Shockwave lithotripsy compared with ureteroscopic stone treatment for adults with ureteric stones: the TISU non-inferiority RCT.

BACKGROUND: Urinary stone disease affects 2-3% of the general population. Ureteric stones are associated with severe pain and can have a significant impact on a patient's quality of life. Most ureteric stones are expected to pass spontaneously with supportive care; however, between one-fifth and one-third of patients require an active intervention. The two standard interventions are shockwave lithotripsy and ureteroscopic stone treatment. Both treatments are effective, but they differ in terms of invasiveness, anaesthetic requirement, treatment setting, number of procedures, complications, patient-reported outcomes and cost. There is uncertainty around which is the more clinically effective and cost-effective treatment. OBJECTIVES: To determine if shockwave lithotripsy is clinically effective and cost-effective compared with ureteroscopic stone treatment in adults with ureteric stones who are judged to require active intervention. DESIGN: A pragmatic, multicentre, non-inferiority, randomised controlled trial of shockwave lithotripsy as a first-line treatment option compared with primary ureteroscopic stone treatment for ureteric stones. SETTING: Urology departments in 25 NHS hospitals in the UK. PARTICIPANTS: Adults aged ≥ 16 years presenting with a single ureteric stone in any segment of the ureter, confirmed by computerised tomography, who were able to undergo either shockwave lithotripsy or ureteroscopic stone treatment and to complete trial procedures. INTERVENTION: Eligible participants were randomised 1 : 1 to shockwave lithotripsy (up to two sessions) or ureteroscopic stone treatment. MAIN OUTCOME MEASURES: The primary clinical outcome measure was resolution of the stone episode (stone clearance), which was operationally defined as 'no further intervention required to facilitate stone clearance' up to 6 months from randomisation. This was determined from 8-week and 6-month case report forms and any additional hospital visit case report form that was completed by research staff. The primary economic outcome measure was the incremental cost per quality-adjusted life-year gained at 6 months from randomisation. We estimated costs from NHS resources and calculated quality-adjusted life-years from participant completion of the EuroQol-5 Dimensions, three-level version, at baseline, pre intervention, 1 week post intervention and 8 weeks and 6 months post randomisation. RESULTS: In the shockwave lithotripsy arm, 67 out of 302 (22.2%) participants needed further treatment. In the ureteroscopic stone treatment arm, 31 out of 302 (10.3%) participants needed further treatment. The absolute risk difference was 11.4% (95% confidence interval 5.0% to 17.8%); the upper bound of the 95% confidence interval ruled out the prespecified margin of non-inferiority (which was 20%). The mean quality-adjusted life-year difference (shockwave lithotripsy vs. ureteroscopic stone treatment) was -0.021 (95% confidence interval 0.033 to -0.010) and the mean cost difference was -£809 (95% confidence interval -£1061 to -£551). The probability that shockwave lithotripsy is cost-effective is 79% at a threshold of society's willingness to pay for a quality-adjusted life-year of £30,000. The CEAC is derived from the joint distribution of incremental costs and incremental effects. Most of the results fall in the south-west quadrant of the cost effectiveness plane as SWL always costs less but is less effective. LIMITATIONS: A limitation of the trial was low return and completion rates of patient questionnaires. The study was initially powered for 500 patients in each arm; however, the total number of patients recruited was only 307 and 306 patients in the ureteroscopic stone treatment and shockwave lithotripsy arms, respectively. CONCLUSIONS: Patients receiving shockwave lithotripsy needed more further interventions than those receiving primary ureteroscopic retrieval, although the overall costs for those receiving the shockwave treatment were lower. The absolute risk difference between the two clinical pathways (11.4%) was lower than expected and at a level that is acceptable to clinicians and patients. The shockwave lithotripsy pathway is more cost-effective in an NHS setting, but results in lower quality of life. FUTURE WORK: (1) The generic health-related quality-of-life tools used in this study do not fully capture the impact of the various treatment pathways on patients. A condition-specific health-related quality-of-life tool should be developed. (2) Reporting of ureteric stone trials would benefit from agreement on a core outcome set that would ensure that future trials are easier to compare. TRIAL REGISTRATION: This trial is registered as ISRCTN92289221. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 19. See the NIHR Journals Library website for further project information.

Approximately 1 in 20 people suffers from kidney stones that pass down the urine drainage tube (ureter) into the urinary bladder and cause episodes of severe pain (ureteric colic). People with ureteric colic attend hospital for pain relief and diagnosis. Although most stones smaller than 10 mm eventually reach the bladder and are passed during urination, some get stuck and have to be removed using telescopic surgery (called ureteroscopic stone treatment) or shockwave therapy (called shockwave lithotripsy). Ureteroscopic stone treatment involves passing a telescope-containing instrument through the bladder and into the ureter to fragment and/or remove the stone. This is usually carried out under general anaesthetic as a day case. For shockwave lithotripsy, the patient lies flat on a couch and the apparatus underneath them generates shockwaves that pass through the skin to the ureter and break the stones into smaller fragments, which can be passed naturally in the urine. This involves using X-ray or ultrasound to locate the stone, but can be carried out on an outpatient basis and without general anaesthetic. Telescopic surgery is known to be more successful at removing stones after just one treatment, but it requires more time in hospital and has a higher risk of complications than shockwave lithotripsy (however, shockwave lithotripsy may require more than one session of treatment). Our study, the Therapeutic Interventions for Stones of the Ureter trial, was designed to establish if treatment for ureteric colic should start with telescopic surgery or shockwave therapy. Over 600 NHS patients took part and they were split into two groups. Each patient had an equal chance of their treatment starting with either telescopic surgery or shockwave lithotripsy, which was decided by a computer program (via random allocation). We counted how many patients in each group had further procedures to remove their stone. We found that telescopic surgery was 11% more effective overall, with an associated slightly better quality of life (10 more healthy days over the 6-month period), but was more expensive in an NHS setting. The finding of a lack of any significant additional clinical benefit leads to the conclusion that the more cost-effective treatment pathway is shockwave lithotripsy with telescopic surgery used only in those patients in whom shockwave lithotripsy is unsuccessful.

TISU: Extracorporeal shockwave lithotripsy, as first treatment option, compared with direct progression to ureteroscopic treatment, for ureteric stones: study protocol for a randomised controlled trial.

BACKGROUND: Urinary stone disease is very common with an estimated prevalence among the general population of 2-3%. Ureteric stones are associated with severe pain as they pass through the urinary tract and have significant impact on patients' quality of life due to the detrimental effect on their ability to work and need for hospitalisation. Most ureteric stones can be expected to pass spontaneously with supportive care. However, between one-fifth and one-third of cases require an intervention. The two standard active intervention options are extracorporeal shockwave lithotripsy (ESWL) and ureteroscopic stone retrieval. ESWL and ureteroscopy are effective in terms of stone clearance; however, they differ in terms of invasiveness, anaesthetic requirement, treatment setting, complications, patient-reported outcomes (e.g. pain after intervention, time off work) and cost. There is uncertainty around which is the most clinically effective in terms of stone clearance and the true cost to the NHS and to society (in terms of impact on patient-reported health and economic burden). The aim of this trial is to determine whether, in adults with ureteric stones, judged to require active intervention, ESWL is not inferior and is more cost-effective compared to ureteroscopic treatment as the initial management option. METHODS: The TISU study is a pragmatic multicentre non-inferiority randomised controlled trial of ESWL as the first treatment option compared with direct progression to ureteroscopic treatment for ureteric stones. Patients aged over 16 years with a ureteric stone confirmed by non-contrast computed tomography of the kidney, ureter and bladder (CTKUB) will be randomised to either ESWL or ureteroscopy. The primary clinical outcome is resolution of the stone episode (no further intervention required to facilitate stone clearance) up to six months from randomisation. The primary economic outcome is the incremental cost per quality-adjusted life years (QALYs) gained at six months from randomisation. DISCUSSION: Determining whether ESWL is not inferior clinically and is cost-effective compared to ureteroscopic treatment as the initial management in adults with ureteric stones who are judged to require active treatment is relevant not only to patients and clinicians but also to healthcare providers, both in the UK and globally. TRIAL REGISTRATION: ISRCTN registry, ISRCTN92289221 . Registered on 21 February 2013.

Use of drug therapy in the management of symptomatic ureteric stones in hospitalised adults: a multicentre, placebo-controlled, randomised controlled trial and cost-effectiveness analysis of a calcium channel blocker (nifedipine) and an alpha-blocker (tamsulosin) (the SUSPEND trial).

BACKGROUND: Ureteric colic, the term used to describe the pain felt when a stone passes down the ureter from the kidney to the bladder, is a frequent reason for people to seek emergency health care. Treatment with the muscle-relaxant drugs tamsulosin hydrochloride (Petyme, TEVA UK Ltd) and nifedipine (Coracten(®), UCB Pharma Ltd) as medical expulsive therapy (MET) is increasingly being used to improve the likelihood of spontaneous stone passage and lessen the need for interventional procedures. However, there remains considerable uncertainty around the effectiveness of these drugs for routine use. OBJECTIVES: To determine whether or not treatment with either tamsulosin 400 µg or nifedipine 30 mg for up to 4 weeks increases the rate of spontaneous stone passage for people with ureteric colic compared with placebo, and whether or not it is cost-effective for the UK NHS. DESIGN: A pragmatic, randomised controlled trial comparing two active drugs, tamsulosin and nifedipine, against placebo. Participants, clinicians and trial staff were blinded to treatment allocation. A cost-utility analysis was performed using data gathered during trial participation. SETTING: Urology departments in 24 UK NHS hospitals. PARTICIPANTS: Adults aged between 18 and 65 years admitted as an emergency with a single ureteric stone measuring ≤ 10 mm, localised by computerised tomography, who were able to take trial medications and complete trial procedures. INTERVENTIONS: Eligible participants were randomised 1 : 1 : 1 to take tamsulosin 400 µg, nifedipine 30 mg or placebo once daily for up to 4 weeks to make the following comparisons: tamsulosin or nifedipine (MET) versus placebo and tamsulosin versus nifedipine. MAIN OUTCOME MEASURES: The primary effectiveness outcome was the proportion of participants who spontaneously passed their stone. This was defined as the lack of need for active intervention for ureteric stones at up to 4 weeks after randomisation. This was determined from 4- and 12-week case-report forms completed by research staff, and from the 4-week participant self-reported questionnaire. The primary economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained over 12 weeks. We estimated costs from NHS sources and calculated QALYs from participant completion of the European Quality of Life-5 Dimensions health status questionnaire 3-level response (EQ-5D-3L™) at baseline, 4 weeks and 12 weeks. RESULTS: Primary outcome analysis included 97% of the 1167 participants randomised (378/391 tamsulosin, 379/387 nifedipine and 379/399 placebo participants). The proportion of participants who spontaneously passed their stone did not differ between MET and placebo [odds ratio (OR) 1.04, 95% confidence interval (CI) 0.77 to 1.43; absolute difference 0.8%, 95% CI -4.1% to 5.7%] or between tamsulosin and nifedipine [OR 1.06, 95% CI 0.74 to 1.53; absolute difference 1%, 95% CI -4.6% to 6.6%]. There was no evidence of a difference in QALYs gained or in cost between the trial groups, which means that the use of MET would be very unlikely to be considered cost-effective. These findings were unchanged by extensive sensitivity analyses around predictors of stone passage, including sex, stone size and stone location. CONCLUSIONS: Tamsulosin and nifedipine did not increase the likelihood of stone passage over 4 weeks for people with ureteric colic, and use of these drugs is very unlikely to be cost-effective for the NHS. Further work is required to investigate the phenomenon of large, high-quality trials showing smaller effect size than meta-analysis of several small, lower-quality studies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN69423238. European Clinical Trials Database (EudraCT) number 2010-019469-26. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 63. See the NIHR Journals Library website for further project information.

Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial.

BACKGROUND: Meta-analyses of previous randomised controlled trials concluded that the smooth muscle relaxant drugs tamsulosin and nifedipine assisted stone passage for people managed expectantly for ureteric colic, but emphasised the need for high-quality trials with wide inclusion criteria. We aimed to fulfil this need by testing effectiveness of these drugs in a standard clinical care setting. METHODS: For this multicentre, randomised, placebo-controlled trial, we recruited adults (aged 18-65 years) undergoing expectant management for a single ureteric stone identified by CT at 24 UK hospitals. Participants were randomly assigned by a remote randomisation system to tamsulosin 400 µg, nifedipine 30 mg, or placebo taken daily for up to 4 weeks, using an algorithm with centre, stone size (≤5 mm or >5 mm), and stone location (upper, mid, or lower ureter) as minimisation covariates. Participants, clinicians, and trial personnel were masked to treatment assignment. The primary outcome was the proportion of participants who did not need further intervention for stone clearance within 4 weeks of randomisation, analysed in a modified intention-to-treat population defined as all eligible patients for whom we had primary outcome data. This trial is registered with the European Clinical Trials Database, EudraCT number 2010-019469-26, and as an International Standard Randomised Controlled Trial, number 69423238. FINDINGS: Between Jan 11, 2011, and Dec 20, 2013, we randomly assigned 1167 participants, 1136 (97%) of whom were included in the primary analysis (17 were excluded because of ineligibility and 14 participants were lost to follow-up). 303 (80%) of 379 participants in the placebo group did not need further intervention by 4 weeks, compared with 307 (81%) of 378 in the tamsulosin group (adjusted risk difference 1·3% [95% CI -5·7 to 8·3]; p=0·73) and 304 (80%) of 379 in the nifedipine group (0·5% [-5·6 to 6·5]; p=0·88). No difference was noted between active treatment and placebo (p=0·78), or between tamsulosin and nifedipine (p=0·77). Serious adverse events were reported in three participants in the nifedipine group (one had right loin pain, diarrhoea, and vomiting; one had malaise, headache, and chest pain; and one had severe chest pain, difficulty breathing, and left arm pain) and in one participant in the placebo group (headache, dizziness, lightheadedness, and chronic abdominal pain). INTERPRETATION: Tamsulosin 400 µg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Pazopanib for the first-line treatment of patients with advanced and/or metastatic renal cell carcinoma : a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of pazopanib hydrochloride (GlaxoSmithKline) to submit evidence of the clinical and cost effectiveness of the drug for the first-line treatment of advanced and/or metastatic renal cell carcinoma, as part of the Institute's single technology appraisal (STA) process. The Aberdeen Health Technology Assessment Group were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The objective of this paper is to summarize the independent review and critique of the evidence submitted for the consideration of the NICE Appraisal Committee and NICE's subsequently issued guidance. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. For progression-free survival (PFS), there was a statistically significant longer survival for pazopanib compared with placebo (as assessed by the ERG, based upon the original manufacturer submission with a clinical cut-off date of 23 May 2008) [median 11.1 vs. 2.8 months; hazard ratio (HR) 0.40; 95 % CI 0.27, 0.60]. Data from the indirect comparison suggested that pazopanib had a greater survival than interferon alpha (IFN-α) [HR 0.512; 95 % CI 0.326, 0.802] but provided no evidence of any difference compared with sunitinib (HR 0.949; 95 % CI 0.575, 1.568). With regard to overall survival, 64 % (n = 99) of patients in the pazopanib arm and 63 % (n = 49) of patients in the placebo arm had died and a total of 51 % (n = 40) of placebo patients had crossed over to receive pazopanib. Although data were provided on an intention-to-treat basis, crossover between therapies made such data difficult to interpret. There was no evidence of any statistically significant difference between pazopanib and best supportive care (HR 0.501; 95 % CI 0.136, 2.348). In the indirect comparison, there were no statistically significant differences between pazopanib and IFN-α (HR 0.627; 95 % CI 0.173, 2.269) or between pazopanib and sunitinib (HR 0.969; 95 % CI 0.359, 2.608). Based upon the work presented including a 12.5 % discount for pazopanib, sunitinib was extendedly dominated by a combination of pazopanib and IFN-α. As a consequence, the incremental cost per QALY for pazopanib versus IFN-α was £38,925. The results were not greatly altered over the range of univariate deterministic sensitivity analyses conducted by the manufacturer but pair-wise probabilistic sensitivity analyses suggested that given a threshold value of £30,000, there is a 54 % probability that pazopanib was preferred to sunitinib, 40 % chance against IFN-α and 47 % chance against best supportive care. The Appraisal Committee concluded that pazopanib should be recommended as a first-line treatment option for people with advanced renal cell carcinoma who have not received prior cytokine therapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and if the manufacturer provides pazopanib with a 12.5 % discount on the list price and provides a possible future rebate linked to the outcome of the head-to-head COMPARZ trial, as agreed under the terms of the patient access scheme and to be confirmed when the COMPARZ trial data are made available.

Surgical treatments for men with benign prostatic enlargement: cost effectiveness study.

OBJECTIVE: To determine which surgical treatment for lower urinary tract symptoms suggestive of benign prostate enlargement is cost effective. DESIGN: Care pathways describing credible treatment strategies were decided by consensus. Cost-utility analysis used Markov modelling and Monte Carlo simulation. DATA SOURCES: Clinical effectiveness data came from a systematic review and an individual level dataset. Utility values came from previous economic evaluations. Costs were calculated from National Health Service (NHS) and commercial sources. METHODS: The Markov model included parameters with associated measures of uncertainty describing health states between which individuals might move at three monthly intervals over 10 years. Successive annual cohorts of 25,000 men were entered into the model and the probability that treatment strategies were cost effective was assessed with Monte Carlo simulation with 10,000 iterations. RESULTS: A treatment strategy of initial diathermy vaporisation of the prostate followed by endoscopic holmium laser enucleation of the prostate in case of failure to benefit or subsequent relapse had an 85% probability of being cost effective at a willingness to pay value of pound20,000 (euro21,595, $28,686)/quality adjusted life year (QALY) gained. Other strategies with diathermy vaporisation as the initial treatment were generally cheaper and more effective than the current standard of transurethral resection repeated once if necessary. The use of potassium titanyl phosphate laser vaporisation incurred higher costs and was less effective than transurethral resection, and strategies involving initial minimally invasive treatment with microwave thermotherapy were not cost effective. Findings were unchanged by wide ranging sensitivity analyses. CONCLUSION: The outcome of this economic model should be interpreted cautiously because of the limitations of the data used. The finding that initial vaporisation followed by holmium laser enucleation for failure or relapse might be advantageous both to men with lower urinary tract symptoms and to healthcare providers requires confirmation in a good quality prospective clinical trial before any change in current practice. Potassium titanyl phosphate laser vaporisation was unlikely to be cost effective in our model, which argues against its unrestricted use until further evidence of effectiveness and cost reduction is obtained.