Cisapride treatment for gastro-oesophageal reflux in children.
BACKGROUND
Gastro-oesophageal reflux (GOR) is an extremely common and usually self limiting condition in infants. When treatment is required, Cisapride, a pro-kinetic agent, has been commonly prescribed for the symptomatic management of GOR. There have been recent reports of possibly serious adverse events e.g. an increased QTc interval, cardiac arrhythmias, and death, associated with the use of Cisapride.


OBJECTIVE
To determine the effectiveness of Cisapride for symptoms of GOR in children compared with placebo or any other non-surgical treatments.


METHODS
Searches were conducted of the Cochrane Central Trials Register and the specialised Trials register of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group, MEDLINE and Embase. Reference lists of relevant review articles and identified trials were scrutinised and forward citation searches were performed in the Science Citation Index on all trials identified.


METHODS
Randomised controlled trials that compared oral Cisapride therapy with placebo or with other non-surgical treatments for children with a diagnosis of GOR were included. Only studies in which Cisapride was administered orally for a minimum of one week and which documented at least one of the primary outcomes were included.


METHODS
The primary outcomes were defined as a change in symptoms at the end of treatment, presence of adverse events, occurrence of clinical complications, and weight gain. The secondary outcomes included physiological measures of GOR or histological evidence of oesophagitis. We dichotomised symptoms into 'same or worse' vs 'improved' and calculated summary odds ratios. Continuous measures of GOR (e.g. reflux index) were summarised as a weighted mean difference. All outcomes were analysed using a random effects method. Sensitivity analyses were also performed.


RESULTS
Searches identified eight trials which met the inclusion criteria. Seven trials (a total of 236 participants) compared Cisapride with placebo. The odds ratio for 'same or worse' vs 'improved symptoms' at the end of treatment was 0.34 (95%CI 0.10, 1.19), thus showing no statistically significant difference between the two interventions. There was significant heterogeneity between the studies and the funnel plot suggested substantial publication bias. In the sensitivity analysis, the definition of outcomes was changed to 'any symptoms' vs 'no symptoms'. This resulted in the exclusion of three trials (one of them the largest, best quality trial). The resulting pooled odds ratio showed a significant effect of Cisapride (OR 0.19, 95%CI 0.08, 0.44). There were fewer adverse events with placebo than with Cisapride, but the difference was not statistically significant (OR 1.80, 95%CI 0.87, 3.70) and the result was based on small numbers. Cisapride compared with placebo produced a statistically significant reduction in the reflux index (weighted mean difference -6.49, 95%CI -10.13, -2.85), but as reflux index and clinical symptoms are poorly correlated, the clinical importance of this finding is uncertain. Other measures of oesophageal pH monitoring did not reach significance. One included study compared Cisapride with Gaviscon (or Gaviscon and Carobel). The odds ratio for 'same or worse' vs 'improvement' in the Cisapride group compared with Gaviscon was 3.26 (95%CI 0.93, 11.38).


CONCLUSIONS
We found no clear evidence that Cisapride reduces symptoms of GOR. The results suggested substantial publication bias favouring studies showing a positive effect of Cisapride. Due to reports of serious adverse events, the company will stop marketing the drug as of July 14th, 2000 and therefore a larger study to provide more conclusive evidence of the effect of Cisapride is no longer possible.
Augood
C
C
Epidemiology and Public Health, Institute of Child Health, 30 Guilford Street, London, UK, WC1N 1EH. C.Augood@ich.ucl.ac.uk
MacLennan
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S
Gilbert
R
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Logan
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S
D000464:Alginates / Q000627:therapeutic use; D000536:Aluminum Hydroxide / Q000627:therapeutic use; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D020117:Cisapride / Q000627:therapeutic use*; D004338:Drug Combinations; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017063:Outcome Assessment, Health Care; D016032:Randomized Controlled Trials as Topic; D012824:Silicic Acid / Q000627:therapeutic use; D017693:Sodium Bicarbonate / Q000627:therapeutic use
D000464:Alginates; D000897:Anti-Ulcer Agents; D004338:Drug Combinations; D005765:Gastrointestinal Agents; D012824:Silicic Acid; D000536:Aluminum Hydroxide; C007829:alginate, aluminium hydroxide, magnesium trisilicate, sodium bicarbonate drug combination; D017693:Sodium Bicarbonate; D020117:Cisapride