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Original Research: Cardiovascular Disease |

Incidence of Myocardial Infarction and Vascular Death in Elderly Patients With Atrial Fibrillation Taking AnticoagulantsAtrial Fibrillation and Myocardial Infarction: Relation to Atherosclerotic Risk Factors FREE TO VIEW

Daniele Pastori, MD; Pasquale Pignatelli, MD; Francesco Angelico, MD; Alessio Farcomeni, PhD; Maria Del Ben, MD; Tommasa Vicario, MD; Tommaso Bucci, MD; Valeria Raparelli, MD; Roberto Cangemi, MD; Gaetano Tanzilli, MD; Gregory Y. H. Lip, MD; Francesco Violi, MD
Author and Funding Information

From I Clinica Medica, the Department of Internal Medicine and Medical Specialties (Drs Pastori, Pignatelli, Del Ben, Vicario, Bucci, Raparelli, Cangemi, and Violi), the Department of Science of Public Health and Infectious Diseases (Drs Angelico and Farcomeni), and the Department of the Heart and Great Vessels Attilio Reale (Dr Tanzilli), Sapienza University of Rome, Rome, Italy; and University of Birmingham Centre for Cardiovascular Sciences (Prof Lip), City Hospital, Birmingham, England.

CORRESPONDENCE TO: Francesco Violi, MD, I Clinica Medica, Viale del Policlinico 155, Rome, 00161, Italy; e-mail: francesco.violi@uniroma1.it


Prof Lip and Dr Violi are the joint senior authors of this article. Drs Pastori and Pignatelli contributed equally to this article.

FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(6):1644-1650. doi:10.1378/chest.14-2414
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BACKGROUND:  Recent findings suggest that patients with atrial fibrillation (AF), in addition being at thromboembolic risk, are at risk of myocardial infarction (MI). Our aim was to investigate predictors of MI and cardiovascular death in a cohort of patients with AF who were taking anticoagulants.

METHODS:  We prospectively followed up 1,019 patients with AF for a median of 33.7 months (3,223 person-years). All patients were treated with oral vitamin K antagonists. Primary outcome was a composite end point of cardiovascular events (CVEs) including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death.

RESULTS:  The mean age of the patients was 73.2 years, and 43.8% were women. At follow-up, 111 CVEs (3.43%/y) had occurred: 47 fatal-nonfatal MI/revascularization and 64 cardiovascular deaths. In addition, 31 stroke/transient ischemic attacks (0.96%/y) were recorded. Patients experiencing CVEs were older (P < .001) and had a higher prevalence of metabolic syndrome (MetS) (P = .005), heart failure (P = .001), and prior cardiac (P < .001) and cerebrovascular events (P < .001). On a Cox proportional hazard analysis, age (hazard ratio [HR], 1.083; 95% CI, 1.053-1.113; P < .001), smoking (HR, 2.158; 95% CI, 1.193-3.901; P = .011), history of cerebrovascular (HR, 1.704; 95% CI, 1.119-2.597; P = .013) and cardiac (HR, 1.658; 95% CI, 1.105-2.489; P = .015) events, MetS (HR, 1.663; 95% CI, 1.107-2.499; P = .014), heart failure (HR, 1.584; 95% CI, 1.021-2.456; P = .040), and male sex (HR, 1.499; 95% CI, 1.010-2.223; P = .044) predicted CVEs.

CONCLUSIONS:  Patients with AF still experience a high rate of CVEs despite receiving anticoagulant treatment. MetS is a common clinical feature in patients with AF, which increases the risk of CVEs. A holistic approach is needed to reduce the cardiovascular risk in patients with AF.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT01882114; URL: www.clinicaltrials.gov

Atrial fibrillation (AF) is the most common cause of cardiac arrhythmia and is known to be associated with a high risk of thromboembolic stroke.1 Current evidence also suggests that patients with AF are at higher risk of experiencing myocardial infarction (MI),2,3 with a rate ranging from 0.5% to 4%/y.2 The relationship between AF and MI has been investigated recently in a cohort of approximately 1,600 patients with AF in whom the age-adjusted incidence rate of MI was 1.2 per 100 person-years,3 which was significantly higher than in patients without AF. However, the real impact of cardiovascular events (CVEs) in AF cannot be fully deduced by the study by Soliman et al3 because < 50% of the AF population were taking an anticoagulant (warfarin). Furthermore, the relatively young population (66 years of age on average) suggests that the incidence of MI could be even higher among the elderly AF population.

Common atherosclerotic risk factors are observed in the majority of elderly patients with AF, the most frequent being represented by arterial hypertension, diabetes, and dyslipidemia.4 Thus, patients with AF show early signs of atherosclerosis, which has been detected in > 20% of elderly patients with AF, as assessed by an altered ankle/brachial index.5 Some of these factors, which are used to identify patients at high risk of stroke, are also associated with incident MI.

Until now, the impact of MI in elderly patients with AF receiving oral anticoagulation treatment has been unknown. Based on this, we prospectively investigated the rate of MI and cardiovascular death in the elderly AF population established on oral anticoagulation treatment. Furthermore, we assessed whether the classic risk factors of atherosclerosis are associated with MI, including the metabolic syndrome (MetS), whose prevalence in the white AF population is still poorly defined.

Study Design and Patient Selection

This prospective single-center study included 1,105 patients with nonvalvular AF who were referred to our center at the Department of Internal Medicine and Medical Specialties of Sapienza University of Rome for monitoring and management of antithrombotic therapies. All patients were treated with vitamin K antagonists (VKAs) (warfarin/acenocumarol) after appropriate thrombotic risk stratification, initially according to CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes, prior stroke or transient ischemic attack [doubled]) score,6 and afterward according to the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65 to 74 years, sex category [female]) score,7 when the new score was recommended by international guidelines. International normalized ratio values were maintained in an intended range of between 2.0 and 3.0, and the time in therapeutic range was calculated to assess the quality of anticoagulation.8 Exclusion criteria were prosthetic heart valves or the presence of any severe valvulopathies, severe cognitive impairment, chronic infections (HIV infection, hepatitis C virus, hepatitis B virus), or systemic autoimmune diseases. Subjects were also excluded from the study if they had active cancer or liver insufficiency (eg, cirrhosis).

Based on these criteria, 86 patients (7.5%) were excluded, and 1,019 patients with AF were included in the prospective study cohort. Forty-seven patients (4.6%) were lost to follow-up (13 cancer, one hepatic cirrhosis, one fatal hemorrhage, one mitral valvuloplasty, and 31 noncardiovascular death). At baseline, each patient provided written informed consent and the patient’s medical history was recorded. Anthropometric data were collected, as well as data regarding concomitant diseases and drug therapies. At baseline, ECG and transthoracic echocardiography were performed. Cardiovascular risk factors were defined as follows. Arterial hypertension: repeated elevated BP (≥ 140/≥ 90 mm Hg) or taking antihypertensive drugs9; diabetes: a casual plasma glucose ≥ 200 mg/dL (11.1 mmol/L), or fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L), or 2-h plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test or taking antidiabetic drugs10; and heart failure (HF): presence of signs and symptoms typical of HF or reduced ejection fraction (≤ 40%).11

MetS was defined according to modified Adult Treatment Panel III criteria: elevated waist circumference (men, > 102 cm [> 40 in]; women, > 88 cm [> 35 in]); elevated triglycerides ≥ 150 mg/dL (1.7 mmol/L) or receiving drug treatment of elevated triglycerides; reduced high-density lipoprotein cholesterol (men, < 40 mg/dL [1.03 mmol/L]; women, < 50 mg/dL [1.3 mmol/L]) or receiving drug treatment of reduced high-density lipoprotein cholesterol; elevated BP ≥ 130 (≥ 85 mm Hg); and elevated fasting glucose ≥ 100 mg/dL or receiving drug treatment of elevated glucose.12

Outcome Events

The primary outcome of the study was a combined end point of CVEs, including fatal/nonfatal MI, cardiac revascularization (stent or coronary artery bypass surgery), and cardiovascular death. A diagnosis of MI was made according to the definition proposed by the Joint European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and the World Heart Federation Task Force.13 If a patient died within 4 weeks of MI, this event was recorded as fatal MI.

Death was classified as vascular unless the central adjudication committee (see later discussion) confirmed an unequivocal noncardiovascular cause of death. Cardiovascular death included sudden death; progressive congestive HF; procedure-related death (surgical or percutaneous revascularization); and presumed cardiovascular deaths (ie, those for which a noncardiovascular cause had not been clearly established). Only the first event that occurred during follow-up was used in the analysis. In addition, the occurrence of any ischemic stroke or transient ischemic attack (TIA) was recorded. Ischemic stroke was determined on clinical manifestations and confirmed by radiologic findings. TIA was defined according to the Classification of Cerebrovascular Diseases III.14

Validation of End Points

Data on CVEs were collected prospectively during follow-up. When a CVE occurred, a standardized form was filled in by the investigators. Details on CVEs were registered; death certificates, hospital discharge letter or copy of the medical records of hospitalization, and other clinical documentation (ie, radiology and laboratory data) were also obtained from patients, or in case of death, from the relatives of patients or from the general practitioner. Adjudication of CVEs was performed by a committee composed of three physicians (F. V., P. P., F. A.) who did not participate in the recruitment of patients and were unaware of the clinical and laboratory characteristics of any enrolled patient. Each member of the committee independently evaluated and adjudicated CVEs in a blinded manner. In the case of discordant evaluation or difficult adjudication of an event, the committee made the decision regarding the event in a collegial way. All patients provided written informed consent. The study protocol was approved by the local ethical board of Sapienza University of Rome (No. 1306/2007), and the study was conducted according to principles of the Declaration of Helsinki.15

Power Calculation

A minimal sample size of 792 patients was planned, to have a power of about 80%, with significance level α set to 5%, to reject a log-rank test, calculating an expected survival probability at the end of the study period of 0.87 for the group with the MetS and 0.93 in the group without the syndrome and a MetS prevalence of about 46%.16

Statistical Analyses

Categorical variables were reported as counts (percentage); continuous variables were expressed as mean and SD or median and interquartile range, as appropriate. The Pearson χ2 test was used to compare proportions. Bivariate analysis was performed with the Pearson linear correlation. Appropriate nonparametric tests (Mann-Whitney U test and Spearman rank correlation test) were used for all the other variables. Cox proportional hazards analysis was used to calculate the adjusted relative hazards of outcome events by each clinical variable. The multivariate analysis was determined with a forward stepwise variable selection procedure. All tests were two-tailed, and analyses were performed using computer software packages (SPSS-18.0; IBM). Only P values < .05 were considered as statistically significant.

Baseline characteristics of the whole cohort are described in Table 1. The mean age was 73.2 years (± 8.7 years), and 43.8% were women. The median CHA2DS2-VASc score was 4.0 (2.7-5.0). The quality of anticoagulant treatment was adequate, as shown by the mean time in therapeutic range of 67.5% (± 16.3%). Most patients were affected by arterial hypertension (87.6%) and MetS (52.1%), whereas diabetes was present in 20.6% of patients and HF in 16.3%. In addition, 25.1% of patients had a history of MI/cardiac revascularization, and 16.1% of previous ischemic stroke/TIA.

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics of Whole Cohort and According to the Occurrence of the Primary Outcome

Data are presented as mean ± SD or %. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CVE = cardiovascular event; MI = myocardial infarction; TIA = transient ischemic attack.

Cardiovascular Events

All patients were followed for a median time of 33.7 months (interquartile range, 16.4-58.9 months), yielding 3,223 person-years of observation. At follow-up, 111 patients (3.4%/y) had experienced a primary outcome: 47 MI/revascularization (15 nonfatal MI, 14 fatal MI, 18 stent/coronary artery bypass surgery) and 64 cardiovascular deaths. In addition, 31 strokes/TIAs (0.96%/y) were recorded. Patients who experienced a CVE were older (72.8 ± 8.8 years vs 76.6 ± 7.1 years, P < .001) and had a higher prevalence of MetS (50.6% vs 64.9%, P = .005) and HF (14.9% vs 27.9%, P = .001) and a clinical history complicated by cardiac (22.8% vs 44.1%, P < .001) and cerebrovascular (14.5% vs 28.8%, P < .001) events (Table 1). Significant independent predictors of CVEs are reported in Table 2.

Table Graphic Jump Location
TABLE 2 ]  Significant Predictors of MI and Vascular Death (Multivariable Cox Proportional Hazard Analysis)

See Table 1 legend for expansion of abbreviation.

On Cox proportional hazard analysis, age (hazard ratio [HR], 1.083; 95% CI, 1.053-1.113; P < .001), smoking (HR, 2.158; 95% CI, 1.193-3.901; P = .011), history of cerebrovascular events (HR, 1.704; 95% CI, 1.119-2.597; P = .013), MetS (HR, 1.663; 95% CI, 1.107-2.499; P = .014), history of cardiac events (HR 1.658, 95% CI, 1.105-2.489, P = .015), HF (HR 1.584, 95% CI, 1.021-2.456; P = .040), and sex (male vs female) (HR, 1.499; 95% CI, 1.010-2.223; P = .044) predicted CVEs after adjustment for diabetes mellitus, antiplatelets, angiotensin-converting enzyme inhibitors/sartans, statins, amiodarone, and arterial hypertension.

In this study, we show that patients with AF still experience a high rate of CVEs despite receiving oral anticoagulant treatment. Second, we show that MetS is a common clinical feature in patients with AF, which increases the risk of CVEs.

Previous data suggest that elderly patients with AF have a high risk of mortality; for example, a total mortality rate of 3.84%/y was seen in the Randomized Evaluation of Long-Term Anticoagulation Therapy trial.17 In addition, an accentuated risk of MI/coronary death has been reported, with a rate rising up to 6.83%/y in a cohort of patients with AF with stable coronary artery disease.18 Our data obtained in unselected elderly patients with AF receiving oral anticoagulants are consistent with this finding because the composite end point of CVEs was 3.4%/y, with 1.46%/y for MI/revascularization and 1.98%/y for CVEs. This indicates that in an elderly population with AF receiving adequate oral anticoagulation treatment, the rate of coronary events is still much higher than that of thromboembolic events.

Data regarding predictive factors for CVE in patients with AF are still unclear. Marijon et al17 found many factors associated with coronary mortality. HF, previous MI, diabetes, and hypertension were the most relevant predictors of cardiovascular death. In the current study, analysis of predictors was performed for fatal and nonfatal CVEs. Although we confirm that HF and a history of coronary heart disease is associated with CVEs, the novelty of the study lies in the strong association between MetS and MI, suggesting that in the elderly population with AF, the coexistence of several atherosclerotic risk factors as defined by MetS is associated with an enhanced risk of MI.

MetS represents a worldwide challenge, with a widespread prevalence that appears to be increasing in parallel with obesity.19 About 40% of the population aged 60 years old in the United States have MetS,20 and in Europe, the prevalence ranges from 15% in patients without diabetes21 up to 63%22 and 87.1%23 in different case studies. The few studies that have reported on the prevalence of MetS in the population with AF have reported a prevalence ranging from 18.8% to 49.4%.16,2427 Nevertheless, these data stem from studies on the recurrence of AF after catheter ablation,16,2427 and it is difficult to generalize because of the small sample sizes and the nonhomogeneous definition of waist circumference among people of different races.28 Our finding that 52.1% of white patients with AF had MetS indicates that a high proportion of patients with AF was affected by this condition. Such a prevalence is impressive when considering MetS in comparison with other atherosclerotic risk factors detectable in AF; thus, after hypertension, MetS was the most frequent risk factor in our population with AF. The high prevalence of MetS in the population with AF may provide insights into the high rate of CVEs in AF. Indeed, MetS is associated with not only an enhanced risk of AF,4,29 but also a greater risk of CVEs in the general population.30,31 This association could be explained by MetS being complicated by various pathophysiologic abnormalities, including systemic inflammation, oxidative stress, and a prothrombotic state, which can all predispose to atherosclerotic and thromboembolic complications.32,33

This study has important implications. Our data suggest a major residual risk of CVEs and death in the elderly population with AF, even despite oral anticoagulation treatment. Thus, the actual treatment of this population is still inadequate to counteract coronary heart events, which complicates the clinical course of AF. Appropriate therapy to reduce this risk, in a holistic manner, represents an important future challenge of AF management. In this context, one possible option would be to combine oral anticoagulants with antiplatelet drugs (eg, aspirin), which have the potential to reduce the risk of coronary adverse events; however, the high rate of bleeding complications and the lack of demonstrable benefit3436 discourage the routine use of concomitant oral anticoagulant plus antiplatelet therapy, especially in patients with AF with stable vascular disease.37,38 Combining warfarin with statins, which have an antiatherosclerotic and antithrombotic effect,39,40 could be of interest, but clinical trials are still needed to explore this hypothesis. Stringent attention to the quality of warfarin control, as reflected by a high time in the therapeutic range, may also help in reducing CVEs.41,42

Limitations

We performed our study in a single center and enrolled patients who were all taking oral anticoagulants. The results of the current study are limited to patients with AF receiving treatment with VKAs and cannot be extrapolated to patients with AF who receive treatment with non-VKA oral anticoagulants (NOACs). Comparing the predictors of MI in patients with AF receiving warfarin or NOACs would be interesting, but the number of patients with AF receiving NOACs is still low in Europe.43,44 In addition, the patients included in the study were all white, and hence, our data cannot be extrapolated to other ethnic groups. Finally, given the thresholds of waist circumferences recommended by international societies for different ethnic groups, the prevalence of MetS in our study population cannot be extrapolated to other populations.

In conclusion, elderly patients with AF still experience a high rate of CVEs despite receiving anticoagulant treatment. We also show that MetS is a common clinical feature in patients with AF, which increases the risk of CVEs. A holistic approach is needed to reduce the cardiovascular risk in patients with AF.

Author contributions: D. P., P. P., and F. V. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. F. V. takes responsibility for the integrity of the work as a whole. D. P. and P. P. contributed to the study design and coordination; F. V. contributed to the study coordination; F. A., M. D. B., T. V., T. B., and V. R. contributed to the data collection; A. F. and R. C. contributed to the statistical analysis; D. P. and P. P. contributed to the elaboration of the data analysis for the manuscript; D. P., P. P., F. A., A. F., M. D. B., T. V., T. B., V. R., R. C., G. T., G. Y. H. L., and F. V. contributed to the writing or editing of the manuscript; and F. A. contributed to the draft revision.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Prof Lip has served as a consultant for Bayer AG, Merck & Co Inc, Sanofi SA, Bristol-Meyers Squibb Co/Pfizer Inc, Daiichi-Sankyo, BIOTRONIK SE & Co KG, Medtronic plc, Portola Pharmaceuticals Inc, and Boehringer Ingelheim GmbH and has been on the speakers bureau for Bayer AG, Bristol-Meyers Squibb Co/Pfizer Inc, Boehringer Ingelheim GmbH, Daiichi-Sankyo, and Medtronic plc. Drs Pastori, Pignatelli, Angelico, Farcomeni, Del Ben, Vicario, Bucci, Raparelli, Cangemi, Tanzilli, and Violi have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

AF

atrial fibrillation

CVE

cardiovascular event

HF

heart failure

HR

hazard ratio

MetS

metabolic syndrome

MI

myocardial infarction

NOAC

non-vitamin K antagonist oral anticoagulant

TIA

transient ischemic attack

VKA

vitamin K antagonist

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Steinberg BA, Kim S, Piccini JP, et al; ORBIT-AF Investigators and Patients. Use and associated risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation. 2013;128(7):721-728. [CrossRef] [PubMed]
 
Bernard A, Fauchier L, Pellegrin C, et al. Anticoagulation in patients with atrial fibrillation undergoing coronary stent implantation. Thromb Haemost. 2013;110(3):560-568. [CrossRef] [PubMed]
 
Azoulay L, Dell’Aniello S, Simon T, Renoux C, Suissa S. The concurrent use of antithrombotic therapies and the risk of bleeding in patients with atrial fibrillation. Thromb Haemost. 2013;109(3):431-439. [CrossRef] [PubMed]
 
Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Thromb Haemost. 2011;106(4):572-584. [CrossRef] [PubMed]
 
Lip GY, Windecker S, Huber K, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J. 2014;35(45):3155-3179. [CrossRef] [PubMed]
 
Pignatelli P, Carnevale R, Pastori D, et al. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012;126(1):92-103. [CrossRef] [PubMed]
 
Ruff CT, Bhatt DL, Steg PG, et al; REACH Registry Investigators. Long-term cardiovascular outcomes in patients with atrial fibrillation and atherothrombosis in the REACH Registry. Int J Cardiol. 2014;170(3):413-418. [CrossRef] [PubMed]
 
Clemens A, Fraessdorf M, Friedman J. Cardiovascular outcomes during treatment with dabigatran: comprehensive analysis of individual subject data by treatment. Vasc Health Risk Manag. 2013;9:599-615. [CrossRef] [PubMed]
 
De Caterina R, Husted S, Wallentin L, et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease. Thromb Haemost. 2013;110(6):1087-1107. [CrossRef] [PubMed]
 
Lip GY, Laroche C, Dan GA, et al. A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace. 2014;16(3):308-319. [CrossRef] [PubMed]
 
Lip GY, Laroche C, Ioachim PM, et al. Prognosis and treatment of atrial fibrillation patients by European cardiologists: one year follow-up of the EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase (EORP-AF Pilot Registry). Eur Heart J. 2014;35(47):3365-3376. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics of Whole Cohort and According to the Occurrence of the Primary Outcome

Data are presented as mean ± SD or %. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CVE = cardiovascular event; MI = myocardial infarction; TIA = transient ischemic attack.

Table Graphic Jump Location
TABLE 2 ]  Significant Predictors of MI and Vascular Death (Multivariable Cox Proportional Hazard Analysis)

See Table 1 legend for expansion of abbreviation.

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Bernard A, Fauchier L, Pellegrin C, et al. Anticoagulation in patients with atrial fibrillation undergoing coronary stent implantation. Thromb Haemost. 2013;110(3):560-568. [CrossRef] [PubMed]
 
Azoulay L, Dell’Aniello S, Simon T, Renoux C, Suissa S. The concurrent use of antithrombotic therapies and the risk of bleeding in patients with atrial fibrillation. Thromb Haemost. 2013;109(3):431-439. [CrossRef] [PubMed]
 
Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Thromb Haemost. 2011;106(4):572-584. [CrossRef] [PubMed]
 
Lip GY, Windecker S, Huber K, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J. 2014;35(45):3155-3179. [CrossRef] [PubMed]
 
Pignatelli P, Carnevale R, Pastori D, et al. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012;126(1):92-103. [CrossRef] [PubMed]
 
Ruff CT, Bhatt DL, Steg PG, et al; REACH Registry Investigators. Long-term cardiovascular outcomes in patients with atrial fibrillation and atherothrombosis in the REACH Registry. Int J Cardiol. 2014;170(3):413-418. [CrossRef] [PubMed]
 
Clemens A, Fraessdorf M, Friedman J. Cardiovascular outcomes during treatment with dabigatran: comprehensive analysis of individual subject data by treatment. Vasc Health Risk Manag. 2013;9:599-615. [CrossRef] [PubMed]
 
De Caterina R, Husted S, Wallentin L, et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease. Thromb Haemost. 2013;110(6):1087-1107. [CrossRef] [PubMed]
 
Lip GY, Laroche C, Dan GA, et al. A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace. 2014;16(3):308-319. [CrossRef] [PubMed]
 
Lip GY, Laroche C, Ioachim PM, et al. Prognosis and treatment of atrial fibrillation patients by European cardiologists: one year follow-up of the EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase (EORP-AF Pilot Registry). Eur Heart J. 2014;35(47):3365-3376. [CrossRef] [PubMed]
 
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