Beruflich Dokumente
Kultur Dokumente
ABSTRACT
BACKGROUND: Prior studies have shown a treatment gap in oral anticoagulation (OAC) use among patients
with atrial fibrillation yet have incompletely characterized factors associated with failure to treat and
subsequent outcomes in contemporary practice.
METHODS: Using data collected between June 2010 and August 2011 from 174 ambulatory care sites in the
Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we identified factors associated
with absence of OAC via stratified logistic regression. Using weighted Cox regression, we assessed the
association between OAC non-use and subsequent outcomes over 2.5 years.
RESULTS: Among 9553 patients, 2202 (23.0%) were not on OAC. Among OAC nonrecipients, 1846 (83.8%)
had a CHA2DS2-VASc score 2. Factors independently associated with OAC non-use included atrial
fibrillation type (paroxysmal odds ratio [OR] 0.73, 95% confidence interval [CI] 0.54-0.99; persistent OR
0.14, 95% CI 0.10-0.21; permanent OR 0.35, 95% CI 0.25-0.49; reference ¼ new-onset), left atrial diameter
enlargement (mild OR 0.80, 95% CI 0.66-0.97; moderate 0.58, 95% CI 0.47-0.73; severe 0.53, 95% CI
0.42-0.68; reference ¼ normal diameter), and age >80 years (OR 1.04, 95% CI 1.02-1.08). Untreated
patients had a higher risk of death (adjusted hazard ratio [HR] 1.22, 95% CI 1.05-1.41), a lower bleeding risk
(adjusted HR 0.35, 95% CI 0.15-0.81), and a nonsignificant trend toward higher risk of stroke/non-central
nervous system embolism/transient ischemic attack than those treated (adjusted HR 1.18, 95% CI 0.91-1.54).
CONCLUSIONS: A majority of atrial fibrillation patients not treated with an OAC in current community
practice meet guideline indications for treatment. Atrial fibrillation burden, chronicity, and comorbidity are
associated with nontreatment. Untreated patients are at increased risk for adverse outcomes.
Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/). The American Journal of Medicine (2017) 130, 449-456
Funding: See last page of article. Requests for reprints should be addressed to Paul L. Hess, MD, MHS,
Conflict of Interest: See last page of article. Denver VA Medical Center, Cardiology Section (111B), 1055 Clermont
Authorship: See last page of article. Street, Denver, CO 80220.
E-mail address: paul.hess@ucdenver.edu
0002-9343/Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.amjmed.2016.11.001
450 The American Journal of Medicine, Vol 130, No 4, April 2017
Oral anticoagulation (OAC) prevents stroke and improves Those missing data on OAC status at baseline (n ¼ 1) or
all-cause survival in patients with atrial fibrillation. In his- without any follow-up (n ¼ 329) were also excluded. In an
torical clinical trials, vitamin K antagonists reduced the risk analysis dedicated to patients with unequivocal American
of thromboembolism by 64% and all-cause death by 26%, Heart Association/American College of Cardiology/Heart
with an acceptable increase in bleeding risk compared with Rhythm Society guideline indications for OAC,8 we excluded
1
no treatment. Trials of non-vitamin K OACs have patients with a CHA2DS2-VASc (Congestive heart failure;
demonstrated efficacy and safety Hypertension; Age 75 years;
equivalent or superior to vitamin Diabetes mellitus; prior Stroke,
K antagonism.2-5 CLINICAL SIGNIFICANCE TIA, or thromboembolism;
Clinical guidelines recommend In ORBIT-AF, a national, ongoing regis- Vascular disease; Age 65-74 years;
that atrial fibrillation patients who try of outpatients with atrial fibrillation, Sex category) score <2 (n ¼ 930).
are at moderate to high risk of stroke To identify factors associated with
a majority of atrial fibrillation patients
without a known contraindication non-use of OAC, sites with >95%
not treated with oral anticoagulation
should be treated with OAC. 6-8
OAC use and/or <20 patients were
Despite demonstrated efficacy and meet guideline indications for excluded (n ¼ 2564). For the pur-
professional guideline recommen- treatment. pose of the outcomes assessment
dations, OAC treatment rates are Atrial fibrillation burden, chronicity, and among patients with a CHA2DS2-
generally below 60%9 and have comorbidity are associated with VASc score <2, sites with >95%
remained low over time.10 Howev- nontreatment. OAC use and/or <20 patients were
er, factors underlying absence of included.
OAC therapy and associated out- Untreated patients are at elevated risk
comes in the current therapeutic era for death.
are incompletely understood. Future quality improvement initiatives Outcome Measures
Accordingly, the present analysis The condition of interest was
should emphasize appropriate risk
sought to identify factors associated OAC use at baseline. Outcomes of
with the absence of OAC therapy in
stratification and underscore the survival interest included all-cause death,
US clinical practice. Additionally, benefit of oral anticoagulation use. stroke or systemic embolism, and
we sought to describe outcomes in major bleeding. In ORBIT-AF,
patients who were not treated with patients were evaluated every 6
OAC in contemporary US outpatient practice. months, and the time and date of intervening cardiovascular
events were recorded, including but not limited to stroke,
bleeding events, and death. Stroke was defined as a new,
METHODS sudden, focal neurologic deficit that persisted beyond 24
Data Source hours and was not due to a readily identifiable, nonvascular
Outcomes Registry for Better Informed Treatment of Atrial cause (eg, seizure). All stroke and systemic embolism events
Fibrillation (ORBIT-AF) is a national registry of US out- were verified and adjudicated using source documentation.
patients with atrial fibrillation. The rationale, study design, Major bleeding was defined according to the International
data collection, and methods have been described previ- Society of Thrombosis and Haemostasis criteria.12 Interna-
ously.11 The primary dataset for the present analysis con- tional Society of Thrombosis and Haemostasis acute major
sisted of baseline data collected from 174 primary care, bleeding events were those that were fatal; occurred in a
cardiology, or electrophysiology sites between June 2010 critical area or organ such as intracranial, intraspinal,
and August 2011. Trained personnel abstracted data on intraocular, retroperitoneal, intra-articular, pericardial, or
eligible atrial fibrillation outpatients and submitted them to intramuscular with compartment syndrome; and/or led to a
the ORBIT-AF registry by means of a Web-enabled case fall in hemoglobin level of 2 g/L or more, leading to
report form. Data included demographic and clinical char- transfusion of 2 or more units of whole or red blood cells.12
acteristics, medical history, heart rhythm history, and
pharmacologic treatment, including OAC use. The Duke
Clinical Research Institute serves as the data and coordi-
Statistical Analysis
nating center for the registry. In the overall study population, we compared the baseline
characteristics of patients who did not receive OAC with
those of patients who did, using c2 tests for categorical
Study Population variables and Wilcoxon rank-sum tests for continuous var-
A total of 10,135 patients aged 18 years with electrocar- iables. Percentages for categorical variables and medians
diographically documented atrial fibrillation were enrolled in and interquartile ranges (IQRs) for continuous variables are
ORBIT-AF. For the present analysis, patients with an abso- reported. An analysis of only patients with guideline in-
lute contraindication to OAC use, including prior intracranial dications for OAC was performed among patients with a
hemorrhage, allergy, and pregnancy, were excluded (n ¼ 89). CHA2DS2-VASc score 2.
Hess et al Oral Anticoagulation and Outcomes in AF Outpatients 451
To identify factors associated with OAC non-use in the persistent (12.9% vs 17.9%) or permanent (14.9% vs
total study population, we used stratified logistic regression 32.0%) atrial fibrillation. They had slightly higher systolic
modeling after excluding sites with >95% OAC use and/or blood pressure (126 [IQR 116-138] mm Hg vs 125 [IQR
sites with fewer than 20 patients. Covariates missing <14% 116-138] mm Hg). They more commonly had a prior
were imputed using multiple imputation by the Markov myocardial infarction (16.9% vs 15.7%) and less frequently
chain Monte Carlo and regression methods. Estimates and had a prior cerebrovascular event (10.9% vs 16.8%). They
associated standard errors reflect the combined analysis over had a lower burden of cardiovascular comorbidities and risk
5 imputed data sets. We then explored relationships between factors such as heart failure (27.0% vs 34.5%) and advanced
demographic and clinical variables and OAC non-use using heart failure symptoms (5.5% vs 8.5% had New York Heart
multivariable logistic regression modeling. Continuous Association class III or IV), diabetes mellitus (26.1% vs
variables were tested for linearity, and nonlinear relation- 30.5%), hypertension (77.7% vs 84.8%), or a history of
ships were accounted for with the use of splines. Using valve replacement or repair (4.4% vs 9.5%). Patients
logistic regression with generalized estimating equations, without OAC more commonly had preserved systolic
candidate baseline characteristics were backward selected function (74.3% vs 70.0%) and less frequently had enlarged
using an a level of 0.15. The final regression model was left atrial diameters (13.5% vs 22.8% had severely enlarged
then fitted using backward selection in stratified logistic left atrial diameters). Among those not on OAC, 1332
regression with an a level >0.05. An analogous analysis (60.4%) had a CHADS2 score 2 and 1846 (83.8%) had a
was performed among patients with a CHA2DS2-VASc CHA2DS2-VASc score 2. Similar between-group
score 2. A sensitivity analysis was performed among differences were observed among patients with a
patients with a CHADS2 (Congestive heart failure; Hyper- CHA2DS2-VASc score 2.
tension; Age 75 years; Diabetes mellitus; prior Stroke, Table 2 shows factors independently associated with non-
TIA, or thromboembolism) score 2. use of OAC at baseline in the overall cohort (all
To assess the association of baseline OAC use with subse- CHA2DS2DVASc scores included), including age >80 years
quent outcomes in guideline eligible/recommended patients (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02-
without contraindications, we constructed Cox regression 1.08), type of atrial fibrillation (paroxysmal OR 0.73, 95% CI
models for each outcome weighted for a patient’s inverse 0.54-0.99; persistent OR 0.14, 95% CI 0.10-0.21; permanent
propensity score of getting OAC for each outcome. Markov OR 0.35, 95% CI 0.25-0.49; reference ¼ new-onset) and left
chain Monte Carlo and regression methods were used. The atrial diameter enlargement (mild OR 0.80, 95% CI 0.66-
propensity score of predicting OAC use at baseline was 0.97; moderate 0.58, 95% CI 0.47-0.73; severe 0.53, 95% CI
calculated from the logistic regression adjusted for all clinically 0.42-0.68; reference ¼ normal diameter). Systolic blood
relevant covariates, as well as independent predictors of each pressure >120 mm Hg was not associated with OAC non-use.
outcome identified using backward selection. Covariates with a Prior stroke or transient ischemic attack (OR 0.52, 95% CI
P value <.05 were maintained in the model. Linearity was 0.41-0.65), heart failure symptoms (New York Heart Asso-
checked, and splines were used as needed. Models were ciation class II vs none OR 0.62, 95% CI 0.48-0.80), and left
adjusted for demographic and clinical covariates. ventricular dysfunction (severe dysfunction vs normal OR
P values <.05 were considered statistically significant. 0.51, 95% CI 0.31-0.83) were negatively associated with
Tests were 2-sided. Analyses were performed using SAS OAC non-use. Most of the factors observed in the overall
software version 9.4 (SAS Institute, Cary, NC). The population were also seen among patients with CHA2DS2-
ORBIT-AF registry was approved by the institutional re- VASc scores 2. A sensitivity analysis among patients with
view board of the Duke University Health System and the CHADS2 score 2 (Supplementary Table 1, available online)
local institutional review board at each enrolling center. yielded similar results.
Analyses were performed in aggregate using deidentified Table 3 shows outcomes associated with OAC non-
data. PLH and JPP had full access to all of the data in the receipt among patients with a CHA2DS2-VASc score 2
study and take responsibility for the integrity of the data and after a median follow-up of 2.5 years. Rates of death, stroke
the accuracy of the data analysis. All authors read the final or non-central nervous system embolism, and stroke or non-
manuscript and agree to it as written. central nervous system embolism or transient ischemic
attack were numerically higher among patients not receiving
OAC. Bleeding rates were numerically lower. After
RESULTS adjustment for the propensity to receive treatment, absence
Overall, the median age of the cohort was 75 (IQR 67-82) of OAC was associated with a higher likelihood of death
years, 57.5% were male, and 89.5% were white. Table 1 (hazard ratio [HR] 1.22, 95% CI 1.05-1.41) and a nonsig-
shows the baseline characteristics of the overall study nificant increase in rates of the composite outcomes of
cohort stratified by OAC use. Compared with patients stroke and non-central nervous system embolism (HR 1.14,
receiving OAC, those not receiving OAC were younger 95% CI 0.79-1.64) and stroke, non-central nervous system
(73 [IQR 64-82] years vs 75 [IQR 68-82] years), more embolism, and transient ischemic attack (HR 1.18, 95% CI
frequently had new-onset (6.7% vs 3.8%) or paroxysmal 0.91-1.54), as well as lower rates of bleeding (HR 0.35, 95%
(65.5% vs 46.3%) atrial fibrillation, and less frequently had CI 0.74-0.96).
452 The American Journal of Medicine, Vol 130, No 4, April 2017
Table 1 Continued
Total Study Population Patients with CHA2DS2-VASc Score 2
anticoagulation. Second, factors unrelated to recommended non-use was associated with a significantly higher risk of death
stroke risk stratification, including atrial fibrillation duration, among eligible patients with a CHA2S2DVASc score 2.
chronicity, and comorbidity, were all independently associated Most patients not receiving OAC had multiple risk
with OAC non-use. Finally, compared with OAC use, OAC factors and a class I guideline indication for OAC. Fewer
Table 3 Outcomes According to Oral Anticoagulation Use and Associations with Non-Use Among Patients with a CHA2DS2-VASc Score 2
Outcome No OAC* OAC* Unadjusted HR (95% CI) P Adjusted HR (95% CI) P
Death 287 (7.42) 895 (5.78) 1.29 (1.14-1.49) .0002 1.22 (1.05-1.41) .0060
Stroke/non-central nervous 43 (1.12) 158 (1.03) 1.10 (0.79-1.52) .5917 1.14 (0.79-1.64) .4755
system embolism
Stroke/non-central nervous 72 (1.89) 252 (1.65) 1.15 (0.90-1.47) .2550 1.18 (0.91-1.54) .2191
system embolism/transient
ischemic attack
International Society of Thrombosis 9 (0.23) 95 (0.62) 0.38 (0.18-0.79) .0102 0.35 (0.15-0.81) .0147
and Haemostasis bleeding
Composite 338 (8.90) 1103 (7.25) 1.23 (1.09-1.41) .0010 1.19 (1.04-1.35) .0098
CI ¼ confidence interval; HR ¼ hazard ratio; OAC ¼ oral anticoagulation.
*Data are expressed as number of events (number of events per 100 patient-years).
Hess et al Oral Anticoagulation and Outcomes in AF Outpatients 455
than 1 in 5 patients who were not receiving OAC were low explanations include limited power or patient selection
risk (CHA2DS2VASc score of 0-1). That elevated blood bias. Although absence of OAC is associated with less
pressure above 120 mm Hg was not a significant factor bleeding, prior studies have demonstrated net clinical
suggests hypertension may be overlooked in favor of benefit from OAC therapy even in those with high
weighting of other CHADS2 score components. Prior work bleeding risk.24
has in fact shown that prescribers often underestimate Compared with other registries, the use of OAC in
stroke risk.13 Patients and/or providers may also prioritize ORBIT-AF is relatively high.25 This is in contrast to prior
bleeding risk over stroke risk, as indicated by the lower studies, reporting a rate generally below 60% among
use of OAC in those older than 80 years in the present eligible patients.9 Participation in ORBIT-AF is voluntary
analysis. Further study of OAC in patients with frailty, and may reflect an interest in atrial fibrillation quality of
which is common in octogenarians and nonagenarians, care. Stated another way, the data in ORBIT-AF probably
may help address equipoise for treatment in this special represent an “optimistic” estimation of the problem of un-
and growing population. derutilization. In this setting, that factors not related to
Initially, investigators hypothesized that patients with recommended stroke risk stratification are operative in OAC
more sustained forms of atrial fibrillation have higher risks non-use, the high proportion of patients not receiving OAC
of thromboembolism due to longer duration of atrial stasis with a class I indication for it, and the observed mortality
and potential for thrombus formation. This hypothesis was signal are all the more striking.
supported by early reports assessing stroke risk according to The present analysis should inform future quality
atrial fibrillation duration.14,15 However, an analysis of improvement initiatives to improve low OAC treatment
pooled data from the Stroke Prevention in Atrial Fibrillation rates among guideline-eligible patients. Future efforts
trials indicated stroke rates were comparable between should include an educational component regarding appro-
groups stratified by atrial fibrillation duration on aspirin.16 priate risk stratification as well as the survival benefit of
An analysis of the Euro Heart Survey yielded similar re- OAC use. Specifically, the relative importance of older age
sults.17 By contrast, more recent studies with more granular and hypertension versus atrial fibrillation duration and
data than those preceding them show that the stroke risk chronicity should be underscored. In addition, the signifi-
associated with paroxysmal atrial fibrillation is indeed lower cance of the mortality benefit vis-à-vis the bleeding risk of
than that of persistent or permanent atrial fibrillation.18,19 OAC use should be discussed among physicians and pa-
Although patients with paroxysmal atrial fibrillation and a tients within a shared decision-making framework.
CHA2DS2VASc score 2 likely have lower rates of This study has some limitations. Participation in ORBIT-
thromboembolism, they nonetheless have sufficient stroke AF is voluntary, and enrolled patients may not fully repre-
risk to derive net clinical benefit from OAC.8 Despite clear sent atrial fibrillation outpatients in the United States.
professional guideline recommendations, prior reports Specifically, our findings may not be generalizable to mi-
indicate that atrial fibrillation burden has been an important nority and female populations, because they were under-
determinant of whether patients receive OAC.20,21 The represented in our study sample. Further, the inclusion of
present analysis confirms this trend persists in the current specialty practices in ORBIT-AF may have led to higher
therapeutic era among US outpatients. Our study also shows rates of OAC use than that seen in primary care practices.
that left atrial diameter, a marker of atrial fibrillation chro- Contraindications to OAC may have been present but not
nicity,22 also influences treatment decisions. These data adequately documented in the medical record or abstracted.
suggest that efforts to improve OAC use should emphasize Our analysis was observational and thus subject to residual
the importance of therapy in patients with paroxysmal atrial or unmeasured confounding.
fibrillation and those earlier in the course of the disease.
Potential explanations for the observed association be-
tween the absence of OAC and death among guideline- CONCLUSIONS
eligible patients are several. First, OAC may have been In the largest dedicated registry of US ambulatory patients
withheld in the setting of more advanced illness, as sug- with atrial fibrillation, the majority of patients untreated with
gested by a higher burden of a number of several comor- OAC have a guideline recommendation to receive it. Factors
bidities among patients not on OAC. Although the present unrelated to recommended stroke risk stratification,
analysis accounted for multiple comorbidities in multi- including atrial fibrillation duration, chronicity, and co-
variable adjustment, residual confounding may exist. morbidity, were associated with absence of OAC. Finally,
Second, patients on OAC may have more regular exposure consistent with prior studies of net clinical benefit, absence
to healthcare providers, as required by anticoagulation of OAC among CHA2DS2 VASc score 2 patients was
monitoring, or receive higher quality of care not related to associated with an increased risk of death. These data
OAC status. Alternatively, the finding may reflect a true highlight the need to improve atrial fibrillation patients’
survival benefit of OAC, as seen in many clinical trials.1,23 outcomes by eliminating the OAC treatment gap. Quality
Importantly, adjusted rates of stroke and systemic embo- improvement efforts should focus attention on patients less
lism were nonsignificantly increased among patients not likely to receive OAC, including those with paroxysmal
receiving OAC compared with those receiving it. Potential atrial fibrillation, older age, and multiple comorbidities.
456 The American Journal of Medicine, Vol 130, No 4, April 2017
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