EUROPEAN UROLOGY 56 (2009) 413417
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Platinum Priority Editorial and Rebuttal from Authors
Referring to the article published on pp. 407412 of this issue
Recommending Medical Expulsive Therapy for Distal Ureteric
Calculi: A Step Back?
Gianluca Giannarini a,*, Riccardo Autorino b
a
Department of Urology, University of Pisa, Pisa, Italy
b
Department of Urology, Second University of Naples, Naples, Italy
The idea of an effective and safe medical treatment that is
also noninvasive and preferably outpatient has undisputed
appeal to patients diagnosed with symptomatic ureter-
olithiasis who wish to eliminate their stones as rapidly as
possible. Such a treatment has been the object of intensive
basic and clinical research for more than a decade and has
been identified in what is now referred to as medical
expulsive therapy (MET). MET is part of the established
therapeutic armamentarium for ureteric calculi alongside
observation, shock wave lithotripsy, ureteroscopy, and
ureterolithotomy [1].
MET developed from several physiologic and pathophy-
siologic premises. The ureter is lined by smooth muscle cells
that respond to variations in calcium ion concentrations. An
increase in calcium levels causes ureteric muscle contrac-
tion, whilst a decrease determines relaxation [2]. Further-
more, smooth muscle cells are densely populated with
a-1-adrenergic receptors, especially in the distal third of the
ureter. Receptor blockade inhibits basal smooth muscle
tone and hyperperistaltic uncoordinated frequency whilst
maintaining tonic propulsive contractions [3]. Calculi may
induce ureteric spasms that interfere with calculi expul-
sion; thus, muscle relaxation with maintenance of normal
antegrade peristaltic activity may facilitate passage. Finally,
it has been shown that larger calculi particularly tend to
provoke intense inflammatory changes in the ureteric wall
and that submucosal oedema in proximity to a stone may
worsen ureteric obstruction, heightening the risk of
impaction and retention [4].
Researchers have therefore sought substances that are
capable of either relaxing the ureteric wall or preventing
mucosal oedema, albeit the exact dynamics of ureteric
DOI of original article: 10.1016/j.eururo.2009.03.076
* Corresponding author. Department of Urology, University of Pisa, Ospedale Santa Chiara, via Roma 67, I-56126 Pisa, Italy. Tel. +39 050 992081;
Fax: +39 050 992081.
E-mail address: gianluca.giannarini@hotmail.it (G. Giannarini).
0302-2838/$ see back matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
motility and stone passage are not fully understood yet. Such
substances include calcium channel blockers, a-adrenergic
receptor blockers, and anti-inflammatory drugs. A number of
randomised clinical trials (RCTs) have tested these drugs, and
the resulting findings have almost always been interpreted
and proclaimed as proof of efficacy [1].
There is, however, a current reappraisal of the role of
MET in the management of distal ureteric calculi. In the
nearest past, it was believed a fact that these drugs, either
alone or in combination, could eventually increase the stone
expulsion rate; however, the efficacy of MET has recently
been reassessed by a critical analysis of the published
studies, including meta-analyses, which has disclosed
several methodological flaws [1,57]. Heterogeneity in
methods of stone-size calculation, in reporting of data, and
in statistical analyses; in some cases, inappropriateness of
trial design and chosen end points; and lack of stone-
location analysis and previous stone-passage history have
clearly emerged. Moreover, the first and, until the release of
the present study [8], only double-blind, placebo-controlled
RCT testing an a-blocker (ie, alfuzosin) as MET demon-
strated a benefit for the active therapy solely in expediting
stone passage and alleviating pain, not in increasing the
expulsion rate [9].
In this context, the study by Hermanns et al [8] which
appears in the present issue of European Urology is to be
welcomed with great interest. In a well-conducted RCT, the
authors assessed, for the first time in a double-blind fashion,
the efficacy and safety of tamsulosin versus placebo as MET
for distal ureteric calculi 7 mm in size. Notably, expulsion
rate and time to expulsion were comparable in the two
arms, whilst consumption of analgesics was significantly
414 EUROPEAN UROLOGY 56 (2009) 413417
lower in the active-treatment arm. Approximately 9% of
patients in the tamsulosin group reported side-effects,
which were of mild severity and resulted in a single case of
treatment discontinuation.
As strong supporters of evidence-based medicine, it is
slightly uncomfortable for us to note that high-quality RCTs
on MET have only recently been conducted, long after the
introduction of such therapy into routine practice. This
situation is even more uncomfortable if one considers that
uncomplicated distal ureteric lithiasis is one of those
medical conditions that are easily lent to the conduct of
such trials. Additionally, a growing number of RCTs are
testing novel dosages (ie, low-dose tamsulosin [10]) or
schedules (ie, repeat tamsulosin cycle [11]) for potential
MET drugs, and even cost-effectiveness analyses have
appeared [12] in the absence of formal and robust evidence
of efficacy. Similar to other cases, this study [8] is
paradigmatic, since it raises clinical and ethical issues
regarding the advancement of novel therapies and their
rigorous evaluation prior to market launch or to dissemina-
tion in routine practice.
Several strengths notwithstanding (ie, inclusion of a
placebo arm, double-blind design, computed tomography
diagnosis, measurement and follow-up of calculi), some
limitations must be acknowledged. First, and of paramount
importance, one may argue that the trial design is not
entirely correct, since only small to medium-sized calculi
(median: 3.9 mm) were included, for which a relatively high
rate of spontaneous elimination is to be expected. In fact,
4685% of ureteric calculi of 5 mm are destined to pass
spontaneously [1]; thus, a possible effect of the drug might
become apparent only with a larger sample size. The real
effect of the drug should be tested in medium- to large-
sized calculi, which is a blank field so far. It can, however, be
anticipated that these cases may be numerically low, since
larger calculi tend to impact in the proximal ureter and are
unlikely to migrate in the distal part; thus, the need for
Fig. 1 Proposed algorithm for the emergency management of distal ureteric calculi. MET = medical expulsive therapy; SWL = shock wave lithotripsy;
URS = ureteroscopy.
multicentre trials is advocated. Additionally, the time to
expulsion, albeit a secondary end point, is unknown for one
out of three patients, possibly biasing the findings and their
interpretation.
Having said this, we believe that for a candidate drug for
MET to be really effective, both an increase in expulsion rate
and a decrease in time to expulsion should be produced. In
all studies on MET, treatment success is defined as the
fulfilment of either criterion, possibly generating the
aforementioned misconception about METs real efficacy.
But why should an effective drug result in only one of these
effects? Compared to an inert substance, for example, an
effective antimicrobial agent is meant to cure an infection,
and if it cures the infection, it does so rapidly. A sensible
proposal to gain advances in the area of MET would be to set
up an RCT enrolling patients with ureteric calculi that have
not passed after a reasonably long period, say 34 wk. In this
case, the potential confounding effect of spontaneous stone
passage would become negligible. Additionally, the difficult
cases should also be evaluated, including those patients
with not only larger calculi, but also obstructing ones, and
with no complications that would require immediate
removal. We now have promising noninvasive and radia-
tion-free imaging, such as functional magnetic resonance
[13], which may be used to reliably diagnose and monitor
ureteric obstruction.
Controversial issues that remain to be elucidated are the
duration of MET (ie, short-term vs long-term course) and
the role of combination therapy (ie, a muscle relaxant plus
an antioedema substance, be it a steroidal or nonsteroidal
anti-inflammatory drug). Optimisation of these factors
could result in proven efficacy but clearly needs to be
investigated within the frame of methodologically sound
and adequately powered RCTs [14]. Furthermore, if the
potential (direct or indirect) analgesic effect of tamsulosin
were to be confirmed in future studies, this drug could be
tested in the acute phase of renal colic, for which the
 EUROPEAN UROLOGY 56 (2009) 413417
eventual pain relief would be of a higher clinical
magnitude.
Finally, but equally relevant, we would like to remind the
reader that a-blockers are not currently licensed as MET. It
remains to be determined whether this situation is due to
the low pressure of the pharmaceutical companies towards
sponsored RCTs because of a presumed insufficient
economic return, as claimed by some authors [15], or to
a limited efficacy of MET as perceived by practicing
clinicians, as put forward by us.
We wish to conclude with a provocative reflection. Is
MET really the standard of care to pursue for any patients
with distal ureteric calculi? Studies comparing the currently
available treatment modalities in terms of either efficacy
and safety or quality of life and patients preference are
disappointingly scarce, although practical recommenda-
tions can be reasonably provided based on current evidence
(Fig. 1). If patients with newly diagnosed, symptomatic
distal ureteric calculi are admitted to an emergency
department, they may be offered several treatment options.
The first option is a possibly long course of oral medication
with off-label indication, not yet established expulsive
efficacy, potential systemic side-effects, and a need for
frequent follow-up visits. The second option is an immedi-
ate, minimally invasive treatment (ureteroscopy [16]), and,
even better, a third option is an immediate noninvasive,
pain- and radiation-free treatment (shock wave lithotripsy
[17]) which have already been shown to achieve very high
and rapid stone clearance with minimal need for ancillary
procedures and very low morbidity. When presented with
this choice, will most patients indeed elect the first option?
The question is open.
Conicts of interest: The authors have nothing to disclose.
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