Recent trends in management and outcome of ...

IJCA-25349; No of Pages 7 International Journal of Cardiology xxx (2017) xxx–xxx

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Recent trends in management and outcome of patients with acute coronary syndromes and atrial fibrillation Leonardo De Luca a, Gianni Casella b, Andrea Rubboli b, Lucio Gonzini c, Donata Lucci c, Alessandro Boccanelli d, Francesco Chiarella e, Antonio Di Chiara f, Stefano De Servi g, Andrea Di Lenarda h, Giuseppe Di Pasquale b, Stefano Savonitto i,⁎ a

Division of Cardiology, San Giovanni Evangelista Hospital, Tivoli, Rome, Italy Department of Cardiology, Maggiore Hospital, Bologna, Italy c ANMCO Research Center, Florence, Italy d Department of Cardiovascular Diseases, S. Giovanni-Addolorata Hospital, Rome, Italy e Division of Cardiology, Azienda Ospedaliera-Universitaria S. Martino, Genova, Italy f Division of Cardiology, Ospedale Sant'Antonio Abate, Tolmezzo, Italy g Division of Cardiology, IRCCS Multimedica, Sesto San Giovanni, Milano, Italy h Division of Cardiology, Azienda Sanitaria Universitaria Integrata di Trieste, Italy i Division of Cardiology, Ospedale A. Manzoni, Lecco, Italy b

a r t i c l e

i n f o

Article history: Received 24 April 2017 Received in revised form 15 July 2017 Accepted 8 August 2017 Available online xxxx Keywords: Acute coronary syndromes Atrial fibrillation Epidemiology Registries

a b s t r a c t Aims: To describe the clinical characteristics, contemporary trends of in-hospital management and outcome of patients admitted for an acute coronary syndrome (ACS) with associated atrial fibrillation (AF). Methods: We analyzed data from four Italian nationwide prospective registries, conducted between 2001 and 2014, including consecutive ACS patients. Results: Out of 16,803 ACS patients, 1019 (6.1%) presented with concomitant AF: 668 with non-ST elevation (NSTE)-ACS and 351 with ST-elevation myocardial infarction (STEMI). As compared to no-AF patients, those with AF were older and had significantly more prior cardiac events and comorbidities (all p b 0.005). A progressive increase occurred over time in the rates of coronary angiography and percutaneous coronary intervention, both in NSTE-ACS (p for trend = 0.0002 and 0.0008, respectively) and STEMI patients with AF at admission (both p for trend b 0.0001), with trends similar to those observed in non-AF patients. Among STEMI patients, in-hospital mortality decreased by 50% in those without AF (7.5% in 2001 to 3.3% in 2014, p b 0.0001), with a similar decrease in those with AF (20% vs 10.7%, p = 0.20), even though not statistically significant. At multivariable analysis, AF on admission was not an independent predictor of in-hospital mortality [odds ratio (OR): 0.82; 95% confidence intervals (CI): 0.52–1.30; p = 0.41 for NSTE-ACS, and OR: 1.07; 95% CI: 0.73–1.57; p = 0.74 for STEMI]. Conclusions: Over the last 14 years, the in-hospital management of ACS patients with AF has significantly improved as for patients without AF, with comparable effect in terms of outcome. © 2017 Published by Elsevier Ireland Ltd.

1. Introduction Across the spectrum of acute coronary syndrome (ACS), patients with atrial fibrillation (AF) represent a challenging population, with multiple aspects to manage during hospitalization and an increased mortality risk compared to patients without AF [1,2]. There are very limited data available, particularly from a representative, population-based perspective, to describe contemporary and

⁎ Corresponding author at: Division of Cardiology, Alessandro Manzoni Hospital, Via dell'Eremo, 9/11, 23900 Lecco, Italy. E-mail addresses: [email protected], [email protected] (S. Savonitto).

changing trends in the epidemiology, treatments and clinical event rates for patients with ACS and AF [3,4]. In the present study, we describe the evolution of in-hospital management and outcome for ACS patients with AF admitted to cardiac care units (CCUs) from 2001 to 2014 in Italy. 2. Methods Four prospective registries designed by the Italian Association of Hospital Cardiologists (ANMCO) in patients with ACS were conducted in Italy between 2001 and 2014: BLITZ in 2001 [5], IN-ACS Outcome (Italian Network on Acute Coronary Syndromes Outcome) in 2006–2007 [6], MANTRA (Management of patients with ACS in the real world practice in Italy: an outcome research study focused on the use of ANTithRombotic Agents) in 2009–2010 [7], and EYESHOT (EmploYEd antithrombotic therapies in patients

http://dx.doi.org/10.1016/j.ijcard.2017.08.019 0167-5273/© 2017 Published by Elsevier Ireland Ltd.

Please cite this article as: L. De Luca, et al., Recent trends in management and outcome of patients with acute coronary syndromes and atrial fibrillation, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.08.019 Downloaded for Anonymous User (n/a) at GOT-CILEA - Local Health Agency Unit Bologna from ClinicalKey.com by Elsevier on August 20, 2017. For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.

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L. De Luca et al. / International Journal of Cardiology xxx (2017) xxx–xxx

with acute coronary Syndromes HOspitalized in iTalian cardiac care units) in 2013–2014 [8]. All surveys were nationwide and included patients with ACS consecutively admitted to the participating CCUs during a pre-specified period (few weeks for the BLITZ and EYESHOT registries and 1 year for IN-ACS Outcome and MANTRA) (Table 1 Supplemental material). The methods used for each registry have been described previously [5–8]. Briefly, their primary objectives were to evaluate the clinical characteristics, management, and outcomes of consecutive patients with ACS admitted to Italian CCUs, using a catchment method broad enough to provide data representative of the entire country. Participation in the various registries had been offered to all institutions in BLITZ and EYESHOT and to a representative sample of CCUs (balanced by geographical region and hospital complexity) in IN-ACS Outcome and MANTRA. Physicians were instructed that participation in the registries should not affect clinical care or management. Informed consent was obtained from all patients who were aware of the nature and aims of the registries. Local Institutional Review Boards were informed of the study according to the Italian rules and approved the protocol.

2.1. Data collection Data on baseline characteristics, including demographics, risk factors and medical history, were collected as previously described [5–8]. Information on the use of cardiac procedures, including coronary angiography, type of revascularization therapy (if any), use of medications during hospitalization and at hospital discharge, and in-hospital major clinical events, were recorded. For the present analysis, we focused on patients with a documented AF on admission, comparing them to patients without AF on admission. The definitions of inclusion criteria and outcome events were consistent throughout the surveys. ST-segment elevation myocardial infarction (STEMI) was defined in the case of an ECG showing ST-segment elevation N1 mm (0.1 mV) in 2 or more contiguous precordial leads or in 2 or more adjacent limb leads lasting for N20 min, or new or presumed new left bundle branch block associated with symptoms suggestive of ACS [9]. All other cases with a clinical presentation suggestive of acute myocardial ischemia, with or without acute ischemic changes on the ECG were define as non-ST-elevation ACS (NSTE-ACS) [10]. Re-infarction during initial hospitalization was diagnosed in the presence of new ischemic symptoms and a re-elevation of biochemical myocardial necrosis markers with or without concurrent ECG changes. Major bleeding was classified according to the Thrombolysis In Myocardial Infarction (TIMI) criteria [11]. Stroke was identified as an acute neurologic deficit lasting N24 h and affecting the ability to perform daily activities with or without confirmation by imaging techniques. All data were collected using a case report form (CRF) at the participating centers and entered in a centralized database located at the ANMCO Research Center (Florence, Italy). By using a validation plan integrated in the data entry software, data were checked with data queries for missing or contradictory entries and values out of the normal range. The data were also centrally audited at the coordinating center.

area, and no reperfusion for reperfusive strategy). All tests were 2-sided; a p value b0.05 was considered statistically significant. All analyses were conducted with SAS system software version 9.2 (SAS Institute Inc., Cary, NC, USA).

3. Results 3.1. Patient characteristics Out of 16,803 patients with ACS enrolled in the 4 registries (9247 with NSTE-ACS and 7556 with STEMI), 1019 (6.1%) had AF on admission [668 of those with NSTE-ACS (7.2%) and 351 with STEMI (4.7%), p b 0.0001 for NSTEACS vs STEMI]. The rates of patients with AF enrolled in each registry are reported in Table 1 Supplemental material. As compared to patients without AF, those with AF were significantly older, more frequently women, had significantly more diabetes, hypertension and chronic kidney dysfunction, as well as a more prevalent history of angina, myocardial infarction and stroke/TIA. Patients with AF also had a worse haemodynamic condition on admission, including lower systolic BP, higher heart rate, lower ejection fraction and a higher rate of Killip IV class (Table 1). These differences were highly consistent in STEMI and NSTE-ACS, and reflect into a significantly higher CHA2DS2-VASc score among AF patients (Table 1).

Table 1 Clinical characteristics of ACS patients according to AF status at admission.

Age, yrs. (mean ± SD) Male BMI (mean ± SD) Active smokers Diabetes mellitus

2.2. Statistical analysis Categorical variables were reported as numbers and percentages and compared by Chi-square test, whereas continuous variables were reported as means and standard deviations and compared by t-test or analysis of variance (ANOVA), if normally distributed, or by Mann-Whitney U test and Kruskal–Wallis test, if not. All the analyses were performed considering the index ACS diagnosis at hospital admission (i.e. NSTE-ACS or STEMI). Temporal trends were tested using the Cochran-Armitage test for binary variables and the Kendall Tau rank correlation coefficient with the Jonckheere-Terpstra test for continuous variables. A multivariable analysis (logistic regression) was performed to estimate the risk of in-hospital mortality over time, both in STEMI and in NSTE-ACS patients, adjusting for study cohort, atrial fibrillation at entry, reperfusion therapy (for STEMI), revascularization (for NSTE-ACS), type of hospital (for NSTE-ACS), geographic area, and for risk factors and baseline characteristics significantly associated with in-hospital mortality at a previous univariate analysis. Also, female sex, age (as continuous), smoking, diabetes mellitus, hypertension on treatment, prior angina, prior MI, prior heart failure, peripheral artery disease, prior stroke/TIA, prior renal dysfunction, Killip IV class at entry, anterior MI, systolic blood pressure (as continuous), and heart rate at entry (as continuous), were considered for STEMI patients, while female sex, age (as continuous), smoking, diabetes mellitus, prior MI, prior revascularization [percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)], prior heart failure, peripheral artery disease, prior stroke/TIA, prior renal dysfunction, Killip IV class at entry, ECG changes, systolic blood pressure at entry (as continuous), heart rate at entry (as continuous), were considered for NSTE-ACS patients. Furthermore, a logistic regression analysis on in-hospital mortality was performed, separately for STEMI e NSTE-ACS, only among patients with AF at entry, adjusting for the following variables of clinical interest: CHA2DS2-VASc ≥2, previous renal dysfunction, Killip class IV at entry, systolic blood pressure and heart rate (continuous) at entry, ejection fraction at entry/during hospital stay ≤40%, reperfusion strategy (for STEMI), and revascularization (for NSTE-ACS). Finally, a logistic regression analysis on OAT therapy prescription at discharge was performed, separately for STEMI and NSTE-ACS, on patients with AF at entry adjusting for the following variables of clinical interest: CHA2DS2-VASc ≥2, previous renal dysfunction, reinfarction, ischemic stroke and major bleedings during hospital stay, reperfusion strategy (for STEMI) and revascularization (for NSTE-ACS). When more than two categories were present, dummy variables were introduced to define a reference group (i.e., year 2001 for study cohort, north for geographic

Hypertension Chronic kidney disease PAD Previous stroke/TIA History of HF History of angina Previous MI Previous PCI/CABG CHA2DS2-VASc Killip IV, n (%) SBP, mm Hg (mean ± SD) HR, bpm (mean ± SD) LVEF, % (mean ± SD)a

NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI

No AF (NSTEACS = 8579, STEMI = 7205)

AF (NSTEACS = 668, STEMI = 351)

p value

68.0 ± 12.3 65.1 ± 12.9 5928 (69.1) 5216 (72.4) 26.9 ± 4.1 26.9 ± 4.2 2316 (27.0) 2837 (39.4) 2545 (29.7) 1541 (21.4) 5289 (61.6) 3399 (47.2) 929 (10.8) 328 (4.5) 1210 (14.1) 558 (7.7) 605 (7.0) 366 (5.1) 405 (4.7) 142 (2.0) 1758 (20.5) 671 (9.3) 2150 (25.1) 935 (13.0) 2036 (23.7) 692 (9.6) 2.5 ± 1.7 1.9 ± 1.6 105 (1.2) 160 (2.2) 141.5 ± 26.0 134.3 ± 27.3 77.7 ± 17.7 76.8 ± 18.2 51.5 ± 10.4 48.4 ± 10.0

77.1 ± 8.4 74.7 ± 11.8 397 (59.4) 212 (60.4) 27.0 ± 4.6 26.3 ± 4.1 63 (9.4) 74 (21.1) 226 (33.8) 88 (25.1) 533 (79.8) 208 (59.3) 128 (19.2) 35 (10.0) 141 (21.1) 37 (10.5) 78 (11.7) 43 (12.2) 89 (13.3) 24 (6.8) 158 (23.6) 37 (10.5) 213 (31.9) 57 (16.2) 174 (26.0) 34 (9.7) 3.7 ± 1.5 3.0 ± 1.7 19 (2.8) 36 (10.3) 137.1 ± 28.4 125.2 ± 30.6 101.3 ± 32.2 94.4 ± 29.8 47.3 ± 11.6 43.0 ± 11.2

b0.0001 b0.0001 b0.0001 b0.0001 0.80 0.03 b0.0001 b0.0001 0.02 0.10 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 0.06 b0.0001 b0.0001 b0.0001 b0.0001 0.05 0.44 b0.0001 0.08 0.18 0.96 b0.0001 b0.0001 0.0005 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001

CHA2DS2-VASc: congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65 to 74 years, sex category; ECG: electrocardiogram; HF: heart failure, HR: heart rate; LVEF: left ventricular ejection fraction; MI: myocardial infarction; NSTEACS: non-ST elevation acute coronary syndrome; PAD: peripheral artery disease; SBP: systolic blood pressure; HR: heart rate; STEMI: ST-elevation myocardial infarction; TIA: transient ischemic attack. a During hospital stay.



3.2. Evolution in the clinical characteristics of patients with AF The overall incidence of AF did not change over time (p for trend = 0.56), neither among NSTE-ACS (p for trend = 0.52) nor among STEMI patients (p for trend = 0.48) (Fig. 1-Supplemental material). Among AF patients with NSTE-ACS, during the 14-year period, the rate of subjects with a history of angina significantly declined, whereas the proportions of those with hypertension, renal dysfunction, prior revascularization, and Killip class IV increased (Table 2 Supplemental material). On the other hand, among patients with AF and STEMI the mean age significantly decreased over time as did the rate of history of heart failure, whereas the proportions of active smokers and patients with renal dysfunction and Killip class IV at admission increased (Table 2 Supplemental material). The mean CHA2DS2-VASc score significantly increased in NSTE-ACS patients (p for trend = 0.008) and decreased in STEMI patients (p for trend = 0.02). 3.3. Coronary angiography and revascularization As shown in Fig. 1, during the 14-year period the rates of coronary angiography and PCI significantly increased in both NSTE-ACS and STEMI patients with and without AF. Among AF patients with NSTE-ACS, a bare-metal stent (BMS) was implanted in all PCI patients in 2001 and in 36% of cases in 2014 (p for trend = 0.0007), while drug-eluting stents (DES) were not used in 2001 and implanted in 64% of PCI patients in 2014 (p for trend = 0.003). BMS were implanted in all AF patients with STEMI undergoing PCI in 2001 and in 36% of cases in 2014 (p for trend b 0.0001), while DES were not used in 2001 and implanted in 57% of cases in 2014 (p for trend b 0.0001). The shift from BMS to DES was similar in

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NSTE-ACS (from 100% and 0% in 2001 to 20% and 80% in 2014 for BMS and DES, respectively; both p for trend b 0.0001) and STEMI patients (from 100% and 0% in 2001 to 28% and 72% in 2014; both p for trend b 0.0001) without AF. 3.4. Antithrombotic therapy at discharge in AF patients With regard to antithrombotic treatment during hospital stay among AF patients, the rate of dual antiplatelet therapy (DAPT) significantly increased (p b 0.0001), while the use of low-molecular-weight heparins decreased (p = 0.01) over time, in both NSTE-ACS and STEMI patients. Among AF patients undergoing PCI, glycoprotein IIb/IIIa inhibitoruse (GPI) declined non-significantly from 20% in 2001 to 6% in 2014 in NSTE-ACS (p for trend = 0.24), and from 52% in 2001 to 38% in 2014 in STEMI (p for trend = 0.43),and these trends were similar in patients without AF (from 47% in 2001 to 12% in 2014 in NSTE-ACS and from 46% to 31% in STEMI). Among AF patients, the use of single antithrombotic therapy at discharge, using either aspirin or oral anticoagulant therapy (OAT) significantly declined in NSTE-ACS patients only, while DAPT and a strategy of triple therapy increased significantly over time, in both NSTE-ACS and STEMI (Fig. 2A and B). On the other hand, the rate of dual therapy using single anti platelet agent and OAT did not change over time in all ACS patients, even considering separately a strategy of OAT + aspirin (from 16% and 0% in 2001 to 8% and 2% in 2014 for NSTEACS and STEMI, respectively), or OAT + clopidogrel (from 0% and 2% in 2001 to 5% and 0% in 2014). At multivariable analysis, a CHADS2VASC2 ≥ 2 was the only independent predictor of OAT prescription at discharge in AF patients with

Fig. 1. In-hospital rates of coronary angiography and revascularization procedures in NSTE-ACS patients with (panel A) or without AF (panel B) and in STEMI patients with (panel C) or without AF (panel D). Abbreviations. CABG: coronary artery by-pass grafting; PCI: percutaneous coronary intervention.


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Fig. 2. Prescription of antithrombotic strategies at discharge over time in AF patients with NSTE-ACS (panel A) and STEMI (panel B). Abbreviations. ASA: aspirin; DAPT: dual antiplatelet therapy; DT: dual therapy (OAT + 1 antiplatelet agent); OAT: oral anticoagulation therapy; TT: triple therapy (OAT + DAPT).

STEMI [odds ratio (OR): 2.72; 95% confidence intervals (CI): 1.24–5.98; p = 0.01], while no predictors of OAT use in NSTE-ACS patients with AF were found in our clinical model. 3.5. In-hospital outcomes As shown in Table 2, as compared to patients without AF crude inhospital mortality was almost twice as high among AF patients in NSTE-ACS and three times in STEMI. Mortality did not change significantly over time in NSTE-ACS patients, irrespective of AF status, but was reduced by about 50% in STEMI patients both with (p for trend not significant) and without AF (p b 0.0001). There was a sensible decline in the re-infarction rates, which was statistically significant in all STEMI patients and in NSTE-ACS without AF. The rate of major bleeding significantly increased over time in NSTE-ACS patients without AF. At multivariable analysis in the whole ACS population, the risk of death was significantly lower in subsequent years, as compared to 2001. Atrial fibrillation at admission was not found to be significantly related to in-hospital death (OR: 0.82; 95% CI: 0.52–1.30; p = 0.41 for NSTE-ACS, and OR: 1.07; 95% CI: 0.73–1.57; p = 0.74 for STEMI) (Fig. 2-Supplemental material).

Among patients with AF, cardiogenic shock at admission (OR 4.44; 95% CI: 1.29–15.26; p = 0.02 and OR 5.62; 95% CI: 2.18–14.48; p = 0.0004) and an ejection fraction of ≤40% (OR 3.35; 95% CI: 1.29–8.70; p = 0.01 and OR 6.61; 95% CI: 2.08–21.00; p b 0.0001) resulted as independent predictors of in-hospital mortality for NSTE-ACS and STEMI, respectively. 4. Discussion The main findings of the present analysis of consecutive, nationwide, real-world registries covering 14 years of observation, are the following: 1. AF at admission is present in 5.9–7.4% of the ACS cases admitted to CCUs, significantly more frequent in NSTE-ACS, without a significant trend over the years; 2. As compared to patients without AF, those with AF are older and have significantly worse clinical characteristics, both as prior cardiovascular history and as clinical presentation; 3. the use of coronary angiography and PCI in the acute phase has dramatically increased in AF patients both with NSTE-ACS and STEMI; 4. at multivariable analysis, the risk of in-hospital death was significantly lower in subsequent years as compared to 2001, both in STEMI and in NSTE-ACS patients, while AF on admission did not result to be an



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Table 2 In-hospital major clinical events of patients with and without AF, according to diagnosis at entry (NSTE-ACS or STEMI).

Death

AF No AF

Re-MI

AF No AF

Stroke

AF No AF

Major bleeding

AF No AF

BLITZ-1 2001

In-ACS outcome 2005–2008

MANTRA 2009–2010

EYESHOT 2013–2014

AF

(NSTE-ACS = 49, STEMI = 65)




No AF


(NSTE-ACS = 3361, STEMI = 2165)

(NSTE-ACS = 3302, STEMI = 2744)


NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI NSTE-ACS STEMI

4 (8.2) 13 (20.0) 26 (4.9) 98 (7.5) 2 (4.1) 4 (6.2) 15 (2.8) 39 (3.0) 0 (0.0) 2 (3.1) 6 (1.1) 18 (1.4) 1 (2.0) 1 (1.5) 6 (1.1) 33 (2.5)

5 (2.0) 17 (14.7) 55 (1.6) 89 (4.1) 6 (2.4) 2 (1.7) 67 (2.0) 33 (1.5) 2 (0.8) 1 (0.9) 10 (0.3) 22 (1.0) 1 (0.4) 4 (3.5) 17 (0.5) 23 (1.1)

13 (5.6) 16 (14.0) 76 (2.3) 104 (3.8) 5 (2.1) 1 (0.9) 66 (2.0) 47 (1.7) 8 (3.4) 1 (0.9) 12 (0.4) 21 (0.8) 3 (1.3) 4 (3.5) 36 (1.1) 36 (1.3)

8 (6.0) 6 (10.7) 27 (2.0) 33 (3.3) 1 (0.8) 0 (0.0) 14 (1.0) 7 (0.7) 0 (0.0) 0 (0.0) 4 (0.3) 8 (0.8) 2 (1.5) 0 (0.0) 21 (1.5) 14 (1.4)

p for trend

0.19 0.20 0.48 b0.0001 0.21 0.02 0.03 0.001 0.37 0.18 0.26 0.07 0.49 0.72 0.003 0.08

MI: myocardial infarction.

independent predictor of in-hospital mortality; 5. the rate of triple therapy at discharge, even if still suboptimal, has been significantly increasing in the recent period. Patients presenting with ACS and AF were nine years older than those without AF, a difference in age which, per se, has an enormous prognostic impact. Also, AF at admission was associated with several well-known powerful predictors of short- and long-term mortality in cardiovascular disease, such as chronic kidney dysfunction, peripheral artery disease, and history of heart failure and stroke. Therefore, it is not surprising that, although patients presenting with AF had twice the mortality rate as compared to no-AF patients among NSTE-ACS, and three times among STEMI patients, AF on admission did not come out as an independent predictor of mortality, a finding consistent with the concept of AF as a marker, rather than a cause, of worse outcome [12]. This concept may not apply to AF developing during, and complicating, the course of an ACS that may further impair the coronary circulation and left ventricular function, in addition to the adverse consequences of neurohormonal activation, as a consequence of rapid and irregular ventricular rates [1]. The frequent occurrence of risk factors such as advanced age and chronic renal dysfunction among patients with AF and ACS could decrease the indications to coronary angiography. Nevertheless, the present analysis suggests that the adverse clinical conditions and comorbidities of the AF patients do not seem to deter contemporary cardiologists to treat ACS invasively, since the rates of coronary angiography and revascularization procedures during admission increased by a similar amount across the ACS spectrum, irrespective of the AF status. As previously reported [13], after adjustment for the changing characteristics of the ACS patients admitted to the Italian CCU network during the 14-years observation period, mortality rates among ACS patients were significantly reduced over time in all age groups, in both sexes, and even in patients with cardiogenic shock. However, may be due to the relatively smaller numbers, we cannot conclude from the present analysis that this was also true for the AF patients, though absolute mortality rates were reduced by 30% in NSTEACS and 50% in STEMI. As a matter of fact, in-hospital mortality reductions among STEMI patients were quantitatively similar in AF and no AF patients, even though a significant trend was not observed, whereas no changes in in-hospital mortality are expected from an increase in an invasive approach in NSTE-ACS. An important issue in the management of AF patients is the recourse to coronary revascularization and the choice of stents. Patients with AF

receiving OAT are usually at high bleeding risk and long-term DAPT after PCI poses safety concerns [14]. Therefore, some studies suggested that these patients receive PCI less frequently in the setting of ACS and, when PCI is performed, a BMS is more often used as compared to patients without AF [15]. In our registries, the use of revascularization and the rates of DES implantation dramatically increased over time (bearing in mind that DES were not available in our country in 2001), together with an increase in the prescription of recommended antithrombotic strategies at discharge. In this regard, the optimal association between oral antiplatelet agents and OAT in AF patients with ACS remains cumbersome and renders the clinical management more difficult [14]. Indeed, DAPT is the gold standard treatment after ACS and PCI, and chronic OAT therapy is the mainstay of stroke prevention in patients with AF at high cardio-embolic risk [16,17]. Therefore, in ACS patients with AF current guidelines and consensus documents empirically recommend a short-course of triple therapy (OAT + DAPT) that is associated with a high rate of major bleeding and poses risk-benefit challenges in clinical practice [16,17], particularly considering the clinical characteristics of patients with AF. In our series the use of triple therapy at discharge increased over time but remained below standards, probably due to the perceived risk of bleeding of this strategy and/or the lack of proper educational programmes on this issue. The present analysis represents an important complement to the recently published data on antithrombotic strategies for AF patients treated with stent implantation. Indeed, new evidence has emerged suggesting that the increased bleeding risk may outweigh the benefits of triple therapy in these patients, and new strategies of OAT and a single oral antiplatelet agent have been recently published [18,19] or are under investigation [20]. The multicenter, randomized, open-label PIONEER AF-PCI trial (OpenLabel, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention) demonstrated that the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months [18]. The secondary analyses showed that three groups had similar efficacy rates, although the trial was not powered for such endpoints [18]. Due to the lack of solid data, although the rate of triple therapy significantly increased in our series over time reaching 1/5 of NSTE-ACS and 1/4 of STEMI cases in 2014, the vast


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majority of ACS patients with AF received DAPT without OAT at the time of discharge, indicating a strong attention to stent protection and recurrent ischemic events, disregarding the residual thromboembolic risk related to AF. This finding, which refer to a time prior to the more recent specific guidelines on AF [16,17] highlights the need for educational campaigns aimed at increasing guidelines adherence in this setting, also in the light of upcoming clinical trials evaluating the combination of novel oral anticoagulation therapies with single thienopyridines or DAPT [20]. 4.1. Limitations There are some limitations to our analysis. First, although every effort was made in each registry to capture the greatest possible proportion of hospitals with CCU in the entire country, the ratio between invited and participating centers varies across registries. However, the geographical distribution and the availability of facilities of CCUs participating in different registries may be considered representative of the entire country. Second, we did not collect timing, type, and duration of AF. Since we analyzed AF at admission it is possible that we have included some patients who developed an AF few hours before the ACS onset. In addition, we did not collect information on rationale for treatment selection at the time of discharge. Finally, since no follow-up was available, we have not been able to assess how specific antiarrhythmic and/or anticoagulant drugs affected the outcomes. 5. Conclusions Despite the worse clinical characteristics of ACS patients presenting with AF, the use of invasive procedures during the hospitalization and the prescription of recommended antithrombotic strategies at discharge increased over time. In-hospital mortality rates were reduced to a similar extent among STEMI patients with and without AF, whereas changes in NSTE-ACS mortality were smaller and nonsignificant. The observation period preceded the recent recommendations on antithrombotic treatment for ACS patients with AF, whose impact will need to be determined in future observational studies. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2017.08.019. Conflict of interest Dr. De Luca reports personal fees from Astra Zeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, Daiichi Sankyo, Menarini and The Medicines Company, outside the submitted work; Dr. Rubboli reports grants and personal fees from Astra Zeneca, Boehringer Ingelheim, Bayer, Daiichi Sankyo and Pfizer BMS outside the submitted work; Dr. Gonzini and Lucci, employers of Heart Care Foundation which conducted the studies, report Institutional grants from GlaxoSmithKline, Italy, grants from Merck, Sharp&Dohme, Italy, outside the submitted work; Dr. De Servi reports personal fees from Astra Zeneca, Eli Lilly, Daiichi Sankyo and The Medicines Company, outside the submitted work; Dr. Di Pasquale reports grants and personal fees from Boheringer Ingelheim, Bayer, Pfizer, and Daiichi Sankyo, outside the submitted work; Dr. Savonitto reports grants and personal fees from Eli Lilly, Novartis, Iroko, Daiichi Sankyo and Pfizer, outside the submitted work; Dr. Di Lenarda reports personal fees from Astra Zeneca, Bayer, Pfizer, BMS, Boehringer-Ingelheim, Daiichi Sankyo, Novartis, Merck Sharp&Dohme, Menarini; Dr. Di Chiara, Dr. Casella, Dr. Chiarella and Dr. Boccanelli have nothing to disclose. Acknowledgements The authors thank all the patients and investigators from all participating centers of the studies, as well as Barbara Bartolomei Mecatti from the ANMCO Research Center.

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