The use of medical therapy to facilitate passage of kidney stones

1
The use of medical therapy to facilitate passage
of kidney stones

• Brett Spitnale, MD
• University of California, San Francisco
• San Francisco General Hospital

2
Introduction

• Incidence of kidney stones in general population
  is increasing
• Number of outpatient and ED visits have doubled
  from 1994-2000
• Nearly 2.1 billion dollars in health care
  expenditures

3
Introduction

• Traditional therapy includes hydration, pain
  relief (NSAIDs), and watchful waiting for passage
  of ureteral stone
• Most individuals have small stones (lt5mm),
  located in distal ureter that can pass
  spontaneously
• Urologic intervention is recommended for ureteral
  stones persisting gt2 months

4
The use of a-antagonist and calcium channel
blockers

• The autonomic nervous system increases
  intracellular calcium, which triggers contraction
  of ureteral smooth muscle
• Using a-antagonists or CCBs may improve rates of
  spontaneous stone expulsion and decrease transit
  time by inhibiting ureteral muscle contraction
  and allowing for stone passage

5
Goals of meta-analysis

• Primary Outcome percent of patients who passed
  stones with addition of a-antagonist or CCB
  compared to those patients not receiving this
  additional therapy
• Secondary Outcome time to stone expulsion

6
Methods

• Inclusion criteria
• randomized or controlled clinical trials
• gt18 years old
• clinical and radiographic diagnosis of acute
  ureteral colic
• therapy begun in inpatient or outpatient setting,
  including the ED, or on referral to Urology
• use of a-antagonist or CCB compared to a control
  group
• studies included the primary outcome measure

7
Methods

• Quality of studies assessed using Jadad scale,
  giving each study a score of 0-5 (higher scores
  indicate better study quality)
• 2 of the authors selected trials and gathered
  data
• Heterogeneity expected
• the use of different drugs with the same MOA
• combining studies that used additional therapies
  (anticholinergics, steroids, and antibiotics)
• Sub-group analyses conducted to evaluate
  differences by treatment drug, additional
  therapies, an by study quality

8
Results

• 22 RCTs included in meta-analysis
• 13 using a-antagonists
• 6 using CCBs
• 3 using both a-antagonist and CCBs
• Jadad scores ranged from 0-3 in both a-antagonist
  and CCB trials
• Only 1 trial was blinded

9
Results

• Tamsulosin used in 13 of 16 trials
• Nifedipine used in all 9 trials
• All trials allowed for pain control (NSAIDs) and
  encouraged hydration
• Median follow-up was 4 weeks from time of
  enrollment
• Many trials included additional medications
  (steroids, antibiotics, GI protective agents,
  anticholinergics, anxiolytics, antiemetics) which
  were not always matched in treatment and control
  groups

10
Results a-antagonists

• 1235 patients from 16 trials
• stone size range 3-18mm
• all located in distal portion of ureter
• Mean stone size ranged from 4 to 8 mm
• Combined results suggest a benefit in stone
  expulsion when combined with standard therapy
• RR 1.59 95 CI 1.44 to 1.75
• NNT 3.3 95 CI 2.1 to 4.5

11
Results a-antagonists
12
Results a-antagonists

• 9 trials evaluated time to stone expulsion
• 2-6 day average improvement observed in
  a-antagonist group compared to control
• mean time in treatment group lt14 days
• Adverse effects were not consistently reported
• overall rate of 4 (dizziness, HA, N/V,
  asthenia) transient hypotension occurred in 8
  patients (not requiring discontinuation)
• one patient experienced severe asthenia and
  dropped out of study
• no reports of impotence, ejaculatory failure, or
  decreased libido

13
Results CCBs

• 686 patients from 9 trials
• mean stone size 4 to 7 mm in all but 1 study
• all evaluated stones in the distal ureter, but 3
  also included the upper and middle ureter
• Combined results suggest a benefit in stone
  expulsion when combined with standard therapy
• RR 1.50 95 CI 1.34 to 1.68
• NNT 3.9 95 CI 3.2 to 4.6

14
Results CCBs
15
Results CCBs

• All 9 trials evaluated time to stone expulsion
• reduction of time seen in 7 trials
• mean time in treatment group lt28 days
• Adverse effects not consistently reported
• overall rate of 15.2 (N/V, asthenia, dyspepsia,
  HA, drowsiness, euphoria) transient hypotension
  occurred in 3 patients (not requiring
  discontinuation
• 10 patients discontinued therapy (4 with
  hypotension or palpitations 6 with erythema or
  edema)
• mean decrease in SBP 15mmHg, DBP 8mmHg, HR 8bpm

16
Results

• Sequential exclusion of each study from the
  analysis of the a-antagonist and CCB trials
  resulted in only minor changes in the pooled RR
  for each group

17
Results

• Subgroup analysis found no difference by study
  quality
• analyzed 386 patients in 5 a-antagonist trials
  with a Jadad score of 3
• Results RR 1.66 (95 CI 1.45 to 1.89)
• analyzed 380 patients in 4 CCB trials with Jadad
  score 3
• Results RR 1.60 (95 CI 1.28 to 2.01)

18
Results Subgroup Analysis

• Results did not differ by presence or absence of
  other medications (anticholinergic agents,
  low-dose steroids, antibiotics)
• Results did not differ when tamsulosin was
  compared to other a-antagonists

19
Limitations

• Heterogeneity of a-antagonist studies
• Overall poor quality of individual studies
• Did not report on number lost to follow-up for
  each study
• Search results limited by publication bias
  (overestimation of treatment effect)
• Pain was not evaluated as outcome measure
• Did not report or examine dosages of agents

20
Discussion

• Results of this meta-analysis suggest a
  significant benefit in stone expulsion rate when
  a-antagonist or CCB is added to standard therapy
  in medical management of moderately sized (4 to 8
  mm) distal ureteral stones

21
Discussion

• It is important to find medical means that
  promote expulsion rate and shorten time before
  passage
• Complications during watchful waiting include
• repeated renal colic
• urinary infection
• hydronephrosis
• Although endoscopic treatment with ureteroscopy
  or extracorporeal shockwave lithotripsy improve
  stone passage rates, they require referral to
  Urology and are expensive

22
Discussion

• Further research
• medical expulsive therapy for larger stones
• role of steroids
• proposed benefit from preventing edema around the
  stone and thus facilitating passagerole of
  prophylactic antibiotics
• proposed benefit from preventing UTI, which may
  slow passage of stone
• role of other a-antagonists
• Tamsulosin 0.4mg daily for 1 month was most
  common in these studies however, Terazosin
  5-10mg daily and Doxazosin 4mg daily appeared to
  be equally effective

23
Discussion

• Further Research, cont.
• evaluating combinations of a-antagonists and CCBs
  to facilitate stone passage
• determining the most appropriate time course of
  therapy
• this meta-analysis suggests 2-4 wk time course

24
Conclusion

• Should you use medical management in patients you
  see with ureteral stones?
• moderate size, distal ureteral stones
• use in addition to traditional therapies
  including pain control (NSAIDs) and hydration (gt2
  liters/day)
• a-antagonists seem to have fewer side effects and
  are better tolerated by patients than CCBs

25
References

• Singh, et al. A Systematic Review of
• Medical Therapy to Facilitate Passage of
  Ureteral Caliculi. Annals of Emergency
  Medicine, Volume 50, Issue 5, Pages 552-563