Two Antihypertensives Plus NSAID Ups Risk of Acute Kidney Injury

January 09, 2013

MONTREAL — Taking two antihypertensive medications--a diuretic and an ACE inhibitor or angiotensin-receptor blocker (ARB)--along with nonsteroidal anti-inflammatory drugs (NSAIDs) significantly increases the risk of hospitalization for acute kidney injury, particularly in the first 30 days of treatment, a new retrospective case-control study demonstrates [1].

And although the absolute risk for individuals is low, physicians and patients need to be aware of this potential problem, and doctors will need to prescribe alternative anti-inflammatory and/or analgesic agents where warranted, say Dr Francesco Lapi (Jewish General Hospital, Montreal, QC) and colleagues in their report published online January 8, 2013 in BMJ.

"More and more patients, especially the elderly, are taking many medications at the same time, and drug-drug interactions are always important. With the size of the population that we have access to now, we are able to study questions we could not address before," senior author Dr Samy Suissa (McGill University, Montreal, QC) told heartwire . "The message to clinicians is to be vigilant during that early period of treatment," he added.

In an editorial accompanying the paper [2], Drs Dorothea Nitsch and Laurie A Tomlinson (London School of Hygiene and Tropical Medicine, UK) agree. "Clinicians must advise patients who are prescribed diuretics, ACE inhibitors, or ARBs of the risks associated with NSAID use, and they must also be vigilant for signs of drug-associated acute kidney injury in all patients," they observe.

"Triple" Therapy Ups Risk of Kidney Injury by 80% in First 30 Days of Use

 
Clinicians must advise patients who are prescribed diuretics, ACE inhibitors, or ARBs of the risks associated with NSAID use, and they must also be vigilant for signs of drug associated acute kidney injury.
 

Lapi and colleagues say that acute kidney injury is a major public-health concern, which has been associated with a mortality rate exceeding 50%. To study the question of how often this occurs with concurrent use of antihypertensives and NSAIDs, they used the UK Clinical Practice Research Datalink (previously known as the General Practice Research Database)--which is the world's largest computerized store of primary-care records--to assess a cohort of 487 372 users of antihypertensive drugs between 1997 and 2008. This was linked to the Hospital Episodes Statistics database to see whether a double therapy combination of a diuretic, ACE inhibitor, or ARB with an NSAID or the triple therapy combination of two of those antihypertensives plus an NSAID was associated with increased risk of hospitalization for acute kidney injury.

During a mean follow-up of almost six years, 2215 cases of acute kidney injury were identified (incidence rate of seven per 10 000 person-years), and each was compared with up to 10 matched controls.

Overall, current use of double therapy was not associated with an increased risk of acute kidney injury, but current use of triple therapy--two antihypertensives plus an NSAID--was associated with an increased rate of this end point (rate ratio 1.31, 95% CI 1.12–1.53). And the highest risk was seen in the first 30 days of use (rate ratio 1.82, 95% CI 1.35–2.46). These results remained consistent after adjustment for potential confounders.

"If you are taking two antihypertensive medications--a diuretic and an ACE inhibitor or ARB--and then you add on an NSAID, the adding of the NSAID increases the risk of acute kidney injury, particularly in the first 30 days, so you are identifying some susceptible patients when you expose them to NSAIDs in that first month," Suissa explains.

He adds that those who get through the 30-day period without any problem will likely be fine, "at least in terms of acute kidney injury"; he noted that the study was not designed to assess the issue of chronic renal problems.

But Is "Double" Therapy Safe?

But Nitsch and Tomlinson go on to question the finding that an NSAID added to one of the three antihypertensives is not associated with acute kidney injury.

 
I don't think we can say we are absolutely confident that [double therapy] is safe, but it is certainly not a high risk.
 

The confidence intervals for the estimates of risk for double drug combinations were "wide," they note, so the study "probably underestimates the true burden of drug-associated kidney injury. The jury is still out on whether double drug combinations are indeed safe," they state.

Suissa acknowledges that the number of patients taking this double therapy was small, "so we cannot exclude a small increased risk. I don't think we can say we are absolutely confident that it is safe, but it is certainly not a high risk," he told heartwire .

He adds that the study findings are indicative of how hypertension is now being managed. "It's being controlled with two drugs, not just one, and then if you have pain, we will add an NSAID to that. In our cohort of antihypertensive-drug patients, 11% were treated with this triple therapy, which is quite large. We were surprised."

Suissa has received research grants from and participated in advisory board meetings and/or served as a speaker at conferences for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, and Merck. Lapi has no conflicts of interest; disclosures for the coauthors are listed in the paper. The editorialists have no disclosures.

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