Parts of this chapter are reproduced with permission from Wiseman et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, even for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes additions and formatting changes to the original text.
Renal tract stone disease is very common, with a lifetime prevalence of approximately 10% across the world.2 It mainly affects adults of working age and the incidence has been increasing over recent decades.3,4 Approximately 50% of people with renal tract stones will experience symptoms, typically kidney pain, and about 25% of patients with stones will require active treatment.5–7 Some people with stones can develop more serious problems including visible blood in the urine (haematuria), uncontrolled pain, infection, sepsis, impaired kidney function and kidney failure. Despite successful removal of the initial stone, there is a lifetime recurrence risk of 50% for the development of a further stone.8 Kidney pain from stones (renal colic) is the most common cause of emergency admission to urology departments in the UK and, given the age group most commonly affected, it results in time off work and loss of economic activity.9 The ongoing need for painkillers and the detriment to family, social and work activity reduces quality of life (QoL) and incurs additional costs.
Renal stones are a major burden on the NHS in the UK, resulting in over 88,000 upper urinary tract stone episodes and over 35,000 day case procedures carried out to remove stones in England in 2019–20.3 Compared to the 5-year period from 2014 to 2015, the number of urinary tract stone episodes has increased by 2.2%, while the number of day case procedures has increased by 14.7% from just over 31,000.10
Stones commonly develop in the lower part (pole) of the kidney, accounting for up to 35% of cases.11 There are currently three technologies available to treat lower pole kidney stones: extracorporeal shockwave lithotripsy (ESWL); flexible ureterorenoscopy (FURS) with laser lithotripsy and percutaneous nephrolithotomy (PCNL). The choice of treatment can be guided by stone size, likely stone composition, and the anatomy of the drainage system of the affected kidney. Clinician and patient preference and availability of equipment and expertise also plays a part.12 Current evidence indicates that the success rate in terms of stone clearance differs between these technologies particularly in relation to stone size. These technologies are also distinct in terms of degree of invasiveness, anaesthetic requirement, treatment setting, number of procedures required to clear the stone, and type and rate of complications.12,13
Extracorporeal shockwave lithotripsy is non-invasive, has a low risk of complications, and does not require general anaesthesia. Current evidence suggests it has reasonable efficacy in terms of stone clearance for smaller lower pole stones (LPSs) at 3 months (63–74% clearance rate for stones ≤ 10 mm).14 However, 3-month stone clearance rates for LPSs > 10 mm appear to be lower (23–56% for 11–20 mm stones, and 14–33% for 21–30 mm stones).15 If the stone is not cleared, additional treatments may be required using either repeated ESWL or more invasive options, such as FURS or PCNL. Following ESWL, small residual stone fragments can be left in the kidney and may result in recurrent stone formation over time (20% at 5 years).7,16
Flexible ureterorenoscopy (with laser fragmentation) and PCNL are more invasive than ESWL, require a general anaesthetic, and carry a greater risk of complications.17,18 A single FURS treatment appears to result in good clearance rate for stones up to 15 mm with repeat procedures or combined procedures often required for larger stones. PCNL is the most invasive treatment option and is associated with a higher risk of complications, but it also appears to result in the highest stone clearance rates, which are close to 100% for stones ≤ 10 mm, 93% for stones 11–20 mm, and 86% for stones 21–30 mm.19 Stone clearance rates for FURS appear to lie between those of ESWL and PCNL.20–26
Rationale for the trials
Guidance issued by the European Association of Urology (EAU)12 at the time of study design (in 2014), which was widely followed in UK clinical practice, recommended ESWL or FURS as first-line options for LPSs ≤ 10 mm. For stones > 20 mm, PCNL was recommended as the first-line treatment option. For stones between these two sizes, in the lower pole, the recommendation depended on whether there were unfavourable factors for ESWL, these being detailed as; shockwave resistant stones; the presence of a steep infundibulo-pelvic angle to the lower pole; a long (> 10 mm) lower pole calyx; or where the infundibulum is narrow (< 5 mm). If unfavourable factors were present then PCNL or FURS were the first-line recommended options, with ESWL being second-line. If unfavourable factors were not present, then ESWL or PCNL or FURS were all possible first-line treatment options. The EAU Guideline also commented that there remained considerable uncertainty regarding the management of LPSs, with each treatment option having advantages and disadvantages. The current EAU guidance remains unchanged.27 Subsequently published National Institute for Health and Care Excellence (NICE) guidance in 201928 recommends ESWL for a renal stone < 10 mm but to consider FURS if there are contraindications for ESWL, if a previous course of ESWL has failed or because of adverse intrarenal anatomy. PCNL is regarded as an option to consider if ESWL and FURS have failed to treat the stone. For larger renal stones between 10 and 20 mm, FURS or ESWL are considered equal options, with PCNL the next step if these interventions have failed. Like the EAU guidelines, PCNL is the first-line treatment for a renal stone larger than 20 mm, including staghorn stones, but FURS can be considered if PCNL is not an option.
A Cochrane review and meta-analysis (2014) of randomised controlled trials (RCTs) compared ESWL with either FURS or PCNL for the treatment of stones located anywhere within the kidney, not solely in the lower pole.13 The review concluded that PCNL had a better stone-free rate (SFR) than ESWL at 3 months [relative risk (RR) 0.39, 95% confidence interval (CI) 0.27 to 0.56], whereas FURS appeared to have similar SFRs to ESWL (RR 0.91, 95% CI 0.64 to 1.30). They included 5 RCTs (338 participants); however, only 3 focused on LPSs. Of these 3 RCTs (160 participants), 2 compared ESWL against PCNL, 1 for stones up to 30 mm15 and 1 for stones up to 20 mm.29 The third compared ESWL with FURS for LPSs ≤ 10 mm.30 The review concluded that the included trials were small and of low methodological quality. The authors had planned to undertake subgroup analyses by size and location of stone, but this was not performed ‘because of insufficient data’.13
A systematic review performed by some of the PUrE investigators,31 focusing solely on stones located in the lower pole of the kidney, included trials comparing PCNL with FURS (a comparison not considered in the Cochrane review). This review identified 4 additional relevant trials involving 408 participants32–35 and we undertook subgroup analyses by stone size (< 10 and 10–20 mm). Taking the seven trials involving participants with lower pole kidney stones as a whole, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) certainty of evidence ratings for the outcome of SFRs indicated they were of ‘moderate’ quality. The meta-analyses found PCNL and FURS produce significantly higher SFRs than ESWL for LPSs ≤ 20 mm at 3 months. Combining 2 RCTs (155 participants), SFRs for those participants with stones ≤ 20 mm were higher following PCNL than ESWL (RR 2.04, 95% CI 1.50 to 2.77). Combining 5 RCTs (508 participants) showed that FURS resulted in a higher stone clearance rate compared to ESWL (RR 1.31, 95% CI 1.08 to 1.59). However, in a subgroup meta-analysis combining 3 studies (300 participants) for stones ≤ 10 mm, the advantage of FURS over ESWL was less although still statistically significant (RR 1.11, 95% CI 1.03 to 1.19). One RCT (n = 93),15 which reported SFR categorised by stone size for PCNL versus ESWL, found that the degree of superiority of PCNL was lower for stones sized ≤ 10 mm compared to those sized > 10 to ≤ 20 mm (RR 1.56, 95% CI 1.11 to 2.21; RR 4.02, 95% CI 1.98 to 8.18, respectively). One small RCT (n = 28)35 showed that the stone free rates were higher when treated with PCNL compared to FURS (11-25 mm LPSs), but with considerable uncertainty around this estimate of effect.
Few of these trials reported data on patient-centred outcomes (such as QoL) or on resource use and none on cost-effectiveness. Pearle30 suggested that ESWL gave better QoL, shorter convalescence (days to 100% recovered), and had fewer analgesic requirements than FURS (participants had LPSs ≤ 10 mm). Conversely, Singh36 reported significantly higher participant satisfaction with FURS and comparable convalescence (time to return to routine activity) after having three or fewer ESWL sessions (participants had stones sizes of 10–20 mm). Convalescence was shorter after just a single ESWL session. There were conflicting data on patients’ willingness to undergo the procedure again. In one trial, participants30 favoured ESWL whereas in another36 FURS was preferred. ESWL (one session) was associated with a shorter hospital stay than either PCNL15 or FURS.30 One trial also suggested shorter treatment duration for ESWL (one session) compared to FURS.30
In summary, there is some evidence to inform estimates of the relative clinical effectiveness (based on SFR) of ESWL, FURS and PCNL in the treatment of LPSs and to guide clinical practice, but for most outcomes there is only moderate or low certainty in the evidence.31 There is sparse evidence on the impact of these treatments on patient-reported health status and QoL outcomes (such as severity and duration of pain after intervention), their care pathway (such as the need for additional treatments), and resource use. The EAU Guideline, which differs somewhat from the previously mentioned UK-specific 2019 NICE guidance,28 recommends either ESWL or FURS for LPSs under 10 mm, FURS or PCNL for LPSs between 10 and 20 mm, where there are unfavourable factors for ESWL, and any of the three treatment options if there is an absence of unfavourable factors for ESWL. This Percutaneous nephrolithotomy, flexible Ureterenoscopy and Extracorporeal shockwave lithotripsy for lower pole stone (PUrE) study aimed to provide robust evidence on health status, QoL, clinical outcomes and resource use to both the NHS and society to close this gap in evidence. The results aimed to benefit patients, clinicians, and the NHS and to inform provision, guidance, and decision-making about which of the competing interventions ‒ ESWL, FURS or PCNL ‒ is the most suitable (clinically effective and cost-effective) for the treatment of people with lower pole kidney stones of varying sizes.
Trial objectives
The aim of the PUrE study was to determine which of ESWL, FURS and PCNL offer the best treatment outcomes in terms of clinical effectiveness and cost-effectiveness for people with lower pole kidney stones seeking treatment within the UK NHS. The research question addressed was: In people requiring treatment for LPSs of the kidney, does FURS result in better health than standard treatment with ESWL or PCNL according to stone size, and is it cost-effective for the UK NHS?
The PUrE study was two separate RCTs run in parallel – the first (referred to as RCT1) for LPSs ≤ 10 mm in maximum dimension and the second (RCT2) for LPSs > 10 and ≤ 25 mm.
PUrE was designed to determine the clinical effectiveness and cost-effectiveness of FURS as the first treatment option in a treatment pathway in comparison to ESWL as a first treatment option in a treatment pathway for stones ≤ 10 mm in maximum dimension, or to PCNL as a first treatment option in a treatment pathway for stones > 10 and ≤ 25 mm in maximum dimension with respect to:
- patient-reported health status measured as area under the curve (AUC) comprised of the score from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L) questionnaire completed at multiple time points up to 12 weeks post intervention
- incremental cost per quality-adjusted life-years (QALYs) at 12 months post randomisation
- successful stone clearance at 12 weeks
- further interventions required to treat stones up to 12 months after randomisation and
- treatment-related harms experienced up to 12 months after randomisation.
The null hypotheses being tested were:
- The use of FURS to treat lower pole kidney stones ≤ 10 mm will not be different to ESWL as assessed by the EuroQol-5 Dimensions (EQ-5D) score AUC up to 12 weeks post treatment.
- The use of FURS to treat LPSs of the kidney > 10 and ≤ 25 mm will not be different to PCNL as assessed by the EQ-5D score AUC up to 12 weeks post treatment.
Chapter 2 describes the PUrE study design and methods. Chapters 3 and 4 present the clinical effectiveness results from RCT1 and RCT2, respectively. The health economic evaluation is presented in Chapter 5, and in Chapter 6 we discuss the results and present conclusions.