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Drug Saf. 2007;30(12):1143-9.

Detection of spironolactone-associated hyperkalaemia following the Randomized Aldactone Evaluation Study (RALES).

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  • 1Risk Management Strategy, Pfizer Inc, New York, NY 10017, USA.



A population-based analysis has suggested that the publication of the RALES (Randomized Aldactone Evaluation Study) in late 1999 was associated with both the wider use of spironolactone to treat heart failure and a corresponding increase in hyperkalaemia-associated morbidity and mortality in patients also being treated with ACE inhibitors.


To gain further insight into the reporting of spironolactone-associated hyperkalaemia in an independent dataset by analysing the spontaneous reporting experience in relation to the publication of RALES, and to determine whether the implementation of a commonly used data mining algorithm (DMA) might have directed the attention of safety reviewers to the spironolactone/hyperkalaemia association in advance of epidemiological findings.


We calculated the reporting rate of spironolactone-associated hyperkalaemia per 1,000 reports per year from 1970 through to the end of 2005 by identifying relevant cases in the US FDA Adverse Event Reporting System. We did this for reports of spironolactone-associated hyperkalaemia (where spironolactone was listed as a suspect drug) and according to whether the reports listed an ACE inhibitor as a co-suspect or concomitant medication. A further statistical analysis of the overall reporting of spironolactone (suspect drug)-associated hyperkalaemia was also performed. We also performed 3-dimensional (3-D; drug-drug-event) disproportionality analyses using a DMA known as the multi-item gamma-Poisson shrinker, which allows the calculation and display of a 3-D disproportionality metric known as the 'interaction signal score' (INTSS). This metric is a measure of the strength of a higher order reporting relationship of a triplet (i.e. drug-drug-event) association above and beyond what would be expected from the largest disproportionalities associated with the individual 2-way associations.


Visual inspection of a graph of the reporting frequency of spironolactone (suspect drug)-associated hyperkalaemia per 1,000 reports was highly suggestive of a change point. The t-test on the arcsine-transformed data showed a significant difference in reporting of spironolactone-hyperkalaemia combination through 1999 compared with 2000 onwards (p < 0.001). When examining the reporting time trends according to the presence or absence of an ACE inhibitor, the change point seemed to be mostly attributable to an increase in the number of spironolactone (suspect drug)-associated hyperkalaemia reports with ACE inhibitors listed as a co-suspect drug. No obvious change points in INTSSs for spironolactone-ACE inhibitor-hyperkalaemia reports were observed.


Although we could not pinpoint the relative contribution of many possible artifacts in the reporting process, as well as increased drug exposure, increased adverse event incidence and/or a change in patient monitoring practices, to our findings, we observed a notable change in reporting frequency of spironolactone-associated hyperkalaemia in temporal proximity to the publication of RALES. Evidence of this was provided by a trend analysis depicted in a simple graph that was supported by statistical analysis. The observed trend was in large part due to increased reporting of spironolactone-associated hyperkalaemia with reported co-medication with ACE inhibitors.


These findings are consistent with those originally reported in an epidemiological analysis. In this retrospective exercise, a simple graph was more illuminating than more complex data mining analyses.

[PubMed - indexed for MEDLINE]
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