Meta-analysis with individual data of functional outcomes following Aquablation for lower urinary tract symptoms due to BPH in various prostate anatomies

Introduction

Multiple treatment modalities for benign prostatic hyperplasia (BPH) are available, including watchful waiting, medications, transurethral surgical procedures where adenoma is not removed at the time of procedure, and several techniques for transurethral surgical prostate resection where adenoma is removed. It is generally accepted that resective techniques are most efficacious at symptom relief but carry the highest perioperative risk. Recent data have suggested that an obstructive median lobe may play a critical role in response to resective prostate treatments for BPH.1 2 The median lobe is variably enlarged, with 10%–42% of men having a severe intravesical prostatic protrusion (IPP).3 In the presence of IPP, medical therapy is less effective at reducing International Prostate Symptom Score (IPSS) and improving Qmax.1 Median lobe-only transurethral resection of the prostate (TURP) has been reported to be safe and effective, with improved postoperative symptoms and uroflow while simultaneously preserving ejaculatory function.2 One of the explanations is preservation of the para-collicular tissue where the ejaculatory ducts emerge at the verumontanum. Other resective procedures focused on anatomy preservation may also prevent postoperative anejaculation commonly seen after a typical TURP.4 Non-resective procedures for BPH, such as convective water vapour ablation of the prostate, can also address men with enlarged median lobes. The American Urology Aassociation does not recommend other minimally invasive procedures (eg, prostatic urethral lift) for men with BPH and enlarged median lobes, despite some recent evidence of effectiveness.5

Treatment options (eg, photoselective vaporisation of the prostate (PVP), holmium laser enucleation of the prostate (HoLEP), thulium laser enucleation of the prostate (ThuLEP)) for men with large prostates, exceeding 80–100 mL, is a rapidly growing area. However, procedure times are long and in many cases, a simple prostatectomy may be required. Aquablation is a relatively new technique that resects the prostate using image guidance and robotic execution under surgeon control. A blinded randomised trial showed superior efficacy in prostates>50 mL and prostates with median lobes versus TURP6 and a lower rate of postoperative anejaculation.7 To date, four prospective international studies of Aquablation have been performed showing consistent results in symptom reduction and low rates of irreversible complications in prostate sizes up to 150 mL.8–11 Herein, we report a combined individual-patient meta-analysis undergoing the Aquablation procedure; combining data enabled more detailed analysis (subgroup analysis) of men with larger prostate size (>100 mL) and presence of an obstructive median lobe. While most guidelines reference 80 mL as the prostate size cut-off to consider alternative surgical options, common practice may push this up to 100 mL. By defining large prostates as over 100 mL, there should not be a debate as to whether this is a true large prostate population. Our analysis focuses on both storage and voiding symptom improvement, uroflowmetry, and impact on incontinence, a common finding in men with moderate-to-severe lower urinary tract symptoms (LUTS) due to BPH.

Methods

The analysis methodology undertaken is categorised as a type III meta-analysis defined as a reanalysis of individual data based on primary clinical studies as described by Blettner et al.12 This type of analysis may also be referred to as a pooled analysis.

Results

A total of 425 men underwent Aquablation in the four studies where 91% completed the 1-year visit. Baseline characteristics by study are shown in table 3. There was no relationship between prostate volume (categorised as ≥or <100 mL or as a continuous variable) or presence/absence of an obstructive median lobe and baseline IPSS or IPSS quality of life (QOL) score. Seventy per cent of the median lobes had an intravesical component. The average procedure time, defined as TRUS insertion to urinary catheter placement, was 40 min (median 38, range 8–111 min).

The mean baseline IPSS was approximately 23 points (median 24, range 12–35); baseline score was slightly lower in FRANCAIS WATER (p=0.0467). IPSS scores improved significantly in all studies; at 1 year, the mean improvement from baseline was 16 points with no variation across studies. One year IPSS scores were independent of baseline IPSS score, providing strong evidence for near-maximal improvement (ie, a ceiling effect). The IPSS data were assessed by region (North America, Europe and Australia/New Zealand) and showed no effect on IPSS changes scores. Additionally, 16% of procedures used cautery for haemostasis following Aquablation and observed no systematic effect on change in IPSS. Similarly, mean IPSS QOL improved from 4.7 at baseline to 1.4 at 1 year. There was no variation in baseline IPSS QOL or 1-year change score across studies. Similar to IPSS, IPSS QOL scores were only slightly related to baseline IPSS QOL, indicating near-maximal improvements (ceiling effect).

Baseline Qmax averaged 9.4 mL/s (median 9 mL/s, range 2–36). Statistically significant variation in baseline Qmax was observed across studies, but the differences were modest (at most 1.3 mL/s). The 1-year change in Qmax was independent of studies. The average Qmax at 1 year was 20.5 mL/s, an improvement of 9.4 mL/. Mean baseline PVR was 109.8 mL (median 80.5 mL, range 0–762) with larger values in WATER II, consistent with men having larger prostates by design in this study. One year improvement in PVR averaged 62 mL (median 41 mL) with larger improvements in WATER II compared with other studies. The improvement in PVR was strongly dependent on baseline PVR and was largest in WATER II. In men with elevated (>50 mL) baseline PVR, PVR at follow-up improved. For example, in men with PVR of 51–100 mL, the mean 1-year improvement was 31 mL (42%); for men with PVR of 101–200, mean improvement was 97 mL (66%); for men with PVR >200 mL, mean improvement was 204 mL (68%).

Improvements in these four key parameters (IPSS, IPSS QOL, Qmax and PVR) were independent of both prostate size and presence/absence of median lobe (figure 1). Not surprisingly, baseline PVR was higher in patients with large prostates and those with median lobes; similarly, baseline Qmax was lowest in men with large prostates. However, improvements in both Qmax and PVR were large and clinically important across all subgroups. Improvements in PVR depended strongly on baseline PVR (higher baseline PVR led to a larger decrease in PVR); in multivariate regression models controlling for prostate size and baseline PVR, improvements were slightly smaller (by 17 mL, p=0.0161) in men with middle lobe versus without.

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Analysis of individual components of IPSS showed statistically significant improvement in each component over time (figure 2); improvements were independent of prostate size and presence/absence of median lobe. The IPSS-Voiding subdomain is the sum of the answers to question 1 (incomplete emptying), question 3 (intermittency), question 5 (weak stream) and question 6 (straining to void). By contrast, the IPSS-Storage subdomain is the sum of the answers to question 2 (frequency), question 4 (urgency) and question 7 (nocturia). Significant and sustained improvements were observed in both subdomains. This indicates Aquablation’s removing tissue to a significant degree so as to see not just obstructive voiding symptoms improve but also bladder voiding function as well. The clinically significant improvement in symptom reduction translated into a low surgical retreatment in 0.7% (95% CI 0.1%–2.0%) patients while preserving erectile and ejaculatory function. Across the 425 men, there were no reports of postoperative de novo ED, whereas postoperative de novo ejaculatory dysfunction, defined as losing the ability to emit seminal fluid, was observed in 10.8% of men. Clavien-Dindo II-IV adverse events were similar across studies. In the only randomised study, the Clavien-Dindo II-IV adverse events were similar between Aquablation and TURP.

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Many men with BPH also experience urge incontinence, mostly due to bladder overactivity (detrusor instability). Subjects with low baseline ISI scores (4 or less) had modest perioperative rises in ISI score, but values reduced back to baseline in subjects with all prostate volumes (figure 3). In patients with clinically significant incontinence (baseline score>4), ISI scores improved in men with both small and large prostates.

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Discussion

The individual patient data meta-anlaysis performed from four studies of Aquablation resulted in 425 patients, the largest dataset to date, which enabled more detailed analyses of response to treatment compared with those restricted to single smaller studies.

First, the late (6 month and 1 year) IPSS scores were nearly independent of the baseline score. That is, no matter what initial degree of symptoms was present (baseline score), final scores were low (5–8 points, ie, near normal, reflected by a near flat linear fit in figure 1). This phenomenon, which was observed for both IPSS and IPSS QOL scores, indicates a ceiling effect, namely that robotically executed, waterjet-based prostate resection and relief of bladder outlet obstruction likely restore bladder function maximally. This finding may explain why long-term (3 years) results to date indicate sustained improvement.8 With high rates of follow-up indicating a complete data set and little loss to attrition, Aquablation was able to achieve exceptionally low rates of retreatment, 0.7%, across prostate sizes up to 150 mL. Hwang et al published a Cochrane Review paper assessing the WATER study.22 The authors assigned the WATER 1-year retreatment rate as low-certainty evidence. Their conclusions were likely due to a low sample size from a single study. The data presented in this manuscript are more than 3.5 times as large and demonstrates a remarkably low retreatment rate. Newer BPH technologies, which have reported data only in prostate sizes <80 mL with less pronounced efficacy as compared with tissue-resective procedures, include Rezum with a surgical retreatment rate of 4.4%23 at 5 years and UroLift (study excluded obstructive median lobe anatomy) with a surgical retreatment rate of 13.6%24 at 5 years. More applicable are the tissue-resective procedures where Gilfrich et al reported on 43 041 men undergoing TURP, PVP, enucleation or open simple prostatectomy with an approximated 3-year freedom from surgical retreatment of 93%, 89%, 94% and 96%, respectively.25

Second, there were statistically significant and clinically important improvements in all key parameters (IPSS, IPSS QOL, Qmax and PVR) across subgroups of prostate size (<100 vs ≥100 and obstructive median lobe present or absent). These findings suggest that more complex anatomy (larger prostates with median lobes) can be more than adequately treated with Aquablation. For other technologies, these prostate subgroups are challenging, such as prostatic urethral lift and convective water vapour ablation, which are contraindicated in prostates over 100 mL and 80 mL, respectively. TURP and PVP are typically performed in prostates less than 80 mL due to the amount of time needed to properly address the amount of tissue.26 Enucleation and simple prostatectomy are applicable for large prostates but have their limitations. In further analysis, improvements in these parameters were similar among men with both large prostate volume (≥100 mL) and a median lobe.

There were statistically significant and clinically important improvement across all IPSS individual questions and in men with both simple and complex prostate anatomy. Several studies have shown improvements in storage symptoms after transurethral surgery for bladder outlet obstruction.27–30 As was seen in the current study, storage symptoms often take slightly longer to improve compared with voiding symptoms, likely as a result of neuromuscular changes that must take place in the detrusor muscle once the obstruction is removed.

Finally, urgency incontinence is a common symptom in men with LUTS/BPH. Incontinence is likely due to overactive bladder, which develops as a direct result of chronic bladder outlet obstruction through the increased sensitivity of cholinergic receptors and structural changes due to ischaemia of the detrusor muscle.31 For men with incontinence at baseline, relief of bladder outlet obstruction through waterjet-based prostate resection resulted in improved frequency and severity of incontinence. For men with low baseline incontinence scores (indicating no or only minor problems with incontinence), late scores returned to preoperative values after a brief perioperative rise.

The advantages of our study include (1) sufficient sample size as a result of combining multiple studies from a diverse set of surgeons with a high follow-up rate, (2) availability of individual patient data from monitored clinical trials, (3) structured follow-up at similar time points and (4) a uniform set of symptom questionnaires and uroflowmetry analyses. All of these enabled us to perform detailed subgroup analyses, including multivariate analyses. All studies were prospective, multicentre trials, and all were conducted with similar eligibility criteria, treatments, and assessment tools. The trial data were sufficiently homogeneous to allow pooling across trials.

The disadvantages to the analysis include: Data after 1 year were not available in all studies, limiting the potential to examine longer-term outcomes. However, 3-year outcomes after Aquablation appear to be sustained from the published WATER trial data.8 The enrolled patient populations and settings were slightly different: WATER (international) and FRANCAIS (France only) enrolled men with smaller prostates (30–80 mL); WATER II (North America) enrolled men with larger prostates only (80–150 mL); WATER and WATER II were conducted in a pre-market setting whereas FRANCAIS and OPEN WATER were conducted in the postmarket setting. The technique using the loop for haemostasis following Aquablation has evolved since the conduct of these trials. Although a thorough review and process was completed to conduct this systematic review, the research was not governed by a registered protocol.

Conclusion

Aquablation improves symptoms and uroflowmetry measures in men with both small and large prostates as well as those with an obstructive median lobe. All functional symptom components of storage and voiding were improved. Incontinence severity improved in men with severe baseline incontinence.