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European Heart Journal: Acute Cardiovascular Care

Prognostic impact of atrial fibrillation in acute coronary syndromes: results from the ARIAM registry

Manuel Almendro-Delia, María José Valle-Caballero, Juan C Garcia-Rubira, Blanca Muñoz-Calero, Angel Garcia-Alcantara, Antonio Reina-Toral, José Benítez-Parejo, Rafael Hidalgo-Urbano and on behalf of the ARIAM Andalucia Study Group European Heart Journal: Acute Cardiovascular Care published online 17 December 2013 DOI: 10.1177/2048872613517370

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517370 ACC0010.1177/2048872613517370European Heart Journal: Acute Cardiovascular CareAlmendro-Delia et al.
517370 ACC0010.1177/2048872613517370European Heart Journal: Acute Cardiovascular CareAlmendro-Delia et al.
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Original scientific paper

research-article2013 EUROPEAN Original scientific paper SOCIETY OF CARDIOLOGY ® Prognostic impact of atrial

SOCIETY OF

CARDIOLOGY ®

Prognostic impact of atrial fibrillation in acute coronary syndromes: results from the ARIAM registry

European Heart Journal: Acute Cardiovascular Care 201X, Vol XX(X) 1–8 © The European Society of Cardiology 2013 Reprints and permissions:

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DOI: 10.1177/2048872613517370 acc.sagepub.com Manuel Almendro-Delia 1 , * , María José

Manuel Almendro-Delia 1,* , María José Valle-Caballero 1,* , Juan C Garcia-Rubira 1 , Blanca Muñoz-Calero 1 , Angel Garcia-Alcantara 2 , Antonio Reina-Toral 3 , José Benítez-Parejo 4 and Rafael Hidalgo- Urbano 1 ; on behalf of the ARIAM Andalucia Study Group

Abstract Aims: The prognostic ability of atrial fibrillation (AF) in acute coronary syndromes (ACS) is unclear. Studies regarding patient outcomes with respect to the timing of AF are scarce and conflicting. The present study aimed to determine the frequency, predictors and impact on clinical outcome of AF in patients with ACS. Methods: We analysed 39,237 consecutive patients with ACS included in the ARIAM registry between January /2001 and December 2011. Patients with AF were compared with patients in sinus rhythm. We differentiate between new-onset AF and previous AF cases to analyse mortality and other major adverse cardiac events (MACE) during hospitalization. Results: Of the patients, 2851 (7.3%) developed AF; 1568 (55%) of these were new-onset AF and 1283 (45%) had previous AF. The AF group had a higher risk profile at baseline and poorer clinical presentation at admission than non-AF patients. Compared with previous AF patients, new-onset AF presented with fewer comorbidities, including hypertension, diabetes, prior myocardial infarction, and chronic renal impairment. The inhospital mortality for new- onset AF, previous AF, and non-AF patients were 14, 11.6, and 5.2%, respectively (new-onset AF unadjusted HR 2.19, 95% CI 1.9–2.53, p<0.001; adjusted HR 1.70, 95% CI 1.12–3.4, p<0.001). After propensity score analysis, only new-onset AF persisted as an independent predictor for mortality (HR 1.62, 95% CI 1.09–2.89, p<0.001). Other MACE such as reinfarction, malignant arrhythmias, and heart failure were also more frequent in new-onset AF patients than in previous AF or non-AF patients. Conclusions: These findings suggest that the presence of new-onset AF during ACS is associated with a significant increase in mortality, even after adjusting for confounding variables.

Keywords Acute coronary syndrome, atrial fibrillation, heart failure, myocardial infarction, propensity score, registry

Received: 12 September 2013; accepted: 28 November 2013

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia observed in clinical practice and a frequent complication of acute coronary syndromes (ACS), with an incidence ranging between 5 and 23%. 113 The prognostic implication of AF in the ACS setting is unclear. Some studies have found an association between AF and increased morbidity and mortality, 6,7,9,1419 whereas other studies have failed to detect this association. 1,8,20 The

1 Virgen Macarena University Hospital, Seville, Spain.

2 Virgen de la Victoria Hospital, Málaga, Spain.

3 Virgen de las Nieves Hospital, Granada, Spain.

4 Coresoft, Málaga, Spain. *These authors contributed equally to this paper.

Corresponding author:

Manuel Almendro-Delia, Coronary Care Unit. Cardiology Department, Virgen Macarena University Hospital, Avd Dr. Fedriani 3, 41071, Seville, Spain. Email: almendrode@secardiologia.es

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majority of these findings were derived from studies using unadjusted multivariate models 210 or post-hoc analyses of randomized control trials; 67,9,14,15,17,21 only few studies differentiated between previous (PrAF) and new-onset AF (NAF). 1425 AF is frequently associated with heart failure (HF) during ACS. 1113,26 Thus, AF may be considered a sur- rogate marker of HF that is associated with increased left ventricle filling pressure. 11,13,2729 Current clinical guidelines for treatment of AF during an ACS provide recommendations based on limited evidence. 29,30 The efficacy of long-term antithrombotic and antiarrhythmic drugs is unclear, especially in NAF that is resolved at discharge. This study aims to determine the incidence of AF in ACS patients, identify risk factors for its development, and determine if AF during ACS is an independent risk factor for inhospital mortality.

Methods

ARIAM registry

The ‘ARIAM Andalucia’ (Análisis del Retraso en el Infarto Agudo de Miocardio/Analysis of Delay in Acute Myocardial Infarction) registry is a multicentre project involving 44 medical centres with the goal of improving the quality of treatment for patients with ischaemic heart disease in Spain. The details of the registry have been pre- viously published. 31,32 In brief, data from patients admit- ted to coronary care units in Andalucia, Spain with the diagnosis of ACS were collected from January 2001 to December 2011. Case inclusion was prospective, although data interpretation and the development of the study were retrospective. The categorization and identification of events and clinical variables were determined by individ- ual investigators using the protocol definitions. The study and this article followed the ethics and privacy guidelines of the independent local ethics and research committees related to the ARIAM project. The approval of ARIAM primary investigators was obtained, and all of the patients gave informed consent.

Study group

The study group consisted of patients with ACS who devel- oped AF during hospitalization. AF was defined as an irreg- ular rhythm with the absence of discrete atrial activation (atrial fibrillation or flutter) recorded in a 12-lead ECG. 29 We differentiated between those patients with previous clear documentation or records of either paroxysmal, per- sistent, or permanent AF (PrAF), and those with new-onset AF (NAF), which was defined as the absence of medical records of AF but the development of arrhythmia, either at admission or during hospitalization.

Variables

ST-segment elevation myocardial infarction (STEMI) was defined based on the following criteria: acute ischaemic symptoms and ST-segment elevation ≥2 mV in two con- tiguous precordial leads as well as ≥1 mV in inferior leads or a presumed/new left bundle branch block on initial elec- trocardiogram. Non-ST-segment elevation myocardial infarction (NSTEMI) was defined as the elevation of car- diac enzymes above the upper limit of normal in patients with ischaemic symptoms but without persistent ST seg- ment elevation or new left bundle branch block. Unstable angina was defined as the presence of symptoms of angina at rest, new-onset angina, or accelerated ischaemic symp- toms with or without electrocardiographic changes but without elevation of cardiac enzymes. Stroke was defined as the occurrence of a new neurological deficit caused by an ischaemic event with residual symptoms lasting for at least 24 h after the onset of the ischaemic event. Cardiogenic shock was defined as having clinical signs of pulmonary congestion and impaired end-organ perfusion with persis- tent hypotension defined as a systolic blood pressure less than 90 mmHg for more than 30 min or the need for vaso- pressor therapy to maintain a systolic pressure above 90 mmHg. Major and minor bleeding were defined according to the TIMI definitions. 33

Statistical analysis

Data are expressed as the mean±standard deviation for quantitative normally distributed variables, median (inter- quartile range), or n (%). The differences between categori- cal variables were compared using Chi-squared or Fisher exact tests and two-tailed Student t-test or Mann–Whitney U-test for continuous variables, as appropriate. Stepwise logistic regression was used to assess AF predictors. A Cox proportional-hazards model was used to assess predictors for inhospital mortality using the hazard ratio (HR) with a 95% confidence interval (CI). Parsimonious models were developed in a forward manner using prede- fined covariates. The model was adjusted to account for the presence of malignant arrhythmias (either ventricular fibril- lation (VF) and/or sustained ventricular tachycardia (SVT)) or cardiogenic shock, the two variables with the highest statistical weight for hospital mortality as determined by univariate analysis. The model was also adjusted for base- line characteristics related to mortality by univariate analy- sis (p<0.2), including age, diabetes mellitus, blood pressure, renal impairment (creatinine clearance), previous myocar- dial infarction (MI), heart failure (Killip class), GRACE risk score, mechanical complications of MI, and myocar- dial revascularization. Kaplan–Meier curves were also per- formed to examine outcomes based on AF status. The propensity score model (PS) for the appearance of AF was obtained by logistic regression using baseline

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Table 1. Baseline characteristics.

Characteristic

Non AF

AF (n=2851)

p

Previous AF

New AF

p

(n=36,386)

(n=1283)

(n=1568)

Female Age (years) Smoking BMI ≥30 kg/m 2 ) Diabetes Hypertension Previous MI Prior CHF Prior stroke AF history Peripheral arterial disease Renal impairment (CrCl <60 ml/min) Previous PCI Prior CV surgery

Clinical presentation at admission VF SVT 3-grade AV block

9305 (25.6)

986 (34.6)

<0.001

423 (34)

529 (35)

0.533

63.8±12.6

71.2±9.8

<0.001

71±10

71±9.6

0.634

12,661 (35.6)

546 (1.7)

<0.001

225 (19)

311 (21)

0.150

3928 (11)

318 (11.5)

0.520

192 (16)

124 (8.4)

<0.001

11,397 (32)

1097 (39.5)

<0.001

477 (40)

575 (39)

0.614

18,643 (52.5)

1836 (66)

<0.001

842 (70.5)

919 (62.3)

<0.001

6355 (18)

553 (20)

0.01

239 (20.3)

272 (18.5)

0.285

1508 (4.3)

285 (10.4)

<0.001

141 (12)

127 (8.7)

0.005

1903 (5.4)

275 (10)

<0.001

139 (12)

128 (8.7)

0.009

1557 (4.4)

809 (29.4)

<0.001

1283 (100)

<0.001

1759 (5)

226 (8.2)

<0.001

96 (8.1)

121 (8.2)

0.927

494 (1.4)

122 (4.4)

<0.001

94 (8)

28 (1.9)

<0.001

3079 (10)

231 (9.3)

0.31

139 (12)

82 (6.6)

<0.001

909 (2.9)

133 (5.4)

<0.001

75 (6.6)

47 (3.8)

0.002

504 (1.5)

58 (2.1)

0.007

38 (3)

20 (1.3)

<0.001

1170 (3.4)

445 (16.2)

<0.001

23 (2)

422 (28)

<0.001

1039 (3)

88 (3.2)

0.55

20 (2.3)

60 (4)

0.01

Systolic BP (mmHg) Heart rate (bpm) GRACE risk score LVEF (%)

117±26

118±28

0.13

130±32

108±19

<0.001

84±17

94±26

<0.001

93±31

95±19

0.014

130 (108–155)

161 (136–181)

<0.001

160 (136–182)

162 (138–183)

0.432

50.6±13

44.2±14

<0.001

45.3±14

43±14

0.029

Cardiac troponin a STEMI Anterior MI Killip class (%)

10,295 (59)

1009 (70.8)

<0.001

293 (31.2)

196 (40)

<0.001

22,004 (60.5)

1485 (52)

<0.001

540 (43.5)

945 (63)

<0.001

10,454 (39.6)

805 (38.5)

0.312

326 (35)

444 (41)

0.008

I

80

52

<0.001

55

50

<0.001

II

12

25

27

24

III

5

14

12

16

IV

3

9

6

10

Data are mean±standard deviation, n (%), or median (interquartile range). Categories do not add up to 100% for all variables due to missing values. a Cardiac troponin levels >5 times the upper limit of normal. Data from 20,228 patients with available and valid cardiac troponin values AF, atrial fibrillation; AV, atrioventricular; BMI, body mass index; BP, blood pressure; CHF, chronic heart failure; CrCl, creatinine clearance; CV surgery, cardiovascular surgery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; RI, renal impairment; SVT, sustained ventricular tachycardia; VF, ventricular fibrillation.

clinical characteristics as covariates. 34 Nearest neighbour PS matching was used in terms of Mahalanobis distance (calliper 0.2). Goodness of fit was achieved if the standard- ized differences were 10%. 35 A two-sided p-value <0.05 was considered statistically significant. The analyses were performed using SPSS version 18.0 (SPSS, Chicago, IL, USA) and R version 2.10.0 (The R Foundation for Statistical Computing).

Results

This study included 39,237 patients. Among these, 2851 patients (7.3%) developed AF during hospitalization. Of these, 1568 (55%) developed NAF and 1283 (45%) developed PrAF. Of all of the included patients, 52%

STEMI and 48% were NSTE-ACS, with 41% NSTEMI and 7% unstable angina.

Clinical data

The baseline characteristics are shown in Table 1. AF patients were more likely to be female, older, and sicker than those with sinus rhythm. At the time of admission, the AF group had a higher incidence of malignant arrhythmias (VF/SVT) and higher heart rates and plasma cardiac tro- ponin levels than non-AF. Killip class at admission was worse and the left ventricle ejection fraction (LVEF) was lower in AF patients than in non-AF patients. Compared with the PrAF group, the NAF patients presented with fewer comorbidities but showed a worse clinical presentation at

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Table 2. Treatments.

 

Non AF

AF (n=2851)

p

Previous AF

New AF

p

(n=36,386)

(n=1283)

(n=1 568)

Pharmacological treatment (at discharge)

 

Aspirin Clopidogrel ACE Inhibitors Beta-blockers Digoxin Diuretics GP inhibitors a Inotropes a Aldosterone antagonist b Statins b Vitamin K antagonists b Reperfusion treatment c Thrombolysis pPCI No reperfusion PCI during hospitalization

27,162 (78)

2176 (78.8)

0.26

1141 (93)

967 (67.2)

<0.001

21,506 (61.7)

1753 (63.5)

0.06

1021 (84)

694 (48.2)

<0.001

21,579 (67.5)

1600 (65.5)

0.05

589 (48)

736 (51)

0.134

21,738 (68)

1273 (52.2)

<0.001

545 (45)

589 (41)

0.05

87 (0.3)

131 (5.4)

<0.001

73 (6)

10 (1)

<0.001

2545 (8)

566 (23.2)

<0.001

410 (41)

564 (45)

0.05

7139 (26)

449 (19.3)

<0.001

147 (15)

275 (22)

<0.001

2071 (5.9)

512 (18.5)

<0.001

202 (16.5)

297 (21)

0.007

554/4395 (12.6)

88/433 (18.5)

<0.001

59 (12)

297 (21)

0.016

2349/4395 (53.4)

209/433 (48.3)

0.039

885 (84)

761 (59)

<0.001

86/4395 (2)

86/433 (20)

<0.001

67 (25)

8 (9.2)

0.002

12,711 (57.8)

804 (54.1)

0.006

239 (44)

565 (60)

<0.001

2607 (11.8)

194 (13.1)

0.16

112 (21)

82 (9)

<0.001

6691 (30.4)

487 (32.8)

0.04

189 (35)

298 (31)

0.002

15,092 (68.6)

975 (65.7)

0.02

351 (65)

624 (66)

0.687

Data are n (%). Categories do not add up to 100% for all variables due to missing values. a Drugs used in the acute stage. b Data from 4828 patients. c Data from 20,403 patients with STEMI diagnosis. ACE, angiotensin-converting enzyme; AF, atrial fibrillation; GP, glycoprotein; pPCI, primary percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.

admission with a greater proportion of patients with STEMI and anterior MI, a higher Killip class, and cardiac troponin levels and lower LVEF, together with more ventricular arrhythmias.

Pharmacological and reperfusion treatment

Table 2 summarizes the pharmacological treatment and revascularization strategies during hospitalization. In gen- eral, the AF group was less likely to be treated with evi- dence-based therapies. Thrombolysis was applied less frequently to AF patients diagnosed with STEMI than to non-AF STEMI patients. During hospitalization, AF patients as a group received less reperfusion, although in the STEMI cohort, more AF patients received primary percutaneous coronary intervention (pPCI) than the non- AF STEMI patients. Compared with PrAF patients, the NAF group was less likely to receive antiplatelet agents, statins, vitamin K antagonist, beta-blockers, and pPCI. Thrombolysis was more frequently performed in the NAF group than in the PrAF group, but NAF and PrAF patients underwent similar numbers of PCI procedures during hospitalization.

Predictors of AF

The predictor variables for AF development included age, being female, prior history of AF, elevated heart rate at

being female, prior history of AF, elevated heart rate at Figure 1. Predictors of atrial fibrillation.

Figure 1. Predictors of atrial fibrillation.

*, Every ten years increased; †, Every 5 bpm increased; ‡, Every 5 points increased. AF, atrial fibrillation; HR, heart rate; LVEF, left ventricular ejection fraction. C-statistic: 0.79 (0.72-0.86 95% CI; p<0.0001).

admission, and heart failure, whereas a better ejection frac- tion behaved as a protective factor (Figure 1).

Hospital outcomes

AF patients had a poorer prognosis, with a higher incidence of malignant arrhythmias, reinfarction, ischaemic mitral regurgitation, heart failure, cardiogenic shock, and inhospi- tal mortality than non-AF patients. NAF patients had a poorer outcome than PrAF patients (Table 3). There was no difference in bleeding between AF and non-AF patients. Table 4 summarizes the impact of AF on hospital mortality. In the unadjusted analysis, both PrAF and NAF patients had an approximately 2-fold increase in mortality compared with

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Table 3. Differences in outcomes in patients with and without atrial fibrillation during hospitalization.

 

Non AF

AF

p

Previous AF

New AF

p

(n=36,386)

(n=2851)

(n=1283)

(n=1568)

Ventricular fibrillation SVT AV block Asystolia Reinfarction Cardiac rupture VSR Ischaemic MR Stroke HF (KC ≥2) Cardiogenic shock Total bleeding (major and minor) Total inhospital mortality CCU stay (days) Hospital stay (days)

1165 (3.2)

147 (5.2)

<0.001

51 (4)

95 (6.3)

0.01

1994 (5.5)

565 (19.8)

<0.001

62 (5)

500 (33.3)

<0.001

2119 (5.8)

259 (9.1)

0.02

19 (1.5)

103 (7)

<0.001

542 (1.5)

99(3.5)

<0.001

40 (32)

55 (35)

0.531

532 (1.9)

62 (2.2)

0.003

18 (1.6)

44 (2.9)

0.009

93 (0.3)

13 (0.5)

0.22

5 (0.4)

8 (0.5)

0.750

45 (0.2)

4 (0.1)

0.85

1 (0.1)

3 (0.2)

0.472

67 (0.2)

16 (0.6)

0.001

8 (0.7)

8 (0.5)

0.558

99 (2.4)

21 (2.9)

0.44

6 (2.6)

14 (3)

0.765

8174 (22.6)

1590 (56)

<0.001

648 (52)

881 (59)

0.001

1473 (4.1)

396 (14)

<0.001

156 (12,6)

231 (15.4)

0.035

587 (14.5)

90 (13)

0.196

32 (14)

35 (12)

0.434

1881(5.2)

365 (12.8)

<0.001

144 (11.6)

210 (14)

0.001

1 (1–2)

2 (1–3)

<0.001

1 (1–2)

1 (1–4)

<0.001

2 (1–6)

3 (1–7)

<0.001

3 (1–7)

4 (2–7)

0.001

Data are n (%)or median (interquartile range). Categories do not add up to 100% for all variables due to missing values. AF, atrial fibrilation; AV, atrioventricular; CCU, coronary care unit; HF, heart failure; KC, Killip class; MR, mitral regurgitation; SVT, sustained ven- tricular tachycardia; VSR, ventricular septal rupture.

Table 4. Predictors of mortality: multivariate analysis.

 

Unadjusted

Adjusted

PS cohort

HR

p

HR

p

HR

p

PrAF

1.89 (1.6–2.4)

<0.001

NAF

2.19 (1.9–2.53)

<0.001

1.70 (1.12–3.40)

<0.001

1.62 (1.09–2.89)

<0.001

Values are hazard ratios (95% confidence interval). NAF, new atrial fibrillation; PrAF, previous atrial fibrillation; PS, propensity score.

non-AF patients; the increase was slightly more pronounced for NAF patients (Supplementary Table S1, available online).

After adjustment, NAF but not PrAF remained an independent predictor of mortality (Figure 2 and Supplementary Table S2). By using PS matching, 1908 pairs of AF and non-AF patients were matched with both groups balanced with respect to base-

line characteristics (Supplementary Table S3). After matching,

only NAF remained as an independent predictor of inhospital mortality, with a slight reduction in HR (Table 4 and Supplementary Table S4).

Discussion

We have demonstrated an increased risk of mortality asso-

ciated with the presence of AF in the setting of ACS. NAF is associated with an almost 70% increase in mortality risk. This increased risk was not demonstrated for PrAF after a two well-conducted adjustment analyses. The results of previous studies are conflicting regarding the prognostic

impact of AF types in MI. 16,8,9 However, our results are consistent with some previous reports. 213 The predictors and significance of AF in the setting of

MI reviewed by Schmitt et al. 11 are fairly consistent with

our findings. Schmitt et al. concluded that AF during MI

implied worse short- and long-term outcomes, independent

of MI treatment strategies. Two well-conducted meta-anal- yses focusing on the prognostic implication of AF during

MI have been published. The first one, by Jabre et al., 12

included 43 articles with a total of 278,854 MI patients.

Their analysis indicated that AF led to a 40% increase in the

risk of mortality in the setting of MI, even after adjustment

for the same variables as in our study, and concluded that

NAF and PrAF did not differ in mortality risk. The second

and most recent study, by Angeli et al., 13 was a meta-analy-

sis of 24 studies comparing outcomes in patients with MI and sinus rhythm with those observed for AF patients. In their study, patients with AF had a 2-fold increased risk of inhospital mortality and patients with clear evidence of NAF had a 3-fold higher risk of mortality than sinus rhythm patients, although the study did not adjust for the Killip class, an important confounding variable. 15,2628

It is important to note that in the meta-analysis by Jabre

et al., 12 the association between AF and mortality was sim-

ilar for NAF and PrAF. These results persisted even after

adjusting for confounding variables such as heart failure

and revascularization, although only four of the 43 studies

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6 European Heart Journal: Acute Cardiovascular Care XX(X) Figure 2. Kaplan Meier survival curves for inhospital

Figure 2. Kaplan Meier survival curves for inhospital mortality.

included in his work performed such important adjust- ments. These results are consistent with ours with respect to risk ratios for NAF patients but differ in relation to PrAF patients. To understand these conflicting results, we per- formed a PS analysis, demonstrating that only NAF per- sists as an independent predictor of inhospital mortality. The association of PrAF with mortality found in the analy- sis of Jabre et al. 12 is most likely explained by the inclusion of studies that analysed long-term mortality and not only inhospital outcomes, as we did in our study. NAF in the setting of ACS reflects a greater ischaemic burden than PrAF, as shown by the lower LVEF, larger infarct sizes, and higher Killip class associated with NAF compared with PrAF in our study. In contrast, PrAF is associated with a worse clinical baseline profile than NAF due to the existence of chronic heart disease. 9,36 Along the same line of reasoning, recent data from a large registry in Canada 37 has showed that patient with prior history of AF receive less evidence-based therapies and inhospital coronary angiography compared to non-AF patients, similarly to our results. As in our observational study, patients with prior AF were older and sicker, 37 and broadly differ to those included in the work by Lopes et al. 38 that examined pooled data from 10 ACS trials, which includes more cases of NAF and STEMI and probably less patients with signifi- cant comorbidities or those receiving warfarin, as is com- mon in patients included in clinical trials compared with those derived from registries. The development of AF may worsen the prognosis of ACS due to several factors. First, AF triggers some adverse haemodynamic effects, including increased oxygen

consumption, loss of atrial contraction, and AV synchrony, which lead to a decrease in effective cardiac output. 7,9,1215,39 Secondly, irregular RR intervals can develop malignant arrhythmias, as was observed in our cohort. 1215,40 However, the mechanism of AF-related mortality in ACS remains elu- sive; the association of AF with higher heart rates, lower LVEF and an increased incidence of HF suggests that haemodynamic impairment is a potential explanation as well as increased adrenergic and neurohormonal activation. 9,12,13,21 The rate of cerebrovascular events in patients with any type of AF in our study was quite low and not significantly different from patients in sinus rhythm. This may have been due to the relatively young age of patients enrolled in our ACS registry, but we cannot rule out other reasons. The current AF guidelines do not provide a better therapeutic approach for treating AF during an ACS. 2930 However, European Society of Cardiology STEMI guidelines clearly recommend optimized triple antithrombotic therapy for patients with a clear indication of oral anticoagulation. 31 The use of oral anticoagulants was quite low in our study, below 30%, clearly not in line with clinical guidelines. 2930 This finding may be due to the use of dual antiplatelet ther- apy, thereby avoiding the risk of bleeding associated with triple therapy. Nonetheless, our data are consistent with those of a Swedish registry (RIKS-HIA), in which long- term oral anticoagulation therapy was only given to 30% of the patients with AF during an acute MI. 41 Likewise, statin use was quite low in our study. Danchin et al. 42 have dem- onstrated that early statin therapy reduces the incidence of AF during MI; thus, the mortality risk associated with AF

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in our study may be greater than expected due to the lack of early use of statin. Considering our results, there is sufficient evidence to consider AF a mortality risk factor in the course of ACS.

Study limitations

Several limitations of the present investigation deserve dis- cussion. First, the study population were derived from an ACS-specific registry, not from an AF-specific registry. The results should be considered only as hypothesis gener- ating, and we cannot exclude the influence of other noncon- trolled confounders in our conclusions. There is also selection bias because we included only patients admitted to coronary care units. Secondly, data concerning the temporal relation between the onset of AF and the appearance of complications were not available, so we can establish an association but not a causality relationship. Silent episodes of AF could not be analysed in the sinus rhythm group. Furthermore, the adjustment of variables that were not measured at baseline (e.g. mechanical complications of MI and revasculariza- tion) in multivariable analysis, and comparison of outcomes which might occur before or after AF (since its timing was not known), should be interpreted with caution. Thirdly, data concerning the causes of death were only available for a minority of patients; thus, the causes of death are not shown. Data concerning treatment strategies used for AF as well as the timing, duration, and final out- come of AF episodes were not assessed. Although rates of reperfusion were low in our registry, the mortality numbers were similar to that reported in the GRACE registry. 18 In the final adjusted model, three-vessel disease was not finally included, because in our study coro- nary angiography rates was low and this might influence the results.

Conclusions

AF is not an infrequent event during ACS. The presence of NAF is associated with nearly an 70% mortality increase in MI patients. Our results suggest that the appearance of NAF during ACS should not be considered an isolated benign event but a severe complication with prognosis implications. These results are hypothesis gen- erating and the prognostic impact of treatment strategies for NAF in MI patients must be assessed in future studies.

ARIAM Andalucia Study Group

A list of investigators is given in the Appendix available online.

Conflict of interest

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. However, the Health Council of the Junta de Andalucia gives support to the vir- tual platform of the Registry.

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