with a very different follow-ups.

Angiography-based methods frequently exhibited bias due to their retrospective analysis. Some patients were excluded because of the poor quality of angiographies or anatomic issues, such as ostial lesion or severe vascular tortuosity. Some angiographies were not obtained optimally according to the specific acquisition guide.

CONCLUSIONS

The assessment of functional indices for NCL during the initial procedure for STEMI is not absolutely reliable. This evidence is due to potential variability of the FFR, the iFR, and the QFR outside the acute phase. Although variation was not significant for muQFR, resting Pd/Pa, and vFFR, retrospective and/or limited data limit the generalizability of these findings.

Both the FFR and the iFR showed consistent directions of change. Therefore, during an acute STEMI, the FFR can guide the revascularization of positive NCL, while the iFR can help defer revascularization of negative NCL. A negative FFR with a positive iFR should be reevaluated.

The FFR shows robust data supporting its use in NLC of NSTEMI during the acute phase, meaning that it is a more reliable index for initial ACS procedures.

DATA AVAILABILITY

Search string for Google Scholar: “acute coronary syndrome”|”myocardial infarction” “fractional flow reserve”|FFR| “hyperemic ind”|”resting ind”|iFR|”instantaneous wave-free ratio”| “angiography-based ind”|”angiography-derived ind”|QFR|”quantitative flow ratio”|OFR staged|repeated|later. The remaining search strings are available upon request.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

Ethical committee and patient’s informed consent: not applicable. We followed the SAGER guidelines with respect to possible sex/gender bias.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Microsoft Copilot was used to help edit the English version of the text.

AUTHORS’ CONTRIBUTIONS

F. Vergni designed the work. F. Vergni, S. Buscarini, L. Ciurlanti, and F.L. Gurgoglione contributed to data acquisition (screening, and/or extraction). F. Vergni, and L. Ciurlanti conducted the critical appraisal. F. Vergni, and S. Buscarini contributed to data interpretation. F. Vergni, and F.L. Gurgoglione drafted, edited and reviewed the work. F. Vergni, S. Buscarini, L. Ciurlanti, F.L. Gurgoglione, F. Pellone, and M. Luzi approved the final version for publication.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Hypertension is highly prevalent worldwide and well recognized as a major risk factor for cardiovascular, cerebrovascular, and renal complications.1 Despite the availability of numerous antihypertensive drugs that effectively mitigate hypertension-related organ damage,1,2 a substantial proportion of patients fail to attain adequate blood pressure (BP) control,3 which may be attributed to factors such as medication non-adherence or the presence of resistant hypertension,4,5 which is defined as the presence of uncontrolled BP of, at least, 130/80 mmHg despite the simultaneous prescription of, at least, 3 or 4 antihypertensive drugs of different classes, or controlled BP despite the prescription of, at least, 4 drugs, at the maximum tolerated doses, including a diuretic.6 The pathophysiology of hypertension is intricate and includes a diverse array of mechanisms, with sympathetic overdrive emerging as a pertinent factor in all forms of hypertension.7 Consequently, novel therapeutic approaches have emerged, including renal denervation (RDN), which aims to decrease renal sympathetic activity thereby reducing BP. RDN has drawn considerable attention as a guideline-recommended BP lowering treatment along with lifestyle changes and pharmacotherapy for patients with resistant hypertension.8,9 Recently, there has been growing consensus that RDN should also be considered for individuals whose hypertension is due to no therapeutic adherence.10-12 Early randomized controlled clinical trials yielded inconsistent findings on the efficacy profile of the intervention, with a substantial proportion of patients failing to respond across the trials.13,14 Potential explanations for the heterogeneous results include insufficient operator experience using the Symplicity Flex catheter (Medtronic, United States), the study participants’ baseline characteristics, and changes of antihypertensive medication.15 Subsequently, sham-controlled trials with better study designs, catheter technologies and procedural techniques have improved the BP-lowering safety and efficacy profile of RDN.16-18 Currently, various catheter systems are used for RDN, utilizing different technologies, such as radiofrequency-based systems like Symplicity Spyral (Medtronic, United States). Ultrasound-based catheters have also been developed, such as the Paradise (Recor Medical, United States), whose efficacy has been evaluated in multiple studies. Finally, there is a system based on alcohol-mediated RDN.19 Recently, the U.S. Food and Drug Administration (FDA) approved Medtronic Symplicity Spyral and Recor Paradise system as adjuvant therapies for the treatment of hypertension.20

The efficacy of the latter was evaluated in a multicenter, randomized, blinded and sham-controlled trial. Subsequently, it was determined in the REQUIRE RADIANCE-HTN SOLO,16 RADIANCE HTN TRIO17 and RADIANCE II,18 and REQUIRE21 trials. Results were heterogeneous between the RADIANCE and REQUIRE trials, which had limitations that may account for the varied results.10 Finally, uRDN was concluded to be safe for the treatment of hypertension, even in patients with resistant hypertension and poor medical adherence.19 The aim of this study is to conduct a systematic review and a meta-analysis to examine the antihypertensive efficacy of uRDN in patients with hypertension vs a sham group treatment.

METHODS

We conducted a systematic review and meta-analysis which strictly followed the clinical practice guidelines established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.22 Methodological procedures were conducted in full compliance with the Cochrane Handbook of Systematic Reviews and Meta-Analysis of Interventions. This meta-analysis protocol was registered on PROSPERO 7 July 2024, under protocol ID: CRD42024562852.

Criteria of the included studies

Inclusion criteria were established to identify relevant studies: patients with resistant hypertension and randomized controlled trials (RCTs) comparing uRDN with sham groups, which did not undergo uRDN; RCTs reporting office, daytime ambulatory, home and 24-h ambulatory BP changes from baseline were included. We excluded those underreporting, at least, 1 of the following outcomes of interest: changes in BP between baseline and, at least, a 2-month follow up. In addition, we excluded non-English publications, case-control studies, case reports, single arm studies, letters to the editors, basic science research, meta-analyses, and review articles.

Literature search strategy

We conducted a comprehensive search across PubMed, EMBASE, and COCHRANE, from their inception until 1 November 2024. Keywords and free-text terms were used to explore literature on hypertension, renal denervation, and ultrasound ablation. Detailed search information for each database is provided in the Search strategy section of the supplementary data.

Screening of literature search strategy

Initially, a comprehensive database search was conducted to compile all relevant records. Duplicate entries were, then, manually removed using Zotero software. Afterwards, references were screened by title and abstract. When necessary, a full-text review was performed to ensure relevance and accuracy. Two authors (C. J. Palomino-Ojeda and L. H. García-Mena) independently assessed each the inclusion and quality of each article. Discrepancies were resolved by a third author (J. M. Guerrero-Hernández). Additionally, references cited in the included studies were scrutinized and included if they fulfilled the eligibility criteria.

Data extraction

Data extraction was conducted using Excel spreadsheets to record the following information: a) baseline characteristics of the study population, b) summaries detailing the characteristics of the included studies, c) outcome measures, and d) domains evaluated for quality assessment.

Assessing the risk of bias

Randomized controlled trials were assessed using Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2)22,23 from the Cochrane Handbook of Systematic Reviews of Interventions. Our analysis included a funnel plot for the primary endpoint daytime ambulatory systolic blood pressure (SBP) shown in figure 1 of the supplementary data.

Figure 1. PRISMA flow diagram. RDN, renal denervation.

Outcome measures

BP changes were assessed by comparing baseline values and follow-up measurements taken, at least, 2 months later. The mean difference was analyzed using the mean and standard deviation.

Data analysis

The efficacy profile of uRDN vs the sham control was analyzed using continuous data to calculate the mean difference with its corresponding 95% confidence interval (95%CI).24 This analysis assessed BP changes across groups with an, at least, 2-month follow-up while evaluating their mean difference.

Furthermore, an examination was conducted to discern any variation among office BP, ambulatory daytime BP, 24-h ambulatory BP, nighttime ambulatory BP, and home BP outcomes in trials that reported these results. This was achieved by computing the mean and its associated standard deviation for the difference between the 2 outcomes. The validated Campbell calculator was used to convert the measures of dispersion from the outcomes in the REQUIRE trial for data analysis.24 The level of heterogeneity was assessed using the I² statistic.

Sensitivity analyses were conducted using a random effects model to account for variability among studies.25 Subgroup analyses were predefined for first and second-generation RDN trials, with tests for interaction for the primary endpoint.

Assessment of heterogeneity

Heterogeneity among the included studies was assessed using Cochran’s Q statistic. Additionally, the I² statistic was used to quantify the proportion of total variation attributed to heterogeneity, with values > 50% indicating high heterogeneity. All statistical analyses (including the calculation of standardized mean difference, relative risk, and mean difference) were performed using RevMan 6.3. software.22

RESULTS

Study selection

A total of 448 studies were identified across database searches. A total of 392 studies were screened after removing duplicate studies, 388 of which were excluded due to single-arm study (n = 6); publication in a language different than English (n = 1); case-control or case report studies and literature review (n = 140); basic scientific research (n = 24); editorial letter (n = 8); different type of RDN studies (n = 83); studies with ≤ 10 participants (n = 6); and does not compare intervention of interest (n = 120). Finally, 4 studies meet all inclusion criteria and were eligible for analysis. An analysis of 642 patients from the 4 selected articles was conducted as they met the inclusion criteria. The PRISMA flow diagram of the study selection process is shown in figure 1.

Study characteristics

The studies included in our analysis included a total of 4 RCTs published from 2018 through 2023.16-18,21 All studies used uRDN and a sham control group. Two studies were performed in the United States/Europe,16,17 1 study only in the United States18 and the rest in Japan and South Korea.21 The baseline characteristics of the included studies were analyzed and summarized in table 1. Characteristics of the entire patient population are shown in table 2.

Table 1. Baseline characteristics and following intervention of the included studies population.

Table 2. Summary of included studies

In the analysis of 642 patients, the mean age was 54.15 years ± 9.95, 70.8% were men, and the mean body mass index was estimated at 30 kg/m2 ± 5.3. Regarding comorbidities, 15.1% had type 2 diabetes mellitus, and 5.6%, cardiovascular disease. The mean glomerular filtration rate (GFR) was estimated at 82.25 mL/min/1.73 m2 ± 16.2. In addition, 9.6% of patients had GFR levels < 60 mL/min/1.73 m2. Of note, eligibility criteria in all trials include an estimated GFR > 40 mL/min/1.73 m2. Two studies— the RADIANCE-HTN SOLO and the RADIANCE II—included patients on 1 to 3 antihypertensive drugs and were designed as “Off Med” studies, meaning patients underwent a washout period with no antihypertensive treatment for 4 weeks in the RADIANCE-HTN SOLO and 8 weeks in the RADIANCE II. Additionally, patients who experienced complications such as high BP were given antihypertensive escape therapy.26 On the other hand, the RADIANCE-HTN TRIO and REQUIRE trials included patients on 3 to 5 antihypertensive drugs and evaluated the uRDN in patients on concomitant antihypertensive therapy. However, only the RADIANCE-HTN TRIO trial standardized antihypertensive treatment over a 4-week regimen with a fixed-dose of 3 drugs in a single pill including amlodipine 10 mg; valsartan 160 mg (or olmesartan 40 mg); and hydrochlorothiazide 25 mg. Additionally, treatment adherence was assessed by mass spectrometry.21,27,28 Enrollment criteria were comparable across the analyzed studies. Similarly, exclusion criteria were consistent in all studies; however, the RADIANCE trials additionally excluded patients with anatomical variations or alterations in renal artery anatomy, as detected on renal computed tomography or magnetic resonance angiography.27 In all studies, patients were blinded prior to the uRDN procedure. Furthermore, in all RADIANCE trials, blinding was implemented after the washout period or after the patients completed the fixed-dose treatment.18,26,27

Daytime ambulatory blood pressure

Patients treated with uRDN for up to 2 months experience a significant reduction of −5.12 mmHg (95%CI, −6.07 to −4.17; P < .00001); I² = 2%) in daytime ambulatory SBP vs the sham group. Similarly, ambulatory diastolic blood pressure (DBP) dropped down to −2.82 mmHg (95%CI, −3.43 to −2.21; P < .00001; I² = 0%) in patients with uRDN vs the sham group (figure 2A).

Figure 2. Meta-analysis of the effect of uRDN on blood pressure va a sham control. A: difference in daytime ambulatory BP up to 2 months; B: difference in 24-hour BP up to 2 months; C: difference in office BP up to 2 months; and D: difference in home BP up to 2 months. Forest plots showing the mean difference and SD from random assignments between the uRDN and sham control groups. 95%CI, 95% confidence interval; BP, blood pressure; SD, standard deviation; uRDN, ultrasound renal denervation. The bibliographical references mentioned in this figure correspond to Azizi et al.,16-18 and Kario et al.21

24-hour ambulatory blood pressure

24-h BP was evaluated up to 2 months after uRDN. Analysis of SBP showed a significant reduction of −4.87 mmHg (95%CI, −6.53 to −3.21; P < .00001; I² = 42%). Meanwhile, 24-h DBP dropped down to −2.55 mmHg (95%CI, −3.83 to −1.26; P < .00001; I² = 62%) in patients on uRDN (figure 2B).

Office blood pressure

SBP dropped down to −5.03 mmHg after 2 months (95%CI, −6.27 to −3.79; P < .00001; I² = 0%) in uRDN patients. DBP showed a significant decrease of −3.68 mmHg (95%CI, −4.57 to −2.78; P < .00001; I² = 31%) with the uRDN intervention (figure 2C).

Home blood pressure

Analysis of home BP after 2 months showed a decrease in SBP of −5.47 mmHg (95%CI, −8.08 to −2.85; P < .0001; I² = 75%), while DBP dropped down to −3.19 mmHg (95%CI, −4.63 to −1.75; P < .0001; I² = 69%) in patients on uRDN (figure 2D).

Nighttime blood pressure

Nighttime BP was evaluated at the 2-month follow-up. We found that SBP dropped down to −3.99 mmHg (95%CI, −7.00 to −0.99; P = 0.009; I² = 70%), while DBP dropped down to −2.30 mmHg (95%CI −4.03 to −0.56; P = .01; I² = 64%) in patients on uRDN (figure 2 of the supplementary data).

Drugs 6 months after uRDN

Patient drugs 6 months after uRDN were only reported in the RADIANCE-HTN SOLO and RADIANCE-HTN TRIO clinical trials. Data analysis revealed that uRDN leads to using fewer antihypertensive drugs by −0.52 (95%CI, −0.91 to −0.13; P = 0.009; I² = 69%) vs the sham control group (figure 3).

Figure 3. Patients on uRDN used less antihypertensive medication prescribed 6 months after the procedure vs the sham group. 95%CI, 95% confidence interval; BP, blood pressure; SD, standard deviation; uRDN, ultrasound renal denervation. The bibliographical references mentioned in this figure correspond to Azizi et al.16 and Azizi et al.17

Risk of bias assessment

Among the 4 studies included, the risk of bias remained consistent at a moderate level, which was attributed to the inability to blind the interventional cardiologist conducting the uRDN, although outcome assessors were blinded to the interventions performed. Studies were categorized as having moderate risk16-18,21 (table 3). Data on risk of bias can be found in table 1 of the supplementary data. In addition, the funnel plot of daytime ambulatory SBP (figure 1 of the supplementary data) showed a slight asymmetry, as points tend to concentrate towards the left side of the combined effect, which could suggest a possible publication bias. In addition, the points closer to the vertex represent studies with lower standard error due to a larger sample size. The heterogeneity of the funnel plot reflects variations in effects across studies. Plot points are within the funnel lines, but one of them towards the lower right seems further away from the rest, which could indicate a possible outlier or methodological or population differences.29

Table 3. Risk of bias summary for randomized studies (RoB 2)

DISCUSSION

This meta-analysis includes data from 4 randomized controlled trials that evaluated the efficacy profile of uRDN in patients with true resistant hypertension and off-medication hypertensive patients vs a sham group. Antihypertensive efficacy was evaluated across different clinical settings such as 24-h ambulatory BP, home BP, office BP, and daytime BP. Our results demonstrated significant BP-lowering efficacy at the 2-month follow-up vs the sham procedure. Furthermore, at the 6-month follow-up, fewer antihypertensive drugs were prescribed to patients on uRDN vs those from the sham group. These results support the use of uRDN as an adjuvant therapy for hypertension and as a valuable option for reducing BP as well as the number of antihypertensive drugs.

Previous studies have demonstrated the safety profile of RDN for the treatment of resistant hypertension, such as the first-generation SIMPLICITY HTN trials.30 However, the SIMPLICITY HTN-3 study showed no differences in the 24-h BP reduction vs the sham group, casting doubts on the benefits of RDN.14 Subsequently, new catheters were developed for performing RDN, and standardized criteria were established for conducting RDN trials with a sham group.12,19 Currently, uRDN has emerged as a novel option as an adjuvant therapy treatment of hypertension. It is based on catheter systems, such as the TIVUS and Paradise systems, which utilize ultrasound energy for the thermal ablation of afferent and efferent renal nerves.19,31

Our results demonstrated a reduction in both SBP and DBP at the 2-month follow-up, with a more pronounced effect on SBP in patients on uRDN vs the sham control group. We observed a reduction of −5.12 mmHg in ambulatory SBP, −4.87 mmHg in 24-h SBP, −5.03 mmHg in office SBP, and −5.47 mmHg in home SBP. These findings are particularly relevant since SBP has turned out to be a strong predictor of future cardiovascular events and mortality, regardless of age in adults.32 The CI values for home BPS had the widest range. Furthermore, the RADIANCE HTN-SOLO trial demonstrated a wide CI in both office and home SBP. This observation is an opportunity for future trials to focus on patient training to standardize home BP measurement since day-to-day home BP has been proposed as a potential predictor of cardiovascular disease.33

Although the observed BP reduction may seem minimal and lack significant clinical relevance, it is important to note that these findings reflect the first 2 months of follow-up after uRDN initiation and literature reports that uRDN has a sustained long-term effect on lowering BP values. For example, the HTN RADIANCE-SOLO trial demonstrated that at the 36-month follow-up, office BP decreased 18/11 ± 15/9 mmHg.34 Related to this, previous studies have demonstrated that a 10 mmHg reduction in SBP is associated with a decrease in the relative risk (RR) of major cardiovascular events (RR, 0.80; 95%CI, 0.77-0.83), coronary heart disease (RR, 0.83; 95%CI, 0.78-0.88), stroke (RR, 0.73; 95%CI, 0.68-0.77), heart failure (RR, 0.72; 95%CI, 0.67-0.78), and a 13% reduction in all-cause mortality rate (RR, 0.87; 95%CI 0.84-0.91).2 However, it has recently been reported that even a 5 mmHg decrease is beneficial to reduce the risk of major cardiovascular events, estimating a hazard ratio (HR) of 0.91 (95%CI, 0.89-0.94) for individuals without previous cardiovascular disease and a HR of 0.89 (95%CI, 0.86-0.92) for those with previous cardiovascular disease.1 In addition, reduction of preventable major cardiovascular events by treating hypertension has a positive economic impact in reducing hospitalization expenses due to complications such as heart attack or stroke.35 Hypertension is a prevalent global health concern, and effective BP control is achieved in only 21% of patients.36 In the United States, individuals with hypertension are estimated to incur an additional $2500 to $3000 in annual expenses vs those without hypertension. Maintaining normal BP not only benefits patients but also supports the economic well-being of the entire health care system.37 In fact, studies evaluating the cost-effectiveness of long-term use of radiofrequency RDN have been conducted in the United States and the United Kingdom concluding that this procedure represents a cost-effective option for the treatment of uncontrolled and resistant hypertension, as its sustained BP-lowering effect favors the reduction of cardiovascular morbidity and mortality.38 Similarly, in Spain, an estimate was made of the impact of radiofrequency RDN on quality-adjusted life years, cardiac events, and patient-related lifetime costs. Radiofrequency RDN was found to reduce the risk of stroke (RR, 0.80), myocardial infarction (RR, 0.88), and heart failure (RR, 0.72) throughout a 10-year period, resulting in improved health outcomes and long-term cost savings. Results presented indicate that radiofrequency RDN is a cost-effective therapeutic option that should be taken into consideration in patients with uncontrolled hypertension, including resistant hypertension.39

In addition to the reduction in BP and the positive cost-effectiveness of uRDN, radiofrequency RDN has been demonstrated to be a safe procedure for the patients. The clinical trials that analyzed this meta-analysis found no safety differences between the treated and sham groups. Furthermore, few postoperative adverse events were reported. Most complications were associated with back pain, which was effectively and uneventfully managed.16-18,21 The long-term safety profile of the procedure has been consistently reported, with no adverse effects being reported from uRDN observed at the 1, 3-, and even 8-year follow-up.34,40,41

Our findings also demonstrated that, at the 6-month follow-up, patients on uRDN used fewer prescribed antihypertensive drugs, which suggests that treatment may potentially improve patient outcomes. However, this outcome was only evaluated in the RADIANCE HTN-TRIO and RADIANCE HTN-SOLO trials. In addition, at the 3-year follow-up the RADIANCE HTN-TRIO reported no differences in the number of drugs used by patients initially identified with uncontrolled hypertension, although they decreased office SBP by 10.8 mmHg.34 This is particularly noteworthy as non-adherence to therapy is a significant contributing factor to uncontrolled BP.42 However, the results suggest that the greatest benefit is observed in the maintenance of low BP levels rather than in the decrease in the number of antihypertensive drugs prescribed.

Of note, the I² value of the outcomes evaluated showed that daytime SBP and DBP had low heterogeneity, while the 24-h SBP and DBP values had moderate-to-high heterogeneity. On the other hand, office SBP and DBP had low-to-moderate heterogeneity. Finally, home SBP and DBP, as well as nighttime SBP and DBP and drug intake had high heterogeneity. Variations in heterogeneity do not necessarily indicate that the results are not useful;43 possibly, the differences in the heterogeneity of the outcomes assessed is due to differences in the methodology of the studies contemplated in this meta-analysis, which will be discussed below.

Our analysis included the REQUIRE trial, which has certain limitations, such as the absence of a blinded design, a non-standardized uRDN intervention, and dose titration. These factors may have introduced bias, potentially explaining the lack of differences observed between the uRDN and sham groups. In addition, the inclusion criteria of the study did not consider the presence of anatomical variations in the renal arteries vs the RADIANCE trials in which an exclusion criterion is the presence of anatomical variations in renal arteries. This factor, along with therapeutic adherence, could impact the BP reduction results.21,28,44 Based on this perspective, the European Society of Cardiology (ESC) Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) have established the characteristics that must be met by studies evaluating RDN with a sham control group to be considered as high quality: a) multicenter design; b) blinding of patients; c) ambulatory BP change as the primary enpoint; d) use of second-generation RDN systems.10 In this context, RADIANCE clinical trials are characterized by a rigorous methodological protocol, which required a 4- or 8-week stabilization of pharmacological therapy prior to randomization to either uRDN or a sham procedure.45,46 Furthermore, RADIANCE trials monitored therapeutic adherence and were designed to assess the effect of uRDN with and without antihypertensive treatment, minimizing the confounding effects.28,47

A key long-term challenge of the RADIANCE trials is to demonstrate sustained BP-lowering effects vs sham groups. Follow-up studies show that patients from the sham group required higher doses of antihypertensive drugs, while those on uRDN used fewer drugs. Although BP differences across groups decreased throughout time, uRDN patients consistently needed fewer prescriptions.26,27

Results from the RADIANCE trials demonstrate the efficacy profile of uRDN for the treatment of resistant hypertension and patients with poor therapeutic adherence, as observed in the off-study population. Additionally, the REQUIRE trial highlights the potential role of anatomical variations in determining patient suitability for uRDN, underscoring the importance of selecting appropriate criteria for patient selection. In addition, RDN has proven to be a safe procedure with a positive long-term cost-benefit ratio. The key question on uRDN may be: Which patient group would benefit most from uRDN, considering anatomical factors and therapeutic adherence?

Study limitations

To make the most out of the study results, it is important to consider its limitations: a) we only analyzed data from trials that used uRDN, which reduces the size of the population; b) data availability from the studies considered covered a short follow-up period, which limits the ability to determine the long-term antihypertensive efficacy of uRDN; c) differences in supervised drug adherence across the methodological designs limit their applicability to real-world settings; d) Since RCTs included patients with true resistant hypertension and off-med hypertension, the heterogeneous population limits the generalizability of the results to a specific hypertension subtype; and e) The funnel plot showed asymmetry, suggesting a possible publication bias, although results should be interpreted with caution because the funnel plot also indicates that there is a limited amount of data.

CONCLUSIONS

This meta-analysis demonstrates that uRDN treatment effectively reduces both SBP and DBP across various contexts, including 24-h, ambulatory, home and office BP at the initial 2-month follow-up in hypertensive patients (figure 4). Additionally, uRDN was associated with reduced antihypertensive drug use 6 months after the procedure. However, further research is needed to assess its long-term effects and identify the patient groups who may benefit the most.

Figure 4. Central illustration. Summary of the effect on the decrease in systolic and diastolic blood pressure in patients on uRDN compared with patients who received the sham procedure at the 2 months postoperative follow-up. uRDN, ultrasound renal denervation.

FUNDING

This manuscript did not receive financial support from any institution or funding agency for its preparation.

ETHICAL CONSIDERATIONS

The present meta-analysis was conducted based on previously published studies. As the study involved secondary data analysis, no new data was collected from human participants or animals, and the use of SAGER guidelines does not apply to this study. Therefore, ethical approval was deemed unnecessary. All included studies were reviewed in full compliance with ethical guidelines set forth by the respective institutions where the original studies were conducted. All authors state that the data used in this study were obtained exclusively from publicly accessible sources, and no confidential or proprietary information was utilized without appropriate authorization.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

During the preparation of this work the authors used ChatGPT-4o to review the document syntaxis and grammar. After using this tool/service, the authors reviewed and edited the content as needed and took full responsibility for the content of the published article.

AUTHORS’ CONTRIBUTIONS

J.M. Guerrero-Hernández: conceptualization, formal analysis, drafting, review and editing; C. J. Palomino-Ojeda: methodology, investigation, drafting, review and editing; L. H. García-Mena: methodology, formal analysis, writing, review and editing; Ó.Á. Vedia-Cruz: investigation; J. L. Maldonado-García: drafting, review and editing; I. J. Núñez-Gil: investigation, supervision and review; J. A. García-Donaire: review and supervision.

CONFLICTS OF INTEREST

I. J. Núñez-Gil served as a consultant for Medtronic and Recor Medical in the denervation field. J. A. García-Donaire served as consultant for Medtronic and Recor Medical in the denervation field. The rest of the authors declared no conflicts of interest whatsoever.

SUPPLEMENTARY DATA

REFERENCES