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.