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long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients
EJINME-03644; No of Pages 5 European Journal of Internal Medicine xxx (2017) xxx–xxx
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients Marco Contoli a,1, Gianluca Campo b,c,1, Rita Pavasini b, Irene Marchi a, Alessia Pauletti a, Cristina Balla b, Antonio Spanevello d, Roberto Ferrari b,c,e, Alberto Papi a,⁎ a
Research Centre on Asthma and COPD, Section of Internal and Cardio-Respiratory Medicine, University of Ferrara, Ferrara, Italy Cardiovascular Institute, Azienda Ospedaliero-Universitaria S. Anna, Cona, FE, Italy Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA) Center, Ferrara, Italy d University of Insubria and Fondazione Maugeri, Varese, Italy e Maria Cecilia Hospital, GVM Care & Research, E.S.: Health Science Foundation, Cotignola, Italy b c
a r t i c l e
i n f o
Article history: Received 20 July 2017 Received in revised form 13 August 2017 Accepted 14 August 2017 Available online xxxx Keywords: Chronic pulmonary obstructive disease Ischemic heart disease ST-segment elevation myocardial infarction Treatment Inhaled corticosteroids
a b s t r a c t Background: Patients with myocardial infarction and concomitant COPD are at increased risk of poor clinical outcomes, including death, as compared to patients without COPD. Aim: To investigate and compare the severity of the clinical presentation of ST-segment elevation myocardial infarction (STEMI) and of the short-(7 days) and long-term-(end of follow up) mortality in COPD patients treated with inhaled corticosteroids (ICS)/long-acting bronchodilator (LABD) - either long-acting beta2 agonist (LABA) or long-acting muscarinic antagonist (LAMA) - vs. any other inhaled treatments. Methods: Data from the REAL (Registro Angioplastiche dell'Emilia-Romagna) Registry were obtained from a large prospective study population of 11,118 patients admitted to hospital for STEMI. Results: From January 2003 to June 2009 we identified 2032 COPD patients admitted to hospital for STEMI. Eight hundred and twenty (40%) COPD patients were on ICS/LABD treatment (of which 55% on ICS/LABA) prior to admission. After adjustment for potential confounding factors, ICS/LABD treatment before STEMI was an independent predictor of reduced risk of pulmonary oedema and cardiogenic shock (OR 0.5, 95%CI 0.3–0.72, p b 0.01; OR 0.7, 95%CI 0.4–0.9, p = 0.03, respectively). ICS/LABD treatment was associated to reduced 7-days mortality (OR 0.54, 95%CI 0.29–0.98, p = 0.045) compared to other inhaled regimens. ICS/LABD-treated did not affect longterm (median 4 years) mortality. After hospital discharge, the proportion of ICS/LABD treated patients decreased significantly at 6 months and afterwards after the STEMI episode. Conclusion: Our data provide preliminary evidence that in COPD patients ICS/LABD treatment reduces the severity of STEMI acute-phase clinical manifestations compared to other inhaled treatments. © 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Ischemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) are major causes of morbidity and mortality worldwide [1,2]. COPD and IHD frequently coexist in a single patient [3]. We recently showed that COPD is frequently undiagnosed in smoker patients admitted to hospital because of acute coronary syndrome [4]. Not only the two diseases frequently coexist but COPD, particularly if undiagnosed, negatively impacts in the short and long term prognosis in patients presenting with acute coronary syndrome and treated with percutaneous coronary intervention (PCI) [5]. In particular it has been shown that ⁎ Corresponding author at: Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Via Rampari di S. Rocco, 27, 44121 Ferrara, Italy. E-mail address: [email protected] (A. Papi). 1 These authors equally contributed to the work.
COPD has negative prognostic impact in patients presenting with STsegment elevation myocardial infarction (STEMI), resulting in increased risk of hemodynamic compromise, hospital readmissions and death as compared to those without COPD [6,7]. Given the burden of the two diseases, this comorbid condition represents a major issue in daily clinical practice. Inhaled corticosteroids (ICSs) in association with long-acting beta2 agonists (LABAs) are recommended treatments for COPD patients at high risk of exacerbation [2]. Exacerbations are events characterized by worsening in respiratory symptoms that punctuate the natural history of the disease [2]. Exacerbations, by hampering quality of life [8], accelerating lung function decline [9,10] and increasing mortality [11], have negative impact on the short- and long term prognosis of COPD. Respiratory infections are considered the most frequent pulmonary cause of COPD exacerbations [12]. However, acute cardiovascular events can trigger (or mimic) a COPD exacerbation [13,14] or coexist with the
http://dx.doi.org/10.1016/j.ejim.2017.08.016 0953-6205/© 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: Contoli M, et al, Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.016
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M. Contoli et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
respiratory mechanisms of the acute event. Indeed, clinically significant myocardial injury is frequently identifiable during COPD exacerbations [15,16], and an increase risk in myocardial infarction has been documented in the 2-month after a COPD exacerbation [17]. Thus, prevention of COPD exacerbation can impact on cardiovascular events in COPD. Overall, available data clearly highlight the need for an integrated cardio-respiratory management and treatment in patients with ischemic heart disease and COPD and emphasize the link between exacerbations of COPD and myocardial infarctions. The role and side effects of ICS in COPD has been largely debated in recent years. No study evaluated the effects of ongoing inhaled treatment in COPD patients presenting with acute STEMI. Here we evaluated the effect of (ICS)/long-acting bronchodilator (LABD), either long-acting beta2 agonist (LABA) or long-acting muscarinic antagonist (LAMA), treatment on the clinical outcomes of acute STEMI in COPD patients. For this purpose, we aimed to investigate and compare the severity of the clinical presentation of STEMI and of the short-(7 days) and long-term-(end of follow up) mortality in COPD patients treated with ICS/LABD vs. any other inhaled treatments. 2. Methods 2.1. Study design Data for the present analysis were obtained from a large prospective study population of 11,118 STEMI patients enrolled from January 2003 to June 2009, as previously reported [6,18]. Here, we focused on 2032 patients with a COPD diagnosis before hospital admission for STEMI [6]. The REAL registry was previously described [19]. Briefly, it is a large prospective World Wide Web–based registry launched in July 2002 and designed to collect clinical and angiographic data on all consecutive PCIs performed in a 4-million-resident region of Italy. Thirteen public and private centres of interventional cardiology participate in the data collection. Procedural data are retrieved directly and continuously from the resident databases of each laboratory, which share a common prespecified data set. These data are open for evaluation, and periodic audits are performed by the Regional Health Care Administration. Since the REAL registry is based on current clinical practice in single institutions, the regulatory authorities only required an ordinary written informed consent for coronary intervention and data collection, which was obtained from all patients. 2.2. COPD classification This study was an observational investigation of outcomes after patients' presentation with STEMI. A patient was considered to have COPD combining three different sources of data: i) COPD marked as comorbidity in the REAL dataset; ii) documented history of hospital admission for COPD; iii) treatment with pharmacologic therapies specific for COPD (e.g. inhaled steroids in addition to long acting bronchodilators, inhaled anticholinergics, inhaled β-agonists or theophylline) [6,20]. Pulmonary function tests were not routinely performed to diagnose and assess the severity of COPD. 2.3. Endpoint of the study and follow-up The cumulative all-cause mortality rate, either in-hospital and out of hospital, was estimated. The endpoints were assessed on June 30, 2011 according to the criteria previously reported [6,18]. Follow-up was obtained directly and independently from the Emilia-Romagna Regional Health Agency via an analysis of the hospital discharge records and the mortality registries. This ensures a complete follow-up for 100% of patients that are resident in the region (this is the reason for the a priori exclusion of patients who live outside the region). All repeat interventions during follow-up were also collected prospectively from the single
institutions and matched with the administrative data to adjust for eventual inconsistency. Hospital records were reviewed for additional information whenever deemed necessary. Also, the cause of death was obtained by the analysis of the mortality registries. 2.4. Medical treatment Information about medical therapy was obtained via an analysis of the two computer based systems (“Assistenza Farmaceutica Territoriale” and “Farmaci a Erogazione Diretta”) recording all drug prescriptions to resident patients. COPD patients were classified as ICS/LABD-treated if at least two prescriptions of ICS and of LABD (separate or in a single inhaler) were documented in the 6 months prior to hospital admission for STEMI, in line with the criteria adopted in recent studies investigating similar real world COPD populations [21]. 2.5. Statistical analysis Continuous variables were expressed as mean ± SD and were compared with Student's unpaired t-test. Categorical variables were expressed as counts and percentages, and the χ2 test was used for comparison. The cumulative probability of survival was determined by the Kaplan-Meier method, whereas statistically significant differences between curves were evaluated with the log-rank test. To compensate for the nonrandomized design of our observational study, a propensity score analysis was performed. Multivariable Cox proportional hazard regression models were performed to identify independent predictors of death using all variables listed in Table 1. These models were fitted with an adjustment for the baseline predictor variables and for all variables differing between patients with concomitant COPD vs. those without. All tests were 2-sided and the statistical significance was defined as p b 0.05. All analyses were performed with the SAS 9.1 system (SAS Institute, Cary, North Carolina). 3. Results 3.1. Study population We identified 2032 patients with COPD (demographic characteristics are reported in Table 1) of whom 1361 (67%) had at least one respiratory consultation and/or lung function testing in the year previous the hospitalization. At the time of hospitalization for STEMI, 820 (40%) COPD patients were on ICS/LABD treatment (of which 55% on ICS/ LABA). Baseline characteristics did not differ between study groups (Table 1). 3.2. Effects of ICS/LABD treatment on the severity of STEMI presentation No difference in the length of hospital stay was found between patients treated with ICS/LABD compared to other inhaled treatment regimens (6 ± 3 vs. 6 ± 4 day, respectively p N 0.05). The acute clinical presentation of STEMI was significantly less severe in patients receiving ICS/LABD before hospital admission in terms of pulmonary oedema and cardiogenic shock (Table 2). Consistently, intra-aortic balloon pump use was less frequent in COPD patients treated with ICS-LABD compared to other inhaled treatment regimens (Table 2). After adjustment for potential confounding factors (age, sex, diabetes mellitus, prior MI, prior coronary revascularization, infarct related artery, time symptom's onsetballoon), ICS/LABD treatment before STEMI was an independent predictor of reduced risk of pulmonary oedema and cardiogenic shock (OR 0.5, 95%CI 0.3–0.72, p b 0.01; OR 0.7, 95%CI 0.4–0.9, p = 0.03, respectively). No difference was found in these outcomes between the ICS/LABA and ICS/LAMA. Among patients not treated with ICS, no difference was found in the severity of STEMI manifestation in relation to different treatments (i.e. SABA, LAMA and/or LABA alone treated patients).
Please cite this article as: Contoli M, et al, Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.016
M. Contoli et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx Table 1 Study population.
Age (yr) BMI Men no. (%) COPD treatment ICS/LABA ICS/LAMA SABA LABA LAMA ICS Others CV risk factors, no. (%) Diabetes mellitus Hypertension Current smoker * Former smoker * Hypercholesterolemia Prior medical history, no. (%) Renal failure Myocardial infarction PCI CABG Procedure data Radial artery access no. (%) Infarct related artery no. (%) Left anterior descending Right coronary artery Circumflex Left main Bypass graft TIMI flow 0/1 before PCI no. (%) TIMI flow 3 after PCI no. (%) Multivessel disease no. (%) Reference vessel diameter (mm) Total lesion length (mm) CV therapy at discharge Aspirin, no. (%) P2Y12 inhibitor, no. (%) ACE-I or A2R antagonist no. (%) Statin no. (%) β-Blocker no. (%) Diuretic no. (%)
COPD patients (n = 2032)
No ICS/LABD (n = 1212)
ICS/LABD p (n = 820)
70 ± 12 26.8 ± 4 1341 (66)
71 ± 12 27 ± 4 795 (65)
70 ± 12 26.8 ± 4 546 (66)
0.3 0.8 0.8
443 (22) 1422 (70) 488 (31) 650 (42) 951 (47)
254 (21) 860 (71) 303 (32) 383 (41) 561 (46)
189 (23) 562 (68) 185 (30) 267 (43) 390 (48)
0.4 0.7 0.4 0.6 0.8
55 (3) 345 (17) 221 (11) 65 (3)
33 (3) 189 (16) 121 (10) 35 (3)
22 (3) 156 (19) 100 (12) 30 (4)
0.9 0.1 0.2 0.3
559 (27)
330 (27)
229 (28)
0.8
955 (47) 752 (37) 284 (14) 18 (1) 22 (1) 1321 (65) 1829 (90) 1483 (73) 3 ± 0.5
543 (46) 453 (37) 177 (15) 11 (1) 14 (1) 788 (65) 1082 (89) 897 (74) 3 ± 0.5
396 (48) 299 (36) 107 (13) 7 (1) 8 (1) 533 (65) 747 (91) 586 (71) 3 ± 0.5
0.6 0.9 0.3 0.9 0.8 0.9 0.7 0.6 0.8
20 ± 10
20 ± 10
20 ± 11
0.4
1959 (96) 1930 (95) 1672 (82) 1764 (87) 1747 (86) 859 (42)
1172 (97) 1151 (95) 995 (82) 1047 (86) 1051 (87) 506 (42)
787 (96) 779 (95) 677 (83) 717 (87) 696 (85) 353 (43)
0.9 0.9 0.7 0.9 0.6 0.9
451 (22%) 369 (18%) 388 (19%) 381 (19%) 329 (16%) 33 (1.6%) 81 (4%)
COPD: chronic obstructive pulmonary disease. ICS: inhaled corticosteroid. LABD: long-acting bronchodilator. LABA: long-acting beta2 agonists. LAMA: long-acting muscarinic antagonists; BMI: body mass index. CV: cardiovascular. CABG: coronary artery bypass graft. PCI: percutaneous coronary intervention. TIMI: thrombolysis in myocardial infarction. ACE-I: angiotensin converting enzyme inhibitor. A2R: angiotensin II receptor.* Smoking habit information was available in the 77% of the study population.
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multivariable analysis (including age, sex, diabetes mellitus, renal failure, prior MI, prior coronary revascularization, infarct related artery, TIMI flow before and after procedure), only ICS/LABD treatment but not LABA, LAMA or SABA alone, was associated to reduced 7-days mortality (OR 0.54, 95%CI 0.29–0.98, p = 0.045), with no difference between the ICS/LABA and ICS/LAMA. The use of ICS/LABD treatment (particularly ICS/LABA) decreased significantly at 6 months and afterwards after the STEMI episode (Fig. 1). At the end of follow-up (median 4 years), we observed 477 (23.5%) deaths. Long-term mortality did not differ between ICS/LABD vs. other inhaled treatment regimens both considering the treatment before hospital admission (22% vs. 24%, p = 0.3, OR 0.73, 95%CI 0.47–1.22) and after discharge (23% vs. 24%, p = 0.7, OR 0.57, 95%CI 0.35–1.77).
4. Discussion Our analysis performed in a large real-life cohort of patients suggests a protective effect of ICS/LABD treatment on the acute clinical severity and short-term mortality, but not on the long-term mortality, of patients with COPD who develop a STEMI. Smoking habit is the common risk factor shared by COPD and IHD. Cigarette smoke exposure causes not only airway and lung inflammation (key elements in the pathogenesis of COPD) but also systemic cellular and humoral inflammation, systemic oxidative stress, changes of vasomotor and endothelial function, and enhances circulating concentrations of several procoagulant factors [22]. Interestingly it has been recently shown that arterial stiffness, an early marker of cardiovascular disease, is increased in symptomatic smokers irrespective from the presence of airflow obstruction [23]. The persistent inflammatory responses (local and systemic) by leading to acute/chronic hypoxia, atherosclerosis, arterial stiffness and by favouring coronary plaque instability and heightened platelet reactivity [24], could contribute to the mechanisms underlying the increased risk and more severe manifestation of acute cardiovascular events in patients with COPD [3]. For these reasons, it appears clear that, from a clinical prospective, a tailored and specific therapy for IHD patients with concomitant COPD should be encouraged. On this regards we recently showed that platelet aggregation inhibitor Ticagrelor is superior to Clopidogrel in improving the markers of endothelial function and in the treatment of platelet reactivity in patients with stable coronary artery disease and concomitant COPD [25]. These data suggest that a more powerful platelet inhibition
3.3. Effects of ICS/LABD treatment on short- and long-term STEMI mortality At day-7 after admission, 129 (6%) deaths were recorded. As compared to the other treatments, mortality rate was significantly lower in COPD patients ICS/LABD-treated (5% vs. 7.5%, p = 0.03). After
Table 2 Clinical presentation of ST-segment elevation myocardial infarction (STEMI).
Pulmonary oedema no. (%) Cardiogenic shock no. (%) IABP use no. (%) Heart rate (bpm) Systolic blood pressure (mm Hg)
COPD patients (n = 2032)
No ICS/LABD (n = 1212)
ICS/LABD (n = 820)
p
353 (17) 236 (12) 136 (7) 78 ± 18 125 ± 28
237 (20) 161 (13) 96 (8) 78 ± 18 123 ± 30
116 (14) 75 (9) 40 (5) 77 ± 19 127 ± 28
0.009 0.01 0.02 0.7 0.02
COPD: chronic obstructive pulmonary disease. ICS: inhaled corticosteroid. LABD: long-acting bronchodilator; IABP: intra-aortic balloon pump.
Fig. 1. Patients receiving ICS/LABD treatment across study follow-up (ICS: inhaled corticosteroid. LABD: long-acting bronchodilator. LABA: long-acting beta2 agonist. LAMA: long-acting muscarinic antagonists).
Please cite this article as: Contoli M, et al, Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.016
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M. Contoli et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
(Ticagrenol vs. Clopidogrel [26]) should be preferred in IHD-COPD comorbid patients. On the other site, the effects of specific COPD pharmacological regimens on cardiovascular events and related clinical outcomes are still debated. While there is evidence that inhaled treatments including ICS/ LABA combinations are safe in term of incidence of cardiovascular adverse events, including acute coronary syndrome, stroke palpitations and arrhythmias, even in COPD patients with heightened CVD risk [27], whether in these patients they result in better clinical outcomes is still debated [28]. The mechanisms of the short-term protective effect of ICS/LABD of the severity of STEMI manifestation here documented (Table 2) are unknown. Systemic inflammation has been proposed as a common underlying condition to both COPD and IHD. The pleiotropic role of glucocorticoids in cardiovascular system is well known; they regulated blood pressure [29], heart rhythm, contractility and vascular tone [30]. It is also well known the protective role of glucocorticoids in the perioperative period of cardiac surgery, because of the modulation of the inflammatory responses [31]; thus corticosteroids acting on the inflammatory burden may favour myocardial healing after acute myocardial infarction. The acute manifestation/complications of STEMI such as, pulmonary oedema and cardiogenic shock, are acute life-threatening conditions characterized by massive local/systemic inflammatory burst [32]. We can speculate that COPD treatment containing ICS could reduce local/systemic inflammatory responses, thus mitigating the severity of STEMI acute-phase. While previous studies failed to report a reduction in the inflammatory cell counts and mediator levels in the sputum or airways of patients with COPD treated with ICS [33,34], it has been also shown showed that the withdrawal of inhaled corticosteroids increased serum CRP levels (a very well-known independent cardiovascular risk factor [35]), and that the reintroduction of inhaled ICS could suppress CRP levels [36]. This data suggests that ICS can reduce the risk of cardiovascular events in COPD patients by modulating systemic inflammation. Lung hyperinflation that occurs in COPD patients can impair cardiac function and contractility [37]. Consistently, lung deflation can improve cardiac function [38]. Very recently it has been shown that ICS treatment, alone or in combination with LABA, leads to sustained bronchodilation and reduced lung function decline compared to nonICS containing pharmacological regimens in COPD patients with heightened cardiovascular risk [39]. These function effects on lung function can be responsible for milder STEMI manifestation observed in ICS/ LABD treated patients. Unexpectedly, we observed a significant reduction in ICS/LABD prescription after hospital discharge. The reasons for this change are unclear (possibly related to some old evidence reporting a corticosteroid-induced delay myocardial scar formation [40]) and deserve further investigations. Nevertheless, the results of our population-based study question this attitude, if confirmed prospectively, and specific strategies are needed on cardiologists' practice to minimize this behavior given: i) the increased risk of reinfarction after a cardiac ischemic event and ii) the protective effects of ICS/LABD on acute manifestation of STEMI. It is tempting to speculate that the significant withdrawal of ICS/LABD may have negatively affected the longterm outcomes in our study. However, the results of the recently published SUMMIT study, showing the lack of effect on long-term mortality of a fixed ICS/LABA combination on overall mortality in patients with COPD and concomitant/at risk of cardiovascular disease including IHD, do not support this interpretation [28]. Our COPD study population significantly differs from that of the SUMMIT trial, in particular because of more severe (acute STEMI) manifestation of the cardiovascular comorbidity. Thus, the interpretation of our results cannot be directly inferred from the conclusion of the SUMMIT study, and a long-term benefit of the ICS/LABD treatment cannot be excluded in our population if the treatment were not withdrawn. Some limitations can be recognized in our study.
First, COPD was largely defined by patient report and documentation in patients' medical records. Lung function testing was not required for the identification of COPD patients. The validity and completeness of the data regarding COPD diagnoses (e.g. lung function measurements and disease history) could not be fully verified by spirometry in all cases but it was available in the vast majority of COPD patients. It is possible that using a clinical definition of COPD, rather than pulmonary function testing, may have led to some misclassification, especially in the small proportion of COPD patients who did not perform a lung function testing or respiratory consultation. However, this methodological approach has been previously adopted and validated not only in our cohort of COPD patients but also in similar registries [6,7,21,41]. In addition, this is an observational study and therefore prone to the inherent weakness of this type of study. The analysis performed in our study on patients' medical records provided information only on the presence of lung function testing or respiratory consultation in the years previous the hospitalization but not on the values of lung function. Therefore, we cannot provide any information on the correlation between severity of lung function and the effects of inhaled treatments on STEMI outcomes. Moreover, and even more generally, our data inform on what happens in real life conditions in patients receiving ICS/LABD treatment irrespective of the spirometric/lung function diagnosis of COPD. Interestingly, it has been recently shown that a significant proportion of former or current smokers are regularly treated with respiratory medications because of the presence of chronic respiratory symptoms and that approximately 50% of these treated patients have normal spirometric lung function [42]. Thus, the spirometric definition and classification of COPD could limit the population of patients who might benefit from an inahaltory treatment. Clinical trials assessing the effects of inahaltory treatments in this symptomatic population are needed. Finally, our study does not provide information on the mechanisms through which ICS/LABD treatments result in reduction of STEMI presentation but it generates working hypothesis that need to be assessed by specific studies. In conclusion, in a large study population of COPD patients admitted to hospital for STEMI, we reported a protective effect on the clinical outcomes of the early phase of STEMI of previous ICS/ LABD treatment compared to any other COPD-treatment regimens. Further studies are clearly on demand to confirm and extend our findings. Acknowledgements We thank Elisa Veratelli (University of Ferrara, Ferrara, Italy) for assistance with manuscript preparation. References [1] 2014 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2014;35: 2541–619. http://dx.doi.org/10.1093/eurheartj/ehu278. [2] Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (UPDATED 2017). Available from: www.Goldcopd.com. [n.d.]. [3] Chen W, Thomas J, Sadatsafavi M, Fitzgerald JM. Risk of cardiovascular comorbidity in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Lancet Respir Med 2015;3:631–9. http://dx.doi.org/10.1016/S22132600(15)00241-6. [4] Campo G, Pavasini R, Barbetta C, MSc EM, Mascetti S, Biscaglia S, et al. Int J Cardiol 2016;222:806–12. http://dx.doi.org/10.1016/j.ijcard.2016.08.030. [5] Almagro P, Lapuente A, Pareja J, Yun S, Garcia ME, Padilla F, et al. Underdiagnosis and prognosis of chronic obstructive pulmonary disease after percutaneous coronary intervention: a prospective study. Int J Chron Obstruct Pulmon Dis 2015;10:1353–61. http://dx.doi.org/10.2147/COPD.S84482. [6] Campo G, Guastaroba P, Marzocchi A, Santarelli A, Varani E, Vignali L, et al. Impact of COPD on long-term outcome after ST-segment elevation myocardial infarction receiving primary percutaneous coronary intervention. Chest 2013;144:750. http:// dx.doi.org/10.1378/chest.12-2313. [7] Wakabayashi K, Gonzalez MA, Delhaye C, Ben-Dor I, Maluenda G, Collins SD, et al. Impact of chronic obstructive pulmonary disease on acute-phase outcome of myocardial infarction. Am J Cardiol 2010;106:305–9. http://dx.doi.org/10.1016/j. amjcard.2010.03.026.
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Please cite this article as: Contoli M, et al, Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.016
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients Marco Contoli a,1, Gianluca Campo b,c,1, Rita Pavasini b, Irene Marchi a, Alessia Pauletti a, Cristina Balla b, Antonio Spanevello d, Roberto Ferrari b,c,e, Alberto Papi a,⁎ a
Research Centre on Asthma and COPD, Section of Internal and Cardio-Respiratory Medicine, University of Ferrara, Ferrara, Italy Cardiovascular Institute, Azienda Ospedaliero-Universitaria S. Anna, Cona, FE, Italy Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA) Center, Ferrara, Italy d University of Insubria and Fondazione Maugeri, Varese, Italy e Maria Cecilia Hospital, GVM Care & Research, E.S.: Health Science Foundation, Cotignola, Italy b c
a r t i c l e
i n f o
Article history: Received 20 July 2017 Received in revised form 13 August 2017 Accepted 14 August 2017 Available online xxxx Keywords: Chronic pulmonary obstructive disease Ischemic heart disease ST-segment elevation myocardial infarction Treatment Inhaled corticosteroids
a b s t r a c t Background: Patients with myocardial infarction and concomitant COPD are at increased risk of poor clinical outcomes, including death, as compared to patients without COPD. Aim: To investigate and compare the severity of the clinical presentation of ST-segment elevation myocardial infarction (STEMI) and of the short-(7 days) and long-term-(end of follow up) mortality in COPD patients treated with inhaled corticosteroids (ICS)/long-acting bronchodilator (LABD) - either long-acting beta2 agonist (LABA) or long-acting muscarinic antagonist (LAMA) - vs. any other inhaled treatments. Methods: Data from the REAL (Registro Angioplastiche dell'Emilia-Romagna) Registry were obtained from a large prospective study population of 11,118 patients admitted to hospital for STEMI. Results: From January 2003 to June 2009 we identified 2032 COPD patients admitted to hospital for STEMI. Eight hundred and twenty (40%) COPD patients were on ICS/LABD treatment (of which 55% on ICS/LABA) prior to admission. After adjustment for potential confounding factors, ICS/LABD treatment before STEMI was an independent predictor of reduced risk of pulmonary oedema and cardiogenic shock (OR 0.5, 95%CI 0.3–0.72, p b 0.01; OR 0.7, 95%CI 0.4–0.9, p = 0.03, respectively). ICS/LABD treatment was associated to reduced 7-days mortality (OR 0.54, 95%CI 0.29–0.98, p = 0.045) compared to other inhaled regimens. ICS/LABD-treated did not affect longterm (median 4 years) mortality. After hospital discharge, the proportion of ICS/LABD treated patients decreased significantly at 6 months and afterwards after the STEMI episode. Conclusion: Our data provide preliminary evidence that in COPD patients ICS/LABD treatment reduces the severity of STEMI acute-phase clinical manifestations compared to other inhaled treatments. © 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Ischemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) are major causes of morbidity and mortality worldwide [1,2]. COPD and IHD frequently coexist in a single patient [3]. We recently showed that COPD is frequently undiagnosed in smoker patients admitted to hospital because of acute coronary syndrome [4]. Not only the two diseases frequently coexist but COPD, particularly if undiagnosed, negatively impacts in the short and long term prognosis in patients presenting with acute coronary syndrome and treated with percutaneous coronary intervention (PCI) [5]. In particular it has been shown that ⁎ Corresponding author at: Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Via Rampari di S. Rocco, 27, 44121 Ferrara, Italy. E-mail address: [email protected] (A. Papi). 1 These authors equally contributed to the work.
COPD has negative prognostic impact in patients presenting with STsegment elevation myocardial infarction (STEMI), resulting in increased risk of hemodynamic compromise, hospital readmissions and death as compared to those without COPD [6,7]. Given the burden of the two diseases, this comorbid condition represents a major issue in daily clinical practice. Inhaled corticosteroids (ICSs) in association with long-acting beta2 agonists (LABAs) are recommended treatments for COPD patients at high risk of exacerbation [2]. Exacerbations are events characterized by worsening in respiratory symptoms that punctuate the natural history of the disease [2]. Exacerbations, by hampering quality of life [8], accelerating lung function decline [9,10] and increasing mortality [11], have negative impact on the short- and long term prognosis of COPD. Respiratory infections are considered the most frequent pulmonary cause of COPD exacerbations [12]. However, acute cardiovascular events can trigger (or mimic) a COPD exacerbation [13,14] or coexist with the
http://dx.doi.org/10.1016/j.ejim.2017.08.016 0953-6205/© 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: Contoli M, et al, Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.016
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M. Contoli et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
respiratory mechanisms of the acute event. Indeed, clinically significant myocardial injury is frequently identifiable during COPD exacerbations [15,16], and an increase risk in myocardial infarction has been documented in the 2-month after a COPD exacerbation [17]. Thus, prevention of COPD exacerbation can impact on cardiovascular events in COPD. Overall, available data clearly highlight the need for an integrated cardio-respiratory management and treatment in patients with ischemic heart disease and COPD and emphasize the link between exacerbations of COPD and myocardial infarctions. The role and side effects of ICS in COPD has been largely debated in recent years. No study evaluated the effects of ongoing inhaled treatment in COPD patients presenting with acute STEMI. Here we evaluated the effect of (ICS)/long-acting bronchodilator (LABD), either long-acting beta2 agonist (LABA) or long-acting muscarinic antagonist (LAMA), treatment on the clinical outcomes of acute STEMI in COPD patients. For this purpose, we aimed to investigate and compare the severity of the clinical presentation of STEMI and of the short-(7 days) and long-term-(end of follow up) mortality in COPD patients treated with ICS/LABD vs. any other inhaled treatments. 2. Methods 2.1. Study design Data for the present analysis were obtained from a large prospective study population of 11,118 STEMI patients enrolled from January 2003 to June 2009, as previously reported [6,18]. Here, we focused on 2032 patients with a COPD diagnosis before hospital admission for STEMI [6]. The REAL registry was previously described [19]. Briefly, it is a large prospective World Wide Web–based registry launched in July 2002 and designed to collect clinical and angiographic data on all consecutive PCIs performed in a 4-million-resident region of Italy. Thirteen public and private centres of interventional cardiology participate in the data collection. Procedural data are retrieved directly and continuously from the resident databases of each laboratory, which share a common prespecified data set. These data are open for evaluation, and periodic audits are performed by the Regional Health Care Administration. Since the REAL registry is based on current clinical practice in single institutions, the regulatory authorities only required an ordinary written informed consent for coronary intervention and data collection, which was obtained from all patients. 2.2. COPD classification This study was an observational investigation of outcomes after patients' presentation with STEMI. A patient was considered to have COPD combining three different sources of data: i) COPD marked as comorbidity in the REAL dataset; ii) documented history of hospital admission for COPD; iii) treatment with pharmacologic therapies specific for COPD (e.g. inhaled steroids in addition to long acting bronchodilators, inhaled anticholinergics, inhaled β-agonists or theophylline) [6,20]. Pulmonary function tests were not routinely performed to diagnose and assess the severity of COPD. 2.3. Endpoint of the study and follow-up The cumulative all-cause mortality rate, either in-hospital and out of hospital, was estimated. The endpoints were assessed on June 30, 2011 according to the criteria previously reported [6,18]. Follow-up was obtained directly and independently from the Emilia-Romagna Regional Health Agency via an analysis of the hospital discharge records and the mortality registries. This ensures a complete follow-up for 100% of patients that are resident in the region (this is the reason for the a priori exclusion of patients who live outside the region). All repeat interventions during follow-up were also collected prospectively from the single
institutions and matched with the administrative data to adjust for eventual inconsistency. Hospital records were reviewed for additional information whenever deemed necessary. Also, the cause of death was obtained by the analysis of the mortality registries. 2.4. Medical treatment Information about medical therapy was obtained via an analysis of the two computer based systems (“Assistenza Farmaceutica Territoriale” and “Farmaci a Erogazione Diretta”) recording all drug prescriptions to resident patients. COPD patients were classified as ICS/LABD-treated if at least two prescriptions of ICS and of LABD (separate or in a single inhaler) were documented in the 6 months prior to hospital admission for STEMI, in line with the criteria adopted in recent studies investigating similar real world COPD populations [21]. 2.5. Statistical analysis Continuous variables were expressed as mean ± SD and were compared with Student's unpaired t-test. Categorical variables were expressed as counts and percentages, and the χ2 test was used for comparison. The cumulative probability of survival was determined by the Kaplan-Meier method, whereas statistically significant differences between curves were evaluated with the log-rank test. To compensate for the nonrandomized design of our observational study, a propensity score analysis was performed. Multivariable Cox proportional hazard regression models were performed to identify independent predictors of death using all variables listed in Table 1. These models were fitted with an adjustment for the baseline predictor variables and for all variables differing between patients with concomitant COPD vs. those without. All tests were 2-sided and the statistical significance was defined as p b 0.05. All analyses were performed with the SAS 9.1 system (SAS Institute, Cary, North Carolina). 3. Results 3.1. Study population We identified 2032 patients with COPD (demographic characteristics are reported in Table 1) of whom 1361 (67%) had at least one respiratory consultation and/or lung function testing in the year previous the hospitalization. At the time of hospitalization for STEMI, 820 (40%) COPD patients were on ICS/LABD treatment (of which 55% on ICS/ LABA). Baseline characteristics did not differ between study groups (Table 1). 3.2. Effects of ICS/LABD treatment on the severity of STEMI presentation No difference in the length of hospital stay was found between patients treated with ICS/LABD compared to other inhaled treatment regimens (6 ± 3 vs. 6 ± 4 day, respectively p N 0.05). The acute clinical presentation of STEMI was significantly less severe in patients receiving ICS/LABD before hospital admission in terms of pulmonary oedema and cardiogenic shock (Table 2). Consistently, intra-aortic balloon pump use was less frequent in COPD patients treated with ICS-LABD compared to other inhaled treatment regimens (Table 2). After adjustment for potential confounding factors (age, sex, diabetes mellitus, prior MI, prior coronary revascularization, infarct related artery, time symptom's onsetballoon), ICS/LABD treatment before STEMI was an independent predictor of reduced risk of pulmonary oedema and cardiogenic shock (OR 0.5, 95%CI 0.3–0.72, p b 0.01; OR 0.7, 95%CI 0.4–0.9, p = 0.03, respectively). No difference was found in these outcomes between the ICS/LABA and ICS/LAMA. Among patients not treated with ICS, no difference was found in the severity of STEMI manifestation in relation to different treatments (i.e. SABA, LAMA and/or LABA alone treated patients).
Please cite this article as: Contoli M, et al, Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.016
M. Contoli et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx Table 1 Study population.
Age (yr) BMI Men no. (%) COPD treatment ICS/LABA ICS/LAMA SABA LABA LAMA ICS Others CV risk factors, no. (%) Diabetes mellitus Hypertension Current smoker * Former smoker * Hypercholesterolemia Prior medical history, no. (%) Renal failure Myocardial infarction PCI CABG Procedure data Radial artery access no. (%) Infarct related artery no. (%) Left anterior descending Right coronary artery Circumflex Left main Bypass graft TIMI flow 0/1 before PCI no. (%) TIMI flow 3 after PCI no. (%) Multivessel disease no. (%) Reference vessel diameter (mm) Total lesion length (mm) CV therapy at discharge Aspirin, no. (%) P2Y12 inhibitor, no. (%) ACE-I or A2R antagonist no. (%) Statin no. (%) β-Blocker no. (%) Diuretic no. (%)
COPD patients (n = 2032)
No ICS/LABD (n = 1212)
ICS/LABD p (n = 820)
70 ± 12 26.8 ± 4 1341 (66)
71 ± 12 27 ± 4 795 (65)
70 ± 12 26.8 ± 4 546 (66)
0.3 0.8 0.8
443 (22) 1422 (70) 488 (31) 650 (42) 951 (47)
254 (21) 860 (71) 303 (32) 383 (41) 561 (46)
189 (23) 562 (68) 185 (30) 267 (43) 390 (48)
0.4 0.7 0.4 0.6 0.8
55 (3) 345 (17) 221 (11) 65 (3)
33 (3) 189 (16) 121 (10) 35 (3)
22 (3) 156 (19) 100 (12) 30 (4)
0.9 0.1 0.2 0.3
559 (27)
330 (27)
229 (28)
0.8
955 (47) 752 (37) 284 (14) 18 (1) 22 (1) 1321 (65) 1829 (90) 1483 (73) 3 ± 0.5
543 (46) 453 (37) 177 (15) 11 (1) 14 (1) 788 (65) 1082 (89) 897 (74) 3 ± 0.5
396 (48) 299 (36) 107 (13) 7 (1) 8 (1) 533 (65) 747 (91) 586 (71) 3 ± 0.5
0.6 0.9 0.3 0.9 0.8 0.9 0.7 0.6 0.8
20 ± 10
20 ± 10
20 ± 11
0.4
1959 (96) 1930 (95) 1672 (82) 1764 (87) 1747 (86) 859 (42)
1172 (97) 1151 (95) 995 (82) 1047 (86) 1051 (87) 506 (42)
787 (96) 779 (95) 677 (83) 717 (87) 696 (85) 353 (43)
0.9 0.9 0.7 0.9 0.6 0.9
451 (22%) 369 (18%) 388 (19%) 381 (19%) 329 (16%) 33 (1.6%) 81 (4%)
COPD: chronic obstructive pulmonary disease. ICS: inhaled corticosteroid. LABD: long-acting bronchodilator. LABA: long-acting beta2 agonists. LAMA: long-acting muscarinic antagonists; BMI: body mass index. CV: cardiovascular. CABG: coronary artery bypass graft. PCI: percutaneous coronary intervention. TIMI: thrombolysis in myocardial infarction. ACE-I: angiotensin converting enzyme inhibitor. A2R: angiotensin II receptor.* Smoking habit information was available in the 77% of the study population.
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multivariable analysis (including age, sex, diabetes mellitus, renal failure, prior MI, prior coronary revascularization, infarct related artery, TIMI flow before and after procedure), only ICS/LABD treatment but not LABA, LAMA or SABA alone, was associated to reduced 7-days mortality (OR 0.54, 95%CI 0.29–0.98, p = 0.045), with no difference between the ICS/LABA and ICS/LAMA. The use of ICS/LABD treatment (particularly ICS/LABA) decreased significantly at 6 months and afterwards after the STEMI episode (Fig. 1). At the end of follow-up (median 4 years), we observed 477 (23.5%) deaths. Long-term mortality did not differ between ICS/LABD vs. other inhaled treatment regimens both considering the treatment before hospital admission (22% vs. 24%, p = 0.3, OR 0.73, 95%CI 0.47–1.22) and after discharge (23% vs. 24%, p = 0.7, OR 0.57, 95%CI 0.35–1.77).
4. Discussion Our analysis performed in a large real-life cohort of patients suggests a protective effect of ICS/LABD treatment on the acute clinical severity and short-term mortality, but not on the long-term mortality, of patients with COPD who develop a STEMI. Smoking habit is the common risk factor shared by COPD and IHD. Cigarette smoke exposure causes not only airway and lung inflammation (key elements in the pathogenesis of COPD) but also systemic cellular and humoral inflammation, systemic oxidative stress, changes of vasomotor and endothelial function, and enhances circulating concentrations of several procoagulant factors [22]. Interestingly it has been recently shown that arterial stiffness, an early marker of cardiovascular disease, is increased in symptomatic smokers irrespective from the presence of airflow obstruction [23]. The persistent inflammatory responses (local and systemic) by leading to acute/chronic hypoxia, atherosclerosis, arterial stiffness and by favouring coronary plaque instability and heightened platelet reactivity [24], could contribute to the mechanisms underlying the increased risk and more severe manifestation of acute cardiovascular events in patients with COPD [3]. For these reasons, it appears clear that, from a clinical prospective, a tailored and specific therapy for IHD patients with concomitant COPD should be encouraged. On this regards we recently showed that platelet aggregation inhibitor Ticagrelor is superior to Clopidogrel in improving the markers of endothelial function and in the treatment of platelet reactivity in patients with stable coronary artery disease and concomitant COPD [25]. These data suggest that a more powerful platelet inhibition
3.3. Effects of ICS/LABD treatment on short- and long-term STEMI mortality At day-7 after admission, 129 (6%) deaths were recorded. As compared to the other treatments, mortality rate was significantly lower in COPD patients ICS/LABD-treated (5% vs. 7.5%, p = 0.03). After
Table 2 Clinical presentation of ST-segment elevation myocardial infarction (STEMI).
Pulmonary oedema no. (%) Cardiogenic shock no. (%) IABP use no. (%) Heart rate (bpm) Systolic blood pressure (mm Hg)
COPD patients (n = 2032)
No ICS/LABD (n = 1212)
ICS/LABD (n = 820)
p
353 (17) 236 (12) 136 (7) 78 ± 18 125 ± 28
237 (20) 161 (13) 96 (8) 78 ± 18 123 ± 30
116 (14) 75 (9) 40 (5) 77 ± 19 127 ± 28
0.009 0.01 0.02 0.7 0.02
COPD: chronic obstructive pulmonary disease. ICS: inhaled corticosteroid. LABD: long-acting bronchodilator; IABP: intra-aortic balloon pump.
Fig. 1. Patients receiving ICS/LABD treatment across study follow-up (ICS: inhaled corticosteroid. LABD: long-acting bronchodilator. LABA: long-acting beta2 agonist. LAMA: long-acting muscarinic antagonists).
Please cite this article as: Contoli M, et al, Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.016
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(Ticagrenol vs. Clopidogrel [26]) should be preferred in IHD-COPD comorbid patients. On the other site, the effects of specific COPD pharmacological regimens on cardiovascular events and related clinical outcomes are still debated. While there is evidence that inhaled treatments including ICS/ LABA combinations are safe in term of incidence of cardiovascular adverse events, including acute coronary syndrome, stroke palpitations and arrhythmias, even in COPD patients with heightened CVD risk [27], whether in these patients they result in better clinical outcomes is still debated [28]. The mechanisms of the short-term protective effect of ICS/LABD of the severity of STEMI manifestation here documented (Table 2) are unknown. Systemic inflammation has been proposed as a common underlying condition to both COPD and IHD. The pleiotropic role of glucocorticoids in cardiovascular system is well known; they regulated blood pressure [29], heart rhythm, contractility and vascular tone [30]. It is also well known the protective role of glucocorticoids in the perioperative period of cardiac surgery, because of the modulation of the inflammatory responses [31]; thus corticosteroids acting on the inflammatory burden may favour myocardial healing after acute myocardial infarction. The acute manifestation/complications of STEMI such as, pulmonary oedema and cardiogenic shock, are acute life-threatening conditions characterized by massive local/systemic inflammatory burst [32]. We can speculate that COPD treatment containing ICS could reduce local/systemic inflammatory responses, thus mitigating the severity of STEMI acute-phase. While previous studies failed to report a reduction in the inflammatory cell counts and mediator levels in the sputum or airways of patients with COPD treated with ICS [33,34], it has been also shown showed that the withdrawal of inhaled corticosteroids increased serum CRP levels (a very well-known independent cardiovascular risk factor [35]), and that the reintroduction of inhaled ICS could suppress CRP levels [36]. This data suggests that ICS can reduce the risk of cardiovascular events in COPD patients by modulating systemic inflammation. Lung hyperinflation that occurs in COPD patients can impair cardiac function and contractility [37]. Consistently, lung deflation can improve cardiac function [38]. Very recently it has been shown that ICS treatment, alone or in combination with LABA, leads to sustained bronchodilation and reduced lung function decline compared to nonICS containing pharmacological regimens in COPD patients with heightened cardiovascular risk [39]. These function effects on lung function can be responsible for milder STEMI manifestation observed in ICS/ LABD treated patients. Unexpectedly, we observed a significant reduction in ICS/LABD prescription after hospital discharge. The reasons for this change are unclear (possibly related to some old evidence reporting a corticosteroid-induced delay myocardial scar formation [40]) and deserve further investigations. Nevertheless, the results of our population-based study question this attitude, if confirmed prospectively, and specific strategies are needed on cardiologists' practice to minimize this behavior given: i) the increased risk of reinfarction after a cardiac ischemic event and ii) the protective effects of ICS/LABD on acute manifestation of STEMI. It is tempting to speculate that the significant withdrawal of ICS/LABD may have negatively affected the longterm outcomes in our study. However, the results of the recently published SUMMIT study, showing the lack of effect on long-term mortality of a fixed ICS/LABA combination on overall mortality in patients with COPD and concomitant/at risk of cardiovascular disease including IHD, do not support this interpretation [28]. Our COPD study population significantly differs from that of the SUMMIT trial, in particular because of more severe (acute STEMI) manifestation of the cardiovascular comorbidity. Thus, the interpretation of our results cannot be directly inferred from the conclusion of the SUMMIT study, and a long-term benefit of the ICS/LABD treatment cannot be excluded in our population if the treatment were not withdrawn. Some limitations can be recognized in our study.
First, COPD was largely defined by patient report and documentation in patients' medical records. Lung function testing was not required for the identification of COPD patients. The validity and completeness of the data regarding COPD diagnoses (e.g. lung function measurements and disease history) could not be fully verified by spirometry in all cases but it was available in the vast majority of COPD patients. It is possible that using a clinical definition of COPD, rather than pulmonary function testing, may have led to some misclassification, especially in the small proportion of COPD patients who did not perform a lung function testing or respiratory consultation. However, this methodological approach has been previously adopted and validated not only in our cohort of COPD patients but also in similar registries [6,7,21,41]. In addition, this is an observational study and therefore prone to the inherent weakness of this type of study. The analysis performed in our study on patients' medical records provided information only on the presence of lung function testing or respiratory consultation in the years previous the hospitalization but not on the values of lung function. Therefore, we cannot provide any information on the correlation between severity of lung function and the effects of inhaled treatments on STEMI outcomes. Moreover, and even more generally, our data inform on what happens in real life conditions in patients receiving ICS/LABD treatment irrespective of the spirometric/lung function diagnosis of COPD. Interestingly, it has been recently shown that a significant proportion of former or current smokers are regularly treated with respiratory medications because of the presence of chronic respiratory symptoms and that approximately 50% of these treated patients have normal spirometric lung function [42]. Thus, the spirometric definition and classification of COPD could limit the population of patients who might benefit from an inahaltory treatment. Clinical trials assessing the effects of inahaltory treatments in this symptomatic population are needed. Finally, our study does not provide information on the mechanisms through which ICS/LABD treatments result in reduction of STEMI presentation but it generates working hypothesis that need to be assessed by specific studies. In conclusion, in a large study population of COPD patients admitted to hospital for STEMI, we reported a protective effect on the clinical outcomes of the early phase of STEMI of previous ICS/ LABD treatment compared to any other COPD-treatment regimens. Further studies are clearly on demand to confirm and extend our findings. Acknowledgements We thank Elisa Veratelli (University of Ferrara, Ferrara, Italy) for assistance with manuscript preparation. References [1] 2014 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2014;35: 2541–619. http://dx.doi.org/10.1093/eurheartj/ehu278. [2] Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (UPDATED 2017). Available from: www.Goldcopd.com. [n.d.]. [3] Chen W, Thomas J, Sadatsafavi M, Fitzgerald JM. Risk of cardiovascular comorbidity in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Lancet Respir Med 2015;3:631–9. http://dx.doi.org/10.1016/S22132600(15)00241-6. [4] Campo G, Pavasini R, Barbetta C, MSc EM, Mascetti S, Biscaglia S, et al. Int J Cardiol 2016;222:806–12. http://dx.doi.org/10.1016/j.ijcard.2016.08.030. [5] Almagro P, Lapuente A, Pareja J, Yun S, Garcia ME, Padilla F, et al. Underdiagnosis and prognosis of chronic obstructive pulmonary disease after percutaneous coronary intervention: a prospective study. Int J Chron Obstruct Pulmon Dis 2015;10:1353–61. http://dx.doi.org/10.2147/COPD.S84482. [6] Campo G, Guastaroba P, Marzocchi A, Santarelli A, Varani E, Vignali L, et al. Impact of COPD on long-term outcome after ST-segment elevation myocardial infarction receiving primary percutaneous coronary intervention. Chest 2013;144:750. http:// dx.doi.org/10.1378/chest.12-2313. [7] Wakabayashi K, Gonzalez MA, Delhaye C, Ben-Dor I, Maluenda G, Collins SD, et al. Impact of chronic obstructive pulmonary disease on acute-phase outcome of myocardial infarction. Am J Cardiol 2010;106:305–9. http://dx.doi.org/10.1016/j. amjcard.2010.03.026.
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Please cite this article as: Contoli M, et al, Inhaled corticosteroid/long-acting bronchodilator treatment mitigates STEMI clinical presentation in COPD patients, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.016