Discussion
Our observational retrospective study of a homogenous population of
eight hundred asthmatic adults in Albania has demonstrated a significant
relationship between the use of montelukast and the reduction of an
ischemic CV event such as IS or MI even after correction for possible
confounders. Thus, our data indicate that, despite the limits of the
present study, LTRAs in general and montelukast in particular may have a
positive impact in the prevention of CV disease in asthmatic patients.
Ischemic events such as MI and IS are among the leading causes of death
worldwide. Atherosclerosis has been recognized to have a crucial
inflammatory component20,21, and there is an unmet
need for an anti-inflammatory treatment capable of reducing CVD
risk34. Since atherosclerotic coronary arteries
respond to cysteinyl-LTs11,12 and the variation of the
gene encoding the 5-lipoxygenase activating protein (FLAP), an essential
protein for cysteinyl-LT biosynthesis, is associated to an increased
risk of MI15,35, we hypothesized that LTRAs may have a
role in CVD prevention29. Asthmatic patients are more
predisposed to CV events than the non-asthmatic
population36,37 and inflammation is a common feature
of both asthma and atherosclerosis, so the use of a LTRA in asthmatic
patients may have additional, complementary therapeutic benefit.
Analysis of montelukast usage in our sample population of asthmatic
patients in Albania showed that patients treated with the drug were on
average four years younger than those in the non-exposed montelukast
group, however, with a median age less than 65 years for both groups.
The clinical relevance of this modest difference between groups is
uncertain, and considering the huge difference in the reported incidence
of CVDs between male and female
(http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf)
we used gender as primarily matching criteria and age as secondary
criteria for inclusion.
As expected, the average age of patients incurring CV events,
irrespective of montelukast treatment, was older than those without CV
events. This age-related increase in ischemic events indicates a
substantial contribution of age to the CV risk, as one might expect in
the aging population38.
Both PS matching and PS adjusted Cox analysis reveals that, despite age
difference, exposure to montelukast remains a significant protective
factor for incident ischemic events, independently from gender. This
observation extends to primary prevention the results of Ingelsson and
co-authors, who observed an effect of montelukast on recurrent MI in
male and of recurrent IS in both genders, but no association of
montelukast use with incident events31. Because asthma
is recognized to be a possible confounder for the association of
montelukast with CV diseases, limiting the sample to asthmatic subjects,
as in our study, could have facilitated the detection of the effect of
montelukast on incident events. All the events observed in our study
occurred among patients taking anti-hypertensive, diuretic,
anti-platelet or anti-cholesterol drugs, namely patients at increased CV
risk of ischemic events.
Notably, analysis of the data relative to the concomitant use of these
drugs, possible confounders for the association of montelukast to CV
risk, excluded their potential influence on the CV event rate. In fact,
while all the other drugs were balanced in the two groups, only the use
of antiplatelet drugs was statistically different. Therefore, to further
corroborate our findings and to exclude that use of antiplatelet drugs
might bias our results, we also performed a PS adjusted Cox analysis
only on patients taking antiplatelet drugs. This, again resulted in a
statistically significant protective effect of montelukast not
substantially different from that obtained in the overall sample.
Event-free Kaplan-Meier survival curves for patients treated and
non-treated with montelukast are statistically different, with a clear
statistical significance observed also if calculated only in patients
taking antiplatelet drugs. Collectively, these observations suggest that
anti-inflammatory drugs such as LTRAs may have a significant protective
effect in the prevention of ischemic events in asthmatics. Finally, our
study could even have underestimated the protective effect of
montelukast, since we considered as exposed also patients that had the
event after stopping the drug. Indeed, only 2 out of 5 events in the
exposed group occurred during the treatment, strengthening our
perception of possible protection associated to montelukast use.
We acknowledge that there are a number of limitations of this study,
such as the relatively limited number of events observed. Yet, our
cohort is perfectly balanced for gender, a significant factor for CV
diseases, and homogeneous with respect to asthma indication, which is
recognized to be a confounding factor in the Ingelsson
study31. Therefore, despite the number of events in
the two studies are largely different, our subject sample might provide
increased sensitivity describe in detecting the protective effect of
montelukast, particularly in a population known to have an higher
incidence of CV diseases. In addition, other possible risk factors such
as systemic blood pressure, body mass index, smoking, obesity, alcohol
or physical inactivity, were not available for the majority of the
patients, similarly to the Ingelsson study31, and
could not be included in our investigation. Conversely, the concomitant
use of other drugs is well balanced between the two cohorts, with
exception of the use of antiplatelet drugs which, nevertheless, does not
seem to have an influence on the CV event rate. Therefore, we are
confident that the significance of montelukast protection evidenced has
not been biased by these possible confounders.
We believe that our data should foster a larger, case-control trial
taking into consideration all the CV risk factors that are missing in
this study and that was only possible to account for using treatments as
proxies. Montelukast patent is, however, expired, limiting the interest
of the pharmaceutical industry to fund such an expensive CV trial. Thus,
despite the impact that a definitive confirmation of these data might
have on public health, only non-profit organization or government
supported grants might provide enough funding for such a large study.
In conclusion, our observational study highlights an additional benefit
of leukotriene modifiers in CVDs, suggesting montelukast as a controller
in asthmatic patients with coronary artery disease risk factors.
Targeting the cysteinyl-LT pathway, or indeed the total LT pathway with
FLAP inhibitors, may be a strategy for primary prevention in populations
at increased CV risk, or secondary prevention in the general population.
LTRAs in general and montelukast in particular are approved drugs used
in the clinical practice since almost two decades, and have been
demonstrated, over the years, to be well tolerated39.
The use of LT antagonists or inhibitors as anti-inflammatory agents in
the CV setting may have a beneficial effect in reducing ischemic events
that are among the leading causes of death in the developed world.