A decade of left atrial appendage closure: from procedural data to long-term clinical benefit

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

	Reference
	RADIANCE HTN SOLO 201816		RADIANCE-HTN TRIO 202117		REQUIRE 202221		RADIANCE II 202318
Demographics
Group	uRDN	SHAM control	uRDN	SHAM control	uRDN	SHAM control	uRDN	SHAM control
N	74	72	69	67	69	67	150	74
Gender, female	28	33	13	14	21	14	47	17
Gender, male	46	39	56	53	48	53	103	57
Age, years, mean (SD)	54.4 (10·2)	53.8 (10·0)	52.3 (7.5)	52,8 (9.1)	50.7 (11.4)	55.6 (12.1)	55.1 (9.9)	54.9 (7.9)
Baseline characteristics
Body mass index, mean (SD)	29.9 (5.9)	29.9 (5.0)	32.8 (5.7)	32.6 (5.4)	29.5 (5.5)	28.4 (4.5)	30.1 (5.2)	30.6 (5.2)
Abdominal obesity	41	44	54	55	–	–	90	46
GFR mL/min/1.73 m2	84.7 (16.2)	83.2 (16.1)	86 (25.2)	82.2 (19.2)	74.2 (16.2)	69.6 (17.1)	81.4 (14.4)	82.3 (14.9)
GFR < 60 mL/min/1.73 m2	1	3	8	7	15	18	7	3
Type 2 diabetes mellitus	2	5	21	17	18	20	9	5
Cardiovascular disease	–	–	8	9	9	9	1	–
Systolic BP at office screening, mm Hg	142.6 (14.7)	144.6 (15.9)	161.9 (15.5)	163.6 (16.8)	157.6 (19.5)	160.4 (14.9)	155.8 (11.1)	154.3 (10.6)
Diastolic BP at office screening, mm Hg	92.3 (10.1)	Mean 93.6 (8.3)	105.1 (11.6)	103.3 (12.7)	97.7 (16.6)	95.3 (14.2)	101.3 (6.7)	99.1 (5.6)
HR at office screening, beats/min	72 (12.1)	72.6 (12.3)	74.5 (11)	77.6 (12.9)	75.3 (10.8)	71.5 (12.8)	74.1 (12.0)	73.6 (11.9)
Number of antihypertensive drugs at screening	1: 33 2: 28 3: 1	1: 28 2: 27 3: 1	3: 27 4: 22 5: 20	3: 28 4: 24 5: 15	3: 32 4: 20 5: 17	3: 29 4: 23 5: 15	1: 52 2: 44 > 2: 0	1: 25 2: 25 > 2: 1
Procedural time	72.3 (23.3)	38.2 (12.6)	83.66 (22.71)	41.33 (12.87)	86.7 (54.0)	40.2 (11.6)	76.7 (25.2)	43.9 (16.6)
Following intervention
Office systolic blood pressure at 2 months	143.7 (16.7)	149.7 (17.4)	147.1 (20.3)	152.1 (22)	–	–	145.8 (15.9)	151.2 (16.4)
Office diastolic blood pressure at 2 months	94.2 (10.1)	98 (10)	96.6 (13.9)	98.7 (13.8)	–	–	96.0 (10.2)	98.1 (11.2)
Daytime ambulatory systolic BP at 2 months	141.9 (11.9)	147.9 (13.3)	141.0 (16.1)	146.3 (18.8)	–	–	135.6 (13)	142.9 (10.5)
Daytime ambulatory diastolic BP at 2 months	87.9 (7.1)	90.9 (7.9)	88.5 (11.6)	90.7 (12.2)	–	–	83.1 (7.6)	87.0 (6.3)
24-hour systolic BP at 2 months	135.6 (11.4)	140.7 (11.8)	135.2 (16.0)	140.5 (18.7)	–	–	135.6 (13.0)	142.9 (10.5)
24-hour diastolic BP at 2 months	83 (6.8)	85.7 (7.1)	83.6 (10.9)	85.8 (12)	–	–	83.1 (7.6)	87.0 (6.3)
Home systolic BP at 2 months	139.4 (11.7)	146.6 (15.4)	144.6 (18.2)	149.9 (18.9)	–	–	143.4 (12.3)	148.8 (12.3)
Home diastolic BP at 2 months	89.9 (7.8)	93.3 (8.5)	93.2 (14.7)	96 (12.8)	–	–	92.7 (7.4)	95.5 (8.1)
Nighttime ambulatory systolic BP at 2 months	125.6 (12.8)	129.4 (13.1)	126.3 (18.4)	76.2 (12.2)	–	–	125.5 (15.0)	132.4 (12.2)
Nighttime ambulatory diastolic BP at 2 months	74.8 (8.5)	77.3 (8.5)	131.9 (20.9)	78.4 (13.2)	–	–	75.1 (9.7)	79.6 (7.5)
BP, blood pressure; GFR, glomerular filtration rate; SD, standard deviation; uRDN, ultrasound renal denervation.

Table 2. Summary of included studies

Study ID	Country	Study design	Total population	Compare interventions	Key findings
RADIANCE HTN SOLO16	United States/Europe	RCT	146	uRDN vs SHAM control	Renal denervation resulted in a greater reduction in daytime ambulatory systolic blood pressure compared with a sham procedure
RADIANCE HTN TRIO17	United States/Europe	RCT	136	uRDN vs SHAM control	Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure
REQUIRE21	Japan and South Korea	RCT	136	uRDN vs SHAM control	Is the first trial of ultrasound renal denervation in Asian patients with hypertension on antihypertensive therapy
					The study did not show a significant difference in ambulatory blood pressure reductions in treated patients with resistant hypertension
RADIANCE II18	United States	RCT	224	uRDN vs SHAM control	The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months
					No major adverse events were reported in either group
RCT: randomized controlled trial; SBP, systolic blood pressure; uRDN: ultrasound renal denervation.

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)

Trials	Risk of bias domains
	D1	D2	D3	D4	D5	Overall
RADIANCE HTN SOLO16	Low	Low	Low	Low	Low	Low
RADIANCE HTN TRIO17	Low	Low	Low	Low	Low	Low
REQUIRE21	Low	Low	Low	Low	Low	Low
RADIANCE II18	Some concerns	Low	Low	Low	Low	Some concerns
D1: bias arising from the randomization process. D2: bias due to deviation from intended intervention. D3: bias due to missing outcome data. D4: bias in outcome measurement. D5: bias in selection of the reported result.

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.

REFERENCES

INTRODUCTION

Atrial fibrillation (AF) increases with age and raises the risk of ischemic stroke, systemic embolism, and death, with stroke or transient ischemic attack (TIA) often being the initial presentation. 1,2 Oral anticoagulation (OAC) with direct OAC (DOAC) or vitamin K antagonists (VKA) is effective in reducing these risks.1,2 However, recent randomized clinical trials suggest a 1.0%–1.5% annual stroke rate in AF patients on OAC.3-5 Up to one-third of AF patients who develop ischemic stroke are on OAC at stroke onset, with 8.8% up to 20% being on DOAC,6-9 which poses a significant challenge for secondary prevention purpose. Additionally, these patients tend to be older and have more comorbidities, sometimes requiring off-label low-dose DOAC.7 The use of off-label low-dose DOAC, atrial enlargement, and increased AF burden further raises the risk of stroke despite OAC therapy, suggesting a possible association with advanced cardiac disease or inadequate anticoagulation.10,11

After an ischemic stroke—despite OAC—there are no clear guidelines on the management of OAC, such as switching drugs, targeting a higher international normalized ratio (INR) with AVK, or adding antiplatelet agents. Network meta-analyses show no differences in stroke risk across different DOAC. Observational studies also found no benefits in changing OAC, suggesting additional stroke mechanisms.7 Stroke workups should identify alternative embolisms or sources of thrombosis, such as large-vessel atherosclerosis or small-vessel disease, which may need specific antithrombotic strategies.7,9,10,12 Although adding antiplatelets may reduce platelet activation, it is associated with a higher bleeding risk.13 Therefore, the best secondary prevention for AF patients after stroke despite OAC remains unclear, highlighting the need for new treatments, including novel non-pharmacological approaches such as left atrial appendage occlusion (LAAO).

Recent data from the STR-OAC cohort—an international LAAO registry—showed promising findings in AF patients with stroke despite OAC. In this study, the LAAO cohort had a 2.2% per patient-year stroke rate vs the 9.8% reported in the non-LAAO cohort (HR, 0.33; 95%CI, 0.19-0.59).14 Despite this positive outcome, no RCTs have assessed the feasibility, safety and efficacy profile of using OAC plus LAAO as adjuvant therapy in this complex population. Herein, we propose oral anticoagulation alone vs oral anticoagulation plus left atrial appendage occlusion in stroke patients despite ongoing anticoagulation (ADD-LAAO trial). This is a pragmatic randomized controlled trial (RCT) designed to evaluate the superiority of a hybrid strategy combining transcatheter left atrial appendage occlusion (LAAO) and long-term continued oral anticoagulation (OAC)—either direct oral anticoagulants (DOAC) or VKA when clinically appropriate—vs medical management with OAC alone. The trial aims to assess the effectiveness of this approach in reducing recurrent ischemic stroke in patients with atrial fibrillation (AF) who have experienced an AF-related acute ischemic stroke despite being anticoagulated at the time of stroke onset.

METHODS

Study design

We conducted a multicenter randomized controlled trial with patients with a past medical history of ischemic stroke within the past 6 months despite OAC. A total of 6 teaching hospital centers are involved in this study. Eligible patients will be screened and included based on specific criteria (figure 1 illustrates the inclusion and exclusion criteria). In general, patients with stroke despite OAC will include the following data: those with VKA with correct or labile INR and those with DOAC with poor compliance. Poor compliance will be defined as missing a maximum of 1 day dose (1 pill for VKA and 2 for DOAC) over the past week before the index stroke. Poor compliant patients will be included as the risk of non-compliance is an inherent characteristic of OAC. In contrast, patients missing > 1 day dose over the past week before the index procedure will not be included as these patients cannot be considered anticoagulated. A crucial inclusion criterion for randomization purposes will be the absence of an absolute contraindication to OAC, as this population is considered a high-risk cohort for thrombotic events, and post-LAAO OAC discontinuation has been reported to increase thrombotic risk.15 The study flow diagram is shown in figure 2.

Figure 1. Inclusion and exclusion criteria. AF, atrial fibrillation; CT, computed tomography; DOAC, direct oral anticoagulant; Hb, hemoglobin; LAAO, left atrial appendage occlusion; NYHA, New York Heart Association; OAC, oral anticoagulation; PFO, patent foramen ovale; TEE, transesophageal echocardiogram; TIA, transient ischemic attack.
^a Cardioembolic ischemic stroke definition: AF-related stroke after ruling out symptomatic ipsilateral great vessel/intracranial vascular disease, and small vessel disease and active endocarditis or neoplasm.
^b > 1 dose per antagonist of vitamin K and > 2 doses per DOAC.
^c > 50% lumen diameter narrowing on CT, magnetic resonance imaging, or transcranial Doppler with symptoms of ipsilateral transient or visual TIA.
^d If general anesthesia is planned for the study procedure.
^e If the patient needs CCTA and cannot undergo TEE.
^f The active treatment group may confound the results of this trial.

Figure 2. Central illustration. Study protocol. CT, computed tomography; DOAC, direct oral anticoagulant; LAAO, left atrial appendage occlusion; OAC, oral anticoagulation; TEE, transesophageal echocardiogram.

Subject screening, enrollment, and randomization

Patients meeting all inclusion and no exclusion criteria will be approached for the study. Prior to inclusion, transesophageal echocardiography (TEE) or coronary computed computed tomography will rule out the presence intra-cardiac thrombus and assess the LAA anatomy. If suitable for LAAO, the study will be explained, and informed consent from the patients will be obtained. Upon consent, patients will be randomized on a 1:1 ratio to the interventional group—receiving LAAO and long-term OAC—or the control group, receiving the optimal medical therapy as decided by neurologists. The interventional procedure will occur within 2 weeks post-randomization. The optimal medical therapy may involve intensified antithrombotic therapy, switching OAC regimens, reinforcing drug compliance, or a combination of these strategies. Randomization will be managed online, allocating patients in groups of 10 to ensure balanced inclusion across both groups.

OAC strategies

The treating neurologist team will decide on the OAC strategy and dosage for the interventional and control groups. Any DOAC (apixaban, dabigatran, rivaroxaban, or edoxaban) will be accepted. DOAC dosages will be down titrated if the patient’s bleeding risk is high or per product label recommendations. In the interventional group, although DOAC is preferred to minimize bleeding risk,16 VKA will be allowed if necessary, such as for patients with mechanical cardiac valves. The protocol does not restrict other concomitant drugs; each will be assessed for additional hemorrhagic risk by the physician. The OAC duration will be indefinite in the 2 groups unless a new formal contraindication emerges, such as in cases of major bleeding. Furthermore, each situation will be managed individually by investigators at each center.

Interventional group

Patients from the interventional group will undergo LAAO following standard practice. ACO will be discontinued prior to the procedure per product label recommendations for DOAC, and with bridging therapy using low-molecular-weight heparin in patients with an indication for VKA. A prophylactic antibiotic—cephalosporin or vancomycin for beta-lactam allergy—will be administered 2 hour prior. Procedure will be performed under general anesthesia or deep sedation with TEE or intracardiac echocardiography guidance. The femoral vein will be used for vascular acces, followed by a transseptal puncture. A 100 IU/kg bolus of IV heparin will be administered to achieve an activated clotting time ≥ 250 seconds. Fluoroscopy and TEE or intracardiac echocardiography will guide the procedure, allowing for LAA measurement, catheter and device positioning, and early complication detection. Approved LAAO devices include Amulet (Abbott Medical, United States), Watchman FLX (Boston Scientific, United States), and LAmbre (Lifetech Scientific [Shenzhen] Co. Ltd., China). Six to 24 hours after the intervention, transthoracic echocardiography will check for any pericardial effusions or device embolizations that may have occurred. If no complications are found, the patient will be discharged the same or the next day (institution protocol). Anticoagulation therapy (DOAC at the same dose as before LAAO or VKA with the initial dose determined by the thrombosis clinic assessment) will be resumed the day after the procedure. No antiplatelet therapy will be added to anticoagulation therapy in the LAAO group.

Study endpoint and outcome definitions

The primary endpoint of the study is the occurrence of a cardioembolic event—ischemic stroke or peripheral arterial embolism— within the first 12 months after inclusion. Secondary endpoints include evaluating the safety and efficacy profile of the strategies and combining cardioembolic events (efficacy) and major bleeding (safety) within the same period. A stroke is defined as the sudden onset of a focal neurologic deficit consistent with a major cerebral artery territory, categorized as ischemic, hemorrhagic, or unspecified, and confirmed through imaging using computed tomography or magnetic resonance imaging. Systemic cardioembolic events are acute vascular occlusions in an extremity or organ, confirmed by imaging, surgery, or autopsy. Major bleeding will follow the Bleeding Academic Research Consortium (BARC) criteria for types 3 and 5.17

Additional endpoints will assess major and minor bleeding (using the BARC classification), all-cause and cardiovascular death, recurrent stroke severity (using the modified Rankin scale), procedural major adverse events in the interventional group, device-related thrombus, additional hospital admissions, and OAC compliance. All clinical events, including primary and secondary endpoints, will be independently allocated.

The success of the intervention is defined as the implantation of the LAAO device without major complications, such as death, stroke, or those requiring surgical or endovascular treatment.18 Procedural safety will be evaluated by including all clinical events within the first 7 after the intervention. Events will be defined following the Valve Academic Research Consortium (VARC) guidelines, including mortality, myocardial infarction, stroke, systemic embolism, major bleeding, and procedural complications.19 Major bleeding will follow the BARC criteria for types 3 and 5.17 A neurologist will independently grade disabling strokes with an m-RS score of ≥ 3.20 Device-related thrombus will be any thrombus > 1 mm on the LAAO device, and peri-device leaks will be classified by TEE jet width (> 3 mm being significant).21 Complete LAAO is defined as the absence of any leaks > 3 mm on the final TEE.22

Clinical and imaging follow-up

Patients will be followed for 12 months. Clinical visits with neurological assessment and modified Rankin scale evaluation will occur on months 3 and 12. A phone follow-up will be conducted on month 6. The interventional group will undergo post-LAAO additional imaging modalities. Two imaging modalities with TEE or coronary computed tomography angiography will assess device-related thrombus and peri-device leaks 3 (2-4 months) and 12 months (10-12 months) after the intervention. Additionally, standard blood tests, including complete blood count and renal function will be performed on the same day as the imaging modalities to detect hidden hemorrhagic events.

Sample size and statistical analysis

Sample size is determined based on observed event rates in major registries, with an estimated 10% rate of recurrent cardioembolic events in the control group and 2% in the interventional group within the first year. To detect an 8% difference between the 2 groups, with a 5% type I error and 90% power, 183 patients per group are needed for a total of 366. Accounting for potential dropouts (~5%), the study will include 380 patients. The primary analysis will be conducted following the intention-to-treat principle, making sure that all randomized patients are analyzed in the group they have been initially allocated to, regardless of protocol deviations, dropouts, or crossover. This approach will provide an unbiased estimation of the treatment effect under real-world conditions and preserve the benefits of randomization. If a patient from the interventional group experiences a primary endpoint prior to the procedure—as they will be on OAC treatment—they will be allocated to the interventional group. An interim analysis will be performed after including 50% of the population (190 patients), and the study will be stopped if significant differences are detected.

Categorical variables will be expressed as frequencies and compared using the chi-square or Fisher’s exact test. Continuous variables will be expressed as mean ± SD or median (IQR), using the Kolmogorov-Smirnov test for normality. Comparisons will use the Student’s t test or the Mann-Whitney U test. Composite endpoints will be assessed as a time-to-first event. Cumulative incidence will be evaluated using the Kaplan-Meier method and compared using the log-rank test, followed by Cox proportional hazards modeling. Treatment effects will be estimated with hazard ratios and 95% confidence intervals, with 2-sided P-values ≤ .05 considered statistically significant. Analyses will be performed using STATA (Version 14.0 (Stata Corp., United States). The trial has been registered on ClinicalTrials.gov, and the registry No. is pending registration approval.

Current study status

Study recruitment is set to commence. The study is expected to be completed in 23 months. The projected study timeline is shown in figure 3.

Figure 3. Projected study timeline.

DISCUSSION AND CLINICAL IMPLICATIONS

The current study is expected to have a significant impact on the scientific community, particularly in the fields of cardiology and neurology. As previously mentioned, the prevalence of AF and the number of patients experiencing ischemic strokes despite being OAC are on the rise,3-5 which presents a significant challenge due to the absence of clear and uniform treatment recommendations for these patients. Intensification of antithrombotic regimens in this population often leads to an elevated risk of major bleeding, especially among elderly and frail individuals.13 Therefore, assessing a novel therapeutic strategy that combines LAAO with DOAC is essential. LAAO targets the left atrial appendage, which is responsible for more than 90% of thrombus formation in non-valvular AF,16 potentially enhancing the efficacy of OAC while maintaining a lower bleeding risk with DOAC. Recent registries evaluating the LAAO + DOAC strategy have reported promising outcomes, demonstrating a significantly reduced rate of recurrent strokes and major bleeding vs optimal medical therapy alone.23-25 Given these encouraging preliminary data, the timing is ideal for a randomized controlled trial to evaluate this combined approach rigorously.

As far as we know, the proposed study is one of the first randomized clinical trials to compare LAAO + DOAC and optimal medical therapy, as determined by a neurologist, in patients who have experienced ischemic strokes despite being on OAC. The ELAPSE trial has also started recruitment with a similar design (NCT05976685). Should trial results confirm the superiority of the LAAO + DOAC strategy over current medical management protocols, our findings will contribute to a paradigm shift in the treatment guidelines for this patient cohort. Specifically, the LAAO + DOAC combo could offer a more effective and safer therapeutic option, addressing the unmet need for reducing stroke recurrence while minimizing bleeding risks, which could impact future clinical practice and guideline recommendations, ultimately improving patient outcomes in those with AF and a history of ischemic stroke. This trial successful completion and positive outcomes can potentially establish a new standard of care, thus significantly impacting clinical practice and patient quality of life alike in this high-risk population.

To achieve these goals, the centers participating in this study have been carefully selected based on their annual volume of candidates for LAAO and their expertise in managing these procedures. These centers are recognized as referral centers for both LAAO and stroke code management. Although randomizing 380 patients across 6 hospitals within a reasonable timeframe may appear challenging, we have implemented measures to streamline the process. Dedicated teams for the early identification of eligible patients and standardized follow-up strategies have been established to facilitate recruitment.

We recognize that this is an ambitious undertaking; however, the study design and the cumulative experience of participant centers provide confidence in achieving the goals set within the anticipated timeline. If successful, this trial has the potential to establish a new standard of care, significantly impacting clinical practice and improving the quality of life of this high-risk population.

FUNDING

This work has been funded by a grant from Fundació La Marató de TV3.

ETHICAL CONSIDERATIONS

The study is being conducted following the recommendations outlined in the Declaration of Helsinki on clinical research, has been approved by Hospital Clinic de Barcelona Research Ethics Committee, and endorsed by the remaining ethics committees of all participant centers. Informed consent acceptance and signature are required prior to performing any elective procedures for the study of the non-culprit lesions. Potential sex and gender biases are considered.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the drafting of this manuscript.

AUTHORS’ CONTRIBUTIONS

X. Freixa and E. Flores-Umanzor drafted this document. The remaining signatories reviewed the document and made changes at their discretion. All the authors revised and approved the final version of the manuscript.

CONFLICTS OF INTEREST

I. Cruz-Gonzalez and X. Freixa are proctors from Abbott Medical, Boston Scientific and Lifetech. R. Estevez-Loureiro and D. Arzamendi are proctors from Abbott Medical, Boston Scientific. L. Nombela- Franco is a proctor from Abbott Medical. The rest of the authors declared no conflicts of interest whatsoever.

REFERENCES

INTRODUCTION

Aortic stenosis (AS) is the second most common valvular heart disease, affecting 12% of people older than 75 years.1,2 Without treatment, the survival rate for symptomatic severe AS is less than 3 years.3 Transcatheter aortic valve implantation (TAVI) is recommended for symptomatic patients and for asymptomatic patients with a reduced left ventricular ejection fraction (LVEF) of less than 50%.4

Reduced LVEF is recognized as an independent risk factor for events and mortality in patients with severe AS.5 However, the prognosis of severe AS in patients with preserved LVEF (> 50%) remains uncertain, especially in the presence of markers of subclinical myocardial injury, such as hypertrophy and fibrosis.6 Among these patients, those with a supranormal LVEF (≥ 70%) may have a worse prognosis after TAVI due to specific ventricular geometry and functional characteristics.7

The aim of this study was to evaluate the prognosis of patients with supranormal LVEF (≥ 70%) undergoing TAVI and study their echocardiographic and clinical characteristics.

METHODS

We conducted a retrospective cohort study of patients with severe AS who underwent TAVI at Hospital Clínico San Carlos in Madrid, Spain, between June 2007 and December 2021. Severe AS was defined according to current guideline criteria: mean gradient > 40 mmHg, peak velocity > 4 m/s, aortic valve area < 1 cm², or indexed aortic valve area < 0.6 cm²/m². The decision to perform TAVI was made by a multidisciplinary medical-surgical team. Patients were categorized into 3 groups based on their preprocedural LVEF, as assessed by echocardiography: reduced (< 50%), normal (50%-69%), and supranormal (≥ 70%). Clinical data were collected from medical records. Patients were excluded if they did not survive the procedure, had previous cardiac valve surgery, had cardiomyopathy unrelated to valvular disease, had a life expectancy of less than 1 year, or had missing data in their preprocedural echocardiographic study or clinical follow-up.

The clinical endpoints used to evaluate the prognosis of patients with supranormal LVEF (≥ 70%) undergoing TAVI were all-cause mortality at 30 days and 1 year, cardiovascular mortality at 1 year, and cardiovascular-related rehospitalization at 1 year. We also assessed their correlation with echocardiographic and clinical characteristics.

The study was conducted in accordance with the principles of the Declaration of Helsinki by the World Medical Association and received approval from the ethics committee of Hospital Clínico San Carlos in Madrid, Spain. Since the study was retrospective and posed no risk to patients, informed consent was not required. All data were handled with the utmost confidentiality by the researchers.

Echocardiography

Two-dimensional Doppler echocardiography was performed using the available equipment and following clinical practice guidelines.8 Measurements included septal thickness, posterior wall thickness, end-diastolic diameter, and left ventricular outflow tract (LVOT) diameter in the parasternal long-axis view. Peak and mean valvular gradients were assessed using continuous Doppler in multiple windows to obtain the highest velocity. The velocity-time integral (VTI) was measured with pulsed Doppler by placing the sample volume just before the aortic valve annulus. The aortic valve area was then calculated using the continuity equation:

Ventricular volumes and LVEF were calculated using the biplane Simpson method. The left ventricular (LV) mass was calculated using the Devereux formula and indexed to body surface area. Relative parietal thickness (RPT) was calculated using the following formula:

The indexed stroke volume was obtained using the following formula:

Statistical analysis

The statistical analysis was conducted using available commercial software (IBM SPSS 28.0). Normally distributed continuous variables are expressed as the mean and standard deviation, with a 95% confidence interval (95%CI). Categorical variables are expressed as absolute numbers and percentages. The Student t-test was used to compare variables with a normal distribution. Analysis of variance and the Tukey post hoc test were used to compare means, while the chi-square test was used to compare prevalences among the 3 groups. A univariable logistic regression analysis was applied to evaluate predictors of hospitalization and mortality. P values < .05 were considered statistically significant.

RESULTS

Of the 1228 patients who underwent TAVI during the study period, 1160 were included in the analysis. Among these, 276 patients (23.7%) had a reduced LVEF (< 50%), 702 patients (60.5%) had a normal LVEF (50%-69%), and 182 patients (15.6%) had a supranormal LVEF (≥ 70%). Sixty-eight patients were excluded based on the following criteria: 23 due to death during the procedure, 15 with previous cardiac valve surgery, 6 with cardiomyopathy unrelated to valvular disease, 18 with a life expectancy of less than 1 year, and 6 with missing data in the preprocedural echocardiographic study or clinical follow-up (figure 1).

Figure 1. Flow chart illustrating the patients included and excluded from the study, the final sample analyzed, and its distribution among the 3 study groups. LVEF, left ventricular ejection fraction.

 

The baseline characteristics of the study population are shown in table 1. The mean age was 82.2 ± 5.8 years and was slightly lower in the reduced LVEF group than in the other 2 groups. Male sex was more common in the group with LVEF ≥ 70% (P < .005). Patients with LVEF < 50% had a higher prevalence of prior myocardial infarction, coronary artery disease, and revascularization, along with a higher EUROSCORE II (22.5 [14.7-32.0]; P < .001). This group also more frequently required the intervention as an emergency procedure (P < .001).

 

Table 1. Patients’ baseline characteristics

Characteristics	LVEF < 50% (n = 276)	LVEF 50%-69% (n = 702)	LVEF ≥ 70% (n = 182)	P value
Age (years)	81.6 ± 6.3	82.2 ± 5.9	82.9 ± 5.3	< .050
Male sex	38.1%	58.2%	68.3%	< .001
Hypertension	80.7%	82.9%	86.0%	.363
Diabetes mellitus	41.7%	35.6%	33.9%	.182
Body mass index	27.1 ± 4.4	28.4 ± 5.2	27.7 ± 5.1	< .002
Hyperlipidemia	56.9%	59.8%	56.0%	.254
Previous PTA	30.6%	19.4%	16.8%	< .001
Previous CABG	9.6%	4.5%	3.3%	< .002
Previous infarction	20.6%	9.1%	7.6%	< .001
Coronary artery disease	45.6%	32.7%	34.7%	< .002
Left main coronary artery disease	5.6%	3.4%	1.8%	.222
Incomplete revascularization	20.7%	30.4%	35.3%	.174
COPD	16.7%	15.1%	14.5%	.714
Smoking	37.2%	41.7%	14.4%	.034
Atrial fibrillation	38.6%	37.8%	42.1%	.570
Glomerular filtration	61.2 (46.0-77.9)	63.1 (46.8-79.4)	60.9 (45.5-75.2)	.311
Cancer	16.0%	15.5%	18.7%	.725
EuroSCORE II	22.5 (14.7-32.0)	14.3 (7.4-18.0)	11.8 (8.9-18.9)	< .001
Dyspnea	87.5%	87.5%	91.7%	.289
Emergency procedure	33.9%	17.5%	14.1%	< .001
Valve-in-valve	3.6%	3.3%	2.7%	.881
Post-TAVI outcome
Peak gradient (mmHg)	18.3 ± 7.3	19.3 ± 8.9	19.4 ± 8.7	.223
Mean gradient (mmHg)	9.3 ± 3.8	9.9 ± 4.8	10.0 ± 5.7	.229
CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejection fraction; PTA, percutaneous transluminal angioplasty; TAVI, transcatheter aortic valve implantation.

 

Echocardiographic data

Patients with LVEF ≥ 70% had smaller LV end-diastolic and end-systolic volumes, and greater septal wall thickness and RPT than the other 2 groups. In this group, left ventricular mass index (LVMI) was 126.3 ± 32.8 g/m², reflecting a predominant phenotype of concentric hypertrophy and remodelling. A similar pattern was observed in patients with normal LVEF (50%-69%), although this group had a larger end-diastolic LV volume (table 2). In contrast, patients with LVEF < 50% had a greater LV mass, with an LVMI of 147.6 ± 40.2 g/m² (P < .001), a low RWT (< 0.42), and an elevated end-diastolic volume, indicating a predominant phenotype of eccentric hypertrophy. In addition, this group had a lower indexed stroke volume (32.5 ± 11.8; P < .001).

 

Table 2. Patients’ baseline characteristics

Characteristics	LVEF < 50%	LVEF 50%-69%	LVEF ≥ 70%	P value
RPT	0.48 (0.41-0.58)	0.57 (0.50-0.65)	0.60 (0.52-0.69)	< .001
Indexed LVESV (mL/m²)	31 (25-39)	38 (31-45)	39 (31-49)	< .001
Indexed LVEDV (mL/m²)	63 (48-80)	48 (38-59)	45 (35-56)	< .001
LVMI (g/m²)	147.6 ± 40.2	128.8 ± 34.2	126.3 ± 32.8	< .001
IVS (mm)	12.1 ± 2.6	13.6 ± 2.4	14.1 ± 2.7	< .001
Indexed stroke volume (mL/m²)	32.5 ± 11.8	38 ± 11.5	40 ± 11.6	< .001
IVS, interventricular septum; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVMI, left ventricular mass index; RPT, relative parietal thickness.

 

Perioperative clinical endpoints

There were no significant differences among the 3 groups regarding intra- and postoperative mortality.

Clinical endpoints at follow-up

During the 1-year follow-up, 164 patients (14.13%) died, with no significant differences among the 3 groups (LVEF < 50%, 14.6%; LVEF 50%-69%, 12.6%; LVEF ≥ 70%, 12.7%; P < .736). However, significant differences were found in the rate of cardiovascular rehospitalization at 1 year, with higher rates in the supranormal LVEF group (LVEF ≥ 70%, 34.4%; LVEF < 50%, 29.2%; LVEF 50%- 69%, 27.4%; P < .043). Clinical endpoints are shown in table 3.

 

Table 3. Clinical endpoints

Variables	LVEF < 50% (n = 276)	LVEF 50%-69% (n = 702)	LVEF ≥ 70% (n = 182)	P value
Perioperative
Intraoperative mortality	0.4%	1.4%	0.6%	.345
Postoperative mortality	2.8%	3.7%	4.3%	.676
Follow-up
All-cause mortality at 30 days	2.4%	3.9%	5.0%	.359
Cardiovascular mortality at 1 year	12.8%	9.6%	15.2%	.370
All-cause mortality at 1 year	14.6%	12.6%	12.7%	.736
Cardiovascular rehospitalization at 1 year	29.2%	27.4%	34.4%	< .043
LVEF, left ventricular ejection fraction.

 

Univariable regression analysis

In patients with supranormal LVEF, coronary artery disease and increased interventricular septal thickness were predictors of cardiovascular hospitalization at 1 year (table 4). In this group, indexed LV end-diastolic volume and a history of coronary artery disease were predictors of all-cause mortality at 1 year (table 5). In the general population, no predictors of 1 year mortality were identified, except for age (table 6).

 

Table 4. Supranormal left ventricular ejection fraction and predictors of cardiovascular hospitalization at 1 year

Characteristics	HR	95%CI	P value	HR
Age	1.077	0.991-1.169	.080
Hypertension	1.687	0.546-5.213	.364
Diabetes mellitus	1.846	0.767-4.440	.171
Body mass index	1.012	0.933-1.099	.770
Coronary artery disease	0.327	0.137-0.780	.012
Smoking	1.796	0.650-4.965	.259
EuroSCORE II	1.046	0.998-1.096	.060
RPT	1.004	0.041-24.392	.998
Indexed LVEDV	0.979	0.949-1.010	.188
IVS	0.965	0.933-0.998	.036
				1.0
95%CI, 95% confidence interval; HR, hazard ratio; IVS, interventricular septum; LVEDV, left ventricular end-diastolic volume; RPT, relative parietal thickness.

Table 5. Supranormal left ventricular ejection fraction and predictors of 1-year mortality

Characteristics	HR	95%CI	P value	HR
Age	1.180	0.976-1.426	.087
Hypertension	2.181	0.167-28.575	.552
Diabetes mellitus	0.875	0.154-4.968	.154
Body mass index	1.004	0.796-1.265	.976
Coronary artery disease	3.372	0.612-18.575	.012
Smoking	7.453	0.691-61.024	.259
EuroSCORE II	0.921	0.831-1.022	.120
RPT	0.011	0.000-154.979	.998
Indexed LVEDV	1.094	1.018-1.177	.015
IVS	1.004	0.943-1.068	.912
				1.0
95%CI, 95% confidence interval; HR, hazard ratio; IVS, interventricular septum; LVEDV, left ventricular end-diastolic volume; RPT, relative parietal thickness.

Table 6. Predictors of 1-year mortality in the general population

Characteristics	HR	95%CI	P value	HR
Age	1.070	1.002-1.143	.043
Hypertension	1.268	0.545-2.947	.582
Diabetes mellitus	1.458	0.764-2.784	.253
Body mass index	0.949	0.882-1.020	.152
Coronary artery disease	1.593	0.867-2.929	.134
Smoking	1.794	0.899-3.581	.097
EuroSCORE II	1.046	0.973-1.033	.868
RPT	0.252	0.022-2.836	.264
Indexed LVEDV	0.986	0.967-1.006	.188
IVS	1.000	0.974-1.027	.036
				1.0
95%CI, 95% confidence interval; HR, hazard ratio; IVS, interventricular septum; LVEDV, left ventricular end-diastolic volume; RPT, relative parietal thickness.

 

DISCUSSION

This study demonstrates that LVEF is an important prognostic factor in patients with severe AS treated with TAVI. While no differences in mortality were observed at 1 month or 1 year, patients with supranormal LVEF (≥ 70%) had a higher rate of rehospitalization at 1 year than those with reduced (< 50%) or normal (50%-69%) LVEF.

LVEF has been widely recognized in the literature as a prognostic factor in various clinical contexts. A study by Wehner et al.9 reported that an LVEF of 60% to 65% is associated with the best prognosis, while patients with LVEF ≥ 70% have a 5-year mortality rate similar to those with reduced LVEF. A study by Gu et al.,10 found higher mortality and hospitalization rates at 5 years in patients hospitalized for heart failure with LVEF > 65% than in those with normal LVEF.

In patients with AS undergoing TAVI, the OCEAN-TAVI registry found that LVEF > 65% was an independent predictor of death and rehospitalization at the 3-year follow-up (hazard ratio [HR], 1.16; 95%CI, 1.02-1.31; P = .023).¹¹ There were no significant differences in mortality among the study groups, except for the rehospitalization rate. It remains to be elucidated whether longer-term follow-up could also detect differences in mortality.

In patients with AS undergoing surgical interventions, LVEF is a recognized prognostic marker. In a study by Dahl et al.,¹² reduced LVEF (< 50%) was a clear predictor of 5-year risk. The study revealed that patients with supranormal LVEF experienced longer hospital stays, increased need for mechanical ventilation, a higher incidence of hemodialysis, and a greater rate of rehospitalization. This latter finding is consistent with the findings of the present study. There is no clear explanation for these results, but they may be related to the persistence of myocardial hypertrophy or diastolic dysfunction following the intervention.13

According to previous studies, increased (> 80 mL/m²) and reduced (< 55 mL/m²) ventricular volumes are risk factors to consider in patients with severe AS.14,15 In this analysis, in the subgroup of patients with supranormal LVEF, indexed LV end-diastolic volume was a predictor of 1-year mortality (HR, 1.094; 95%CI, 1.018-1.177; P < .015). A low indexed stroke volume has also been associated with worse prognosis in patients with AS, both with reduced and preserved LVEF.16 Patients with preserved LVEF may have a low stroke volume when the ventricular cavity is small and they have restrictive physiology that limits the stroke volume, even with a supranormal ejection fraction.17 In most studies, these patients have a worse prognosis, with a higher mortality risk and less event-free time.18,19

Supranormal LVEF represents a new phenotype in patients with preserved LVEF (> 50%), with distinctive clinical and hemodynamic characteristics. There is no universal agreement on the exact LVEF value to define supranormal. According to the American College of Cardiology, a LVEF ≥ 70% is considered supranormal,20 while other groups set this threshold at ≥ 65%. For this study, LVEF ≥ 70% was used as the reference to better highlight clinical and echocardiographic differences among the study groups, which likely influenced the prevalence observed in the population.

In a study by Wehner et al.,9 which reviewed 403 977 echocardiograms from 203 135 patients without prespecified diagnoses, an LVEF ≥ 70% was found in 3% (13 553) of participants. In the present study of patients with severe AS, 15% had LVEFs ≥ 70%. Other studies, such as the OCEAN-TAVI registry,¹¹ reported a higher percentage of patients with supranormal LVEF and AS (47%), likely because they used a lower cutoff for supranormal LVEF (≥ 65%). These findings suggest that severe AS is associated with a higher-than-normal LVEF, likely due to left ventricular (LV) remodelling and concentric hypertrophy resulting from elevated afterload.21-24 In our study, the LVMI was elevated in most patients, regardless of LVEF. Patients with normal and supranormal LVEF predominantly exhibited concentric geometry, characterized by a reduced LV cavity and increased septal thickness. In contrast, patients with reduced LVEF showed predominantly eccentric geometry with a dilated LV.

Finally, our results suggest that while widely used risk scales like EuroSCORE II remain valid, echocardiographic factors should also be considered when determining the timing and type of intervention.25

Limitations

This retrospective, observational study was conducted at a single center. All patients underwent TAVI, and there was no comparison with those treated with surgical valve replacement. The medical and pharmacological treatment were not specified, which is an important omission given recent advancements in heart failure management. In addition, a 1-year follow-up may be too short to detect differences in mortality between the groups and a longer-term follow-up might reveal differences.

CONCLUSIONS

LVEF remains an important prognostic factor in decision-making for patients with severe AS. In this study, patients with reduced (< 50%), normal (50%-69%), or supranormal (≥ 70%) preprocedural LVEF who underwent TAVI showed no differences in 1-year mortality. However, those with supranormal LVEF (≥ 70%) had a higher rate of cardiovascular-related rehospitalization at 1 year, suggesting that this subgroup may have unfavorable factors, such as significant diastolic dysfunction. Further research is needed to investigate and confirm these findings.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

This study adhered to the Declaration of Helsinki and received approval from the ethics committee of Hospital Clínico San Carlos in Madrid, Spain. As the study was retrospective and posed no risk to patients, informed consent was not required. All information was handled with strict confidentiality by the researchers. Consecutive patients were recruited during the study period without sampling or randomization, so sex or gender biases were not considered in the analysis

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence tools were used during the performance of the study.

AUTHORS’ CONTRIBUTIONS

E. Martínez Gómez, X. Solar, D. Faria, L. Nombela Franco, and J.A. de Agustín contributed to the conception and design, data acquisition, analysis, and interpretation of the study. E. Martínez Gómez, X. Solar, D. Faria, L. Nombela Franco, P. Jiménez Quevedo, G. Tirado, E. Pozo Osinalde, C. Olmos Blanco, P. Mahía Casado, P. Marcos Alberca, M. Luaces, J.J. Gómez de Diego, L. Collado Yurrita, A. Fernández-Ortiz, J. Pérez-Villacastín, and J.A. de Agustín contributed to the drafting of the article or its critical revision. All authors approved the final version of the article.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

Pulmonary embolism (PE) is the third leading cause of cardiovascular death and the first avoidable cause of death in hospitalized patients.1 According to the European Society of Cardiology (ESC) guidelines, the treatment of PE is based on patient risk assessment.2 Reperfusion therapy with systemic thrombolysis (ST) is indicated as the first-line therapy in patients with high-risk (HR) PE and in those with intermediate-high risk (IHR) PE who deteriorate on anticoagulant drugs.2 However, ST is underused because of contraindications in roughly 30% of patients and even in those with HR-PE and no formal contraindications.3-5 Moreover, this therapy carries a significant risk of major bleeding (≈10%-15%), especially in patients with advanced age, recent surgery, or active cancer.3

Catheter-directed therapies (CDT) have emerged as an alternative to ST for reperfusion in patients with acute PE.6-10 These techniques may improve surrogate right parameters of ventricular failure and clinical outcomes with lower bleeding rates. In a meta-analysis of observational studies comparing catheter-directed thrombolysis vs ST, the risk of in-hospital death and intracranial hemorrhage was reduced in patients undergoing percutaneous intervention. 11 The current ESC guidelines state that CDT should be considered in patients with HR-PE an unsuccessful attempt at thrombolysis or a contraindication to this treatment, and as a rescue treatment for IHR-PE patients with clinical deterioration.2 However, the penetration of interventional therapies is increasing, showing a discrepancy between guideline recommendations and clinical practice.

There is currently scarce evidence in the literature on the contemporary choice of reperfusion therapy, the parameters leading physicians to select one reperfusion therapy over the others, and the target population who may derive the greatest benefit from CDT. Therefore, the main objective of the present study was to identify the clinical factors associated with the choice of CDT as PE therapy in a contemporary cohort of patients with acute PE.

METHODS

Study design

This study was based on an ambispective multicenter registry that included consecutive patients with intermediate-risk (IR) and HR-PE, evaluated by local Pulmonary Embolism Response Teams (PERT), classified according to ESC guidelines,2 and treated with CDT.12 Two tertiary care centers also recruited patients evaluated by the PERT and treated medically, as previously reported in a single-center experience.13 This study analyzed all consecutive patients evaluated by the local PERT in these 2 hospitals from 2014 to 2022.

The inclusion criteria were patients aged more than 18 years with a confirmed diagnosis of acute IR- or HR-PE (by computed tomography or transthoracic echocardiogram plus clinical suspicion in unstable patients unable to undergo computed tomography). We excluded patients with an uncertain diagnosis of PE, those with > 7 days from symptom onset to diagnosis, and those with low-risk PE according to ESC guidelines.2 The registry was observational, with no recommendation on PE management. Thus, treatment was established according to the criteria of the treating physicians, and the use of CDT was chosen according to availability and the decision of the PERT. The reporting of this study adheres to the Strengthening The Reporting of Observational studies in Epidemiology (STROBE) guideline for cohort studies.14

Data collection and variable definitions

A secure web-based database stored anonymized data in both centers. Data were self-reported by local investigators from digital clinical records and included vital signs and laboratory values. Initial admission to the cardiac intensive care unit included more granular data with recording of hourly clinical vital signs, shock parameters at admission, and worsening during cardiac intensive care unit admission and subsequently after reperfusion (if the patient underwent reperfusion). After hospital discharge, structured follow-up was conducted with visits at 1-month, 3- to 6-months, and 12-months. However, 30-day follow-up results are included in this study. The right ventricle/left ventricle ratio was mainly derived from computed tomography except in patients with no baseline computed tomography due to instability. Bilateral central PE was diagnosed when a thrombus was detected in both main pulmonary arteries by computed tomography or angiography. PE risk was stratified according to ESC guidelines.2 In all patients, we calculated the shock index, defined by the heart rate to systolic blood pressure ratio, Pulmonary Embolism Severity Index score,15 Bova score,16 and Charlson Comorbidity Index.17 For most patients who underwent CDT, hemodynamic parameters (such as systolic and mean pulmonary artery pressure) were measured invasively, with a catheter placed in the pulmonary artery.

Pulmonary embolism therapies

Parenteral anticoagulation was started immediately after PE diagnosis. ST was given through a peripheral vein following the doses recommended in the ESC guidelines.2 CDT included: a) catheter-directed thrombolysis using a multiperforated catheter(s) inserted into the pulmonary artery and left for 6 to 24 hours to infuse low-dose thrombolytics (usually alteplase 0.25 mg/kg or the tenecteplase equivalent); b) mechanical thrombus fragmentation; c) thrombus aspiration using either nondedicated catheters (usually 8-Fr coronary guiding catheters) or dedicated catheters (Indigo 8-Fr [Penumbra, United States], Nautilus 10-Fr [iVascular, Spain], or FlowTriever 24-Fr [Inari medical, United States]); or d) a combination of them. The dose of fibrinolytic therapy (both for ST and catheter-directed thrombolysis) was decided by the treating physician. See figure 1 for an illustration of different CDT options.

Figure 1. Catheter-directed therapies used in the study. Representative images of catheter-directed therapies. A: ultrasound-assisted thrombolysis, EKOS system (Boston Scientific, United States). B: percutaneous thrombectomy with Indigo system (Penumbra, United States). C: large-bore thrombus aspiration, FlowTriever catheter (Inari, United States).

 

Objectives

The main endpoint of the present study was to detect predictors of the use of CDT in patients with IR- or HR-PE requiring reperfusion therapy. Another endpoint was to compare the characteristics of the patients who received the different therapies for acute PE: anticoagulation alone (AC), ST, or CDT. If more than 1 reperfusion therapy was used, the patients were grouped according to the first administered therapy. The analysis focused on identifying variables associated with the choice of different therapies by the treating physician. Thirty-day all-cause mortality was reported as a safety outcome. We also analyzed in-hospital adverse events, such as bleeding events according to the International Society of Thrombosis and Hemostasis classification18 and acute kidney injury. In patients undergoing CDT, we also recorded procedural results (eg, hemodynamic improvement).

Ethics and funding

The registry protocol was approved by the clinical research ethics committee at Hospital Clínico San Carlos as the central committee for the registry, following local research regulations (code 18/010-E). All prospectively included patients signed an informed consent form. An informed consent waiver was granted from the ethics research committee for patients recruited retrospectively. The investigation was an academic, unfunded, investigator-initiated study.

Statistical analysis

Categorical variables are presented as numbers and percentages, and continuous variables as mean ± standard deviation (SD) or median [interquartile range (IQR)], as appropriate. Group comparisons (AC, CDT, and ST) for continuous variables were performed using the ANOVA and chi-square tests for categorical variables. Comparisons between groups were performed with the Student t-test or Wilcoxon test, as appropriate, for continuous variables and the chi-square test for categorical variables. The predictors for using the different reperfusion techniques (ie, CDT or ST) were determined using a logistic regression analysis. The univariate analysis included baseline and clinical variables at PE diagnosis. Variables with P values < .10 in the univariable analysis were included in the multivariable model. Paired t-tests were used to analyze the change in hemodynamic parameters after transcatheter procedures. Missing values for covariates, if any, were not imputed. Statistical analyses were performed using Stata 16 (StataCorp, College Station, United States).

RESULTS

Baseline characteristics and risk stratification

From 2014 to 2022, a total of 274 patients were included in the registry (9.5% with intermediate-low risk, 74.7% with IHR, and 15.8% with HR-PE) (figure 2). Of them, 112 patients (40.9%) received AC only: 57% low molecular weight heparin and 43% unfractionated heparin. The remaining 162 patients (59.1%) underwent reperfusion therapy: 35% received ST as the primary treatment and 24% underwent CDT first. Of the ST group, all the patients received alteplase as fibrinolytic treatment and 5 patients underwent rescue CDT after unsuccessful ST. Notably, 58% of IHR-PE patients in our cohort received reperfusion therapies.

Figure 2. Study patients and selected therapy.

 

Patients’ baseline characteristics according to the treatment strategy are shown in table 1. The study was well balanced regarding gender (52% men); however, there were more men in the AC group than in the ST group (58.0% vs 42.7%, P = .027). Patients in the AC and CDT groups were significantly older than those in the ST group (65.9 ± 16.2 and 62.3 ± 14.7 vs 57.4 ± 16.6 years, respectively, P < .001). Regarding comorbidities, previous cancer was more common among patients in the CDT group than in those in the ST group. The Charlson Comorbidity Index was higher in the CDT group than in the other 2 groups. Among precipitating factors for PE, a history of recent surgery was more frequent in patients in the CDT group than in the other 2 groups, while a recent hospital admission was more frequent in the AC and CDT groups than in the ST group.

 

Table 1. Baseline characteristics

	Total	AC	ST	CDT	P
	N = 274	N = 112	N = 96	N = 66	Global	AC vs ST	AC vs CDT	ST vs CDT
Male sex	142 (51.8%)	65 (58.0%)	41 (42.7%)	36 (54.5%)	.077	.027	.650	.138
Age, years	62.1 (16.4)	65.9 (16.2)	57.4 (16.6)	62.3 (14.7)	< .001	< .001	.136	.056
Body mass index (kg/m2)	29.4 (6.7)	29.4 (6.0)	29.7 (8.8)	29.2 (5.0)	.921	.765	.890	.724
Obesity	133 (48.5%)	52 (46.4%)	54 (56.3%)	27 (40.9%)	.136	.167	.533	.078
Prior venous thromboembolism	53 (19.4%)	20 (17.9%)	22 (23.2%)	11 (16.7%)	.511	.345	.840	.316
Previous cancer	42 (15.3%)	15 (13.4%)	11 (11.5%)	16 (24.2%)	.065	.674	.065	.032
Hypertension	135 (49.5%)	55 (49.1%)	46 (47.9%)	34 (52.3%)	.857	.864	.681	.585
Diabetes mellitus	51 (18.7%)	18 (16.1%)	19 (19.8%)	14 (21.5%)	.628	.484	.362	.788
Heart failure	14 (5.1%)	8 (7.1%)	3 (3.1%)	3 (4.5%)	.411	.197	.487	.638
Chronic kidney disease	20 (7.3%)	10 (8.9%)	4 (4.2%)	6 (9.1%)	.342	.172	.971	.201
Charlson Comorbidity Index	1.0 (1.6)	0.8 (1.4)	0.9 (1.5)	1.5 (1.8)	.026	.676	.010	.043
Recent surgery	35 (12.8%)	12 (10.8%)	4 (4.2%)	19 (28.8%)	< .001	.074	.002	<.001
Recent immobilization	48 (17.5%)	14 (12.5%)	17 (17.7%)	17 (25.8%)	.080	.293	.024	.216
Recent hospital admission	28 (10.3%)	14 (12.6%)	4 (4.2%)	10 (15.2%)	.044	.032	.633	.014
AC, anticoagulation; CDT, catheter-directed therapies; ST, systemic thrombolysis. Data are shown as mean (SD) for continuous variables and No. (%) for categorical variables. P values denote the significance of the differences between the groups for continuous variables analyzed by the ANOVA test and Student t-test, as appropriate. The chi-square test was used to assess the significance of between-group differences for categorical variables. Obesity was defined as body mass index ≥ 30 kg/m2. Statistically significant values are highlighted in bold letters.

 

Clinical and risk stratification parameters at hospital admission are shown in table 2. Patients who received reperfusion therapies, either with CDT or ST, had higher severity parameters than those in the AC group (eg, shock index, right ventricular involvement, or lactate levels). The Pulmonary Embolism Severity Index score, which incorporates comorbidities and PE severity parameters, was higher in CDT patients than in the other 2 groups (P < .001).

 

Table 2. Risk stratification parameters at hospital admission

	Total	AC	ST	CDT	P
	N = 274	N = 112	N = 96	N = 66	Global	AC vs ST	AC vs CDT	ST vs CDT
Systolic blood pressure, mmHga	118.7 (25.3)	126.8 (23.1)	114.5 (25.9)	110.8 (24.6)	< .001	< .001	< .001	.359
Heart rate, bpm	106.9 (18.8)	99.5 (19.7)	112.9 (16.3)	110.9 (16.2)	< .001	< .001	< .001	.459
Shock Index	0.96 (0.36)	0.82 (0.28)	1.06 (0.39)	1.07 (0.35)	< .001	< .001	< .001	.953
Respiratory failure	71 (28.9%)	28 (26.4%)	29 (34.9%)	14 (24.6%)	.314	.205	.796	.191
Syncope	57 (20.8%)	23 (20.5%)	18 (18.8%)	16 (24.2%)	.696	.747	.564	.399
Deep vein thrombosis	74 (27.6%)	34 (30.6%)	23 (24.5%)	17 (27.0%)	.612	.326	.612	.723
Right ventricular involvement	249 (94.0%)	93 (87.7%)	94 (98.9%)	62 (96.9%)	.002	.002	.042	.346
Bilateral pulmonary embolism	175 (63.9%)	70 (62.5%)	57 (59.4%)	48 (72.7%)	.204	.645	.163	.080
Lactate, mmol/L	2.9 (2.9)	2.2 (2.0)	3.7 (3.8)	3.0 (2.6)	.006	.002	.039	.315
Elevated troponin levels	209 (86.0%)	85 (83.3%)	73 (89.0%)	51 (86.4%)	.539	.271	.600	.642
Elevated NT-proBNP levels	167 (78.4%)	74 (77.9%)	57 (78.1%)	36 (80.0%)	.958	.977	.777	.804
High-risk PEb	43 (15.8%)	8 (7.1%)	18 (18.8%)	17 (26.2%)	.002	.012	< .001	.264
PESI score	105.1 (35.1)	97.6 (29.3)	104.9 (36.1)	118.2 (39.4)	< .001	.109	< .001	.028
Bova score	4.7 (1.5)	4.2 (1.5)	5.1 (1.4)	5.0 (1.5)	< .001	< .001	.002	.526
AC, anticoagulation; CDT, catheter-directed therapies; PE, pulmonary embolism; PESI, pulmonary embolism severity index; ST, systemic thrombolysis. Statistically significant values are highlighted in bold. Data are shown as mean ± standard deviation for continuous variables and No. (%) for categorical variables. P values denote the significance of the differences between the groups for continuous variables analyzed by the ANOVA test and Student t-test, as appropriate. The chi-square test tested the significance of between-group differences for categorical variables. aThis variable reflects systolic blood pressure at hospital admission, but some of these patients were under vasopressors, and others were stable on admission and later deteriorated hemodynamically. bAs defined by the European Society of Cardiology guidelines.

 

Reperfusion therapies

Figure 3 shows the trend in the choice between the 2 primary reperfusion therapies over time. There was a progressive increase in the use of CDT and a consequent decrease in the use of ST. The variables that might have led the treating physicians to choose between the 2 reperfusion therapies are shown in table 3. In the univariate analysis, the variables associated with the choice of CDT instead of ST were those reflecting comorbidities, such as older age, previous cancer, and the Charlson Comorbidity Index. Recent surgery and hospital admission were also associated with the choice of CDT. After multivariable analysis in this cohort of patients with acute PE, the only independent predictors of the choice of CDT over ST were the Charlson Comorbidity Index and recent surgery. In addition, this analysis showed that the presence of bilateral central PE was associated with the treating physician’s choice of CDT instead of ST.

Figure 3. Choice of reperfusion therapy over the years.

Table 3. Univariate and multivariable predictors of the choice of CDT over ST or AC as a first-line therapy in acute pulmonary embolism

	Univariable		Multivariable
Variables	OR (95%CI)	P	OR (95%CI)	P
Male sex	1.61 (0.86-3.03)	.139
Age (per year)	1.02 (1.00-1.04)	.058*
Body mass index (per kg/m2)	0.99 (0.94-1.04)	.722
Prior venous thromboembolism	0.66 (0.30-1.48)	.317
Previous cancer	2.47 (1.06-5.75)	.035*
Hypertension	1.19 (0.63-2.24)	.585
Diabetes mellitus	1.11 (0.51-2.42)	.788
Heart failure	1.48 (0.29-7.55)	.640
Chronic kidney disease	2.30 (0.62-8.49)	.211
Recent surgery	9.30 (2.99-28.90)	< .001	11.07 (3.07-39.87)	< .001
Recent immobilization	1.61 (0.75-3.45)	.219
Recent hospital admission	4.11 (1.23-13.72)	.022	1.25 (0.29-5.43)	.767
Systolic blood pressure (per mmHg)	0.99 (0.98-1.01)	.357
Heart rate (per bpm)	0.99 (0.97-1.01)	.457
Respiratory failure	0.61 (0.29-1.29)	.193
Syncope	1.39 (0.65-2.97)	.400
Deep vein thrombosis	1.14 (0.55-2.36)	.723
Right ventricular involvement	0.33 (0.03-3.72)	.369
Bilateral central pulmonary embolism	1.82 (0.93-3.59)	.082	2.42 (1.10-5.32)	.028
Lactate (per mmol/L)	0.94 (0.83-1.06)	.317
Elevated troponin levels	1.00 (1.00-1.00)	.312
Elevated NT-proBNP levels	1.12 (0.45-2.81)	.804
Charlson Comorbidity Index	1.21 (1.00-1.47)	.048	1.29 (1.05-1.59)	.018
OR, ods ratio; 95%CI, 95% confidence interval. Logistic regression was used to detect the predictors leading physicians to choose catheter-directed therapies instead of systemic thrombolysis as reperfusion treatment. Variables with P values < .10 in the univariable analysis were included in the multivariable model. Obesity was defined as body mass index ≥ 30 kg/m2. Statistically significant values are highlighted in bold letters. *Age and previous cancer were not included in the multivariable model despite being significant in the univariate analysis to avoid problems of collinearity because they are included in the Charlson Comorbidity Index.

 

Procedural characteristics in the CDT group are displayed in table 4. The median treatment delay from diagnosis of acute PE to percutaneous treatment was 6.0 [interquartile range [IQR], 3.5-19.0] hours and the mean procedure length was 89.0 ± 44.4 minutes. Catheter-directed thrombolysis was used in 35 patients (53.0%), and the most frequently used thrombolytic drug was alteplase (71.4%), with a mean dose of 16.7 ± 7.2 mg. The median bolus dose in patients treated with alteplase was 4 [IQR, 2.9-6.3] mg and the median perfusion time of the remaining dose was 16.0 [IQR, 12.0-20.0] hours. In all patients treated with tenecteplase, the drug was administered as a bolus. Thrombus aspiration was performed in 42 patients (63.6%). The most commonly used aspiration devices were coronary catheters (42.9%), followed by FlowTriever catheter (Inari Medical, United States) (38.1%). A combined thrombolysis plus aspiration technique was performed in 11 patients. Systolic pulmonary artery pressure decreased from 57.9 ± 15.4 to 47.6 ± 12.6 mmHg (mean: −10.3 ± 11.3 mmHg, P < .001) after the percutaneous procedure, while the mean pulmonary artery pressure decreased from 35.0 ± 9.1 to 28.6 ± 8.8 mmHg (mean: −6.4 ± 6.8 mmHg, P < .001). Systolic blood pressure significantly increased after the procedure from 127.8 ± 23.4 to 138.8 ± 22.0 mmHg (mean: +11.0 ± 24.5 mmHg, P = .028).

 

Table 4. Procedural characteristics in the catheter-directed therapies group

Patients with percutaneous intervention (N = 66)
Therapy delay, hours*	6.0 [3.3-19.0]
Procedure length, minutes	89.0 (44.4)
Vascular access
Femoral	64 (97.0%)
Brachial	2 (3.0%)
Maximum sheath diameter, French	8.0 [6.0-20.0]
Catheter-directed thrombolysis	35 (53.0%)
Thrombolytic drug
Alteplase	25 (71.4%)
Tenecteplase	10 (28.6%)
Drug dose
Alteplase, mg	16.7 (7.2)
Tenecteplase, units	3737.5 (1947.8)
Ultrasound-assisted	2 (5.7%)
Thrombus aspiration	42 (63.6%)
Catheter
Coronary catheters	18 (42.9%)
FlowTriever	16 (38.1%)
Indigo	6 (14.3%)
Nautilus	2 (4.8%)
sPAP change, mmHg	−10.3 (11.3)
mPAP change, mmHg	−6.4 (6.8)
sBP change, mmHg	+11.0 (24.5)
mBP change, mmHg	+5.3 (17.6)
mBP, mean blood pressure; mPAP, mean pulmonary artery pressure; rTPA, alteplase; sBP, systolic blood pressure; sPAP, systolic pulmonary artery pressure; TNK, tenecteplase. Data are shown as mean ± standard deviation or median [interquartile range] for continuous variables, as appropriate, and No. (%) for categorical variables. * Therapy delay was defined as the time that elapsed between diagnosis of pulmonary embolism and the procedure.

 

Safety outcomes

Early clinical outcomes and in-hospital events according to the treatment strategy are shown in table 5. The median length of hospitalization was 8 [IQR, 6.0-13.0] days. In-hospital major bleeding, as defined by the International Society of Thrombosis and Hemostasis, occurred in 7 patients (7.3%) in the ST group and in 9 patients (13.6%) in the CDT group. Intracranial bleeding occurred in 5 patients, all of them in the ST group, during hospital admission. Vascular access complications, including minor and major events, were found in 6 (10.6%) of the patients who underwent CDT. Of note, 5 of these patients received catheter-directed thrombolysis (4 with alteplase and 1 with tenecteplase) and the tenecteplase-treated patient underwent aspiration with a nonspecific catheter. One of the vascular complications was a hematoma related to extracorporeal membrane oxygenation implantation and which, therefore, bore no direct relationship with the CDT procedure. The remaining events were 1 incident of femoral access bleeding leading to hypovolemic shock and eventual death (a local thrombolysis CDT case), 2 hematomas requiring transfusion, and another 2 hematomas not requiring transfusion. The incidence of 30-day all-cause mortality was 4.6%, 10.4% and 15.9% for the AC, ST and CDT groups, respectively (P = .045). Twenty-two patients died due to hemodynamic or respiratory deterioration related to PE, 2 patients died from anoxic encephalopathy (both in the CDT group), and 1 patient died from severe intracranial bleeding (ST group).

 

Table 5. Early safety outcomes in patients with acute pulmonary embolism

	Total	AC	ST	CDT	P
	N = 274	N = 112	N = 96	N = 66	Global	AC vs ST	AC vs CDT	ST vs CDT
Admission length, days	8.0 (6.0-13.0)	7.0 (6.0-11.0)	9.0 (6.0-12.5)	10.0 (6.0-23.0)	.132	0.394	.052	.178
In-hospital events
Major bleeding*	18 (6.6%)	2 (1.8%)	7 (7.3%)	9 (13.6%)	.008	0.052	.002	.184
Intracranial bleeding	5 (1.8%)	0 (0.0%)	5 (5.2%)	0 (0.0%)	.009	0.014	-	.060
Acute kidney injury	22 (8.0%)	11 (9.8%)	9 (9.4%)	2 (3.0%)	.228	0.913	.093	.115
Vascular access complication	-	-	-	6 (10.6%)	-	-	-	-
30-day all-cause death	25 (9.3%)	5 (4.6%)	10 (10.4%)	10 (15.9%)	.045	0.110	.011	.310
AC, anticoagulation; CDT, catheter-directed therapies; ST, systemic thrombolysis. Data are shown as median [interquartile range] for continuous variables and No. (%) for categorical variables. *As defined by the International Society of Thrombosis and Hemostasis.

 

DISCUSSION

The present study explores the clinical characteristics, risk profile and outcomes of patients with IR and HR-PE in 2 tertiary care referral centers with a 24/7 PERT team. The main findings were as follows: a) in this contemporary PE cohort, the factors associated with the choice of CDT over ST in the multivariable analysis were a higher Charlson Comorbidity Index, a history of recent surgery, and a proximal, bilateral PE; b) the choice of CDT as reperfusion therapy has increased; and c) CDT significantly improves hemodynamic parameters, suggesting that the effectiveness of the treatment is preserved in this comorbid population; nonetheless, the risk of complications is not negligible and should be considered in decision-making.

To our knowledge, this is the first study that focuses on the parameters associated with treating physicians’ choice between the available treatment strategies in patients with acute IR and HR-PE. As expected, patients undergoing reperfusion had worse hemodynamic status and more frequently had right ventricular impairment or higher lactate levels. ST was more frequently used in patients with fewer comorbidities (eg, younger age, recent surgery, or hospital admission), which is in agreement with previous studies.3,5 In contrast, CDT was chosen for patients with a greater number of comorbidities and probably with a higher bleeding risk (recent surgery). However, there were no differences in age, sex or previous comorbidities between the group of patients treated with AC and those who underwent CDT, with only PE severity as a driver for CDT reperfusion.

Catheter-directed therapies as an increasingly chosen option

In the last 10 years, CDT has emerged as a promising alternative to ST, but randomized studies vs standard medical therapy are lacking. The PE landscape currently has 2 scenarios on the opposite side of the innovation curve. On the one side, the early adopters (United States scenario) are using CDT with a very low threshold as an elective therapy for submassive PE (including the entire IR spectrum) despite the lack of randomized evidence or strong guideline recommendations. Conversely, awareness of CDT and its availability might be relatively low in late-adopter countries and nonacademic nontertiary centers, leading to inequalities in patients’ access to advanced therapies for PE.

The rise in CDT treatments is due to the growing market and the promising results of early studies showing nearly immediate improvement in right ventricular function and hemodynamic status compared with conservative treatment,7,10,19,20 with very low bleeding risk.21,22 The variety of techniques (figure 1) might add some heterogeneity but discussion of the various CDTs is beyond the scope of this manuscript.

The significant number of patients treated with reperfusion in our cohort (59% of IHR-PE patients and 81% of HR-PE patients) may reflect that PERTs are currently activated only for a higher-risk segment of patients, but also reflects the optimal accessibility to reperfusion when ST and CDT are available together.

Systemic thrombolysis vs catheter-directed therapies

ST is the treatment of choice for patients with hemodynamic instability and PE-related cardiopulmonary arrest, although the mortality benefit is mainly based on a small clinical trial (n = 8) that was prematurely terminated.23 Risk factors for PE are age, multiple comorbidities and especially past or active cancer,24 which also confer an exceedingly high bleeding risk,25 especially when treated with ST. Previous studies have shown that major bleeding occurs in ≈10% to 15% of acute PE patients treated with ST, while intracranial bleeding events occur in around 1.5% to 2% of this patient population.3,4,26,27 It is probably for this reason that this treatment is not frequently applied in older patients with previous comorbidities, as shown in the present study and other previous publications.3-5 Thus, managing older, comorbid and oncologic patients with ongoing acute PE remains a real challenge for clinicians, and in this particular scenario, CDT may be a safe and effective option for PE treatment. In fact, the multivariable analysis performed in our study showed that increasing comorbidities was an independent factor for the use of CDT over ST as the preferred reperfusion therapy. These results suggest a new choice for this group of highly vulnerable patients who would not otherwise be treated with reperfusion and therefore would have a higher mortality risk due to the conservative approach.3 However, these results should be interpreted with caution because of the low percentage of patients treated with ST in the present study (35.0%) and the low percentage of HR-PE patients included (15.8%). Furthermore, given the large time period covered by the study, a significant percentage of IHR-PE patients undergoing ST were included. Following the publication of the PEITHO trial28 and the emergence of specific catheters for PE treatment, the administration of ST in IHR-PE patients became less frequent, even in those with worse progress within this subgroup. Therefore, it is likely that our study population does not accurately represent patients in current clinical practice.

Postsurgical patients are especially complex because surgery is a risk factor for PE and is a formal contraindication for ST. Percutaneous thrombectomy has shown a low incidence of major bleeding in single-arm studies and seems a good alternative in these patients.8,9,29 However, to use these devices, the thrombus must be in the proximal segment of the main pulmonary arteries. Indeed, bilateral central PE was an independent variable that prompted the choice of CDT in our study.

Anticoagulation vs catheter-directed therapies

Anticoagulation only is recommended for low-risk and stable IR-PE patients.2 ST in IR-PE decreased the risk of hemodynamic decompensation but at a high cost of bleeding,28 and consequently reperfusion therapies are intended for patients with hemodynamic deterioration.2 Nonetheless, the irruption of transcatheter therapies, especially large-bore aspiration devices, could provide the advantages of pulmonary reperfusion observed in the PEITHO trial28 without the worrisome adverse effects (mainly bleeding events). Our study shows that the use of CDTs has clearly increased in recent years but they were still being reasonably reserved for the higher-risk PE spectrum. Ongoing large clinical trials, such as PEERLESS (NCT: 05111613), HI-PEITHO (NCT: 04790370), and PE-TRACT (NCT: 05591118), will definitely clarify the indication for CDT in patients with acute IHR-PE.

Early safety outcomes in patients with acute pulmonary embolism

Our study showed an incidence of 30-day all-cause mortality of 9.3%, which is lower than that in other observational studies.21,30 However, the cited studies included only patients undergoing reperfusion therapies (either CDT or ST) and the present study also included patients undergoing conservative management, who can be expected to have lower severity and therefore better prognosis. In contrast to the findings of other published literature,19,21,31 the incidence of in-hospital major bleeding and early all-cause death was relatively high in the CDT group in our cohort. These results can be explained by 2 main reasons: first, patients in the CDT group in our cohort were older and had more comorbidities, with 30% having a formal contraindication for ST; and second, the CDT group included almost 50% of patients receiving thrombolytic drugs, which are associated with a higher risk of bleeding than thrombus aspiration alone. Furthermore, among the group of patients who underwent catheter-guided thrombolysis, tenecteplase was used in 28.6%, with this drug demonstrating a high incidence of major bleeding in the PEITHO trial.28 Finally, the vascular access used in the vast majority of patients in the present study was femoral (97.0%), with an incidence of vascular complications of 10.6% (all of them occurring in patients undergoing catheter-directed thrombolysis or aspiration with a nonspecific catheter). Previous studies have shown a low incidence of major bleeding when catheter-directed thrombolysis is performed through brachial access.32 However, specific devices, especially large-bore aspiration devices, can currently only be used via femoral access due to their large caliber. In addition, there were no intracranial bleeding events in patients undergoing CDT in our cohort.

On the other hand, our study showed a significant hemodynamic improvement in patients who underwent CDT, in accordance with previous studies.7-10,33 This benefit is important, but the futility of interventional treatments must be considered in very old and comorbid patients, balancing cost-effectiveness and clinical judgment.34 More data are needed to establish the risk-benefit balance of CDT compared with anticoagulation and ST in older patients or patients with a high comorbidity burden.

Limitations

Several limitations should be considered when interpreting the results of this study. Due to its observational nature, the presence of unmeasured confounders could have influenced the conclusions of the study. The total number of patients admitted with PE in the study period in the 2 centers is unknown, and consequently a survival bias should be acknowledged. The percentage of intermediate-low risk patients included was relatively low, suggesting that PERT activation was selected for the most severe patients. Thus, a selection bias may have occurred in this study. Specific devices for the percutaneous treatment of PE were not initially available at the beginning of this study, and were incorporated as they became available (first specific devices in 2018). This was a registry with self-reported data without external monitoring, and consequently local investigators are responsible for the integrity of the data.

CONCLUSIONS

The results of this study show that the factors associated with the choice of CDT on multivariable analysis were a higher Charlson comorbidity index, a history of recent surgery, and proximal, bilateral PE. The choice of CDT over ST as reperfusion therapy increased during the study period. CDT was an effective option for older, comorbid patients with PE, but the management of acute PE patients is challenging and should be individualized.

FUNDING

This research did not receive a specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

ETHICAL CONSIDERATIONS

The registry protocol was approved by the clinical research ethics committee at Hospital Clínico San Carlos as the central committee for the registry, following local research regulations (code 18/010-E). All prospectively included patients signed an informed consent form. An informed consent waiver was granted from the ethics research committee for patients recruited retrospectively. Sex but not gender data were included in the database design in 2018.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the preparation of this manuscript.

AUTHORS’ CONTRIBUTIONS

C. Real designed the study outline, performed the statistical analysis, and drafted the article. C. Ferrera designed the study outline and drafted the article. M.E. Vázquez-Álvarez participated in data collection and data interpretation, M. Huanca, F.J. Noriega, E. Gutiérrez-Ibañes, A.M. Mañas-Hernández, N. Ramos-López, M. Juárez, P. Jiménez-Quevedo, J. Elízaga, and A. Viana-Tejedor participated in data collection and critically revised the manuscript. P. Salinas designed the protocol, database and study outline, coordinated the data analysis and interpretation, and critically revised the manuscript. All authors gave final approval of the version to be published.

CONFLICTS OF INTEREST

The authors report no conflicts of interest with respect to the content of this manuscript.

 

 

ACKNOWLEDGMENTS

The authors thank María Beneito-Durá for providing statistical advice.

REFERENCES