Publish in this journal
Journal Information
Visits
Not available
Vol. 72. Issue 11.
Pages 935-943 (November 2019)
Original article
DOI: 10.1016/j.rec.2018.08.026
Full text access
Prevalence and Prognostic Implications of Valve Disease in Patients With Atrial Fibrillation Initiating Direct Oral Anticoagulants
Prevalencia e implicación pronóstica de la enfermedad valvular en pacientes con fibrilación auricular que inician anticoagulantes orales
Visits
...
César Caro Martíneza,b, Ginés Elvira Ruizb,c, Pedro J. Flores Blancob,c, Juan José Cerezo Manchadob,d, Helena Albendín Iglesiasb,e, Alejandro Lova Navarrob,c, Francisco Arregui Montoyab,c, Arcadio García Alberolab,c,f, Domingo Andrés Pascual Figalb,c,f, José Luis Bailén Lorenzoa, Sergio Manzano Fernándezb,c,f,
Corresponding author
sergiomanzanofernandez@gmail.com

Corresponding author: Servicio de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca, Ctra. Madrid-Cartagena s/n, 30120 El Palmar, Murcia, Spain.
a Servicio de Cardiología, Hospital Vega Baja, Orihuela, Alicante, Spain
b Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain
c Servicio de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
d Servicio de Hematología, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
e Servicio de Medicina Interna, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
f Departamento de Medicina Interna, Facultad de Medicina, Universidad de Murcia, Murcia, Spain
This item has received
...
Visits
(Daily data update)
Article information
Abstract
Full Text
Bibliography
Download PDF
Statistics
Figures (2)
Tables (5)
Table 1. Inclusion Criteria for Clinical Trials of Direct Oral Anticoagulants for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation
Table 2. Patient Clinical Characteristics According to the Presence of Heart Valve Disease
Table 3. Patient Characteristics According to Valve Disease Type
Table 4A. Multivariate Cox Proportional Risk Analysis for the Prediction of the Composite Event, Total Mortality, Stroke/TIA/Systemic Embolism, and Bleeding
Table 4B. Multivariate Cox Proportional Risk Analysis for the Prediction of the Composite Event, Total Mortality, Stroke/TIA/Systemic Embolism, and Bleeding
Show moreShow less
Additional material (1)
Abstract
Introduction and objectives

Valvular heart disease in patients with atrial fibrillation included in clinical trials with direct oral anticoagulants (DOAC) is common and is associated with worse prognosis. The aim of this study was to evaluate the prevalence of valvular heart disease and its influence on clinical events in real-world clinical practice.

Methods

We conducted a retrospective multicenter registry including 2297 consecutive patients with nonvalvular atrial fibrillation initiating DOAC between January 2013 and December 2016. Valvular heart disease was defined as moderate or severe involvement. The primary study endopoint was the composite of death, stroke or transient ischemic attack/systemic embolism or major bleeding. A competing risks analysis was carried out using a Fine and Gray regression model, with death being the competing event.

Results

A total of 499 (21.7%) patients had significant valvular heart disease. The most common form was mitral regurgitation (13.7%). Patients with valvular heart disease were older and had more comorbidities. After multivariable analysis, valvular heart disease was associated with a higher risk for the primary endpoint (HR, 1.54; 95%CI, 1.22-1.94; P<.001), death (HR, 1.44; 95%CI, 1.09-1.91, P=.010), and major bleeding (HR, 1.85; 95%CI, 1.23-2.79, P=.003), but there was no association with thromboembolic events (P >.05).

Conclusions

In patients with nonvalvular atrial fibrillation initiating DOACs, valvular heart disease is common and increases the risk of mortality, stroke, transient ischemic attack/systemic embolism, and major bleeding complications. These findings confirm the results of clinical trials and expand them to a real-life clinical setting.

Keywords:
Direct oral anticoagulants
Atrial fibrillation
Valvular disease
Abbreviations:
AF
DOAC
NVAF
TIA
VKA
Resumen
Introducción y objetivos

La enfermedad valvular en los pacientes con fibrilación auricular incluidos en los ensayos clínicos con anticoagulantes orales directos (ACOD) es frecuente y se asocia con peor pronóstico. El objetivo es evaluar la prevalencia de valvulopatía y su influencia en los eventos clínicos en la práctica clínica real.

Métodos

Registro multicéntrico retrospectivo que incluyó a 2.297 pacientes consecutivos con fibrilación auricular no valvular que iniciaron tratamiento con ACOD entre enero de 2013 y diciembre de 2016. La enfermedad valvular se definió como afección moderada o grave. El evento principal fue la combinación de muerte, ictus o accidente isquémico transitorio/embolia sistémica o hemorragia mayor. Se realizó un análisis de riesgos competitivos mediante un modelo de regresión de Fine y Gray, con la muerte como evento competitivo.

Resultados

Tenían valvulopatía 499 pacientes (21,7%), y la insuficiencia mitral fue la más frecuente (13,7%). Los pacientes con valvulopatía eran de más edad y con mayor comorbilidad. Tras el análisis multivariable, la enfermedad valvular fue predictora del evento combinado (HR=1,54; IC95%, 1,22-1,94; p<0,001), muerte (HR=1,44; IC95%, 1,09-1,91, p=0,010) y hemorragia mayor (HR=1,85; IC95%, 1,23-2,79, p=0,003), pero no de eventos tromboembólicos (p >0,05).

Conclusiones

En pacientes con fibrilación auricular no valvular que inician tratamiento con ACOD, la enfermedad valvular es frecuente y se asocia con mayor riesgo de muerte, ictus o accidente isquémico transitorio/embolia sistémica o complicaciones hemorrágicas. Estos hallazgos confirman los resultados de los ensayos clínicos y los expande al ámbito de la práctica clínica real.

Palabras clave:
Anticoagulantes directos
Fibrilación auricular
Enfermedad valvular
Full Text
INTRODUCTION

Extensive research has established the efficacy and safety of direct oral anticoagulants (DOAC) in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). DOAC therapy is currently recommended over treatment with vitamin K antagonists (VKA), especially for patients initiating anticoagulation.1–7 DOAC therapy has been approved for use in patients with nonvalvular atrial fibrillation (NVAF), a broad category based on the exclusion criteria of several randomized clinical trials (Table 1). However, this terminology has led to therapeutic confusion in clinical practice.8,9 The most recent clinical practice guidelines agree that the current definition of valvular AF relates to AF associated with moderate to severe mitral stenosis (usually rheumatic) or mechanical prosthetic valves.6,7,10

Table 1.

Inclusion Criteria for Clinical Trials of Direct Oral Anticoagulants for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation

  Classification criteria for nonvalvular atrial fibrillation 
RE-LY1Excluded: Patients with prosthetic valves, severe mitral stenosis, or valve disease with an indication for intervention before the end of the study 
Included: Other valve disease: mitral, aortic, or tricuspid regurgitation; aortic stenosis; and mild mitral stenosis 
ROCKET-AF2Excluded: Patients with hemodynamically significant mitral stenosis, prosthetic valves, or invasive interventions with a high bleeding risk 
Included: Patients with other valve diseases, annuloplasty (with or without a prosthetic annulus), commissurotomy, and valvuloplasty 
ARISTOTLE3Excluded: Patients with hemodynamically significant mitral stenosis and prosthetic valves 
Included: Patients with previous valve surgery in addition to other valve diseases: mitral, aortic, and tricuspid regurgitation; aortic stenosis; and mild mitral stenosis 
ENGAGE-AF-TIMI 484Excluded: Patients with hemodynamically significant mitral stenosis, mechanical prosthetic valves, or nonresected atrial myxoma 
Included: Other valve diseases, bioprostheses, or surgical interventions 

Heart valve disease and AF often co-occur and can be independent causes of morbidity and mortality. DOAC clinical trials have included a high proportion of patients with significant valve disease. This subgroup has an unfavorable clinical profile, with outcomes similar to VKA-treated patients.11–15 There is currently little evidence available from real-world experience in patients with heart valve disease and no contraindication for DOAC therapy. The goal of the present study was therefore to analyze the presence of heart valve disease in AF patients initiating DOAC therapy in a real-world setting and to assess its influence on the appearance of events.

METHODSStudy Design and Population

A retrospective cohort study was conducted to analyze the prevalence of heart valve disease in patients initiating DOAC therapy in real-world clinical practice and to assess the influence of this therapy on the appearance of clinical events. The study included all consecutive NVAF patients receiving a first DOAC prescription at 3 referral centers between January 1, 2013 and December 31, 2016 and who had had an electrocardiogram. Patients prescribed anticoagulation for an indication other than AF were excluded, as were AF patients treated with anticoagulants for electrical or pharmacological cardioversion but who had no indication for long-term oral anticoagulation. Also excluded were patients with hypertrophic cardiomyopathy, moderate to severe rheumatic mitral stenosis, patients with a mechanical prosthetic valve, and patients with a history of DOAC therapy.

Major medical histories were recorded at the start of DOAC therapy. Patients were considered to have significant valve disease if preinclusion echodardiography showed evidence of aortic or mitral valve regurgitation or moderate to severe aortic valve stenosis. All data related to valvular heart disease were collected at the time of inclusion. Disease severity was assessed according to the criteria recommended in European clinical practice guidelines.16,17 All echocardiography studies were reviewed by 2 cardiologists blinded to clinical events, and the opinion of a third cardiologist was sought if there was disagreement. Kidney disease was defined as a glomerular filtration rate <60mL/min/1.73m2 according to the Chronic Kidney Disease Epidemiology Collaboration equation. Anemia was defined as hemoglobin <12g/dL in women and <13g/dL in men. Data were obtained from digitized clinical records held at the participating hospitals and associated primary care centers. The data were recorded by specially trained cardiologists in a bespoke data collection file containing all codified study variables.

This study conformed to the principles of the Declaration of Helsinki.

Follow-up and Outcome Variables

Patients were followed up from the date of DOAC prescription to the end of the study period, a median of 606 days [interquartile range, 474-731 days]. Follow-up was completed for 99.7% of patients (n=2290). The principal outcome measure was the composite of death, stroke/transient ischemic attack (TIA)/systemic embolism, and major bleeding. Component events of the main outcome measure were also recorded separately during follow-up. Cause of death was categorized as cardiovascular, noncardiovascular, or undetermined according to previously defined criteria.18 Stroke was defined as signs or symptoms of neurological dysfunction secondary to a central nervous system infarction. TIA was defined as signs or symptoms of neurological dysfunction lasting for less than 24hours in the absence of a lesion detectable with neuroimaging techniques.18 Major bleeding was defined according to the International Society on Thrombosis and Haemostasis criteria: fatal bleeding, symptomatic bleeding in a critical area or organ (such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome), or bleeding causing a drop in hemoglobin of ≥20g/L or requiring transfusion of 2 or more units of whole blood or red cells.19

Statistical Analysis

For the analysis of patient characteristics, quantitative variables are expressed as mean ±standard deviation or median [interquartile range] and categorical variables as absolute or relative frequencies. Continuous variables were compared by the Student t test or ANOVA, and categorical variables were compared by the Pearson chi-square test.

To identify factors associated with the studied events, hazard ratios (HR) were calculated by Cox multivariate regression analysis. Because death is a competing risk with embolism and bleeding events, we used the Fine and Gray competing risk model to estimate event incidence and identify predictive factors.20 The independent variables included in the Cox regression models were those showing an association with clinical events in the univariate analysis and judged by the investigators as important for the adjustment. Data collection was preceded by a comprehensive literature search to identify the major variables associated with each event. In addition, the linearity assumption was assessed using Martingale residuals. The proportional risk assumption was verified graphically and statistically for all Cox regression analyses, independently of event type (primary event, death, or competing events). A detailed breakdown of the variables included in the Cox univariate regression analysis is provided in Table 1 of the supplementary data. Differences were considered statistically significant at P <.05. The statistical analysis was performed with the statistical packages SPSS v21 (SPSS Inc; Chicago, Illinois, United States) and STATA v13.0 (Stata Corp LP.; Texas, United States).

RESULTS

In total, 2297 patients were included, of whom 915 (39.8%) received rivaroxaban, 419 (18.2%) dabigatran, 896 (39.0%) apixaban, and 67 (2.9%) edoxaban. Of the total study population, 499 patients (21.7%) had significant heart valve disease. Patients with valve disease tended to be older and have more comorbidity, and thus scored higher on thromboembolic and bleeding risk scales (CHA2DS2-VASc, 4.4 ±1.5 vs 4.0 ±1.7; P <.001; HAS-BLED, 2.6±0.9 vs 2.4±1.0; P <.001). The presence of heart valve disease showed no association with the type of DOAC prescribed (P>.05) (Table 2).

Table 2.

Patient Clinical Characteristics According to the Presence of Heart Valve Disease

  Total  No heart valve disease  Significant heart valve disease  P 
Patients, no.  2297  1798  499   
Sociodemographic variables
Age, y  76±10  75±10  79±<.001 
Women  1216 (52.9)  945 (52.6)  271 (54.3)  .521 
Permanent AF  1309 (57.7)  944 (53.2)  365 (74.2)  <.001 
Cardiovascular risk factors
Hypertension  1999 (87.0)  1546 (86.0)  453 (90.8)  .006 
Diabetes mellitus  741 (32.3)  598 (33.3)  143 (28.7)  .058 
Smoking  146 (6.4)  124 (6.9)  22 (4.4)  .048 
Comorbidities
COPD and/or asthma  321 (14.0)  255 (14.2)  66 (13.2)  .637 
History of stroke and/or TIA  470 (20.5)  370 (20.6)  100 (20.0)  .841 
Ischemic heart disease  384 (16.7)  286 (15.9)  98 (19.7)  .054 
Vascular disease  424 (22.0)  321 (21.3)  103 (24.3)  .201 
Heart failure  449 (19.5)  292 (16.2)  157 (31.5)  <.001 
Chronic kidney diseasea  818 (36.1)  586 (33.2)  232 (46.7)  <.001 
History of cancer  278 (12.1)  211 (11.7)  67 (13.4)  .346 
Intracranial bleeding  60 (2.6)  48 (2.7)  12 (2.4)  .190 
History of major bleeding  200 (8.7)  148 (8.2)  52 (10.4)  .149 
History of major GI bleeding  89 (3.9)  60 (3.3)  29 (5.8)  .190 
Previous labile INRb  425 (68.8)  348 (68.6)  77 (69.4)  .970 
Risk scales
CHADS2  2.4±1.3  2.4±1.3  2.7±1.2  <.001 
CHA2DS2-VASc  4.1±1.6  4.0±1.7  4.4±1.5  <.001 
HAS-BLED  2.4±1.0  2.4±1.0  2.6±0.9  <.001 
Analytical and echocardiography data
GFR, mL/min/1.73m2  68±20  70±20  63±21  <.001 
Hemoglobin, g/dL  13.4±1.9  13.5±1.9  12.8±2.0  <.001 
LVEF ≤ 50%  310 (13.8)  191 (10.9)  119 (23.8)  <.001 
Pharmacological treatment
Aspirin  183 (8.0)  148 (8.2)  35 (7.0)  .423 
Antiplatelet therapy  228 (9.9)  185 (10.3)  43 (8.6)  .307 
History of VKA therapy  1019 (44.4)  816 (45.5)  203 (40.7)  .064 
Beta-blockers  1332 (58.0)  1027 (57.2)  305 (61.1)  .127 
ACE inhibitors/ARB  1545 (67.3)  1197 (66.6)  348 (69.7)  .212 
Aldosterone antagonists  157 (6.8)  100 (5.6)  57 (11.4)  <.001 
Loop diuretics  824 (35.9)  571 (31.8)  253 (50.7)  <.001 
Rivaroxaban  915 (39.8)  725 (40.3)  190 (38.1)  .456 
Dabigatran  419 (18.2)  333 (18.5)  86 (17.2)   
Apixaban  896 (39.0)  686 (38.2)  210 (42.1)   
Edoxaban  67 (2.9)  54 (3.0)  13 (2.6)   
Low-dose anticoagulant therapy  915 (40.0)  661 (36.9)  254 (51.3)  <.001 

ACE, angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; GI, gastrointestinal; INR, international normalized ratio; LVEF, left ventricular ejection fraction; TIA, transient ischemic attack; VKA, vitamin K antagonists.

Data are expressed as mean±standard deviation or No. (%).

a

Chronic kidney disease was defined as a glomerular filtration rate <60mL/min/1.73m2 according to the Chronic Kidney Disease Epidemiology Collaboration equation.

b

Data refer to patients with a history of VKA therapy and a known INR (618 patients).

Clinical characteristics were analyzed according to the predominant valve disease (Table 3). The most frequent valve disease was mitral regurgitation (315 patients; 13.7%), followed by aortic stenosis (100 patients; 4.4%) and aortic regurgitation (84 patients; 3.7%). Population characteristics are stratified according to valve disease type in Table 3.

Table 3.

Patient Characteristics According to Valve Disease Type

  Aortic stenosis  Mitral regurgitation  Aortic regurgitation  P  Pa  Pb  Pc 
Patients, no.  100  315  84         
Variables sociodemográficas
Age, y  80±78±79±.032  .014  .324  .206 
Women  54 (54.0)  183 (58.1)  34 (40.5)  .016  .545  .093  .006 
Permanent AF  70 (71.4)  245 (78.3)  50 (61.7)  .008  .207  .225  .004 
Cardiovascular risk factors
Hypertension  89 (89.0)  284 (90.2)  80 (95.2)  .284  .885  .204  .213 
Diabetes mellitus  35 (35.0)  90 (28.6)  18 (21.4)  .128  .273  .063  .242 
Smoking  3 (3.0)  12 (3.8)  7 (8.3)  .224  .931  .155  .093 
Comorbidities
COPD and/or asthma  17 (17.0)  42 (13.3)  7 (8.3)  .224  .453  .129  .292 
History of stroke and/or TIA  25 (25.0)  51 (16.2)  24 (28.6)  .016  .066  .705  .015 
Ischemic heart disease  20 (20.0)  62 (19.7)  16 (19.3)  .993  1.000  1.000  1.000 
Vascular disease  22 (27.5)  65 (23.5)  16 (24.2)  .760  .553  .797  .675 
Heart failure  39 (39.0)  101 (32.1)  17 (20.2)  .022  .247  .009  .048 
Chronic kidney diseased  51 (51.0)  145 (46.2)  36 (42.9)  .483  .417  .308  1.000 
History of cancer  21 (21.0)  36 (11.4)  10 (11.9)  .045  .024  .149  1.000 
Intracranial bleeding  1 (1.0)  8 (2.5)  3 (3.6)  .156  .241  .060  .209 
History of major bleeding  15 (15.0)  29 (9.2)  8 (9.5)  .245  .146  .371  1.000 
History of major GI bleeding  11 (11.0)  16 (5.1)  2 (2.4)  .156  .241  .060  .209 
Risk scales
CHADS2  3.0±1.2  2.5±1.2  2.7±1.4  .004  .001  .164  .201 
CHA2DS2-VASc  4.8±1.5  4.3±1.5  4.4±1.6  .025  .007  .069  .771 
HAS-BLED  2.8±1.0  2.5±0.9  2.7±0.8  .018  .007  .232  .224 
Analytical and echocardiography data
GFI, mL/min/1.73 m2  62±19  62±22  63±20  .931  .991  .735  .721 
Hemoglobin, g/dL  12.4±1.8  12.8±2.0  13.3±2.1  .007  .047  .002  .054 
LVEF ≤ 50%  20 (20.0)  84 (26.7)  15 (17.9)  .146  .227  .857  .129 
Pharmacological treatment
Antiplatelet therapy  15 (15.0)  27 (8.6)  1 (1.2)  .004  .096  .002  .035 
History of VKA therapy  45 (45.0)  125 (39.7)  33 (39.3)  .615  .409  .528  1.000 
Beta-blockers  59 (59.0)  204 (64.8)  42 (50.0)  .042  .356  .283  .019 
ACE inhibitors/ARB  69 (69.0)  220 (69.8)  59 (70.2)  .981  .972  .983  1.000 
Aldosterone antagonists  11 (11.0)  43 (13.7)  3 (3.6)  .035  .606  .107  .017 
Loop diuretics  61 (61.0)  158 (50.2)  34 (40.5)  .020  .076  .009  .146 
Rivaroxaban  39 (39.0)  119 (37.8)  32 (38.1)  .551  .439  .175  .750 
Dabigatran  11 (11.0)  56 (17.8)  19 (22.6)         
Apixaban  47 (47.0)  132 (41.9)  31 (36.9)         
Edoxaban  3 (3.0)  8 (2.5)  2 (2.4)         
Low-dose anticoagulant therapy  64 (64.6)  150 (47.8)  40 (48.8)  .001  .003  .004  .785 

ACE, angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; GI, gastrointestinal; INR, international normalized ratio; LVEF, left ventricular ejection fraction; TIA, transient ischemic attack; VKA, vitamin K antagonists.

Data are expressed as mean±standard deviation or No. (%).

a

Aortic stenosis vs mitral regurgitation.

b

Aortic stenosis vs aortic regurgitation.

c

Mitral regurgitation vs aortic regurgitation.

d

Chronic kidney disease was defined as a glomerular filtration rate <60mL/min/1.73m2 according to the Chronic Kidney Disease Epidemiology Collaboration equation.

Clinical events recorded during follow-up (606 [474-731] days) are classified according to the presence and type of valve disease in Figure 1 and Figure 2. The presence of valve disease was associated with a higher total event rate: composite event, 17.99 vs 8.56 per 100 person-years (P>.001); death, 11.90 vs 5.27 per 100 person-years (P>.001); and major bleeding, 6.16 vs 2.52 per 100 person-years (P>.001). However, valve disease showed no association with thromboembolic events (ischemic stroke/TIA/ systemic embolism: 1.81 vs 1.83 per100 person-years; P>.05). Similarly, all types of heart valve disease analyzed were associated with higher rates for the composite event, death, and major bleeding, although for aortic regurgitation the association did not reach statistical significance. None of the embolic events analyzed showed an association with higher risk (Figure 2).

Figure 1.

Influence of co-occurring significant heart valve disease on clinical events in NVAF patients. TIA, transient ischemic attack.

(0.12MB).
Figure 2.

Influence of heart valve lesion type on clinical events in NVAF patients. TIA, transient ischemic attack.

(0.21MB).

The univariate Cox proportional risk analysis for the prediction of each event is summarized in Table 1 of the supplementary data. Multivariate adjustment revealed significant valvular heart disease as an independent predictor of the composite event (HR=1.54; 95% confidence interval [95%CI], 1.22-1.94; P <.001), death (HR=1.44; 95%CI, 1.09-1.91; P=.010), and major bleeding (HR=1.85; 95%CI, 1.23-2.79; P=.003). However, the presence of valve disease was not a predictor of stroke/TIA and/or systemic embolism (P>.05) (Table 4A). The composite event, death, and major bleeding were also independently predicted by mitral valve regurgitation and aortic valve stenosis (Table 4B). Finally, discrimination analysis of the regression models showed c-statistics between 0.71 and 0.80 (detail in Table 4A-B).

Table 4A.

Multivariate Cox Proportional Risk Analysis for the Prediction of the Composite Event, Total Mortality, Stroke/TIA/Systemic Embolism, and Bleeding

  Composite eventTotal mortalityStroke/TIA/Systemic EmbolismMajor bleeding
  HR (95%CI)  P  HR (95%CI)  P  HR (95%CI)  P  HR (95%CI)  P 
Age, per 1-y increase  1.04 (1.03-1.06)  <.001  1.07 (1.05-1.09)  <.001  1.03 (1.01-1.07)  .048  1.00 (0.97-1.02)  .891 
Women  0.86 (0.66-1.10)  .230  0.79 (0.58-1.09)  .150  0.96 (0.57-1.61)  .959  1.16 (0.77-1.75)  .470 
Permanent AF  1.11 (0.88-1.39)  .388  0.97 (0.73-1.28)  .805      1.35 (0.90-2.03)  .149 
Hypertension  1.24 (0.86-1.79)  .258  1.11 (0.73-1.71)  .618  1.92 (0.69-5.31)  .210  1.25 (0.65-2.42)  .498 
Diabetes mellitus  1.36 (1.09-1.69)  .007  1.37 (1.05-1.79)  .021  1.56 (0.92-2.65)  .100     
Smoking  1.04 (0.89-1.23)  .606  1.10 (0.91-1.34)  .323         
COPD and/or asthma  1.44 (1.09-1.88)  .008  1.56 (1.13-2.14)  .006      1.71 (1.07-2.71)  .024 
History of stroke and/or TIA  1.69 (1.34-2.14)  <.001  1.54 (1.16-2.05)  .003  3.86 (2.32-6.40)  <.001  1.41 (0.89-2.21)  .138 
Vascular disease  1.44 (1.09-1.89)  .011  1.46 (1.05-2.05)  .025  0.91 (0.45-1.85)  .806  1.43 (0.87-2.36)  .157 
Heart failure  1.54 (1.22-1.96)  <.001  2.12 (1.59-2.81)  <.001         
Chronic kidney disease*  0.86 (0.68-1.09)  .209  0.84 (0.63-1.11)  .216  1.09 (0.65-1.83)  .736  0.64 (0.40-1.03)  .067 
History of cancer  1.95 (1.51-2.52)  <.001  2.08 (1.54-2.83)  <.001  1.07 (0.54-2.15)  .839  2.51 (1.59-3.96)  <.001 
History of major bleeding  0.97 (0.70-1.35)  .862  0.68 (0.45-1.03)  .069  1.64 (0.89-3.03)  .110  0.92 (0.49-1.73)  .805 
Severe heart valve disease  1.54 (1.22-1.94)  <.001  1.44 (1.09-1.91)  .010  0.87 (0.47-1.61)  .661  1.85 (1.23-2.79)  .003 
Hemoglobin, per 1 g/dL  0.85 (0.80-0.91)  <.001  0.83 (0.77-0.89)  <.001      0.81 (0.72-0.91)  <.001 
History of VKA therapy  0.99 (0.78-1.28)  .941  1.02 (0.79-1.33)  .873         
Concomitant antiplatelet therapy  1.04 (0.74-1.48)  .817  0.95 (0.62-1.46)  .813  1.17 (0.52-2.62)  .701  1.07 (0.56-2.04)  .838 
Rivaroxaban  Reference therapy               
Dabigatran  0.95 (0.69-1.32)  .774  1.08 (0.73-1.60)  .711         
Apixaban  0.99 (0.78-1.28)  .996  1.17 (0.86-1.59)  .310         
Edoxaban  1.67 (0.89-3.13)  .107  1.76 (0.80-3.87)  .158         
Low-dose anticoagulant therapy  1.42 (1.03-1.83)  .007  1.54 (1.12-2.12)  .007  1.22 (0.69-2.18)  .461  1.42 (0.88-2.28)  .147 
Table 4B.

Multivariate Cox Proportional Risk Analysis for the Prediction of the Composite Event, Total Mortality, Stroke/TIA/Systemic Embolism, and Bleeding

  Composite eventTotal mortalityStroke/TIA/Systemic EmbolismMajor bleeding
  HR (95%CI)  P  HR (95%CI)  P  HR (95%CI)  P  HR (95%CI)  P 
Age, per 1-y increase  1.04 (1.02-1.06)  <.001  1.07 (1.05-1.09)  <.001  1.03 (0.99-1.06)  .055  0.99 (0.96-1.02)  .844 
Women  0.85 (0.66-1.09)  .199  0.78 (0.57-1.07)  .125  0.98 (0.58-1.66)  .966  1.15 (0.76-1.74)  .497 
Permanent AF  1.11 (0.88-1.39)  .379  0.97 (0.74-1.29)  .847      1.37 (0.91-2.07)  .129 
Hypertension  1.24 (0.86-1.80)  .254  1.08 (0.70-1.66)  .728  1.86 (0.66-5.23)  .234  1.26 (0.65-2.45)  .482 
Diabetes mellitus  1.36 (1.09-1.69)  .007  1.39 (1.06-1.82)  .017  1.56 (0.91-2.65)  .101     
Smoking  1.05 (0.89-1.23)  .596  1.11 (0.91-1.34)  .320         
COPD and/or asthma  1.43 (1.09-1.87)  .010  1.55 (1.13-2.14)  .007      1.70 (1.06-2.72)  .027 
History of stroke and/or TIA  1.72 (1.36-2.17)  <.001  1.57 (1.18-2.09)  .002  3.71 (2.24-6.14)  <.001  1.44 (0.91-2.28)  .115 
Vascular disease  1.43 (1.09-1.89)  .011  1.48 (1.06-2.06)  .023  0.91 (0.45-1.84)  .796  1.42 (0.86-2.34)  .170 
Heart failure  1.56 (1.23-1.98)  <.001  2.16 (1.63-2.87)  <.001         
Chronic kidney disease*  0.87 (.69-1.09)  .218  0.84 (0.63-1.11)  .226  1.09 (0.65-1.83)  .728  0.64 (0.40-1.04)  .077 
History of cancer  1.96 (1.52-2.54)  <.001  2.12 (1.56-2.88)  <.001  1.08 (0.54-2.17)  .813  2.51 (1.60-3.94)  <.001 
History of major bleeding  0.96 (0.69-1.32)  .782  0.66 (0.44-0.99)  .049  1.64 (0.89-3.02)  .108  0.90 (0.48-1.69)  .758 
Mitral regurgitation  1.50 (1.17-1.94)  .002  1.49 (1.10-2.02)  .010  0.52 (0.22-1.21)  .131  1.64 (1.03-2.63)  .036 
Aortic regurgitation  1.29 (0.89-1.89)  .178  1.46 (0.94-2.27)  .090  1.67 (0.72-3.84)  .227  1.18 (0.57-2.43)  .638 
Aortic stenosis  1.37 (0.95-1.98)  .097  0.98 (0.61-1.55)  .914  0.83 (0.25-2.71)  .759  2.07 (1.13-3.73)  .017 
Hemoglobin, per 1 g/dL  0.85 (0.80-0.91)  <.001  0.83 (0.77-0.89)  <.001      0.80 (0.72-0.90)  <.001 
History of VKA therapy  0.99 (0.81-1.24)  .993  1.03 (0.79-1.74)  .828         
Concomitant antiplatelet therapy  1.03 (0.73-1.46)  .876  0.95 (0.62-1.46)  .827  1.22 (0.54-2.78)  .619  1.03 (0.54-1.96)  .917 
Rivaroxaban  Reference therapy      .536         
Dabigatran  0.96 (0.69-1.33)  .816  1.07 (0.72-1.59)  .750         
Apixaban  0.99 (0.77-1.27)  .932  1.16 (0.85-1.58)  .358         
Edoxaban  1.64 (0.88-3.07)  .122  1.70 (0.78-3.74)  .185         
Low-dose anticoagulant therapy  1.42 (1.03-1.83)  .007  1.56 (1.13-2.14)  .006  1.25 (0.72-2.16)  .414  1.40 (0.87-2.25)  .158 

95%CI, 95% confidence interval; AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; TIA, transient ischemic attack; VKA, vitamin K antagonists.

Multivariate model for the composite of death, stroke/TIA/systemic embolism, and major bleeding; c-statistic=0.77 (0.74-0.79).

Multivariate model for total mortality; c-statistic=0.80 (0.78-0.83).

Multivariate model for stroke/TIA/systemic embolism; c-statistic=0.72 (0.67-0.78).

Multivariate models for major bleeding; c-statistic=0.71 (0.67-0.76).

*

Glomerular filtration rate <60mL/min/1.73m2 according to the Chronic Kidney Disease Epidemiology Collaboration equation.

DISCUSSION

The present study evaluated the frequency of heart valve disease and its prognostic value in a contemporary cohort of NVAF patients initiating DOAC therapy. This patient population had a high prevalence of significant valve disease, and this was associated with an elevated risk of adverse events during follow-up. This Spanish multicenter registry is the first to evaluate the frequency and prognostic value of heart valve disease in NVAF patients in a real-world setting, outside the context of a randomized clinical trial. We therefore considered that it would provide important clinical information.

In recent years, the definition of “valvular” AF has provoked controversy, probably due in part to the widely heterogeneous exclusion criteria used in different DOAC clinical trials in AF patients (Table 1).21–24 The appropriateness of the term valvular AF remains a subject of debate. Some authors propose the alternative term ‘mechanical and rheumatic mitral atrial fibrillation’ to describe the condition of patients for whom DOAC therapy is not indicated. Similarly, European guidelines propose the replacement of the current terminology with a classification based on the underlying specific valve disease. In the proposed definition, valve diseases are classified into 2 groups based on the indicated anticoagulant therapy: type 1 disease corresponds to AF patients with heart valve disease requiring VKA therapy (moderate to severe rheumatic mitral stenosis or mechanical valve prosthesis); type 2 disease corresponds to AF patients with heart valve disease requiring therapy with a VKA or a DOAC, also taking into consideration the thromboembolic risk.9,10 Given that valve disease affects up to 30% of AF patients, it would seem prudent, in the absence of consensus, to use the definition provided in the clinical practice guidelines.6,7,10,25

In the present study, the presence of heart valve disease in AF patients was associated with a worse clinical profile, in line with clinical trial substudies.11–14 Similarly, AF patients with significant valve disease treated in real-world clinical practice tended to be older and were more likely than unaffected patients to have ischemic heart disease, a history of major bleeding, heart failure, and renal deterioration. Although this profile would seem to predict higher scores on the main risk scales, published clinical trial substudies present an inconsistent picture. In the ARISTOTLE and ENGAGE-AF trials, patients with heart valve disease had significantly higher scores on the CHADS2 scale than those who did not (2.2 vs 2.1 and 2.9 vs 2.8, respectively; P <.001); however, no such differences were found in the RE-LY and ROCKET-AF studies.11–14 Scores on the HAS-BLED scale in AF patients were recorded in only 2 trials, and the results were once again inconsistent. Whereas the ENGAGE-AF trial found an increased bleeding risk among AF patients with valve disease (2.6 vs 2.5; P=.018), the ROCKET-AF trial showed no effect (2.8 vs 2.8; P=.18).12,14 In the present study, patients with heart valve disease had a higher thrombotic risk and a statistically nonsignificant tendency toward a higher bleeding risk (CHA2DS2-VASc, 3.9±1.6 vs 4.4±1.6; P <.001; HAS-BLED, 1.6±0.9 vs 1.8±0.9; P=.060).

In the present series, the presence of valve disease was one of the most notable independent predictors of death and bleeding complications. In contrast, valve disease showed no association with the risk of thromboembolic events, even though these patients had high scores on thrombotic risk scales. These findings are in broad agreement with the results of clinical trial substudies, especially the ENGAGE-AF trial.14 Patients with heart valve disease in the RE-LY and ROCKET-AF trials had a similar risk of stroke/systemic embolism and death, with an increase in the bleeding risk.11,12 Moreover, the risk of stroke/systemic embolism and death was higher among patients with heart valve disease in the ARISTOTLE trial, whereas there was no evidence of a differential effect on bleeding risk.13 A subsequent meta-analysis including all 4 substudies produced results consistent with the present study.15

The close relationship between valvular heart disease and adverse events during follow-up suggests that valve functional status should be a factor in risk stratification and the design of strategies to improve prognosis in these patients. The mechanisms linking significant valve disease to clinical events remain unclear. AF worsens the prognosis of patients with severe heart valve disease; moreover, valve disease and AF mutually reinforce each other through volume-pressure overload and neurohormonal factors.26–28 It is for this reason, when valve dysfunction is severe, that AF can be considered a marker of progressive disease. Heart valve disease is a major independent predictor of mortality in AF patients, as observed in the present study; in light of this strong association, valve repair or replacement is recommended to reduce mortality in this patient subgroup.29 Moreover, aortic stenosis is known to be associated with gastrointestinal bleeding, which has a major impact on quality of life, hospital admissions, and mortality. Bleeding and angiodysplasia in Heyde syndrome are a consequence of acquired Von Willebrand factor deficiency secondary to the shear forces generated on the surface of the stenotic and calcified aortic valve; even moderate shear forces trigger von Willebrand factor proteolysis.30 Given the bleeding risk associated with oral anticoagulant therapy, it is of fundamental importance to stratify bleeding risk in patients initiating this therapy and to modify factors that increase bleeding risk in this population. Established factors that increase this bleeding risk include concomitant antiplatelet therapy, nonsteroidal antiinflammatory drugs, and poorly controlled hypertension.31

Limitations

The main limitations of this study are related to its retrospective design. However, strengths of the study include its multicenter nature, the number of recorded events, and the low number of patients lost to follow-up. Moreover, these registry data were collected by specifically trained cardiologists and were not obtained from administrative or insurance company databases, strengthening the reliability of the results obtained. In addition, to date there has been little available information on the use of DOAC therapy in NVAF patients in Spain, further supporting the importance of these findings. The major clinical trial substudies showed a similar overall DOAC efficacy and safety in AF patients with or without heart valve disease; however, this question could not be addressed in the present study due to the lack of a control group of VKA-treated patients.15

CONCLUSIONS

NVAF patients initiating DOAC therapy frequently have co-occurring heart valve disease, and this is associated with an elevated risk of death, stroke/TIA/systemic embolism, and bleeding complications. These findings not only confirm the results of clinical trials in similar patient populations, but also extend them to real-world clinical practice.

CONFLICTS OF INTEREST

None declared.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Heart valve disease is highly prevalent in AF patients included in clinical trials of DOAC therapy.

  • Several substudies of these clinical trials have shown an association between heart valve disease and poor prognosis, although valve function does not affect the advantages of DOAC therapy in this context.

  • There is little available evidence on the prevalence or prognostic impact of heart valve disease in patients with NVAF initiating DOAC therapy outside of the clinical trial setting.

WHAT DOES THIS STUDY ADD?

  • Heart valve disease is common in NVAF patients initiating DOAC therapy in real-world clinical practice.

  • Heart valve disease is associated with an unfavorable clinical profile and an increased risk of death and severe bleeding complications but shows no association with thromboembolic events.

  • The current findings confirm clinical trial results in a real-world clinical context.

Appendix A
Material adicional

Supplementary data associated with this article can be found in the online version, at https://doi.org/10.1016/j.rec.2018.08.026.

References
[1]
S.J. Connolly, M.D. Ezekowitz, S. Yusuf, et al.
Dabigatran versus warfarin in patients with atrial fibrillation.
N Engl J Med., 361 (2009), pp. 1139-1151
[2]
M.R. Patel, K.W. Mahaffey, J. Garg, et al.
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
N Engl J Med., 365 (2011), pp. 883-891
[3]
C.B. Granger, J.H. Alexander, J.J.V. McMurray, et al.
Apixaban versus warfarin in patients with atrial fibrillation.
N Engl J Med., 365 (2011), pp. 981-992
[4]
R.P. Giugliano, C.T. Ruff, E. Braunwald, et al.
Edoxaban versus warfarin in patients with atrial fibrillation.
N Engl J Med., 369 (2013), pp. 2093-2104
[5]
R.J. Romanelli, L. Nolting, M. Dolginsky, E. Kym, K.B. Orrico.
Dabigatran versus warfarin for atrial fibrillation in real-world clinical practice: a systematic review and meta-analysis.
Circ Cardiovasc Qual Outcomes., 9 (2016), pp. 126-134
[6]
J. Steffel, P. Verhamme, T.S. Potpara, et al.
The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
Eur Heart J., 39 (2018), pp. 1330-1393
[7]
P. Kirchhof, S. Benussi, D. Kotecha, 2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS, et al.
Rev Esp Cardiol., 70 (2017), pp. e1-e84
[8]
M. Molteni, H. Polo Friz, L. Primitz, G. Marano, P. Boracchi, C. Cimminiello.
The definition of valvular and non-valvular atrial fibrillation: results of a physicians’ survey.
Europace., 16 (2014), pp. 1720-1725
[9]
R. De Caterina, A.J. Camm.
What is «valvular» atrial fibrillation? A reappraisal.
Eur Heart J., 35 (2014), pp. 3328-3335
[10]
G.Y.H. Lip, J.P. Collet, R. De Caterina, Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE), et al.
Europace, 19 (2017), pp. 1757-1758
[11]
M.D. Ezekowitz, R. Nagarakanti, H. Noack, et al.
Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular heart disease: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy).
Circulation., 134 (2016), pp. 589-598
[12]
G. Breithardt, H. Baumgartner, S.D. Berkowitz, et al.
Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial.
Eur Heart J., 35 (2014), pp. 3377-3385
[13]
A. Avezum, R.D. Lopes, P.J. Schulte, et al.
Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.
Circulation., 132 (2015), pp. 624-632
[14]
R. De Caterina, G. Renda, A.P. Carnicelli, et al.
Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI 48 Trial.
J Am Coll Cardiol., 69 (2017), pp. 1372-1382
[15]
G. Renda, F. Ricci, R.P. Giugliano, R. De Caterina.
Non-vitamin k antagonist oral anticoagulants in patients with atrial fibrillation and valvular heart disease.
J Am Coll Cardiol., 69 (2017), pp. 1363-1371
[16]
P. Lancellotti, C. Tribouilloy, A. Hagendorff, et al.
Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging.
Eur Heart J Cardiovasc Imaging., 14 (2013), pp. 611-644
[17]
H. Baumgartner, J. Hung, J. Bermejo, et al.
Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice.
Eur J Echocardiogr., 10 (2009), pp. 1-25
[18]
C.P. Cannon, R.G. Brindis, B.R. Chaitman, et al.
2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards).
Circulation., 127 (2013), pp. 1052-1089
[19]
S. Schulman, C. Kearon.
Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
J Thromb Haemost., 3 (2005), pp. 692-694
[20]
J.P. Fine, R.J. Gray.
A proportional hazards model for the subdistribution of a competing risk.
J Am Stat Assoc., 94 (1999), pp. 496-509
[21]
J.J. You, D.E. Singer, P.A. Howard, et al.
Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Chest., 141 (2012), pp. e531S-e575S
[22]
A.J. Camm, G.Y.H. Lip, R. De Caterina, et al.
2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
Eur Heart J., 33 (2012), pp. 2719-2747
[23]
D.E. Singer, G.W. Albers, J.E. Dalen, et al.
Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Chest., 133 (2008), pp. 546S-592S
[24]
V. Fuster, L.E. Rydén, D.S. Cannom, et al.
ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
Europace, 8 (2006), pp. 651-745
[25]
R. Nieuwlaat, A. Capucci, A.J. Camm, et al.
Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation.
Eur Heart J., 26 (2005), pp. 2422-2434
[26]
D.L. Ngaage, H.V. Schaff, C.J. Mullany, et al.
Influence of preoperative atrial fibrillation on late results of mitral repair: is concomitant ablation justified?.
Ann Thorac Surg., 84 (2007), pp. 434-442
[27]
A. Maan, E.K. Heist, J. Passeri, et al.
Impact of atrial fibrillation on outcomes in patients who underwent transcatheter aortic valve replacement.
Am J Cardiol., 115 (2015), pp. 220-226
[28]
N. Calvo, F. Bisbal, E. Guiu, et al.
Impact of atrial fibrillation-induced tachycardiomyopathy in patients undergoing pulmonary vein isolation.
Int J Cardiol., 168 (2013), pp. 4093-4097
[29]
H. Baumgartner, V. Falk, J.J. Bax, et al.
2017 ESC/EACTS Guidelines for the management of valvular heart disease.
Eur Heart J., 38 (2017), pp. 2739-2791
[30]
R.P. Anderson, K. McGrath, A. Street.
Reversal of aortic stenosis, bleeding gastrointestinal angiodysplasia, and von Willebrand syndrome by aortic valve replacement.
Lancet., 347 (1996), pp. 689-690
[31]
M. Hughes.
Lip GYH; Guideline Development Group for the NICE national clinical guideline for management of atrial fibrillation in primary and secondary care. Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review.
QJM., 100 (2007), pp. 599-607
Idiomas
Revista Española de Cardiología (English Edition)

Subscribe to our newsletter

Article options
Tools
Supplemental materials
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

es en
Política de cookies Cookies policy
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.