Absolute risk is still low, but doctors and patients should be vigilant.

Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study.

Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S.
BMJ. 2013;346:e8525. doi: 10.1136/bmj.e8525.

Background

Acute kidney injury is a major clinical problem, with an incidence rate of mortality up to 50% [1-4]. Adverse drug reactions are an important cause of acute kidney injury, affecting the excretion of drugs and possibly leading to nephropathy [5]. This is often associated with individual drug classes, but the effects of drug-drug interactions are not clear. Among users of antihypertensive medication, who often need multiple drugs, this is particularly relevant.
This study assessed the risk of acute kidney injury associated with the use of a double therapy combination (diuretics + angiotensin converting enzyme inhibitors, or angiotensin receptor blockers + NSAIDs) or a triple therapy combination (two of the antihypertensives mentioned before + NSAIDs).
Data from nearly half a million people taking antihypertensive drugs between 1997 and 2008 were analyzed using the UK Clinical Practice Research Datalink (previously known as the General Practice Research Database).

Main results

• 2,215 cases of acute kidney injury were found after a mean followup of 5.9 years.
• People on dual therapy were not at increased risk for acute kidney injury.
• When NSAID use was added to dual therapy, there was a modest but significant increase in risk (rate ratio 1.31, CI 1.12- 1.53), which was highest in the first month of treatment.

Conclusion

Adding a non-steroidal anti-inflammatory drug (NSAID) to dual antihypertensive therapy is associated with an increase in risk for kidney injury. Physicians and patients need to be aware of this potential problem, especially early in the course of treatment, and doctors will need to prescribe alternative anti-inflammatory and/or analgesic agents where warranted.

Editorial comment [6]

“The safety of dual therapy still remains to be demonstrated. The study likely underestimates the true burden of drug associated acute kidney injury in patients taking antihypertensive therapy and NSAIDs. Physicians should inform patients taking antihypertensive therapy about the possible risks of NSAID use and should be vigilant for signs of drug associated acute kidney injury in all patients.”

References

1. Hsu CY, McCulloch CE, Fan D, et al. Community-based incidence of acute renal failure. Kidney Int 2007;72:208-12.
2. Hsu CY, Chertow GM, McCulloch CE, et al. Nonrecovery of kidney function and death after acute on chronic renal failure. Clin J Am Soc Nephrol 2009;4:891-8.
3. Liangos O, Wald R, O’Bell JW, et al. Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. Clin J Am Soc Nephrol 2006;1:43-51.
4. Kellum JA, Angus DC. Patients are dying of acute renal failure. Crit Care Med 2002;30:2156-7.
5. Schetz M, Dasta J, Goldstein S, Golper T. Drug-induced acute kidney injury. Curr Opin Crit Care 2005;11:555-65.
6. Nitsch D, Tomlinson LA. Safety of coprescribing NSAIDs with multiple antihypertensive agents. BMJ. 2013;346:e8713. doi: 10.1136/bmj.e8713.

Abstract

Objectives:
To assess whether a double therapy combination consisting of diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with addition of non-steroidal anti-inflammatory drugs (NSAIDs) and the triple therapy combination of two of the aforementioned antihypertensive drugs to which NSAIDs are added are associated with an increased risk of acute kidney injury.

Design:
Retrospective cohort study using nested case-control analysis.

Setting:
General practices contributing data to the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database.

Participants:
A cohort of 487 372 users of antihypertensive drugs.

Main outcome measures:
Rate ratios with 95% confidence intervals of acute kidney injury associated with current use of double and triple therapy combinations of antihypertensive drugs with NSAIDs.

Results:
During a mean follow-up of 5.9 (SD 3.4) years, 2215 cases of acute kidney injury were identified (incidence rate 7/10 000 person years). Overall, current use of a double therapy combination containing either diuretics or angiotensin converting enzyme inhibitors or angiotensin receptor blockers with NSAIDs was not associated with an increased rate of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12 to 1.53). In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35 to 2.46).

Conclusions:
A triple therapy combination consisting of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs was associated with an increased risk of acute kidney injury. The risk was greatest at the start of treatment. Although antihypertensive drugs have cardiovascular benefits, vigilance may be warranted when they are used concurrently with NSAIDs.