EUROPEAN UROLOGY 56 (2009) 413417

available at www.sciencedirect.com journal homepage: www.europeanurology.com

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 b

Department of Urology, University of Pisa, Pisa, Italy 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 ureterolithiasis 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 pathophysiologic 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 contraction, whilst a decrease determines relaxation [2]. Furthermore, 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 expulsion; 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

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 stonelocation 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 demonstrated 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

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.

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 dissemination 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 largesized 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

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 radiation-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

Fig. 1 Proposed algorithm for the emergency management of distal ureteric calculi. MET = medical expulsive therapy; SWL = shock wave lithotripsy; URS = ureteroscopy.

EUROPEAN UROLOGY 56 (2009) 413417

415

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 recommendations 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 immediate, 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.

[3] Malin Jr JM, Deane RF, Boyarsky S. Characterisation of adrenergic receptors in human ureter. Br J Urol 1970;42:1714. [4] Yamaguchi K, Minei S, Yamazaki T, Kaya H, Okada K. Characterization of ureteral lesions associated with impacted stones. Int J Urol 1999;6:2815. [5] Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006;368: 11719. [6] Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med 2007;50:55263. [7] Parsons JK, Hergan LA, Sakamoto K, Lakin C. Efcacy of alphablockers for the treatment of ureteral stones. J Urol 2007;177: 9837. [8] Hermanns T, Sauermann P, Rubach K, Frauenfelder T, Sulser T, Strebel RT. Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial. Eur Urol 2009;56:40712. [9] Pedro RN, Hinck B, Hendlin K, Feia K, Canales BK, Monga M. Alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study. J Urol 2008;179:22447. [10] Lojanapiwat B, Kochakarn W, Suparatchatpan N, Lertwuttichaikul K. Effectiveness of low-dose and standard-dose tamsulosin in the treatment of distal ureteric stones: a randomized controlled study. J Int Med Res 2008;36:52936. [11] Porpiglia F, Fiori C, Ghignone G, et al. A second cycle of tamsulosin in patients with distal ureteric stones: a prospective randomized trial. BJU Int 2009;103:17003. [12] Bensalah K, Pearle M, Lotan Y. Cost-effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones. Eur Urol 2008;53:4119. [13] Thoeny HC, Kessler TM, Simon-Zoula S, et al. Renal oxygenation changes during acute unilateral ureteral obstruction: assessment with blood oxygen level-dependent MR imaginginitial experience. Radiology 2008;247:75461. [14] Porpiglia F, Vaccino D, Billia M, et al. Corticosteroids and tamsulosin in the medical expulsive therapy for symptomatic distal ureter stones: single drug or association? Eur Urol 2006;50: 33944. [15] Michel MC, de la Rosette JJMCH. a-blocker treatment of urolithiasis.

References
[1] Preminger GM, Tiselius H-G, Assimos DG, et al. From the American Urological Association Education and Research, Inc. and European Association of Urology. 2007 guideline for the management of ureteral calculi. Eur Urol 2007;52:161031. [2] Andersson KE, Forman A. Effects of calcium channel blockers on urinary tract smooth muscle. Acta Pharmacol Toxicol 1986;58: 193200.

Eur Urol 2006;50:2134. [16] Osorio L, Lima E, Soares J, et al. Emergency ureteroscopic management of ureteral stones: why not? Urology 2007;69:2731. [17] Jermini FR, Danuser H, Mattei A, Burkhard FC, Studer UE. Noninvasive anesthesia, analgesia and radiation-free extracorporeal shock wave lithotripsy for stones in the most distal ureter: experience with 165 patients. J Urol 2002;168:4469.
doi:10.1016/j.eururo.2009.04.044