The control of hypertension by ACE inhibitors and diuretics and their beneficial effects in heart failure are antagonized by NSAIDs*. Concurrent use of NSAIDs and diuretics is associated with a twofold increase in the risk of hospitalization for heart failure compared with diuretics alone (1). Moreover, ACE inhibitors, NSAIDs and diuretics, individually or in combination, are involved in over 50% of cases of iatrogenic acute renal failure reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC).

* Ed. note. Referenced articles not mention use of acetylsalicylic acid as an NSAID.

More specifically, the combined use of ACE inhibitors, diuretics and NSAIDs, termed the "triple whammy", is implicated in a significant number of reports to ADRAC of drug-induced renal failure (2). This effect is also seen with COX-2 inhibitors and angiotensin receptor antagonists ("sartans") (3). In 2002, 28 of the 129 reports to ADRAC of acute renal failure implicated one of these combinations. Most reports to ADRAC of drug-induced renal failure relate to elderly patients, and this applies as well to renal failure associated with the triple therapy (median age 76 years). The fatality rate for ADRAC cases of renal failure with the "triple whammy" is 10%.

The use of ACE inhibitors and angiotensin receptor antagonists is increasing, as is the use of these agents in combination products with a diuretic. Episodes of renal failure appear to be precipitated by mild stress (e.g. diarrhoea, dehydration) in a patient taking the triple combination or by the addition of a third drug (usually an NSAID) to the stable use of the other two. ADRAC suspects that the risk of acute renal failure is underestimated and the syndrome underrecognized.

Extracted from the Australian Adverse Drug Reactions Bulletin, Volume 22, Number 4, August 2003.

References

1. Heerdink, E.R., Leufkens, H.G., Herings, R.M.C. et al. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Archives of Internal Medicine, 158: 1108 - 1112 (1998).

2. ADRAC, Thomas M. Diuretics, ACE inhibitors and NSAIDs - the triple whammy. Medical Journal of Australia, 172: 184 - 185 (2000).

3. Boyd, I.W., Mathew, T.H., Thomas, M.C. COX-2 inhibitors and renal failure: the triple whammy revisited. Medical Journal of Australia, 173: 274 (2000). (corr. MJA 173: 504, 2000).