Physicians who prescribe a combination of two antihypertensive drugs to their patients may want to be extra vigilant if non-steroidal anti-inflammatory drugs (NSAIDs) are added to a patient’s regimen.
A study published Jan. 8 in BMJ found a triple therapy combination was associated with increased risk of acute kidney injury, with a twofold increased risk in the first 30 days of use.
Francesco Lapi, PharmD, PhD, of the Jewish General Hospital in Montreal, and colleagues looked at the use of double therapies and triple therapies to explore possible associations with an increased risk of acute kidney injury. They defined double therapy as the concurrent use of either diuretics, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) with NSAIDs and triple therapy as a combination of diuretics and ARBs or ACE inhibitors with NSAIDs.
To perform their analysis, they accessed two linkable UK databases: the Clinical Practice Research Datalink, a database of longitudinal primary care records; and the Hospital Episodes Statistics repository, a national registry of hospital admissions. Using the first database, they identified 487,372 patients who received blood pressure medications between 1997 and 2008, with a follow-up through 2010.
Patients with a history of cancer, renal disorders, hepatitis systemic connective tissue diseases, rheumatoid arthritis, crush injury, hepatitis, HIV infection and drug misuse were excluded. Patients were followed until first hospital admission for acute kidney injury or for one of the exclusion criteria, death from any cause or until the end of the follow-up period.
They also randomly selected up to 10 controls matched to each case of hospital admission related to acute kidney injury. Patients were grouped into one of three groups—current, past and never—based on the use of double or triple therapy and their index date. Lapi et al then adjusted for potential confounders and performed sensitivity analyses.
With a mean follow-up of 5.9 years, they found 2,215 cases of acute kidney injury. The double therapy combination was not associated with increased risk of acute kidney injury, but use of a triple therapy was associated with a 31% increased risk. They observed an 82 percent increased risk within the first 30 days of use under the triple therapy.
“When we considered the duration of exposure to a triple therapy combination, the highest risk of acute kidney injury was in the first 30 days of use,” they wrote. “Although the basis of this is still unclear, it might be explained by an early and severe deteriorating effect of NSAIDs in susceptible patients, who are heavily dependent on prostacyclins to maintain renal function. Furthermore, patients may initially use a greater number of NSAID pills early on than later, as some causes of pain may abate over time.”
The researchers noted that the prevalence of cardiovascular disease is increasing, and antihypertensive drugs help to prevent adverse events. NSAIDs also are commonly used by patients for chronic conditions such as arthritis or briefly for the flu and other illnesses.
“Given that … a greater incidence rate of acute kidney injury was estimated among antihypertensive drugs users than in the general population, increased vigilance may be warranted when diuretics and angiotensin converting enzyme inhibitors or angiotensin receptor blockers are used concurrently with NSAIDs,” they recommended, particularly in the first 30 days of treatment.
They listed several study limitations, including residual confounding and, because NSAIDs are available over the counter, a possible underestimation of the increased risk of acute kidney injury.