First Multi-Center, Real-World Study on the Temporary Implantable Nitinol Device (iTIND) for the Management of Lower Urinary Tract Symptoms Related to Benign Prostatic Obstruction

Abstract

Background/Objectives: Lower urinary tract symptoms (LUTSs) due to benign prostatic obstruction (BPO) represent a common condition affecting aging men. Transurethral resection of the prostate represents the gold standard surgical treatment but is not without complications such as retrograde ejaculation, bleeding and urinary retention. The temporary implantable nitinol device (iTIND) is considered a minimally invasive surgical technique, designed to treat LUTS while preserving erectile and ejaculatory function. Herein we report the results of a multi-center, real-world assessment of the iTIND procedure. Methods: Data from five international centers treating LUTS with the iTIND device were collected. We recorded changes through an International Prostatic Symptom Score (IPSS) questionnaire with Quality of Life (QoL), International Index of Erectile Function (IIEF5) questionnaire, antegrade ejaculatory function, maximum flow (QMax), post voiding residual volume (PVR) and freedom from repeat intervention. Results: A total of 74 subjects were enrolled; median follow-up was 12 months. IPSS and QoL changed from a median of 23 and 4 points at baseline to 11 and 2 points, respectively, at the last follow-up. A mean improvement in Qmax and PVR from 9 mL/s and 56 mL at baseline to 13 mL/s and 40 mL was noticed at the last follow-up. Total median operative time was 10 min, and the median time of iTIND indwell time was 7 days. The median device removal time was 5 min. There were no changes in IIEF5 scores and antegrade ejaculation rate. No intraoperative complications were reported, and non-serious postoperative complications occurred in six patients (two urinary retention, two mild haematuria, two urinary tract infection). Finally, four patients underwent reoperation during the follow-up period. All procedures were performed as outpatient day cases. Conclusions: Our results confirms that treatment with the iTIND is effective and safe in terms of improving urinary symptoms and quality of life without impacting sexual function. Longer follow-up is required to better define the durability of this minimally invasive procedure.

1. Introduction

Lower urinary tract symptoms (LUTSs) secondary to benign prostatic obstruction (BPO) are one of the most common conditions that negatively impact the quality of life of men during their lifetime. Its onset starts at age 40–45 years, reaches 60% by age 60, and can be 80–100% by age 80 [1].

Among the options for reducing LUTSs secondary to BPO, physicians may offer watchful waiting and implementation of lifestyle changes, and then progress to pharmacological therapy (alpha blockers, with or without 5-alpha reductase inhibitors and phytotherapy) [2,3]. Despite pharmaceutical therapy having been considered as a potential first-line therapy, many patients are dissatisfied with the level of symptomatic relief perceived, or are bothered by drug-related side effects. As a result, medical therapy for LUTSs has a low and disappointing rate of compliance, with only 30% of patients adhering to prescribed treatment during the first 12 months [2].

Considering that BPO represents a mechanical problem, a mechanical solution is desirable. Thus, the gold standard surgical treatment for benign prostatic hyperplasia (BPH) has been the transurethral resection of the prostate (TURP). Unfortunately, this mechanical solution is associated with a 20% morbidity rate, including urinary incontinence (3%), bleeding requiring blood transfusion (2.9%), urethral stricture (7%), transurethral resection (TUR) syndrome (1.4%), erectile dysfunction (10%) and retrograde ejaculation (65%) [4,5,6].

All laser-based alternatives, while also effective in providing relief of BPO-related symptoms and urodynamic obstruction, still carry the risk of complications similar to those seen with TURP [7].

In the last 10 years, various Minimally Invasive Surgical Therapies (MISTs) have been introduced into clinical practice in order to mitigate the occurrence and severity of several common postoperative events (i.e., ejaculatory dysfunction) [8,9]. These techniques, mainly delivered as office procedures, have dramatically changed the individualized treatment approach and could further change the future management of prostatic obstruction [10,11].

Among the different MISTs, the temporary implantable nitinol device (iTIND; Olympus Corporation of the Americas, Center Valley, PA, USA) has been developed to offer an effective alternative for treating LUTSs secondary to BPO through the use of a temporarily implanted device, with a maximal preservation of ejaculatory function. During its short-term placement, it is able to reshape the prostatic urethra and bladder neck through ischemic pressure, improving voiding parameters and preserving sexual function [12,13,14]. In the MT-06 study, iTIND demonstrated preservation of sexual function and urinary continence in all enrolled subjects according to the Incontinence Symptom Index (ISI), Sexual Health Inventory For Men (SHIM) and Male Sexual Health Questionnaire Ejaculatory Dysfunction (MSHQ-EjD) questionnaires [12]. As a result, clinicians are offering more men ejaculation-sparing surgery and, among these, iTIND. However, as a relatively new procedure, without a breadth of experience over-and-above the typical criteria of randomized studies, there is a need to better understand its durability and refine the indications. Moreover, the pivotal iTIND studies found a reasonable surgical retreatment rate with a total cumulative 11,1% rate of retreatments from baseline to >48 months, with 5/81 (6.2%) patients requiring oral medication for BPH from baseline to 36 months [14].

Herein, we report early real-world outcomes after iTIND in a large, unselected multi-center series.

2. Materials and Methods

We conducted a retrospective cohort study of patients affected by LUTSs/BPO, candidates to deobstruction, interested in antegrade ejaculation preservation and treated with iTIND, in a multi-institutional, anonymized and prospectively collected database, in five institutions since January 2022. None of the enrolled patients were previously involved in previous clinical trials. The study is still ongoing.

A comprehensive review of medical history, digital rectal examination (DRE) and a prostate-specific antigen (PSA) was conducted. In the case of suspected prostate cancer, patients underwent a multiparametric magnetic resonance imaging and/or a prostatic biopsy in order to rule it out. To quantify LUTSs and Quality of Life and to assess erectile function, patients were evaluated with the International Prostatic Symptom Score (IPSS and IPSS-Quality of Life (QoL)), and the International Index of Erectile Function score (IIEF5). The rate of pre and postoperative antegrade ejaculation, defined as the emission of semen after orgasm, was subjectively recorded at baseline and during follow-up. All patients underwent a suprapubic ultrasonographic assessment of the prostate volume, cystoscopy and a reliable uroflowmetry with post voiding residual volume (PVR) measurement.

Each patient was informed about the difference in outcomes reported in the literature regarding iTIND and standard therapy (TURP, transurethral incision of the prostate (TUIP), enucleation of the prostate, photoselective vaporization) with their subsequent outcomes on micturition and sexual function. Also, the American Society of Anesthesiology (ASA) score and the Charlson Comorbidity Index (CCI) were collected.

2.1. Eligibility Criteria

Patients whose prostate volume was <20 cc or >70 cc or sexually inactive were excluded from this study. The presence of a median obstructive lobe and a history of urethral or prostatic surgery represented exclusion criteria. Antiplatelet or anticoagulant therapies and antidiabetic or antihypertensive drugs were not interrupted and not considered an exclusion criterion. Signed informed consent, age >18 years and a full data set were mandatory for inclusion in this study.

2.2. Surgical Technique

A preoperative negative urine culture needed to be achieved before treatment. After positioning the patient on a lithotomy position, a 22Ch rigid or flexible cystoscopy was performed and the device inserted as per instruction for use. The iTIND devices were left in situ for 7 days and subsequently removed, as previously described [13]. Alpha blockers were prescribed or continued for the first month after the procedure. Pain killers, antibiotics and antimuscarinic were prescribed according to the surgeon’s preferences.

Follow-up took place at 1, 3, 6 and 12 months and included uroflowmetry, IPSS and IIEF5 questionnaires. Whenever a recurrence of symptoms was suspected, proper assessments, including cystoscopy, took place. Retreatments were also analyzed at all follow-up appointments, together with possible subsequent surgical intervention for bladder outlet obstruction (BOO).

2.3. Statistical Analysis

A simple descriptive statistical analysis of categorical and continuous variables was conducted as appropriate, with the first reported as number and percentage, and the latter as median and interquartile range. A comparison of outcomes from preoperative values to last follow-up was conducted with the Wilcoxon Test or Chi-Square tests as appropriate.

2.4. Ethics

Data of patients consecutively treated with iTIND were anonymized and recorded in the study after ethical committee approval (code: Prot.n. 258 SA_2021 del Registro Pareri RIF. CE 6376_2021 of “Comitato Etico dell’Università “SAPIENZA”, Rome). Each patient gave written informed consent for data collection and to the surgical technique.

3. Results

A total of 74 patients with median (range) age of 52 (46–59) years, prostate volume 30 (26–38) mL, IPSS 23 (20–26) points, maximum flow (Qmax) 9.8 (7.6–11) mL/s and IPSS-QoL score of 4 (4–5) points were enrolled in the study (

Table 1. Descriptive statistical analysis for pre- and intra-operatory variables of patients submitted to iTIND procedure.

			iTIND (n = 74)
Age, years			52 (46–59)
BMI, kg/m2			25.3 (23.0–27.8)
Prostate Volume, mL			30.0 (26.0–38.0)
Pre–operative PSA, ng/mL			1.0 (0.7–2.0)
Pre–operative Hemoglobin (g/dL)			15.4 (14.6–16.0)
ASA score			1 (1–1)
Age adjusted Charlson Comorbidity Index			1 (0–2)
Ongoing BOO therapy, n (%)	None		15 (20.3%)
	Alpha–blocker		59 (79.7%)
Pre–operative IPSS			23 (20–26)
Pre–operative IPSS QoL			4 (4–5)
Pre–operative Maximum Flow, mL/s			9.0 (7.6–11.0)
Pre–operative Post Void Residual, mL			56 (0–120)
Surgical time, minutes			10 (7–15)
Day of discharge, days			0 (0–0)
Immediate post operative complications, n (%)	None		63 (84.3%)
	Acute Urinary Retention		4 (6.3%)
	Pain		5 (6.7%)
	Early removal		2 (2.7%) (1 for pain & 1 for fever and hematuria)
Day of device removal, days			7 (7–7)
Removal time, minutes			5 (4–5)
Pain at removal—VAS			0 (0–0)
Post iTIND removal complications, n (%)		None
		Acute Urinary Retention	4 (5.4%)
		Mild hematuria	6 (8%)
		Urgency/dysuria	6 (8%)
		Infections	5 (6.8%)

LEGEND: ASA = American Society of Anesthesiology; PSA = Prostate-specific antigen; BOO = bladder outlet obstruction; IPSS = International Prostatic Symptom Score; VAS = Visual Analogic Scale. Continuous variables are expressed as median (inter quartile range), categorical as n (%). BMI: body mass index, IPSS QoL: International Prostatic Symptom Score Quality of Life, IIEF5: International Index of Erectile Function, iTIND: temporary implantable nitinol device

). In total, 39% of patients had previously been treated with alpha blockers without sufficient symptom relief.

All the device implantations were efficient (mean time = 10 min) and successful. All procedures were performed as a day case in local anesthesia or conscious sedation (based on the center). The distribution of the cases was LC 31 (42%), SS 18 (24.3%), FAJ 10 (13.5%), DE 9 (12.2%) and CDN 6 (8.1%).

They were well–tolerated by the patients except one. No intraoperative complications nor device failures were recorded. Almost all patients were discharged in the few hours after the implant.

In the first week while the iTIND was in situ, acute urinary retention was observed in four cases (6.3%) and managed by a temporary Nelaton or Mercier catheter (three cases) and by opening of the suprapubic tube in one case, without impact on the effectiveness of the implant. One patient required an early removal of the device 5 h after the implant because of intolerable pain. Five patients required major pain management with tramadol (one was also hospitalized) and another one developed fever and hematuria requiring early device removal 2 days later.

The device removal was carried out on the 7th postoperative day; all these procedures were uneventful.

All post–operative (and post device removal) adverse effects (AEs) were Grade I or II based on the Clavien-Dindo system, with acute urinary retention (AUR) (5%), mild hematuria (8%), micturition urgency/dysuria (8%), and urinary tract infection (UTI) (6.8%), recorded in the first month after the procedure.

The iTIND device efficacy demonstrated stability during the first six months with a slight decrease with recorded improvements from preoperative data as % change of −61% for IPSS, −75% for IPSS–QoL, +55% for Qmax, and −90% for PVR (

Table 2. Functional outcomes of iTIND from baseline to 12 month follow–up.

iTIND	Preoperative	Month 3	p–Value	Month 6	p–Value	Month 12	p–Value
IPSS	23 (20–26)	9 (5–13)	<0.001	9 (5–13)	<0.001	11 (9–14)	<0.001
Maximum Flow, mL/s	9.0 (7.6–11.0)	13.6 (10.0–16.0)	<0.001	14.0 (10.8–15.3)	<0.001	13.4 (11.6–16.8)	0.126
Post Void Residual, mL	56 (0–120)	0 (0–60)	<0.001	0 (0–5)	0.003	40 (0–101)	0.033
IPSS QoL	4 (4–5)	1 (1–2)	<0.001	1 (1–3)	0.003	2 (1–3)	<0.001
IIEF	22 (20–40)	22 (19–25)	0.4	23 (20–24)	0.4	22(19–24)	0.09

LEGEND: Continuous variables are expressed as median (inter quartile range). Comparisons were carried out with Mann–Whitney U Test or Wilcoxon Test for paired samples as appropriate. Comparisons were carried out between baseline and and each follow–up Abbreviations: IPSS: International Prostatic Symptom Score, IPSS QoL: International Prostatic Symptom Score Quality of Life, IIEF: International Index of Erectile Function, iTIND: temporary implantable nitinol device.

). For all these variables a significant difference was recorded from preoperative levels (Table 2).

At median 12-month follow-up (data available for 63/74 patients) a further decrease in functional parameters was recorded, as IPSS demonstrated a small increase (+2 points, from 9 at 6 months to 11) and a minimal reduction in Qmax, whereas IPSS-QoL increased by 1 point. Erectile function was preserved in all cases with no significant variations in terms of IIEF5 scores. The antegrade ejaculation rate increased from 88% to 100% at the last follow-up.

Regarding the retreatment rate, four patients (5.4%) were re-operated (median time from the implant: 21 months, interquartile range (IQR) 17–24) (two TUIP, one TURP, one thulium fiber laser enucleation (Thulep)) and seven (9.4%) patients restarted oral alpha—blockers at last follow-up.

4. Discussion

The results of this real-world, multi-center study demonstrate that the treatment of LUTSs secondary to BPO using the second-generation iTIND is effective with a reasonable safety profile in the short term. All surgical implantations and removals were performed in an outpatient setting, with early discharge of the patients, and excellent intraoperative safety profile. In the first week some issues may arise (i.e., pain, fever and hematuria). Moreover, the majority of the postoperative adverse events within 30 days are low-grade (Clavien-Dindo < 3) and usually self-resolving. No device failure or long-term sequelae were recorded.

The prompt improvements in urinary functional parameters (Table 2) should also be weighted together with the complete absence of effects on erectile or ejaculatory functions.

Even if a slight decline in urinary function parameters is recorded at 12 vs. 6 months, the comparison between baseline and 12 months follow-up remains positive. Moreover, an acceptable total surgical retreatment rate of 4 (5.4%) patients and a restart of medications of 9.4% at 12 months—must be acknowledged.

Being a real-world study, it is appropriate to discuss the results obtained in this study by comparing them with previous data from controlled studies.

In the long-term follow-up data from Amparore et al., patients demonstrated a reduction in IPSS of 48% and an increase in IPSS-QoL of 45% from baseline [14]. Herein, at the best of our follow-up, in an unselected cohort, we recorded an improvement in IPSS by 61% (from 23 to 9), QoL by 50% (from 4 to 2), Qmax by 45% (from 9 to 13.4 mL/s) and PVR by 28% (from 56 to 40 mL), respectively. Taken together all these data suggest that the efficacy of the Qmax improvement appreciated in the pilot studies could be duplicated in real-life clinical practice.

Looking at the immediate postoperative period, we should recognize that significant adverse events have been reported (about a total of approximately 10% of men). It is important to consider them within the broader context of the potential benefits of the technology while balancing the risks and the benefits and identifying strategies to mitigate such complications through more accurate patient selection, improved pain management protocols, procedure optimization and open preoperative discussion. These aspects are quite peculiar to this MIST and their management has been described in detail by Elterman et al. [15]. These authors suggest counselling and preparing the patients for the possibility that they may experience postoperative dysuria. Moreover, they recommend discharging patients with ample analgesics to be taken in a graduated fashion depending on severity of discomfort (from acetaminophen and/or nonsteroidal anti-inflammatory drugs (NSAIDs) to codeine or oral steroids or oxybutinine). Because in this study each center adopted a different postoperative pathway, with the small number of recorded events, it is difficult to suggest a unique discharge policy.

The postoperative adverse events described after the device removal in the Amparore study [13] were 12.3% hematuria, 11.1% urgency, 9.9% pain, 7.4% dysuria, 6.2% UTI. In our series, we see different rates of the same kind of adverse events as 8% hematuria, 8% urgency/dysuria, 6.8% UTI, respectively. These small discrepancies with doubtful clinical significance might be explained by the different ways to collect data or by the different reports from real-life patients who were already well informed and able to tolerate some minor disadvantages.

The absence of AEs after the 30-day postoperative period in previous studies as in the present study confirm the very good postoperative safety profile of the procedure. This is probably related to the non-permanent, non-thermic and non-ablative nature of this device. The median and IQR data for patient age (52 y, 46–59) and prostate size (30 cc, 26–38) is very homogeneous, and demonstrates, in our opinion, that this device is appreciated by different international and experienced groups in a very specific population: relatively young, demanding sexual postoperative safety and affected by a symptomatic small-sized prostate.

The surgical retreatment rate is an important issue in all the MISTs, particularly for the iTIND. Amparore et al. reported that 8.7% of patients reoperated in the middle term (3 y) [13]. The same group in a more recent paper reported an extended follow-up whereby they reported a cumulative surgical reintervention rate of 11.1% up to 79 months after implant.

In our unselected cohort, we observed that with a median of 12 month of follow-up, we had a retreatment rate of 5.4% that is well aligned with what was previously reported.

These data could be erroneously interpreted as a failure of this MIST, but another way to consider these data is to consider the importance of a timely deobstruction in men that typically postpone a BOO intervention because of the risk of retrograde ejaculation perceived as intolerable and unacceptable. When considering the current and future MISTs and their durability, we may conceive of them as potential “bridge treatments”. iTIND, as with other MISTs, allows for an immediate and significant improvement in symptoms and functional parameters, without affecting the patient’s sexual function. This improvement, often maintained over years, can be re-gained with a standard surgical treatment or proposing another MIST in case of failures or recurrences. We should keep in mind that a “non-negligible” (5–35%) percentage of men after TURP need further medical therapy (for both persistent or de novo LUTSs) and that a great proportion of these have perhaps been operated upon too late in terms of obstruction progression due to concern of surgical risks [16]. These are good reasons why “bridge therapy” could be offered to the patient as a real minimally invasive solution that does not impact sexual function but relieves the BPO before it causes irreversible bladder dysfunction [10,17,18,19,20]. Recent evidence support MISTs as effective and cost-saving procedures that can also be considered as appropriate first-line alternatives to medical therapy in men with moderate-to-severe LUTSs requiring fast improvement and no lifelong commitment to daily drugs [21,22].

Within our study, several important limitations must be acknowledged. First, the real-world, multi-center nature of the study without a control group is subject to selection bias. Nevertheless, the good overlap of the functional and subjective outcomes between controlled clinical trials and this real-life study corroborates the efficacy of the iTIND technique. Second, the small cohort and the short follow-up limit the use of multivariate analyses that would be used to explore the predictive factors for reintervention or the selection of the best candidates for this MIST. Moreover, in the future, we agree that contextualizing our findings against the existing literature [including not only studies on iTIND but also those evaluating standard procedures or MISTs (e.g., TURP, Urolift, Rezūm)] is essential.

5. Conclusions

Our results confirms that treatment with the iTIND is effective and safe in terms of improving urinary symptoms and quality of life without impacting sexual function.

By offering a safe, effective and patient-friendly alternative to traditional approaches, iTIND has the potential to redefine the standard of care in the management of benign prostatic conditions, especially when few alternatives exist [23]. Future prospective studies with larger patient numbers, a control arm and long-term follow-up are needed to confirm durability and validate the use of iTIND in the routine practice.