Drug combinations and impaired renal function -- the 'triple whammy'

Br J Clin Pharmacol. 2005 Feb;59(2):239-43. doi: 10.1111/j.0306-5251.2004.2188.x.


Background: Recent studies have identified the 'triple whammy' in which combinations of diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors (ACEI) and/or angiotensin receptor antagonists (ARA) may impair renal function.

Methods: We performed a cross-sectional study of patients admitted to a general medical ward of a teaching hospital. Age, sex, disease status and prior consumption of the 'target' drugs, diuretics, NSAIDs (including aspirin), ACEI and ARA were correlated with creatinine and creatinine clearance on admission.

Results: Three hundred and one patients (48% male) were included, 135 were on no prior target drugs, 87 on one, 60 on two and 19 on three such drugs. There was a significant (P < 0.01) correlation between both creatinine and creatinine clearance with male sex, age and number of target drugs. Multivariate analysis confirmed these associations but did not support associations between renal function and heart failure or total number of diagnoses. Increasing doses of diuretics, possibly because in many cases this included two drugs, but not the other drugs, were significantly (P < 0.001) associated with impaired renal function. For the other three drug groups patients on doses of any drug at lower than the defined daily dose (DDD) did not have significantly different creatinine or creatinine clearance from those on doses at or above the DDD.

Conclusion: Taking two or more of the identified drugs was associated with significant renal impairment but did not correlate with heart failure or other diseases for which the drugs might have been prescribed. Care is necessary to balance the demonstrated advantages of these medications against the risk of inducing renal failure.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Analysis of Variance
  • Angiotensin II Type 1 Receptor Blockers / adverse effects*
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Cross-Sectional Studies
  • Drug Combinations
  • Female
  • Humans
  • Kidney Diseases / chemically induced*
  • Male
  • Middle Aged


  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Anti-Inflammatory Agents, Non-Steroidal
  • Drug Combinations