Medical Expulsion Therapy for Distal Ureteral Stones

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Dallabella M, et al. "Randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi". J Urol. 2005. 174(1):167-172.
PubMed

Clinical Question

In patients with distal ureteric stones <4mm does medical expulsive therapy using tamulosin have a higher expulsion rate compared to nifedipine or phloroclucinol?

Bottom Line

Medical expulsive therapy should be considered as the first step approach for uncomplicated distal ureterolithiasis before ureteroscopy or extracorporeal lithotripsy. In particular, the use of tamsulosin in this treatment regimen produced stone expulsion in almost all cases in a short time, allowing complete home patient treatment, with high efficacy, decreased side effects and excellent patient satisfaction

Major Points

  • Medical expulsive therapy (MET) has been described as an effective conservative treatment option in the initial management of small distal ureteral stones.
  • Superior efficacy of tamsulosin as MET for >4mm distal ureteric stones and as an analgesic agent
  • In addition to ureteral spasm, edema secondary to a mucosal inflammatory reaction, is an important factor in arresting ureteral stone passage. Therefore, the rationale for utilising corticosteroids to reduce local ureteric inflammation as a potential useful adjunct in the medical management of distal stones.

Guidelines

Urology guidelines refer to medical expulsion therapy for distal stones, including the 2018 EAU guidelines. These state that MET should be considered only where active stone removal is contraindicated. [1]

The 2016 AUA guidelines state that patients with distal uretal stones ≤10mm should be offered observation and MET with alpha blockers. [Surgical Management of Stones: AUA/Endourology Society Guideline 2016] [2]

Design

  • Randomized, prospective study. Single center
  • No control group. Unclear blinding
  • 210 randomized
    • Treatment 1 - 70
    • Treatment 2 - 70
    • Treatment 3 - 70
  • Standard - nil standard arm
  • Single urology department in Italy
  • Enrollment: May 2002 to Jul 2003
  • Mean follow-up: 28 days
  • Analysis: Intention-to-treat
  • Primary outcome: Expulsion rate


Population

Inclusion Criteria

  • Men or women older than 18 years
  • Ultrasonographically and/or radiologically visible distal ureteral stones 4mm or larger below the common iliac vessels
  • And if, renal colic resolution was achieved within the first hour after diclofenac administration


Exclusion Criteria

  • Lithiasis of the proximal lumbar or intramural ureteral tract
  • Marked hydronephrosis
  • Acute renal failure
  • Fever
  • Multiple ureteral stones
  • Painful symptoms more than 1 day in duration
  • History of surgery or endoscopic procedures in the urinary tract
  • Chronic renal failure
  • Diabetes
  • Peptic ulcer
  • Concomitant treatment with alphalytic drugs, beta-blockers, calcium antagonists or nitrates
  • Pregnancy
  • Lactation
  • Patient desire for immediate stone removal


Baseline Characteristics

  • Mean age: no significant differences between the groups (group 1 39.8 years +/-12.7
  • Gender: no significant differences between the groups (group 1 50/20)
  • Laterality: no significant differences between the groups (group 1 39/31)
  • Stone size: significantly larger for group 2 (tamulosin – 7.2mm) compared with group 1 (6.2mm) and group 3 (6.2mm), p = 0.002. This statistically significant difference was not deemed clinically relevant.


Interventions

  • All patients were treated on an outpatient basis – treatment period lasted 28 days or until stone expulsion
  • All patients were evaluated by physical examination, serum creatinine measurement, plain abdominal radiography and abdominal ultrasonography at enrolment and then every 7 days in the outpatient clinic – every 7 days physical examination, creatinine and USS, XR on days 10 and 28.
  • All patients received first line treatment for painful manifestations with 1 intramuscular vial of diclofenac (75mg IM)
  • All patients instructed to drink 2L water daily and perform their usual everyday activities

Random number table used by four urologists during their emergency room shifts to allocate patients to 3 treatment groups: 1. 80mg phloroglucinol (3 tablets daily for a maximum of 28 days) - antispasmodic 2. 0.4mg tamsulosin (1 capsule daily for a maximum of 28 days) 3. 30mg nifedipine, slow release (1 tablet daily for a maximum of 28 days)

All patients in each group received Cotrimoxazole (2 tablets daily for 8 days) and 30mg deflazacort (1 tablet daily for 10 days) (this is equivalent to 20mg prednisolone); diclofenac 75mg vials IM PRN. Patients were evaluated at outpatient clinic every 7 days and given a week’s supply of drugs – all free samples except diclofenac which was prescribed Data recorded included:

  • Age and sex
  • Largest radiographic or ultrasonographic stone size, stone lateral location, day and time of stone expulsion
  • Number of analgesic vials used, need for hospitalisation and urgent or scheduled endoscopic procedures
  • Number of work days lost
  • Therapy side effects
  • EuroQoL questionnaire at first visit after stone expulsion or at day 28

Definition of therapy failure:

  • Unsuccessful stone expulsion within 28 days (and URS was scheduled)
  • Hospitalisation due to uncontrollable pain or an increase in creatinine of greater than 2mg/dl
  • Loss to follow-up or study withdrawal after recruitment was considered treatment failure


Outcomes

Primary Outcomes

Stone expulsion confirmed by plain abdominal x ray and/or abdominal ultrasound at follow up.

Group 2 (Tamsulosin) a significantly higher rate of expulsion

  • HR 2.9, 95% CI 1.958 – 4.313, p < 0.0001 times higher than (compared with group 1) (p < 0.0001, 95% CI 1.958 – 4.313)
  • HR 2.5, 95% CI 1.741 – 3.728, p<0.0001. times higher than (compared with group 3 (p < 0.0001, 95% CI 1.741 – 3.728)

Group 3 did not have a significantly increased rate of expulsion compared to Group 1.

  • HR 1.14 (p = 0.517, 95% CI 0.766 – 1.698)


Secondary Outcomes

Time to expulsion – Defined as the number of hours from the beginning of assigned oral therapy to stone expulsion

  • Reported as no statistically significant difference in expulsion time between groups 1 and 3.
  • Stone expulsion more rapid in group 2 compared to group 1 or 3 (p = 0.001 and <0.0001, respectively.

Quantity of analgesics used – The number of analgesic vials used up to expulsion or to day 28

  • Group 2 showed significantly decreased analgesic use compared to groups 1 and 3 (p < 0.0001 and < 0.0001, respectively).

Need for hospitalisation and/or endoscopic procedures

  • Groups 2 and 3 showed a significantly decreased number of urgent hospitalisations compared to Group 1 (p = 0.001 and 0.045 respectively).
  • No significant difference in the need for urgent hospitalisation was observed between groups 2 and 3 (p = 0.245)

Number of workdays lost – Defined as days of real inability to perform the usual daily activities

  • Group 1 lost a significantly greater median number of workdays compared to Groups 2 and 3 (p < 0.0001 and 0.003, respectively).


Subgroup Analysis

Multivariate Cox regression model demonstrated patient age, sex, stone size and stone lateral location were not factors predictive of expulsion.

Adverse Events

The paper reports that side effects were not significantly different between groups (p=0.186) however data is not shown.

Criticisms

  • No control group (NSAIDs alone)
    • Use of corticosteroids - presence of a stone in the ureter creates mucosal inflammation  edema.
    • Use of an anti-inflammatory is thought to reduce local ureteral inflammation and facilitate stone expulsion
  • No mention of patient controlled factors i.e. oral intake (2.5L), avoid excessive salt, protein, ural sachets
  • No mention of other medications e.g. thiazide diuretics, Ca channel blockers
  • No mention of funding source
  • Randomisation technique was not described in detail
  • No robust description of how and what adverse events were measured

Funding

The source of funding is not described.

Further Reading

A prospective study by Porpiglia and colleagues examined the effects of corticosteroids alone and in conjunction with alpha-blockers in the expulsion of distal ureteral stones. [3]

  • Group A received tamsulosin 0.4 mg daily: 60%
  • Group B received deflazacort 30 mg daily: 37.5%
  • Group C received both 0.4 mg tamsulosin + 30 mg deflazacort (gluco) daily: 84.8%
  • Group D received only analgesics control: 33.3%

A multicentre randomised double blind placebo controlled trial examining the efficacy and safety of Tamsulosin for distal ureteral stones is described at: [4]