also possible (that is, physicians refrained from prescribing
NSAIDs to patients at a higher risk of developing acute kidney
injury requiring dialysis),
48
which could have biased the rate
ratios towards the null.
Secondly, because of the observational nature of this study,
residual confounding by indication and disease severity may be
present. However, we specifically dealt with this possibility by
using active treatment comparators (for example, combination
of diuretic and NSAID versus diuretic only). Therefore,
assuming that residual confounding from unmeasured variables
was non-differential between exposure groups is reasonable.
Furthermore, adjusting the models for severity of hypertension
had little effect on the adjusted rate ratios, indicating that this
variable was probably well balanced between groups. Moreover,
we observed similar results when we stratified for diabetes, as
well as in terms of half life of NSAID and duration of use when
we additionally matched cases and controls on general practice,
in an attempt to further control for practice specific prescribing
patterns and social deprivation. Reassuringly, the fact that we
observed a duration-response relation and the point estimates
were consistently lower with a shorter (60 and 30 days) exposure
time window and grace period (that is, the likelihood of being
concurrently exposed to antihypertensive drugs and NSAIDs
was reduced) indicates that residual confounding was probably
minimal.
Thirdly, we were unable to control for exposure to contrast
media injected during in-hospital cardiovascular examinations
(such as angiography) or for other nephrotoxins (such as
aminoglycoside antibiotics) that might have contributed to the
risk of acute kidney injury.
49
However, when we controlled for
immeasurable time bias by excluding patients admitted to
hospital in the current time window,
38
the results remained
consistent with those of the primary analysis, showing that
previous in-hospital exposure to other nephrotoxins as well as
in-hospital exposures to double or triple therapy combinations
were unlikely to have influenced the observed associations.
Finally, whereas antihypertensive drugs are probably well
captured in the CPRD, some misclassification of exposure with
some NSAIDs that are available over the counter is possible.
Such misclassifications of exposure would have diluted the
association towards the null, so the increased risks observed in
this study may have been partly underestimated.
50
However, we
obtained consistent results when we restricted the analyses to
those patients treated for osteoarthritis, a population more likely
to be exposed to NSAIDs by prescription. Nevertheless, given
that over the counter drug information is generally unavailable
in claims databases, other data sources with such information
are needed to better quantify the risk of acute kidney injury
accounting for the over the counter use of NSAIDs.
Conclusions and policy implications
Acute kidney injury is a major public health concern, which has
been associated with a mortality rate exceeding 50%.
2-6 51 52
Although the prevalence of cardiovascular diseases has been
on the rise in Western countries, the proper use of
antihypertensive drugs has been shown to have a favourable
effect in preventing major cardiovascular events.
16 28 53 54
However, the use of such therapies might be concurrent with
chronic (for example, arthritis) and acute (for example, flu and
flu-like syndromes) inflammatory diseases that require
anti-inflammatory or analgesic drug treatment. Given that
NSAIDs are widely used (40-60% as lifetime prevalence in the
general population
29 30
) and 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.
20 55 56
In particular, major attention should be paid
early in the course of treatment, and a more appropriate use and
choice among the available anti-inflammatory or analgesic drugs
could therefore be applied in clinical practice.
Contributors: All authors participated in the study design. SS acquired
the data. FL, LA, and HY did the statistical analyses. FL wrote the initial
draft, and all authors critically revised the manuscript. SS is the
guarantor.
Funding: This study was funded in part by infrastructure grants from
the Drug Safety and Effectiveness Network (DSEN), the Canadian
Institute of Health Research (CIHR), and the Canada Foundation for
Innovation. The funding sources had no role in the design, analysis, or
interpretation of the results, and thus the authors were independent
from the funding sources. FL is the recipient of an LDI post-doctoral
research award, LA is the recipient of a Chercheur-Boursier career
award from the Fonds de recherche en santé du Québec, and SS is
the recipient of the James McGill chair award.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf (available on
request from the corresponding author) and declare: database
acquisitions were funded by the Canadian Institute of Health Research
(CIHR) and the Canada Foundation for Innovation; SS has received
research grants and participated in advisory board meetings and/or as
a speaker at conferences for AstraZeneca, Boehringer-Ingelheim,
GlaxoSmithKline, Novartis, Pfizer, and Merck; SJN has received
speakers’ honorariums from Baxter Healthcare and Merck Frosst; no
other relationships or activities that could appear to have influenced the
submitted work.
Ethical approval: The study protocol was approved by the Independent
Scientific Advisory Committee of the Clinical Practice Research Datalink
and by the Research Ethics Committee of the Jewish General Hospital,
Montreal, Canada.
Data sharing: No additional data available.
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