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Vol. 71. Issue 6.
Pages 500-503 (June 2018)
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Vol. 71. Issue 6.
Pages 500-503 (June 2018)
Scientific letter
DOI: 10.1016/j.rec.2017.03.032
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Causes and Predictors of Death in Atrial Fibrillation Patients Initiating Treatment With Direct Oral Anticoagulants
Causas y predictores de muerte de los pacientes con fibrilación auricular que inician tratamiento con anticoagulantes orales directos
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César Caro Martíneza,
Corresponding author
ccaro1980@gmail.com

Corresponding author:
, José M. Andreu Cayuelasb, Ginés Elvira Ruizb, Helena Albendín Iglesiasc, Arcadio García Alberolab,d, Sergio Manzano Fernándezb,d
a Servicio de Cardiología, Hospital Vega Baja, Orihuela, Alicante, Spain
b Servicio de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, El Palmar, Murcia, Spain
c Servicio de Medicina Interna, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
d Departamento de Medicina Interna, Facultad de Medicina, Universidad de Murcia, Murcia, Spain
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Tables (2)
Table 1. Baseline Characteristics of the Study Population by Survival
Table 2. Multivariate Analysis of Cox Proportional Risks for Prediction of Overall, Cardiovascular, and Noncardivascular Death
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To the Editor,

Patients with atrial fibrillation often have numerous concurrent diseases that are associated with a worse prognosis. Although several studies have addressed the causes of death in these patients, only limited data are available from clinical practice for patients under treatment with direct-acting oral anticoagulants (DAOAs). Given that patients who receive these agents in Spain usually have a different clinical profile to those who receive vitamin K antagonists,2,3 we evaluated the causes and predictors of death in patients with nonvalvular atrial fibrillation (NVAF) who started treatment with DAOAs in 3 Spanish health areas. For our study, we included 973 consecutive patients with NVAF who were prescribed DAOA for the first time between January 2013 and December 2014. Patients were selected from the prescription database, which includes information from all medical prescriptions of all the health areas included in the study, given that electronic prescription is mandatory. Subsequently, all electronic medical records were reviewed to check whether NVAF was present. We excluded patients with an indication for temporary anticoagulation and indications other than atrial fibrillation; patients with hypertrophic cardiomyopathy, moderate/severe rheumatic mitral stenosis, or mechanical valve prosthesis; and those who had already taken DAOAs. Patients were followed up from the date of prescription through to a common end date. The primary outcome measure was death. Information on this outcome was available for 99.8% of the patients. Deaths were reported by the clinical cardiologist, using a standard form that included a structured description of the date and place of death, circumstances in which death occurred, treatments administered, etc. The information was obtained through electronic chart review, death certificates, reports of out-of-hospital emergency personnel, and telephone contact with the family in the event of death. To identify the factors associated with death, a multivariate Cox regression analysis was undertaken, which was used to calculate the hazard ratio. SPSS v21 and STATA v13 statistical packages were used for the statistical analysis. The present study was approved by the ethics committees of the participating centers.

The characteristics of the study population are summarized in Table 1. For a mean follow-up of 646 days (range, 470-839 days), 102 deaths were recorded (5.85/100 patient-years), of which 34 were of cardiac cause (1.95/100 patient-years), 55 of noncardiac cause (3.16/100 patient-years), and 13 of undetermined cause (0.74/100 patient-years). Table 1 of the supplementary material shows the incidence of the causes of death in the study population. The most frequent causes of death were neoplasms (1.20/100 patient-years), infections (0.92/100 patient-years), and heart failure (0.80 patient-years). Patients who died were older and had more concurrent diseases and higher scores on the risk scales for thromboembolic and bleeding events (Table 1). The predictors of overall mortality, whether of cardiovascular origin or not, are shown in Table 2. The C-statistic of the model was 0.82 for overall mortality (95% confidence interval [CI], 0.77-0.87; P < .001), 0.81 for cardiovascular mortality (95% CI, 0.73-0.89; P < .001), and 0.81 for noncardiovascular mortality (95% CI, 0.74-0.87; P < .001) (Hosmer-Lemeshow test, P > .05 in the 3 models). During follow-up, mortality was similar regardless of the type of anticoagulant or cause of death (Tables 2 and 3 of the supplementary material).

Table 1.

Baseline Characteristics of the Study Population by Survival

  Total (n = 973)  DeathP 
    No (n = 869)  Yes (n = 102)   
Sociodemographic
Age, y  76 ± 9  75 ± 9  81 ± 7  < .001 
Caucasian race  970 (99.7)  866 (99.7)  102 (100)  .552 
Female sex  529 (54.4)  471 (54.2)  57 (55.9)  .747 
First episode of AF  296 (30.5)  267 (30.8)  28 (27.7)  .521 
Persistent-permanent AF  602 (61.9)  527 (60.9)  73 (73.0)  .018 
Cardiovascular risk factors
Hypertension  825 (84.8)  732 (84.2)  91 (89.2)  .185 
Diabetes mellitus  291 (29.9)  241 (27.7)  49 (48.0)  < .001 
Current smoker  64 (6.6)  61 (7.0)  3 (2.9)  .290 
Concurrent diseases
Alcohol abuse  17 (1.7)  15 (1.7)  2 (2.0)  .864 
COPD and/or asthma  182 (18.7)  153 (17.6)  29 (28.4)  .008 
Stroke and/or prior TIA  197 (20.2)  164 (18.9)  33 (32.4)  .001 
Systemic embolism  9 (0.9)  7 (0.8)  2 (2.0)  .249 
Ischemic heart disease  118 (12.1)  97 (11.2)  21 (20.6)  .006 
Prior stenting  68 (7.0)  59 (6.8)  9 (8.8)  .446 
Peripheral artery disease  37 (3.8)  28 (3.2)  9 (8.8)  .005 
Vascular disease  139 (14.3)  114 (13.1)  25 (24.5)  .002 
Heart failure  164 (16.9)  121 (13.9)  43 (42.2)  < .001 
Liver disease  7 (0.7)  6 (0.7)  1 (1.0)  .743 
Chronic kidney diseasea  339 (34.9)  289 (33.3)  50 (49.0)  .002 
Renal transplant/hemodialysis  4 (0.4)  1 (0.1)  3 (2.9)  < .001 
History of neoplasms  110 (11.3)  82 (9.4)  28 (27.5)  < .001 
Intracranial bleeding  27 (2.8)  22 (2.5)  5 (4.9)  .168 
Mayor bleeding  82 (8.4)  66 (7.6)  16 (15.7)  .005 
Major digestive tract bleeding  35 (3.6)  27 (3.1)  8 (7.8)  .015 
History of labile INR  243 (65.0)b  211 (65.7)  32 (61.5)  .556 
Risk scales
CHADS2  2.3 ± 1.3  2.2 ± 1.2  3.2 ± 1.3  < .001 
CHA2DS2VASc  3.9 ± 1.6  3.8 ± 1.5  5.1 ± 1.6  < .001 
HAS-BLED  1.6 ± 0.9  1.6 ± 0.9  2.2 ± 0.9  < .001 
Laboratory analysis and echocardiogram
GFR (mL/min/1.73 m2)  69 ± 20  70 ± 19  62 ± 21  < .001 
Hemoglobin, g/dL  13.6 ± 1.8  13.7 ± 1.7  12.5 ± 1.8  < .001 
Biological valve prosthesis  5 (0.5)  4 (0.5)  1 (1.0)  .488 
Significant valve diseasec  168 (18.7)  136 (16.9)  32 (34.8)  < .001 
Mitral regurgitation  109 (12.2)  87 (10.8)  22 (23.9)  < .001 
Aortic stenosis  39 (4.3)  31 (3.9)  8 (8.7)  .031 
Aortic regurgitation  44 (4.9)  37 (4.6)  7 (7.6)  .206 
LVEF ≤ 50%  97 (11.3)  79 (10.2)  18 (20.9)  .003 
Pharmacological treatment
ASA  84 (8.6)  70 (8.1)  14 (13.7)  .054 
Antiplatelet therapy  92 (9.4)  75 (8.6)  17 (16.7)  .009 
Prior VKA  377 (38.8)  323 (37.3)  53 (52)  .004 
Beta-blockers  541 (55.6)  476 (54.8)  63 (61.8)  .179 
ACEI/ARA-II  641 (65.9)  577 (66.4)  63 (61.8)  .350 
Aldosterone antagonists  66 (6.8)  49 (5.6)  17 (16.7)  < .001 
Loop diuretics  315 (32.4)  258 (29.7)  57 (55.9)  < .001 
Rivaroxaban  505 (52.0)  456 (52.5)  49 (52)   
Dabigatran  188 (19.3)  165 (19.0)  22 (21.6)  .680 
Apixaban  280 (28.7)  248 (28.5)  31 (30.4)   

ACEI, angiotensin converting enzyme inhibitor; AF, atrial fibrillation; ASA, acetylsalicylic acid; ARA-II, angiotensin II receptor antagonist; CHADS2, Heart failure, hypertension, age > 90 years, diabetes mellitus, and Stroke (double); CHA2DS2VASc, Heart failure, hypertension, age ≥ 65 years [double], diabetes mellitus, stroke (double); CKD-EP, Chronic Kidney Disease Epidemiology Collaboration; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; HAS-BLED, hypertension, abnormal renal/liver function, stroke, history or predisposition to bleeding, INR lability, age > 65 years, and concomitant medication or alcohol; INR, international normalized ratio; LVEF, left ventricular ejection fraction; TIA, transient ischemic attack; VKA, vitamin K antagonist.

Data expressed as mean ± SD or No. (%).

a

Chronic renal disease is defined as GFR estimated by CKD-EPI < 60 mL/min/1.73 m2.

b

Percentage relative to patients with a history of VKA use.

c

Moderate-severe valve disease.

Table 2.

Multivariate Analysis of Cox Proportional Risks for Prediction of Overall, Cardiovascular, and Noncardivascular Death

  Overall mortalityCardiovascular deathNoncardiovascular death
  HR (95% CI)  P  HR (95% CI)  P  HR (95% CI)  P 
Diabetes mellitus  1.71 (1.13-2.59)  .011         
Ischemic heart disease  1.89 (1.11-3.22)  .020         
Significant valve disease  1.72 (1.08-2.75)  .023  2.40 (1.12-5.13)  .024     
Female sex      0.43 (0.20-0.90)  .025     
GFR (CKD-EPI) (× mL/min/1.73 m2    0.97 (0.95-0.99)  .005  1.02 (1.00-1.04)  0.022 
Hemoglobin (× g/dL)  0.79 (0.69-0.89)  < .001  0.81 (0.66-0.99)  .035  0.73 (0.61-0.87)  < .001 
Heart failure  2.90 (1.80-4.68)  < .001  3.28 (1.46-7.40)  .004  3.23 (1.69-6.18)  < .001 
Prior neoplasm  3.34 (1.99-5.59)  < .001      3.95 (2.04-7.63)  < .001 
Age (× y)  1.07 (1.04-1.11)  < .001      1.11 (1.05-1.17)  < .001 
COPD and/or asthma          2.00 (1.06-3.71)  0.032 

CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; chronic obstructive pulmonary disease; GFR, glomerular filtration rate; HR, hazard ratio; 95% CI, 95% confidence interval; TIA, transient ischemic attack.

Multivariate model adjusted for age, sex, persistent-permanent AF, diabetes mellitus, COPD and/or asthma, stroke and/or prior TIA, ischemic heart disease, peripheral artery disease, heart failure, neoplasm, previous major bleeding, GFR estimated according to CKD-EPI, hemoglobin, significant valve disease, left ventricular ejection fraction, and direct-acting oral anticoagulant received.

This study is the first to assess the causes of death in a recent and multicenter cohort of patients with NVAF who started treatment with DAOA. Our study shows high mortality in this type of patient, and the most frequent causes of death were neoplasms, infections, and heart failure, whereas deaths due to embolic and/or bleeding events were infrequent. In contrast, the main cause of death in pivotal clinical trials was of cardiovascular origin,1–3 which may reflect differences between the clinical profile of the patients included in clinical trials and those who receive DAOAs in daily clinical practice. We therefore believe it is useful to study the causes of death and identify specific predictors for death in these patients in order to improve planning of strategies to increase survival. As shown above, this study identified as predictors risk markers such as age and sex on the one hand and modifiable risk factors such as diabetes mellitus, ischemic heart disease, heart failure, neoplasms, renal failure, anemia, chronic obstructive pulmonary disease, and valve diseases, on the other. These modifiable risk factors can be targeted with preventive and therapeutic measures. Therefore, the main objectives should be to improve cardiovascular risk factor control and achieve adherence to the recommendations of clinical practice guidelines for the management of concurrent diseases associated with atrial fibrillation.4 Finally, the main limitations of this study are its retrospective design and the absence of a control group, as they prevent us from knowing for certain whether the observed increased mortality occurs in all patients with NVAF regardless of the anticoagulant prescribed or whether DAOA therapy somehow selects patients at higher risk.

References
[1]
A. Gómez-Outes, J. Lagunar-Ruíz, A.-I. Terleira-Fernández, G. Calvo-Rojas, M.L. Suárez-Gea, E. Vargas-Castrillón.
Causes of death in anticoagulated patients with atrial fibrillation.
J Am Coll Cardiol., 68 (2016), pp. 2508-2521
[2]
J.B. Olesen, R. Sørensen, M.L. Hansen, et al.
Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naïve atrial fibrillation patients: Danish nationwide descriptive data 2011-2013.
Europace., 17 (2015), pp. 187-193
[3]
J. Moreno-Arribas, V. Bertomeu-González, M. Anguita-Sanchez, et al.
Choice of new oral anticoagulant agents versus vitamin k antagonists in atrial fibrillation: FANTASIIA Study.
J Cardiovasc Pharmacol Ther., 21 (2016), pp. 150-156
[4]
F. Arribas, I. Roldán, J. Luis Merino, et al.
Comentarios a la guía ESC 2016 sobre el diagnóstico y tratamiento de la fibrilación auricular.
Rev Esp Cardiol., 70 (2017), pp. 2-8
Copyright © 2017. Sociedad Española de Cardiología
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