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\begin{document}

\title{Montelukast Use Decreases Cardiovascular Events in Asthmatics}



\author[1]{Malvina Hoxha}%
\author[2]{Calogero Tedesco}%
\author[3]{Silvana Quaglini}%
\author[4]{Visar Malaj}%
\author[5]{Linda Pustina}%
\author[6]{Valerie Capra}%
\author[7]{Jilly Evans}%
\author[6]{Angelo Sala}%
\author[6]{G Enrico Rovati}%
\affil[1]{Catholic University Our Lady of Good Counsel}%
\affil[2]{Centro Cardiologico Monzino IRCCS}%
\affil[3]{University of Pavia}%
\affil[4]{University of Tirana}%
\affil[5]{Ministry of Education and Sports}%
\affil[6]{University of Milan}%
\affil[7]{University of Pennsylvania}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Cysteinyl leukotrienes are pro-inflammatory mediators with a
clinically established role in asthma and a potential human genetic and
preclinical role in cardiovascular diseases. Given that cardiovascular
disease has a critical inflammatory component, the use of a leukotriene
antagonist may represent an innovative therapy to target inflammation in
cardiovascular prevention. Methods: We performed an observational
retrospective (three years) study on eight hundred asthmatic patients 18
years or older in Albania, equally classified in two cohorts, exposed or
non-exposed to montelukast, matched by age and gender. Patients with a
previous history of myocardial infarction or ischemic stroke were
excluded. Results: we considered eight hundred asthmatic patients (368
male and 432 female) 18 years or older. Overall 37 (4.6\%) of the
asthmatic patients, 32 non-exposed and 5 exposed, suffered a major
cardiovascular event during the 3 years observation period. All the
cardiovascular events occurred among patients with an increased
cardiovascular risk. Thus, we used both a propensity score (PS) matching
and a PS adjusted Cox model for analysis. In both analyses exposure to
montelukast remained a significant protective factor for incident
ischemic events (HR = 0.222; HR = 0.241, respectively), independently
from gender. The event-free Kaplan-Meier survival curves confirmed the
lower cardiovascular incidence of patients exposed to montelukast (p =
\textless{}0.0001). Conclusion: Collectively, our data indicates that
there is a potential protective role of montelukast for incident
ischemic events in the older asthmatic population, suggesting a
co-morbidity benefit of montelukast in asthmatics and possible
innovative therapy to target inflammation for cardiovascular prevention.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Inflammation is a physiological reaction that can become a pathological
effect, associated with several diseases and characterized by the
release of mediators, including metabolites of the arachidonic acid
cascade. Cysteinyl leukotrienes (cysteinyl-LTs), namely
LTC\textsubscript{4}, LTD\textsubscript{4}, and LTE\textsubscript{4},
are potent pro-inflammatory lipid mediators long known to play an
important role in asthma\textsuperscript{1}, that have also been
implicated in other inflammatory conditions, such as allergic rhinitis
(AR), atopic dermatitis, and urticarial\textsuperscript{2}.
Additionally, their involvement has been hypothesized in several
cardiovascular diseases (CVDs), such as acute myocardial infarction
(MI), ischemic stroke (IS), atherosclerosis, aortic aneurysms and
intimal hyperplasia\textsuperscript{3-6}. Increased intracoronary
production of cysteinyl-LTs was detected in patients undergoing coronary
angioplasty\textsuperscript{7} and by systemic urinary
LTE\textsubscript{4} excretion in acute MI and ischemic heart disease
patients\textsuperscript{8-10}. Several proteins in the 5-lipoxygenase
pathway, including both CysLT receptors, were found in the arterial wall
of patients at different stages of
atherosclerosis\textsuperscript{11-14}. Finally, besides the increase in
cysteinyl-LTs concentration in CVDs, a number of genetic studies also
support a link between cysteinyl-LTs, their receptors and
CVD\textsuperscript{15-18}.

In the 1990s, after the discovery that cysteinyl-LTs were implicated in
asthma, a number of LT modifiers, i.e. 5-lipoxygenase pathway
inhibitors, but particularly CysLT\textsubscript{1} receptor antagonists
(LTRAs), were developed and are now widely used to treat asthma and
other allergic conditions\textsuperscript{19}. However, CVDs,
particularly atherosclerosis, have a crucial inflammatory
component\textsuperscript{20,21}, and given the role of cysteinyl-LTs in
modulating vascular tone and inflammation\textsuperscript{22-24}, LTRAs
have been proposed as potential therapeutics for such
diseases\textsuperscript{6,25}. The potent and selective
CysLT\textsubscript{1} receptor antagonist montelukast was first
approved by the Food and Drug Administration to be used in different
stages of asthma both in adults and children and later on also for the
treatment of seasonal and perennial AR\textsuperscript{19}. In addition,
in preclinical animal models, montelukast has been shown to
significantly reduce the formation of atherosclerotic plaques and
intimal hyperplasia, and to reduce the level of reactive oxygen species
production and apoptosis, demonstrating beneficial effects on
endothelial cells functions and myocardial remodeling
(see\textsuperscript{26} and\textsuperscript{6} for recent reviews).
Furthermore, montelukast has been demonstrated to inhibit oxidized
low-density lipoprotein-induced monocyte adhesion to endothelial cells,
suggesting a protective role in the early stages of
atherosclerosis\textsuperscript{27}. Montelukast also protects against
aorta dilatation and reduces aortic rupture and aneurism development in
three independent animal models of abdominal aortic
aneurysm\textsuperscript{28}.

Therefore, considerable data exists in CVD for a role of LTRAs in
general, and of montelukast in particular, in controlling and reducing
CV risk\textsuperscript{25,29}. Indeed, asthmatic patients receiving
montelukast have lower levels of CV disease-associated inflammatory
biomarkers and lipid levels\textsuperscript{30}, while a recent
nationwide cohort study on incident or recurrent ischemic events
provided a first indication for a role of montelukast for secondary
prevention of CVDs\textsuperscript{31}. In order to explore a potential
complementary approach to other agents for CVD prevention, we performed
an observational retrospective study including eight hundred asthmatic
patients exposed or non-exposed to montelukast to assess the efficacy of
montelukast in prevention of a major CV event such as MI o

\textbf{Methods}

\emph{Data collection}

To obtain a significant sample of Albanian asthmatic population, a
number of allergists/pathologists around the country were enrolled to
contribute to the study by providing data about asthmatic subjects (18
years or older) based on their patient register and medical history. The
study was retrospective, and medical records of 400 asthmatic subjects
receiving montelukast (10 mg daily) and 400 asthmatic subjects not
receiving montelukast were evaluated (from January
1\textsuperscript{st}, 2012 to December 31\textsuperscript{st}, 2014).
Asthmatic subjects (International Classification of Diseases (ICD-10
v:2016) code 493) were diagnosed on the basis of GINA (Global Initiative
for Asthma) criteria (https://ginasthma.org) on objective evidence of
variable airflow obstruction. As the number of patients taking
montelukast was the limiting factor of the study, we considered exposed
all patients taking the drug for a period of at least three months,
excluding all subjects with a previous history of MI or IS, as reported
in their medical records (ICD: MI-I21 or IS-I63). These patients were
randomly matched with patients not receiving montelukast as an
anti-asthmatic drug primarily by gender and secondly by age. In order to
identify a predisposition of the monitored patients to an increased CV
risk for MI and IS, information was obtained on drug therapies for major
chronic conditions such as hypertension, diabetes mellitus,
dyslipidemia, cerebrovascular disease, anemia, arrhythmias, epilepsy,
allergies, psychosis, ulcers, cancer, and depression. General
information such as age, gender, patient education level, residence and
income were also recorded, while systemic blood pressure, body mass
index, smoking, obesity or cholesterol were not available for the
majority of the patients and for this reason were not taken into account
in our analysis. According to ICD, the two groups were finally
classified for the presence or absence of MI or IS.

\emph{Study power}

We calculated that, for a two groups survival analysis comparison on a
total time of 3 years and 400 patients per group, we able to detect as
significant an HR of 0.8 or lower with a type 1 error alpha = 0.05 and a
power of 80\%.

\subsection*{\texorpdfstring{\emph{Statistical
analysis}}{Statistical analysis}}

{\label{statistical-analysis}}

Median and interquartile range (Q1 -- Q3) was used to describe age
distribution due to its non-normality. As well, the non-parametric
Wilcoxon test was used to assess the difference of age between the two
groups of patients exposed or non-exposed to montelukast. Pearson's
Chi-square test for association was used to test the association of
montelukast exposure with the qualitative variables. All the available
variables were, potentially, considered as predictors of a CV event.
However, because some drugs were used by less than 10 patients, those
were not considered in the subsequent analysis. Cox (proportional
hazards) regression analysis was performed pooling IS and MI as target
events. All the CV events occurred among patients taking
anti-hypertensive, anti-platelet, or anti-cholesterol drugs, i.e. among
patients at increased `CV risk'. For this reason, those variables could
not be included in a classical Cox regression models, but rather we used
both a propensity score (PS) matching using different calipers (0.4-01)
and a Cox model adjusted for PS. Since our study is a retrospective one,
PS method was used for reducing the effects of confounders. PS has been
calculated using a logistic regression on the treatment variable (i.e.
exposure to montelukast), considering age, gender, residence, education,
income, as well as anti-hypertensive, anti-platelet, diuretic,
hypoglycemic, anti-hypercholesterolemic and anti-androgen drugs as
potential predictors of taking treatment. Concerning qualitative ordinal
variables with more than two levels, analyses were performed both using
all levels and aggregating levels in order to obtain binary variables.
IS or MI were considered as events for survival analysis. For every
patient the observation started January 1\textsuperscript{st}, 2012. All
the patients have been observed up to three years (no drop out) or until
the first event. Event-free Kaplan-Meier survival curves were drawn for
major CV events, and the difference between two curves was tested using
the log-rank statistics. For all the analyses, p-values lower than 0.05
were considered statistically significant. All statistical analyses were
performed using SAS 9.4 (SAS Institute, Cary, NC, USA)

\textbf{Results}

Baseline characteristics and variable distribution in the patient
sample, overall and according to montelukast use, are reported in Table
1.

We first analysed possible relationships between demographic features
and montelukast usage. A significant difference was observed in the age
of patients exposed (median = 60, 46 Q1 - 68 Q3) and non-exposed to
montelukast (median = 64, 55.75 Q1 - 70 Q3). In addition, 77.7\% of
rural zones asthmatic (108/139) were exposed to montelukast, compared to
only 44.2\% of urban patients (292/661), while within low-education
patients only 28.1\% were exposed to montelukast (68/242), compared to
59.5\% within mid+high education (332/558). Income did not show a
significant relationship to montelukast use. The use of additional drugs
appeared to be very balanced between the two cohorts, exposed and
non-exposed to montelukast, with the exception of antiplatelet (5\% vs.
9.75\%) and antitumoral drugs. Overall, 37 (4.6\%) of our asthmatic
patients suffered a major CV event during the observation period.
Interestingly, the overall incidence of an ischemic event in our
asthmatic population (15.4 events per 1000 patient-years) is similar to
the expected rate in a general population (between 8 and 18.1, depending
on level of blood pressure\textsuperscript{32}). However, considering
only patients not exposed to montelukast, the incidence is higher (26.7
events per 1000 patient-years) than that observed in the non-asthmatic
population, while the incidence in patients exposed to the drug is 4.17
events per 1000 patient-years, which is lower than expected in the
general population\textsuperscript{32}. The analysis of the incidence of
CV events showed that the age of patients that did not experience a CV
event (median = 62) was significantly (Wilcoxon test, p \textless{}
0.00004) lower when compared to patients suffering a CV event (median =
74), with 12 years difference between the two groups (Figure 1).

Results from Cox model using a PS matching, are shown in Tables 2. We
performed PS matching with different calipers but we focused on a
caliper = 0.2 because it has been demonstrated to be optimal in many
settings\textsuperscript{33} to look for predictors of a major CV event.
PS matching lead to 269 patients in each group with a number of events
of 22 resulting in a significant (p = 0.0065) protection in CV events
(HR = 0.222) due to montelukast use.

Because in the PS matching analysis we lost some of the events (15 out
of 37, Table 2) we also used a Cox regression model adjusted for PS,
which allowed us to take all the events into consideration (Table 3).
Even though patients exposed to montelukast were overall younger than
the ones not exposed to the drug, montelukast remained a significant (p
= 0.0046 protective factor (HR = 0.241) for CV events. In addition, as
the use of antiplatelet drugs was significantly different between
exposed and not exposed to montelukast (Table 1), we also performed a
Cox model adjusted for PS only on patients taking antiplatelet drugs. As
shown in Table 3, the results are still statistically significant and
not substantially different from those considering the whole sample.

In Figure 2 are reported the event-free Kaplan-Meier survival curves of
patients exposed or not exposed to montelukast. On the left panel, the
whole patient sample was considered, while on the right panel were
considered only patients using antiplatelet drugs. In both cases the two
curves resulted statistically different, while, as expected, the
difference in survival probability was higher when limiting the analysis
to patients treated with antiplatelets (Logrank test, p =
\textless{}0.0001 vs. p = \textless{}0.0001).

\textbf{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 component\textsuperscript{20,21}, and there is an unmet
need for an anti-inflammatory treatment capable of reducing CVD
risk\textsuperscript{34}. Since atherosclerotic coronary arteries
respond to cysteinyl-LTs\textsuperscript{11,12} 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 MI\textsuperscript{15,35}, we hypothesized that LTRAs may have a
role in CVD prevention\textsuperscript{29}. Asthmatic patients are more
predisposed to CV events than the non-asthmatic
population\textsuperscript{36,37} 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 population\textsuperscript{38}.

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 events\textsuperscript{31}. 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
study\textsuperscript{31}. 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 study\textsuperscript{31}, 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 tolerated\textsuperscript{39}.
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.

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asthmatics. \emph{Chest.} 2007;132(3):868-874.

31. Ingelsson E, Yin L, Back M. Nationwide cohort study of the
leukotriene receptor antagonist montelukast and incident or recurrent
cardiovascular disease. \emph{J Allergy Clin
Immunol.}2012;129(3):702-707.

32. Tajeu GS, Booth JN, 3rd, Colantonio LD, et al. Incident
Cardiovascular Disease Among Adults With Blood Pressure
\textless{}140/90 mm Hg. \emph{Circulation.} 2017;136(9):798-812.

33. Austin PC. Optimal caliper widths for propensity-score matching when
estimating differences in means and differences in proportions in
observational studies. \emph{Pharm Stat.} 2011;10(2):150-161.

34. Rovati GE, Sala A, Capra V, Dahlen SE, Folco G. Dual COXIB/TP
antagonists: a possible new twist in NSAID pharmacology and
cardiovascular risk. \emph{Trends Pharmacol Sci.} 2010;31(3):102-107.

35. Hakonarson H, Thorvaldsson S, Helgadottir A, et al. Effects of a
5-lipoxygenase-activating protein inhibitor on biomarkers associated
with risk of myocardial infarction: a randomized trial.
\emph{Jama.}2005;293(18):2245-2256.

36. Iribarren C, Tolstykh IV, Miller MK, Sobel E, Eisner MD. Adult
asthma and risk of coronary heart disease, cerebrovascular disease, and
heart failure: a prospective study of 2 matched cohorts. \emph{Am J
Epidemiol.} 2012;176(11):1014-1024.

37. Tattersall MC, Guo M, Korcarz CE, et al. Asthma predicts
cardiovascular disease events: the multi-ethnic study of
atherosclerosis. \emph{Arterioscler Thromb Vasc
Biol.}2015;35(6):1520-1525.

38. Dhingra R, Vasan RS. Age as a risk factor. \emph{Med Clin North
Am.}2012;96(1):87-91.

39. Bisgaard H, Skoner D, Boza ML, et al. Safety and tolerability of
montelukast in placebo-controlled pediatric studies and their open-label
extensions. \emph{Pediatr Pulmonol.} 2009;44(6):568-579.

\textbf{Table 1. General characteristics of both montelukast exposed and
non-exposed patients.}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Total}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Exposed} \textbf{(400)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Non-exposed} \textbf{(400)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{p-value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Gender\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
368M/432F\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
184M/216F\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
184M/216F\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.504\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Median Age, Q1 - Q3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60, 46 - 68\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
64, 55.75 - 70\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{} 0.0001\#\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Events\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
37* \textbar{} 4.6\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 \textbar{} 1.25\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32 \textbar{} 8\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{} 0.00001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Mean montelukast exposure\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
7.83 months\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Residence\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Rural\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
139 \textbar{} 17\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
108 \textbar{} 27\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31 \textbar{} 8\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{} 0.00001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Urban\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
661 \textbar{} 83\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
292 \textbar{} 73\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
369 \textbar{} 92\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Educational level\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Low\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
242 \textbar{} 30\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
68 \textbar{} 17\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
174\textbar{} 43.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{} 0.00001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mid + High\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
558 \textbar{} 70\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
332 \textbar{} 83\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
226 \textbar{} 56.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Income\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Low\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
371 \textbar{} 46\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
175 \textbar{} 44\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
196\textbar{} 49\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.08\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mid + High\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
429 \textbar{} 54\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
225 \textbar{} 56\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
204 \textbar{} 51\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Drug prescription\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antihypertensive\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
399 \textbar{} 49.9\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
198 \textbar{} 49.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
201 \textbar{} 50.25\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.89\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antiplatelet\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
59 \textbar{}7.37\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 \textbar{} 5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
39 \textbar{} 9.75\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Diuretic\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
167 \textbar{} 20.87\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
84 \textbar{} 21\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
83 \textbar{} 20.75\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.99\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antipsychotic\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 \textbar{} 0.37\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 \textbar{} 0.75\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.25\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antiandrogens\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 \textbar{} 2\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 \textbar{} 1.25\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11 \textbar{} 2.75\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.21\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antithyroid\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7 \textbar{} 0.875\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 \textbar{} 0.75\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 \textbar{} 1\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.99\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Anti-hypercholesterolemic\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
132 \textbar{} 16.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
58 \textbar{} 14.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
74 \textbar{} 18.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.15\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antihistamines\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9 \textbar{} 1.125\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 \textbar{} 1\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 \textbar{} 1.25\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.99\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antipeptics\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 \textbar{} 0.375\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 \textbar{} 0.75\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.24\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antiarrythmics\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 \textbar{} 0.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 \textbar{} 0.25\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 \textbar{} 0.75\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.62\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antianemics\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 \textbar{} 0.25\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 \textbar{} 0.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.48\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hypoglycemics\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
49 \textbar{} 6.125\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 \textbar{} 5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 \textbar{} 7.25\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.24\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antiepileptics\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 \textbar{} 0.25\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.48\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antitumorals\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7 \textbar{} 0.875\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7 \textbar{} 1.75\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.022\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antibiotics\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 \textbar{} 0.375\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 \textbar{} 0,75\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.25\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antidepressants\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 \textbar{} 0.125\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 \textbar{} 0.25\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.99\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CV risk\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
415\textbar{} 51.87\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
206\textbar{} 51.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
209\textbar{} 52.25\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.89\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

* Two patients suffered from both MI and IS; \# Wilcoxon test; all the
other p value refer to Pearson Chi-square test for association.

\textbf{Table 2.} Hazard ratio (HR) for CV events derived from
propensity score matching\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\textbf{Caliper} & \textbf{N. of Patients in each group} & \textbf{N. of
Events} & \textbf{HR} & \textbf{95\% CI low} & \textbf{95\% CI up} &
\textbf{p-value}\tabularnewline
\midrule
\endhead
0.4 & 299 & 24 & 0.2 & 0.068 & 0.585 & 0.0033\tabularnewline
0.3 & 284 & 23 & 0.211 & 0.072 & 0.619 & 0.0046\tabularnewline
\textbf{0.2} & \textbf{269} & \textbf{22} & \textbf{0.222} &
\textbf{0.075} & \textbf{0.657} & \textbf{0.0065}\tabularnewline
0.1 & 245 & 20 & 0.176 & 0.052 & 0.602 & 0.0056\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3} . Hazard ratio (HR) for CV events derived from Cox
regression model using PS as correction factor.\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{N. of Patients in each group}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{N. of Events}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{HR}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{95\% CI low}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{95\% CI up}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{p-value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
400 (all sample)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
37\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.241\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.09\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.644\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.0046\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
59 (patients taking antiplatelet drug)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
37\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.17\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.065\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.438\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.0003\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figures legends}

Figure 1 -- Box plot of age of patients without CV events (median = 62,
51 Q1 - 68 Q3) vs. patients that suffered an ischemic event (median =
74, 64 Q1 - 77 Q3).

Figure 2 -- Event-free survival curves according to montelukast use.

\textbf{Hosted file}

\verb`Figure-new.pptx`  available at \url{https://authorea.com/users/338558/articles/465052-montelukast-use-decreases-cardiovascular-events-in-asthmatics}

\selectlanguage{english}
\FloatBarrier
\end{document}

