Category: Urology

And The Stoning Continues

A couple months ago, the world of ureterolithiasis was upended by The Lancet and its publication of a trial examining medical expulsive therapy.  In direct contrast to the prior (worthless) Cochrane Review, this large, reasonably-designed trial, does away with the notion of universal benefit of alpha- and calcium channel-blockers for MET.

Following on its heels comes the publication of another trial of moderate size, but with even more rigorous follow-up.  Rather than previously mentioned trial’s “urologic intervention” as the patient-oriented outcome, this trial used a disease-oriented outcome.  This trial, enrolling patients with distal ureteral stones, required patients to under go CT at 28 days to definitively assess for stone passage.

The trial randomized 403 patients to either tamsulosin 0.4mg daily for 28 days or identical placebo, but, unfortunately, 87 did not ultimately undergo second CT.  Of the patients that did undergo CT, there was no statistically significant difference in stone passage: 87.0% tamsulosin vs. 81.9% placebo, an absolute difference of 5.0% (95% CI -3.0 to 13.0).  Of the 87, 77 were available for follow-up regarding urologic intervention.  If a combined endpoint of CT passage and lack of urologic intervention is used, the results remain unchanged.

However, the trial was designed specifically to enroll adequate numbers of patients with stones of 5-10mm in size – targeting adequate sample size with which to include at least 49 patients to detect a difference in stone passage of 5 to 25%.  They ultimately randomized 103 large stones and completed imaging or clinical follow-up on 77.  The difference in stone passage rate in the large stones was 83.3% in the tamsulosin group, compared with 61.0% with placebo, for an absolute difference of 22.4% (95% CI 3.1 to 41.6).

So, what’s the takeaway – from decades of poor-quality studies, the recent Lancet publication, and now this?  There’s probably some signal in the noise – and that signal, all along, has probably been these large, distal stones.  Unless there’s a truly diminished risk of stone passage, there’s never been any reasonableness to the use of MET – but if passage rates are ~60%, the likelihood of a clinically meaningful benefit is finally possible.

If I’ve obtained a CT in a patient and diagnosed a large, distal stone – I am offering tamsulosin.  Otherwise, no.

Rory Spiegel also shares his typically excellent similar evaluation of the evidence: EM Nerd

“Distal Ureteric Stones and Tamsulosin: A Double-Blind, Placebo-Controlled, Randomized, Multicenter Trial”

Finally, an End to Tamulosin for Renal Colic?

Most urologic professional societies recommend “medical expulsive therapy” for ureterolithiasis, with an expectation of increased stone expulsion, improved time-to-passage, and reduced need for analgesia.

As I’ve covered before – breaking down a pro-tamulosin Cochrane Review – the evidence in support of this practice is junk.  David Newman, Anand Swaminathan, and Salim Rezaie agree.  The last time I posted, I posited there was probably some small benefit to a subgroup of patient with renal colic, but, alas, we would probably never have high-quality evidence.

I was wrong.

This study in The Lancet tested MET by randomizing patients with CT-confirmed ureterolithiasis to three arms – placebo, nifedipine, or tamulosin.  The randomization algorithm balanced the arms between stone size and stone location.  The primary outcome was need for urologic intervention at 4 weeks, with secondary outcomes of patient-reported time to stone passage and pain medication use.

With 1,167 patients randomized – 31 of which were excluded or lost to follow-up – there was no difference in need for urologic intervention between groups: 20% placebo, 19% tamulosin, 20% nifedipine.  Secondary outcomes – measured by follow-up questionnaire – were likewise similar, with no differences detected in the number of pain medication nor days until stone passage.

Now, urologic intervention is a rather imprecise surrogate outcome for evaluating the efficacy of MET for promoting stone passage.  And, only 62% of patients returned the surveys regarding the secondary outcomes of subjective stone passage and analgesic use.  This is high-quality evidence, but hardly infalliable.  The authors also state no subgroup showed benefit – which is not entirely true.  MET was slightly beneficial (86% vs. 82%) for patients with lower ureteral tract stones, with a p-value of 0.099.  Giving into the tyranny of p-values, yes, there’s no benefit – but using the p-value akin to a likelihood ratio, judged against the larger context of other (albeit, low-quality) trials showing benefit, I would not find it unreasonable to contest the totality of these authors’ conclusion.

Regardless, the empiric use of tamulosin has simply been an urban legend taken one step too far.  Short of large stones in the lower urinary tract, the benefit is fleeting at best – and the magnitude of the benefit may be too low to matter.

“Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60933-3/abstract (oa)

Flank Pain – Ureterolithiasis or Nothin’?

There is a school of practice in which patients are evaluated for potential ureterolithiasis primarily by history, physical, and urinalysis.  If the stars align, it’s ureterolithiasis.  Simple.

But, how do you know?  What if it isn’t?  Then you have a misdiagnosis, diagnostic inertia, and the patient will obviously go wander off and expire somewhere inconvenient.

I fall into the minimalist category for advanced imaging, and I do quite prefer to manage ureterolithiasis with as little fuss as possible.  So, an article like this one – clearly stating in the title the conclusion I want to hear – ought to be precisely my cup of tea.

But, it’s a retrospective chart review.  And, over half of the 291 patients identified as having “flank pain” didn’t receive any documented imaging.  And, finally, even though the ultimate conclusion addresses the benign outcomes of patients with suspected renal colic – any sort of follow-up occurred only if patients re-presented to the same ED.  So, yes, based on initial evaluation, few patients required urologic intervention and no critical alternative diagnoses were on advanced imaging.  But, beyond the initial visit, there’s simply completely inadequate capture of any downstream adverse outcomes.  No vital records, no telephone contact – nothing.

Their title is still probably correct.  However, their study design only weakly supports said conclusion.

“Young Patients with Suspected Uncomplicated Renal Colic are Unlikely to Have Dangerous Alternative Diagnoses or Need Emergent Intervention”
http://www.ncbi.nlm.nih.gov/pubmed/25834669

Farewell, CT Stone Protocol

Ureterolthiasis has become a poster child for over-utilization of advanced imaging.  Despite the relative level of distress kidney stones cause our patients, the use of computed tomography has never been associated with improved outcomes – yet, CT is widespread for its diagnostic utility, contributing substantially to $2 billion in annual healthcare expenditures for this condition in the U.S. alone.

This, however, is a comparative effectiveness evaluation promoting ultrasound for the diagnosis of ureterolithiasis in the Emergency Department, a three-pronged evaluation comparing CT, formal ultrasonography by radiology technicians, and bedside Emergency Department ultrasonography.  Essentially, the objective of this study was to compare safety – regarding, in a sense, whether the additional information supplied by CT was valuable for the detection of life-threatening alternative diagnoses.  And, with respect to this outcome all strategies had, essentially, the same number of “misses” during the follow-up period – mostly acute cholecystitis, one case of appendicitis, and a smattering of other thoracoabdominal diagnoses.  And so – ultrasonography, even our amateur sort in the ED, is “just as good”.

Of course, there are a few oddities associated with this publication.   There are, bizarrely, three “primary outcomes”, and the authors explicitly choose to report only two of them.  Total costs of care was intended to be an outcome, but the authors simply state those results will not be reported in this paper.  This study also has an interestingly low incidence of ~33% confirmed ureterolithiasis – which may result from their lack of a “gold standard” for diagnosis of stone, relying on patient-reported stone passage or follow-up for stone removal.  Or, it could be enrollment of a population with an oddly low incidence of hematuria – only ~63% of enrolled patients exhibited this common finding with a sensitivity of >80%.  I’d be curious to see the incidence of hematuria in the cases with alternative diagnoses, although there would likely be too few to draw any substantial conclusions.

There was also substantial crossover from the ultrasonography cohorts.  40.7% of those randomized to ED ultrasonography and 27.0% randomized to radiology ultrasonography ultimately underwent CT.  And, this crossover reveals the limitation of ED ultrasonography: a “sensitivity” of 54%, compared with a “sensitivity” of 88% for CT (the unreliable gold standard for diagnosis limits test characteristic calculations).  There was also a major exclusion relevant to the U.S. population: women over 250 lbs and men over 285 lbs.  Unfortunately, a substantial portion of the U.S. exceeds such superlative mass – and the generalizability of these results to that population is open to reasonable variability.

The take home point, however, is a little less reliable.  Yes, if you select patients for imaging similarly to these authors and visualize unilateral hydronephrosis in the setting of suspected ureterolithiasis, it is fair to terminate your diagnostic pathway.  However, the primary fallacy of this study design is predicated on the debatable necessity of performing imaging for all suspected ureterolithiasis.  One can make a very reasonable argument ureterolithiasis can be adequately diagnosed on clinical grounds, and advanced imaging is required only in the minority of cases, regardless of the findings on bedside ultrasound.  The vast majority of ureterolithiasis carries a relatively benign prognosis of recurring and remitting pain of a few weeks duration, and return precautions or outpatient follow-up for persistent symptoms is likewise a reasonable course of action.

“Ultrasonography versus Computed Tomography for Suspected Nephrolithiasis”
http://www.nejm.org/doi/full/10.1056/NEJMoa1404446

Sadly Inadequate Cochrane Review of Renal Colic

With little fanfare (probably because this Tamiflu document was published the same week), the Cochrane Collaboration published a review of the efficacy of alpha-blockers for stone expulsion.  The authors strongly approve of this therapy.  They also grievously downplay the tragic disutility of the data reviewed.

Only 7 of 32 included studies had adequate blinding to treatment for physicians and patients.  Only 6 studies report a blinded mechanism for randomization.  8 studies did not report outcomes matching the methods.  They are, frankly, a catastrophic mix of tiny samples, non-peer-reviewed abstracts, and low-quality study design:

  • Abdel-Meguid 2010 – 150 patients from Saudi Arabia, could not access.
  • Agrawal 2009a – 102 patients from India, multiple interventions, no disclosures statement.
  • Al Ansari 2010 – 100 patients from Qatar, no disclosures statement.
  • Aldemir 2011 – 90 patients from Turkey, multiple interventions, no disclosures statement.
  • Autorino 2005 – 96 patients in Italy, no disclosures statement.
  • Ayubov 2007 – Only published as conference abstract.
  • Cervenakov 2002 – 104 patients in Slovak Republic, could not access.
  • Dong 2009 – Korean Journal of Urology not indexed in PubMed.
  • Erturhan 2007 – 120 patients from Turkey, multiple interventions, no disclosures statement.
  • Ferre 2009 – 77 patients from USA, funded by academic grant.
  • Han 2006 – Korean Journal of Urology not indexed in PubMed.
  • Hermanns 2009 – 90 patients from Switzerland, authors state no COI.
  • Hong 2008 – Only published as conference abstract, ”furosemide-based expulsive therapy”.
  • Kaneko 2010 – 71 patients from Japan, no disclosures statement.
  • Kim 2007b – Only published as conference abstract.
  • Kupeli 2004 – 78 patients from Turkey, multiple interventions, no disclosures statement.
  • Liatsikos 2007 – 73 patients from Greece, multiple interventions, no disclosures statement.
  • Lojanapiwat 2008 – 75 patients from Thailand, multiple interventions, Astellas supplied tamulosin.
  • Mukhtarov 2007 – Only published as conference abstract, multiple interventions.
  • Pedro 2008 – 76 patients from Minnesota, supported by Sanofi-Aventis.
  • Porpiglia 2004 – 86 patients from Italy, multiple interventions, no disclosures statement.
  • Porpiglia 2009 – 91 patients from Italy, multiple interventions, authors state no COI.
  • Sayed 2008 – 90 patients from Egypt, could not access.
  • Sun 2009 – 60 patients from China, no disclosures statement.
  • Taghavi 2005 – Only published as conference abstract, multiple interventions.
  • Vincendeau 2010 – 129 patients from France, multiple pharma COI.
  • Wang 2008 – 95 patients from Taiwan, multiple interventions, could not access.
  • Ye 2011 – 3,189 patients from China, multiple interventions, supported by Astellas.
  • Yencilek 2010 – 92 patients from Turkey, no disclosures statement.
  • Yilmaz 2005 – 114 patients from Turkey, multiple interventions, no disclosures statement.
  • Zehri 2010 – 65 patients from Pakistan, no disclosures statement.
  • Zhang 2009b – 314 patients from China, multiple interventions, no disclosures statement.

This is a classic case of “Garbage In, Garbage Out”, where pooling studies for statistical power in a systematic review obfuscates the heterogeneity and poor underlying data quality.  From what I can gather, only two of these trials – Pedro 2008 and Vincendeau 2010 – registered as clinical trials and subscribed to methods and follow-up of sufficient integrity.  Both of these studies showed no or minimal benefit to alpha-blockers.

Patients will have adverse effects from these medications.  They may, however, also derive some stone passage and symptomatic benefit – although the magnitude of benefit cannot be reliably known.  Ultimately, the evidence collated by this systematic review is not of sufficient quality to support the authors’ conclusion:

“The use of alpha-blockers in patients with ureteral stones results in a higher stone-free rate and a shorter time to stone expulsion.”  

This statement ought to be significantly tempered by a declaration of the limitations of the underlying data.  It is probably still reasonable to offer a generic alpha-blocker to patients, but the expectation of ever knowing the true value of the therapy is basically nil.

“Alpha-blockers as medical expulsive therapy for ureteral stones (Review)”

Nothing Reliably Predicts Infected Stone

…but the obvious predictors are, well, obvious.

Ureterolithiasis sounds miserable.  Luckily, it is typically self-limited, temporary, and results in minimal lasting morbidity.  However, infected ureterolithiasis is a higher-risk clinical syndrome – and, even worse, infected, obstructed ureterolithiasis is a potential urologic emergency.  Thus, suspected infected ureterolithiasis certainly ought to be considered for imaging.

In this review of consecutive patients with suspected ureterolithiasis, 7.8% had concomitant urinary tract infection verified by urine culture.  Female, fever, and history of urinary tract infection were fair predictors of UTI, and increasing levels of pyuria and nitrates on urinalysis were strong predictors.  Overall, the presence of greater than 5 WBCs/hpf on microscopic examination was 86% sensitive and 79% specific for UTI.  No predictive feature was universally present, and specificity could be increased only at significant cost to sensitivity.

So, UTI complicating ureterolithiasis is uncommon and inconclusively diagnosed – but the strongest predictors are the obvious ones we’ve been accounting for already.

Fun tidbit:  Stone size ranged from 1 to 50mm.  50mm!

Somewhat-related plea:  These folks performed CT on ~90% of patients.  Many cases of ureterolithiasis can be diagnosed to reasonable certainty simply on clinical grounds.  Stop the cost/irradiation madness!

Somewhat-related plea #2:  There isn’t any proven pro-expulsion therapy.  All the tamulosin trials are small, manufacturer-sponsored, and non-compelling.  IV fluids also don’t help.  If the benefits aren’t proven, then all you have left are costs & potential harms.

“Association of Pyuria and Clinical Characteristics With the Presence of Urinary Tract Infection Among Patients With Acute Nephrolithiasis”
http://www.ncbi.nlm.nih.gov/pubmed/23850311