Tag Archive for: MET

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Trustworthy ‘Rapid Recommendations’ for Urology

BJU International has a longstanding track record of promoting the principles of evidence-based clinical practice to an international audience of urologists. Recent initiatives include the “guidelines of guidelines” series which appraises and contrasts clinical practice guidelines from different professional organizations on the same topic, for example on microscopic hematuria and non-muscle-invasive bladder cancer. It also co-publishes high quality, urology-relevant guidance by the UK’s National Institute for Health and Care Excellence (NICE), for example on the preoperative testing for elective surgery (https://www.bjuinternational.com/learning-2/urology-guidelines/nice-guidance-routine-preoperative-tests-elective-surgery/).

In collaboration with the MAGIC research and innovation program (www.magicproject.org), BJU International has published its first Rapid Recommendation guidance document on the use of medical expulsive therapy (MET) with alpha-blockers that was triggered by the recent rigorous Cochrane review on the same topic. Its purpose is to provide trustworthy, timely and practical guidance on this topic based on the entire body of evidence, given several recently published trials with contradictory findings. To develop this trustworthy guidance, an international team that included patients with a personal history of ureteral stones, general practitioners (GPs), emergency clinicians, urologists familiar with treating renal colic, epidemiologists, and methodologists followed a rigorous and transparent GRADE-based process in accordance with The National Academy of Science, Engineering and Medicine (formerly: Institute of Medicine) (https://www.nationalacademies.org/hmd/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust/Standards.aspx) standards for trustworthy guidelines. Panel member had no financial conflicts of interest and intellectual and professional conflicts of interests were described and carefully minimized. All meetings were conducted by web conference and the process was completed within 90 days of publication of the Cochrane review, which is co-published in BJU International in this same issue.

Initially pioneered in collaboration with the BMJ for questions of broader interest (https://www.bmj.com/rapid-recommendations) such as the use of corticosteroids for the treatment of a sore throat, this Rapid Recommendation breaks new ground for evidence-based guidance in urology, complementing the efforts by professional organizations such as the European Association of Urology (EAU) and American Urological Association (AUA). Rapid Recommendations stand out for their focus on patient-important outcomes, the use of an explicit and transparent process for moving from evidence to recommendations and its timely development process. Rapid Recommendations provide actionable guidance as well as information on the underlying evidence and supporting judgments that are summarized in an infographic that is easily understood by patients. The Rapid Recommendation on MET is intended to be the first of many to help inform patients, providers and policy-makers but also to seeks to provide a strong impetus for more trustworthy and useful guidelines in urology in general.

 

 

By Philipp Dahm1 2 and Per Olav Vandvik3 4 5

1 Minneapolis VA Medical Center, Urology Section, Minneapolis, MN, USA

2 University of Minnesota, Department of Urology, Minneapolis, MN, USA

3 Norwegian Institute of Public Health, Oslo, Norway

 

Disclosures:

Philipp Dahm serves as Coordinating Editor of Cochrane Urology, is member of the GRADE Working Group and served as a panel member of this Rapid Recommendation project

Per Olav Vandvik is member of the GRADE Working Group, is the leader of the MAGIC Foundation and BMJ Rapid Recommendations project and served as a panel member of this Rapid Recommendation project.

 

The Drugs Don’t Work … Or Do They?

The Verve made millions out of the hit single “The Drugs Don’t Work” … I doubt they would have made any money if they called it “The Drugs Don’t Work … Or Do They ?” but that is where we are in 2017 with medical expulsive therapy (MET) for ureteric stones.

In 2015, “The Drugs Don’t Work” was the most read blog of the year and for that won the “Best Blog of the Year” award at the BJUI Social Media awards. And it was all about SUSPEND. The trial that changed everything. We had been giving MET out like smarties. We loved it. Patients loved it. But many of us had doubts. The evidence was weak. “Large randomised trials are needed to confirm” the authors of small trials said. And so we did it in British Urology and it did change practice for many people. Doubts crept in around the world. More trials confirmed this. The Furyk study … MET doesn’t work in Australia (apart from a small advantage on small subgroup analysis). It doesn’t work in America either. Silodosin … promising but little benefit. But wait … the NIH are doing a trial. This will confirm once and for all. And as I was about to debate John Hollingsworth at the Rock Society at #AUA17 – thrown into the lion’s den of believers – it was released, a late breaking abstract – The STONE study and NO BENEFIT TO MET. Game over … MET is dead. Even non-believers were convinced in another debate with John in Vancouver at #WCE17.

So imagine the surprise as this month in European Urology, the largest study ever conducted was released. 3450 patients. A good quality double-blind placebo-controlled RCT. The headline … Overall MET does work (86% vs. 79%). And this was judged on a fairly hardcore follow-up schedule of CT scans weekly for 4 weeks – how many people do that in their practice? On subgroup analysis stones >5mm show greatest benefit (87 vs. 75% stone passage). Stones ≤ 5mm showed no benefit (88% vs 87%) although there is some advantages for time to passage (148 vs.249 hours), colic episodes (1.9 vs.9.4%) and analgesia requirements (89 vs.236mg). So what do we do now? Firstly I suspect this has just cemented the current position of the 2017 #EAUGuidelines which already states “the greatest benefit might be among those with large (distal) stones”. I do also feel this trial requires greater scrutiny – does this really change everything again?

Some facts: 3296 patients included in the analysis. Only 15 patients declined entry to the study – that is amazing! Recruited in 30 centres in China over 2 years which finished in 2013. The inclusion criteria was for distal ureteric stones from 4-7mm (interestingly a fact not expressed in the abstract). Not 3mm; not 8mm; 4-7mm only. So a narrow window which probably represents the potential target benefit for MET. There are lots of exclusion criteria – diabetes, previous stone on that side, previous ureteroscopy on that side and ‘severe hydronephrosis’. So if the emergency departments are to follow this study they need to select stones of 6 or 7mm in longest diameter, only in the distal ureter and without “severe hydronephrosis” whatever that means. I’m not sure I totally know and I’m a urologist. Good luck to the ED docs with that one!

I need to ask, why has it taken 4 years for this to be published? There is no long-term follow-up required in this study. Outcomes should be known within 28 days. With such international controversy surely this should have been a priority to publish? Only the authors can answer this question but such delayed publication suggests to me some issue with the data. This was a company sponsored trial – so why weren’t they pushing for publication? Only they know. Company involvement to me automatically introduces a degree of murkiness about the outcomes in any trial – just look at the problem with oncology trials. Even more so when they are “involved with preparation of the manuscript”. That gives them a controlling interest in the publication of the outcomes and that really concerns me. It probably shouldn’t … the results are the results … but it still concerns me. It’s one thing supplying the medications for a trial but having control of the manuscript? What data is missing? For example, how many people in each group complied with the imaging protocols? We don’t know. How many patients didn’t undergo any follow-up imaging at all? We don’t know. How many patients did not attend (DNA) for follow-up at each stipulated week (as DNA rates are often high for colic patients)? We don’t know. Any small differences between the groups might explain the differences in final outcome. How many returned the analgesia and pain questionnaires? We don’t know. What were the compliance rates with medication? We don’t know. Importantly, why were the side-effects the same in both groups in such a big sample? That worries me a lot. This trial is powered to show small differences and even the most ardent MET supporters will concede that MET comes with a tolerable increase in side-effects – other studies have clearly shown that. That concerns me. Is that actually a surrogate marker of quality for this study?

Don’t get me wrong, other studies definitely have their limitations as well. Furyk – underpowered for larger stones. STONE – confounded by small stones? SUSPEND – real-life follow-up without mandated imaging. There is no doubt this trial will shift the balance in the debate. I thought MET was dead but, as per the EAU guidelines, MET may confer benefit for stones >5mm but in reality only those measuring 6 or 7mm – an absolute benefit of 12% for that specific group. It definitely doesn’t help stone passage for ≤ 5mm stones. It is interesting that whilst SUSPEND was criticised for having such high stone passage rates of ~ 80% – that is exactly what is seen in this paper and in a more select larger stone group. That is curious. Placebo did very well again. It’s a shame we can’t prescribe that!

What will I do? I might use MET a bit more for the carefully selected and counselled “larger stone” – I did anyway – but I certainly don’t feel we are back to giving this out to everyone who walks through the door.

 

Matthew Bultitude

Consultant Urologist, Guy’s and St. Thomas’ Hospital

Associate Editor, BJUI

 

Highlights from BAUS 2016

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In the week following Britain’s exit from Europe after the BREXIT referendum, BAUS 2016 got underway in Liverpool’s BT convention Centre. This was the 72nd meeting of the British Association of Urological Surgeons and it was well attended with 1120 delegates (50% Consultant Member Urologists, 30% Trainees, 10% Non member Urologists/Other, 10% Nurses, HCP’S, Scientists).

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Monday saw a cautionary session on medicolegal aspects in Andrology, focusing on lawsuits over the last year. Mr Mark Speakman presented on the management issue of testicular torsion. This sparked further discussion on emergency cover for paediatrics with particular uncertainty noted at 4 and 5 year olds and great variation in approach dependent on local trust policy. Mr Julian Shah noted the most litigious areas of andrology, with focus on cosmesis following circumcisions. Therefore serving a reminder on the importance of good consent to manage patients’ expectations.

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In the Dragons’ Den, like the TV show, junior urologists pitched their ideas for collaborative research projects, to an expert panel. This year’s panel was made up of – Mark Emberton, Ian Pearce, and Graeme MacLennan. The session was chaired by Veeru Kasivisvanathan, Chair of the BURST Research Collaborative.

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Eventual winner Ben Lamb, a trainee from London, presented “Just add water”. The pitch was for an RCT to investigate the efficacy of water irrigation following TURBT against MMC in reducing tumour recurrence. Ben proposed that water, with its experimental tumouricidal properties, might provide a low risk, low cost alternative as an adjuvant agent following TURBT. Judges liked the scientific basis for this study and the initial planning for an RCT. The panel discussed the merits of non-inferiority vs. superiority methodology, and whether the team might compare MMC to MMC with the addition of water, or water instead of MMC. They Dragons’ suggested that an initial focus group to investigate patients’ views on chemotherapy might help to focus the investigation and give credence to the final research question, important when making the next pitch- to a funding body, or ethics committee.

Other proposals were from Ryad Chebbout, working with Marcus Cumberbatch, an academic trainee from Sheffield. Proposing to address the current controversy over the optimal surgical technique for orchidopexy following testicular torsion. His idea involved conducting a systematic review, a national survey of current practice followed by a Delphi consensus meeting to produce evidence based statement of best practice. The final presentation was from Sophia Cashman, East of England Trainee for an RCT to assess the optimal timing for a TWOC after urinary retention. The panel liked the idea of finally nailing down an answer to this age-old question.

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Waking up on Tuesday with England out of the European football cup as well as Europe the conference got underway with an update from the PROMIS trial (use of MRI to detect prostate cancer). Early data shows that multi-parametric MRI may be accurate enough to help avoid some prostate biopsies.

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The SURG meeting provided useful information for trainees, with advice on progressing through training and Consultant interviews. A debate was held over run through training, which may well be returning in the future. The Silver cystoscope was awarded to Professor Rob Pickard voted for by the trainees in his deanery, for his devotion to their training.
Wednesday continued the debate on medical expulsion therapy (MET) for ureteric stones following the SUSPEND trial. Most UK Urologists seem to follow the results of the trial and have stopped prescribing alpha blockers to try and aid stone passage and symptoms. However the AUA are yet to adopt this stance and feel that a sub analysis shows some benefit for stones >5mm, although this is not significant and pragmatic outcomes. Assistant Professor John Hollingsworth (USA) argued for MET, with Professor Sam McClinton (UK) against. A live poll at the end of the session showed 62.9% of the audience persuaded to follow the SUSPEND trial evidence and stop prescribing MET.

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In the debate of digital versus fibreoptic scopes for flexible ureteroscopy digital triumphed, but with a narrow margin.

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In other updates and breaking news it appears that BCG is back! However during the shortage EMDA has shown itself to be a promising alternative in the treatment of high grade superficial bladder cancer.
The latest BAUS nephrectomy data shows that 90% are performed by consultant, with 16 on average per consultant per year. This raises some issues for registrar training, however with BAUS guidelines likely to suggest 20 as indicative numbers this is looking to be an achievable target for most consultants. Robotic advocates will be encouraged, as robotic partial nephrectomy numbers have overtaken open this year. The data shows 36% of kidney tumours in the under 40 years old are benign. Will we have to consider biopsying more often? However data suggests we should be offering more cytoreductive nephrectomies, with only roughly 1/10 in the UK performed compared to 3/10 in the USA.

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The andrology section called for more recruitment to The MASTER trial (Male slings vs artificial urinary sphincters), whereas the OPEN trial has recruited(open urethroplasty vs optical urethotomy). In the treatment of Peyronie’s disease collagenase has been approved by NICE but not yet within the NHS.

Endoluminal endourology presentation showed big increases in operative numbers with ureteroscopy up by 50% and flexible ureteroscopy up by 100%. Stents on strings were advocated to avoid troubling stent symptoms experienced by most patients. New evidence may help provide a consensus on defining “stone free” post operation. Any residual stones post-operatively less than 2mm were shown to pass spontaneously and therefore perhaps may be classed as “stone free”.

Big changes seem likely in the treatment of benign prostatic hyperplasia, with a race to replace the old favorite TURP. Trials have of TURP (mono and bipolar) vs greenlight laser are already showing similar 2 year outcomes with the added benefit of shorter hospital stays and less blood loss. UROLIFT is an ever more popular alternative with data showing superiority to TURP in lifestyle measures, likely because it preserves sexual function, and we are told it can be performed as a 15 minute day case operation. The latest new therapy is apparently “Aquabeam Aquablation”, using high pressured water to remove the prostate. Non surgical treatments are also advancing with ever more accurate super selective embolisation of the prostatic blood supply.

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This year all accepted abstracts were presented in moderated EPoster sessions. The format was extremely successful removing the need for paper at future conferences? A total of 538 abstracts were submitted and 168 EPosters displayed. The winner of best EPoster was P5-5 Altaf Mangera: Bladder Cancer in the Neuropathic Bladder.

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The best Academic Paper winner was Mark Salji of the CRUK Beatson institute, titled “A Urinary Peptide Biomarker Panel to Identify Significant Prostate Cancer”. Using capillary electrophoresis coupled to mass spectrometry (CE-MS) they analysed 313 urine samples from significant prostate cancer patients (Gleason 8-10 or T3/4 disease) and low grade control disease. They identified 94 peptide urine biomarkers which may provide a useful adjunct in identifying significant prostate cancer from insignificant disease.

The Office of Education offered 20 courses. Popular off-site courses were ultrasound for the Urologist, at Broadgreen Hospital, a slightly painful 30 min drive from the conference centre. However well worth the trip, delivered by Radiology consultants this included the chance to scan patients volunteers under guidance, with separate stations for kidneys, bladder and testicles and learning the “knobology” of the machines.

Organised by Tamsin Greenwell with other consultant experts in female, andrology and retroperitoneal cancer, a human cadaveric anatomy course was held at Liverpool university. The anatomy teaching was delivered by both Urology consultants and anatomists allowing for an excellent combination of theory and functional anatomy.

BAUS social events are renowned and with multiple events planned most evenings were pretty lively. The official drinks reception was held at the beautiful Royal Liver Building. The venue was stunning with great views over the waterfront and the sun finally shining. Several awards were presented including the Gold cystoscope to Mr John McGrath for significant contribution to Urology within 10 years appointment as consultant. The Keith Yeates medal was awarded to Mr Raj Pal, the most outstanding candidate in the first sitting of the intercollegiate specilaity examination, with a score of over 80%.

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During the conference other BAUS awards presented include the St Peter’s medal was awarded to Margeret Knowles, Head of section of molecular oncology, Leeds Institute of Cancer and Pathology, St James University hospital Leeds. The St Paul’s medal awarded to Professor Joseph A. Smith, Vanderbilt University, Nashville, USA. The Gold medal went to Mr. Tim Terry, Leicester General Hospital.

An excellent industry exhibition was on display, with 75 Exhibiting Companies present. My personal fun highlight was a flexible cystoscope with integrated stent remover, which sparked Top Gear style competiveness when the manufacturer set up a time-trial leaderboard. Obviously this best demonstrated the speed of stent removal with some interesting results…

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Social media review shows good contribution daily.

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Thanks BAUS a great conference, very well organised and delivered with a great educational and social content, looking forward to Glasgow 2017! #BAUS2017 #Glasgow #BAUSurology

Nishant Bedi

Specialist Training Registrar North West London 

Twitter: @nishbedi

 

West Coast Urology: Highlights from the AUA 2016 in San Diego… Part 2

By Ben Challacombe (@benchallacombe) and Jonathan Makanjuola (@jonmakurology)

 

The AUA meeting was starting to hot up with the anticipation of the Crossfire sessions, PSA screening and the MET debate that appeared to rumble on.  We attended the MUSIC (Michigan Urological Surgery Improvement Collaborative) session. It is a fantastic physician led program including >200 urologists, which aims to improve the quality of care for men with urological diseases. It is a forum for urologists across Michigan, USA to come together to collect clinical data, share best practices and implement evidence based quality improvement activities. One of their projects is crowd reviewing of RALP by international experts for quality of the nerve spare in order to improve surgical outcomes.

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The MET debate continues to cause controversy. In the UK there has been almost uniform abandonment of the use of tamsulosin for ureteric stones following The Lancet SUSPEND RCT.

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The MET crossfire debate was eagerly awaited. The debate was led by James N’Dow (@NDowJames) arguing against and Philipp Dahm (@EBMUrology) in favour of MET. Many have criticised the SUSPEND paper for lack of CT confirmation of stone passage. Dr Matlaga (@BrianMatlaga) stated that comparing previous studies of MET to SUSPEND is like comparing apples to oranges due to different outcome measures. He recommended urologists continue MET until more data is published. More conflicting statements were made suggesting that MET is effective in all patients especially for large stones in the ureter. The AUA guidelines update was released and stated that MET can be offered for distal ureteric stones less than 10mm.

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In a packed Endourology video session there were many high quality video presentations. One such video was a demonstration of the robotic management for a missed JJ ureteric stent. Khurshid Ghani (@peepeeDoctor) presented a video demonstrating the pop-corning and pop-dusting technique with a 100w laser machine.

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One of the highlights of the Sunday was the panel discussion plenary session, Screening for Prostate Cancer: Past, Present and Future. In a packed auditorium Stacy Loeb (@LoebStacy), gave an excellent overview of PSA screening with present techniques including phi, 4K and targeted biopsies. Freddie Hamdy looked into the crystal ball and gave a talk on future directions of PSA testing and three important research questions that still needed to be answered. Dr. Catalona presented the data on PSA screening and the impact of the PLCO trial. He argued that due to inaccurate reporting, national organisations should restore PSA screening as he felt it saved lives.

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There was a twitter competition for residents and fellows requiring participants to  tweet an answer to a previously tweeted question including the hashtag #scopesmart and #aua16. The prize was Apple Watch. Some of the questions asked included; who performed the 1st fURS? And what is the depth of penetration of the Holmium laser?

UK trainees picked up the prizes on the first two days.

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The British Association of Urological Surgeons (BAUS) / BJU International (BJUI) / Urological Society of Australia and New Zealand (USANZ) session was a real highlight of day three of the AUA meeting. There were high quality talks from opinion leaders in their sub specialities. Freddie Hamdy from Oxford University outlined early thoughts from the protecT study and the likely direction of travel for management of clinically localised prostate cancer. Prof Emberton (@EmbertonMark) summarised the current evidence for the role of MRI in prostate cancer diagnosis including his thoughts on the on going PROMIS trial. Hashim Ahmed was asked if HIFU was ready for the primetime and bought us up to speed with the latest evidence.

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The eagerly awaited RCT comparing open prostatectomy vs RALP by the Brisbane group was summarised with regards to study design and inclusion criteria. It is due for publication on the 18th May 2016 so there was a restriction of presenting results.  Dr Coughlin left the audience wanting more despite Prof. Dasgupta’s best effort to get a sneak preview of the results!  We learnt from BAUS president Mark Speakman (@Parabolics) about the UK effort to improve the quality of national outcomes database for a number of index urological procedures.

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Oliver Wiseman (@OJWiseman) gave us a flavour of outcomes from the BAUS national PCNL database and how they are trying drive up standards to improve patient care. A paediatric surgery update was given by Dr Gundeti. The outcomes of another trial comparing open vs laparoscopic vs RALP was presented. There was no difference in outcomes between the treatment modalities but Prof. Fydenburg summarised by saying that the surgeon was more important determinant of outcome than the tool. Stacy Loeb closed the meeting with an excellent overview of the use of twitter in Urology, followed by a drinks reception.

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It was not all about stones and robots. The results of the Refractory Overactive Bladder: Sacral NEuromodulation vs. BoTulinum Toxin Assessment (ROSETTA) trial results were presented. Botox came out on top against neuromodulation in urgency urinary incontinence episodes over 6 months, as well as other lower urinary tract symptoms.

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The late breaking abstract session presented by Stacy Loeb highlighted a paper suggesting a 56% reduction in high-grade prostate cancer for men on long term testosterone. This was a controversial abstract and generated a lot of discussion on social media.

 

 

 

 

 

 

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It has been an excellent meeting in San Diego and we caught up with old and met new friends. It was nice to meet urologists from across the globe with differing priorities and pressures. There was a good British, Irish and Australian contingent flying the flag for their respective countries. It was another record-breaking year for the #AUA16 on twitter. It surpassed the stats for #AUA15 with over 30M impressions, 16,659 tweets 2,377 participants. See you all in Boston for AUA 2017.

 

Here comes the sun

BJUI-on-the-beach

Sun, sea, sand and stones: BJUI on the beach.

Welcome to this month’s BJUI and whether you are relaxing on a sun-drenched beach or villa somewhere having a hard-earned break, or back at your hospital covering for everyone else having their time off, we hope you will enjoy another fantastic issue. After an action packed BAUS meeting with important trial results, innovation, social media and the BJUI fully to the fore, this is a great moment to update yourself on what is hot in urology. This is probably the time of year when most urologists have a little extra time to take the BJUI out of its cover or open up the iPad and dig a little deeper into the articles, and we do not think you will be disappointed with this issue, which certainly has something for everyone.

In the ‘Article of the Month’, we feature an important paper from Egypt [1] examining factors associated with effective delayed primary repair of pelvic fractures that are associated with a urethral injury. Do be careful whilst you are travelling around the world, as most of the injuries in this paper were due to road traffic accidents. They reported 76/86 successful outcomes over a 7-year period. When a range of preoperative variables was assessed, four had particular significance for successful treatment outcomes. The paper really highlights that in the current urological world of robotics, laparoscopy and endourology, in some conditions traditional open surgery with delicate and precise tissue handling and real attention to surgical detail are the key components of a successful outcome.

Whilst you are eating and drinking more than usual over the summer, we have some food for thought on surgery and metabolic syndrome with one of our ‘Articles of the Week’. This paper contains an important message for all those performing bladder outflow surgery. This paper by Gacci et al. [2] from an international group of consecutive patients clearly shows that men with a waist circumference of >102 cm had a far higher risk of persistent symptoms after TURP or open prostatectomy. This was particularly true for storage symptoms in this group of men and should influence the consenting practice of all urologists carrying out this common surgery.

Make sure you are staying well hydrated on your beach this August, as the summer months often lead to increased numbers of patients presenting to emergency departments with acute ureteric colic, so it seems timely to focus on this area. To this end I would like to highlight one of our important ‘Guideline of Guidelines’ series featuring kidney stones [3] to add to the earlier ones on prostate cancer screening [4]and prostate cancer imaging [5]. This series serve to assimilate all of the major national and international guidelines into one easily digestible format with specific reference to the strength of evidence for each recommendation. Specifically, we look at the initial evaluation, diagnostic imaging selection, symptomatic management, surgical treatment, medical therapy, and prevention of recurrence for both ureteric and renal stones. Quite how the recent surprising results of the SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial will impact on the use of medical expulsive therapy remains to be seen [6].

So whether you are sitting watching the sunset with a drink in your hand or quietly working in your home at night, please dig a little deeper into this month’s BJUI on paper, online or on tablet. It will not disappoint and might just change your future practice.

 

References

 

 

3 Ziemba JB, Matlaga BR. Guideline of guidelines: kidney stones. BJU Int 2015; 116: 1849

 

4 Loeb S. Guideline of guidelines: prostate cancer screening. BJU Int 2014; 114: 3235

 

5 Wollin DA, Makarov DV. Guideline of guidelines: prostate cancer imaging. BJU Int 2015; [Epub ahead of print]. DOI: 10.1111/bju.13104

 

 

Ben Challacombe
Associate Editor, BJUI 

 

Give the pill, or not give the pill. SUSPEND tries to end the debate

Christopher BayneJune 2015 #UROJC Summary

News of a landmark paper on medical expulsive therapy (MET) for ureteric colic swirled through the convention halls on the last day of the American Urological Association’s Annual Meeting in New Orleans, Louisiana. I watched the Twitter feeds evolve from my desk at home: the first tweets just mentioned the title, then the conclusion, followed by snippets about the abstract. As time passed and people had time to read the manuscript, discussion escalated. Without data to prove it, there seemed to be more Twitter chatter about the SUSPEND trial, even among conference attendees, than the actual AUA sessions.

Robert Pickard and Samuel McClinton’s group utilized a “real-world” study design to publish what many urologists consider to be the “best data” on MET. The study (SUSPEND) randomized 1167 participants with a single 1-10 mm calculi in the proximal, mid, or distal ureter across 24 UK hospitals to 1:1:1 MET with daily tamsulosin 0.4 mg, nifedipine 30 mg, or placebo. The study’s primary outcome was the need for intervention at 4 weeks after randomization. Secondary outcomes assessed via follow-up surveys were analgesic use, pain, and time to stone passage. Though the outcomes were evaluated at 4 weeks after randomization, patients were followed out to 12 weeks.

Some of the study design minutiae are worth specific mention before discussing the results and #urojc chat:

  • Treatment allotment was robustly blinded. Participants were handed 28 days of unmarked over-encapsulated medication by sources uninvolved in the remaining portions of the study
  • Medication compliance was not verified
  • The study protocol didn’t mandate additional imaging or tests at any point
  • Participants weren’t asked to strain their urine
  • Secondary outcomes assessed by follow-up surveys were incomplete: 62 and 49% of participants completed the 4- and 12-week questionnaires, respectively

The groups were well balanced, and the results were nullifying. A similar percentage of tamsulosin- , nifedipine-, and placebo-group patients did not require intervention (81%, 80%, and 80%, respectively). A similar percentage of tamsulosin-, nifedipine-, and placebo-group participants had interventions planned at 12 weeks (7%, 6%, and 8%). There were no differences in secondary outcomes, including stone passage. There was a trend toward significance for MET, specifically with tamsulosin, in women, calculi >5 mm, and calculi located in the lower ureter (see image taken from Figure 2).

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The authors concluded their paper was iron-clad with results that don’t need replication.

“Our judgment is that the results of our trial provide conclusive evidence that the effect of both tamsulosin and nifedipine in increasing the likelihood of stone passage as measured by the need for intervention is close to zero. Our trial results suggest that these drugs, with a 30-day cost of about US$20 (£13; €18), should not be offered to patients with ureteric colic managed expectantly, giving providers of health care an opportunity to reallocate resources elsewhere. The precision of our result, ruling out any clinically meaningful benefit, suggests that further trials involving these agents for increasing spontaneous stone passage rates will be futile. Additionally, subgroup analyses did not suggest any patient or stone characteristics predictive of benefit from MET.”

Much of the early discussion focused on the trend toward benefit for MET in cases of calculi >5 mm in the distal ureter:

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Journal Club participants raised eyebrows to the use of nifedipine and placebo medication in the trial:

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A few hours in, discussion shifted toward the study design, particularly the primary endpoint of absence of intervention at 4 weeks rather than stone passage or radiographic endpoints. The overall consensus was that that this study was a microcosm of “real world” patient care with direct implications for emergency physicians, primary physicians, and urologists.

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The $20 question (cost of 4 weeks of tamsulosin according to SUSPEND) is whether or not the trial will change urologists’ practice patterns. Perhaps not surprisingly, opinions differed between American and European urologists.

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We owe SUSPEND authors Robert Pickard and Sam McClinton special thanks for their availability during the discussion. In the end, the #urojc banter for June 2015 was the largest and most-interactive monthly installment of International Urology Journal Club to date.

June urojc 26Christopher Bayne is a PGY-4 urology resident at The George Washington University Hospital in Washington, DC and tweets @chrbayne.

 

The Drugs Don’t Work

1212For those pop enthusiasts amongst you, “The drugs don’t work” – the year was 1997; The band: The Verve. Secret of Premium Supplements for Lean Muscle In the quest to reinforce body physique, many of us do exactly about anything to enhance how they appear . From taking lean muscle supplements, dieting to workouts / exercise, there are indeed some ways to urge a complete body transformation. However, one method that’s becoming increasingly popular is that the use of legal steroids and helping those looking the way to gain weight fast, with absolute safest and therefore the best performance enhancements. These sorts of premium lean muscle supplements have given numerous athletes, weightlifters and most short-time users the choices of dumping dangerous drugs, and changing their physical form, such a lot in order that users are experiencing amazing body transformation – without side effects. Many companies make these premium supplements to create muscle, but some brands are more reliable than others… For example, Crazy Bulk happens to be one among the more trusted companies. So, what are you able to expect from this brand and therefore the muscle building supplements that they provide? Well, the simplest thanks to get a solution to the present question is by reading about experiences people have had when using these supplements. With that in mind, here’s a testimonial from one among the various users of Crazy Bulk steroid alternatives. You’ll also get to ascertain before and after photos along side an in depth account of the user’s progress and results. For getting information about muscle supplements, read this news.

Many people spend countless hours at home or at the gym exercising exercising EXERCISING. All for the hope of achieving that coveted well muscled body. That’s all good and great, but there is a little bit more to building a well defined, great looking, well muscled body. Well… at least for MOST people it is. Read on and I will show you a few “tricks of the trade”.

Really, there are THREE main concepts to keep in mind if you’re looking to build muscles. Of course the first one is YOU have to go do it! NO ONE ELSE can do it for you. It’s not as much work as some might tend to believe. After all… Good things happen with hard work.

Second… Repetition. To build muscles you need to do repetitive exercises. Repeat any exercise 9 times. If that becomes to easy up the repetition to 18. The 27. And so on, and so on. Also don’t forget about increasing the resistance before you increase your repetition.

It is also VERY important to remember to give your body a day to “heal”. That is really when the muscles are “growing” or “building”. For example, workout on Day 1, Day 2, and Day 3. Then rest (Don’t exercise) on Day 4. Then exercise again on Day 5 Day 6 and Day 7. then rest on Day 8. Repeat… That is how rock hard muscles are formed.

Third… Supplements. Working an adult body to a point that it needs to grow new tissue is strenuous on the system. Building muscles ensues building new cells. That’s where taking the right kind of supplements come into play. They help feed the blood steam to feed the starved cells so they can reproduce new cells FASTER. And with a lot less pain and sore muscles. That is very important. Almost as important as the second concept. But not just any supplements. You need to get the RIGHT supplements.

For those more urologically minded, you will immediately be thinking of the recent publication in the Lancet reporting on the use of tamsulosin and nifedipine vs. placebo for the medical expulsive therapy (MET) of ureteric stones. Current national (BAUS) and international (EAU guidelines) recommend the use of MET, usually with an alpha blocker – and often tamsulosin, and it has certainly become common practice in most Emergency and urology departments certainly across the UK and likely worldwide.

There have however always been doubts regarding the use of these with many small heterogenous studies with variable inclusion/exclusion criteria, various blinding protocols and suspicion of publication bias when only positive trials get published. Regardless, the clear outcome from the Hollingsworth meta-analysis was that both alpha blockers and calcium channel blockers are effective for helping stone passage and so they crept into routine clinical use. This trial should change all of that with headline results:

  • No change in spontaneous stone passage at 4 weeks for either drug vs. placebo or compared against each other
  • No difference when analysed by stone size or location
  • No difference in analgesic use or time to stone passage

Aren’t those all the reasons we prescribe them? The first question of course is whether this trial is accurate. It certainly is a large trial with 1167 patients, randomised to the three double-blind arms in 24 centres in the UK. The trial (like many modern studies) is described as pragmatic. This has pros and cons. The advantages are that it replicates real life clinical practice allowing for variations in decision making (e.g. follow-up imaging in this paper) thus making it generally applicable. The downside of course is the lack of precision that this can introduce with stone passage possibly being only patient reported, or based on ultrasound, plain x-ray, IVU or CT. I guess we have to decide which type of trial we prefer, although it would be very difficult to mandate CT follow-up, with concerns about radiation safety, in this trial if that isn’t part of routine practice. Thus maybe this study is actually applicable to the vast amount of units around the world.

Secondly did it include the right type of patient? Well the current guidelines suggest using MET for any stone measuring up to 1cm in any part of the ureter … and that is what this trial did. And this is thus a strength given that it didn’t just focus on the distal ureter. Thus the trial population seems reasonable. One possibility is that if MET only works in the distal ureter (as almost all the studies only look at this), this could this explain the negative findings. Sub-group analysis of this based on location or stone size seems to suggest not unless it was underpowered to show a difference for this cohort of patients.

Whilst the odds ratios (see table) seem clear, the Forest plot shows the breakdown of subgroup by sex, stone size and location. Whilst not statistically significant, this does suggest a trend towards favouring MET for lower ureteric stones.

Screen Shot 2015-05-19 at 9.36.39 amScreen Shot 2015-05-19 at 9.36.54 am

Thirdly, is it possible this trial is wrong … a type II error ? Well of course anything is possible, and the trial may be criticised for the follow-up mentioned above. However it does seem to provide easily the best evidence to date. Thus why has the use of MET been allowed to become routine practice based on a number of small trials all introducing inherent bias which is then amplified when a meta-analysis is performed. I guess it was the best evidence around at the time although it makes you wonder how many other interventions there are that we currently use that are based on smallish trials, and would they actually stand up to the rigour of a well conducted big multicentre trial?

My last question is will this change practice again? Well it should, but with no alternative (except time, fluids and NSAID’s) to offer patients with ureteric stones and given that alpha blockers are usually well-tolerated, I wonder whether people will continue to prescribe MET for the foreseeable future. But if we believe in evidence based medicine, and we do, then surely we should no longer prescribe MET for ureteric stones which after all is an off-licence indication.

Finally congratulations must go to the NIHR and the research team for answering a very important clinical question. Was the whole ‘MET’ story a placebo effect all along … or to quote another less well known song title from The Verve, was it “All in the mind”? The conclusion from this excellent study has to be yes.

Conflict of interest: Acted as PI for Guy’s and St. Thomas’ Hospital for this trial recruiting patients although have no part of study design, data analysis or publication.

Matthew Bultitude

Consultant Urologist, Guy’s and St. Thomas’ Hospital

Associate Editor, BJUI

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