Keywords:
Dabigatran - warfarin - atrial fibrillation - atrial flutter - stroke
Palavras-chave:
Dabigatrana - varfarina - fibrilação atrial - flutter atrial - acidente vascular cerebral
Atrial fibrillation and atrial flutter are common cardiac arrhythmias that increase
the risk of thromboembolic events. Preventive therapy can be accomplished through
oral anticoagulants with vitamin K inhibitors, such as warfarin, the main drug used
for this purpose. Warfarin is difficult to manage because it has multiple food and
medication interactions, a considerable frequency of interruptions, requires frequent
laboratory monitoring and it is not uncommon to find the international normalized
ratio (INR) outside the therapeutic range[1].
In the last years, the introduction of new oral anticoagulants has marked a major
change in therapy for patients with nonvalvular atrial fibrillation, providing an
alternative to warfarin for prevention of arterial thromboembolism (ischemic stroke
or systemic embolism). Large multicenter randomized controlled trials have demonstrated
dabigatran etexilate[2], rivaroxaban[3] and apixaban[4] to be noninferior, or even superior, to warfarin in stroke and systemic embolism
prevention, with reduced bleeding rates.
Despite the RE-LY trial results[2], to date there are a lack of data about dabigatran etexilate use in the Brazilian
population for prevention of thromboembolic events, which makes the conduction of
national studies in this area essential. This study aimed to compare these drugs for
thromboembolic event prevention in patients with atrial flutter or nonvalvular atrial
fibrillation.
METHODS
This was a retrospective cohort study of participants using dabigatran etexilate or
warfarin followed in the outpatient clinics of Cerebrovascular Diseases and Cardiology
at the Complexo Hospitalar Universitário Professor Edgard Santos in Salvador, Brazil,
from January 2011 to December 2014. Patients were referred to these specialized services
through the Brazil public health system network. Inclusion criteria were patients
with nonvalvular atrial fibrillation or atrial flutter, using oral anticoagulation
with warfarin or dabigatran etexilate and age > 18 years. Exclusion criteria were
the absence of follow-up period data, clinical and anticoagulation characteristics
in the medical records. Patients with fewer than three medical appointments were excluded.
The choice for warfarin or dabigatran was based on agreement among attending physicians
from our service and patients, taking into consideration benefits, harm effects and
costs of each medication. Only warfarin was available free of charge in our service.
This study aimed to compare these two drugs, and other novel oral anticoagulants were
not evaluated.
Primary outcomes were defined as an embolic event or major bleeding during the follow-up
period, and secondary outcomes as the number of medical appointments per year or person-years
of follow-up, an INR in the therapeutic range, drug change, poor adherence and minor
bleeding. Sociodemographic, clinical and laboratory data were collected from medical
records. Atrial fibrillation risk scores were calculated at baseline characteristics
as CHADS2 (congestive heart failure, hypertension, age [≥ 75 years], diabetes, stroke/ transient
ischemic attack)[5], CHA2DS2-VASc (congestive heart failure, hypertension, age [≥ 75 years], diabetes, stroke/transient
ischemic attack, vascular disease, age [65-74 years], sex [female])[6] and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history
of predisposition, labile INR, age ≥ 65 years, drugs/alcohol concomitantly)[7].
An INR within therapeutic range was defined as between 2.0 and 3.0. We defined inadequate
adherence as the number of medical appointments in which the medical prescription
was not used properly. Interruptions were drug discontinuation for any reason. Major
bleeding was defined as fatal or symptomatic intracranial bleeding, transfusion or
surgical intervention requirements. Gingival and genital bleeding, increased menstrual
flow, or spontaneous hematoma that did not require transfusion or surgical intervention
were considered minor bleeding[2].
Statistical analysis
Groups were analyzed according to dabigatran etexilate or warfarin use. A longitudinal
analysis was performed to evaluate the number of medical appointments per person-year
of follow-up for total medical reviews, INR in range, interruption, adherence and
bleeding. A transversal analysis was performed to compare clinical baseline characteristics
and the median of medical appointments per year for total medical reviews, INR out
range, interruption, adherence and bleeding. Student's t, Mann Whitney U, Fisher or
chi-square tests were used when appropriate. Results were described as mean ± squared
deviation, median [interquartile range] or proportion (%). The p value is shown for
an exact and twotailed test. Analyses were done using SPSS 21.0.
This study was approved by the Research Ethics Committee of the School of Medicine
of the Federal University of Bahia (Statement 856 694).
RESULTS
Data was obtained from 112 patients, with 62 (55.3%) of them using warfarin. The mean
age was 65.5 years (± 12.3) and the female gender was almost half of the sample (49.1%).
Black ethnicity was reported in 24.6%. Nonvalvular atrial fibrillation was classified
as persistent in 86.7%. The baseline characteristics between patients using warfarin
or dabigatran etexilate are shown in the [Table]. Patients using warfarin had a median of CHADS2 of 3 [2-4], CHA2DS2VASc of 4 [3-5] and HAS-BLED of 3 [2-3]. Those using dabigatran, had a median of CHADS2 of 3 [1-4], CHA2DS2VASc of 4 [2-6] and HAS-BLED of 2 [1-3].
Table
Baseline characteristics between warfarin and dabigatran etexilate patients.
|
Characteristics
|
Warfarin (n = 62)
|
Dabigatran etexilate (n = 50)
|
p-value
|
|
Age, mean ± standard deviation
|
64.2 ± 11.4
|
672 ± 13.4
|
0.199
|
|
Female gender (%)
|
56.4
|
40.0
|
0.091
|
|
Non-white ethnicity (%)
|
40.3
|
59.7
|
0.752
|
|
Prior stroke (%)
|
35.5
|
42.0
|
0.559
|
|
Chagas disease (%)
|
33.9
|
18.0
|
0.085
|
|
Diabetes mellitus (%)
|
30.6
|
24.0
|
0.526
|
|
Hypertension (%)
|
91.9
|
80.0
|
0.093
|
|
Chronic renal disease (%)
|
11.3
|
6.0
|
0.508
|
|
Coronary artery disease (%)
|
25.8
|
16.0
|
0.368
|
|
Heart failure (%)
|
64.5
|
44.0
|
0.036
|
|
Statins use (%)
|
41.9
|
40.0
|
0.702
|
The median time of follow-up was 1.9 years for the warfarin group [0.7-3.8] and 1.6
years for the dabigatran etexilate group [1.1-1.9] (p = 0.167). The median number
of medical appointments per year was higher in warfarin patients (8.3 [6.8-10.4] vs
3.1 [2.3-4.2], p < 0.001). Among patients using warfarin, 98.4% had more than four
medical appointments per year and in those using dabigatran, this frequency was 30%
(p < 0.001). There was no major bleeding during the study period, but the frequency
of minor bleeding was more than four times higher in warfarin patients than in dabigatran
etexilate patients (17.7% vs 4.0%, p = 0.035). The median INR outside the therapeutic
range per year was 4.3 [2.6-6.6]. The median frequency of medical appointments with
an INR within the therapeutic range was 50.0% during all follow-up periods.
In a longitudinal analysis, the warfarin group had 7.9 medical appointments per person-year
of follow-up and the dabigatran etexilate group had 3.1. Among patients with prior
ischemic stroke (35.6% in the warfarin group and 42% in the dabigatran group), those
using warfarin had 2.6 times more medical appointments per person-year of follow-up
(8.5 vs 3.3). Minor bleeding occurred in 11 patients in the warfarin group and two
patients in dabigatran group. In the warfarin group, 35.5% of patients interrupted
their medication at some point during their follow-up, and the dose was changed in
95.2%. Of the patients in the warfarin group, 61.3% failed to follow medical instructions
regarding medication use. The number of medical appointments with an INR in the therapeutic
range was 4.2 per person-year of follow-up.
In the dabigatran group, 46% started with 150 mg twice a day. The dose was decreased
in 12 (24%) patients due to reduced creatinine clearance in two patients, minor bleeding
in two, dyspepsia in one and for other medical reasons in the remainder. The drug
was stopped in 11 patients (22%) because four patients could not afford to buy it,
one had dyspepsia, one had reduced creatinine clearance and for other medical reasons
in the remainder. During the follow-up period, 8 (16%) patients complained of dyspepsia.
There was no major bleeding during the follow-up period. However, two patients in
the dabigatran etexilate group had an embolic ischemic stroke after stopping medication.
One patient interrupted their dabigatran use for their own reason and had a new embolic
event eight weeks later. In the other patient, dabigatran was suspended, and changed
to warfarin immediately, due to reduced creatinine clearance levels. This patient
had an embolic ischemic stroke eight days after stopping medication and required hospitalization,
during which they had other events, and died from complications. These patients were
censured before the events, due to the absence of medical records after the events.
In the dabigatran group, the prior use of warfarin was reported in 9 (38%) patients.
There was insufficient data about patients using one medication and changing to another
during the follow-up period to enable analysis.
DISCUSSION
This is the first published study to compare warfarin and dabigatran etexilate in
nonvalvular atrial fibrillation and atrial flutter for prevention of thromboembolic
events in Brazil. We studied 112 patients, of whom 62 used warfarin and 50 used dabigatran
etexilate. Warfarin patients presented with a greater frequency of medical appointments
and minor bleeding. There was no major bleeding, but two embolic events occurred in
the dabigatran etexilate group, both due to discontinuation of this drug, with one
death from complications. There was no recurrence of an event in the warfarin group.
The follow-up period was similar and the rates of drug discontinuation were more frequent
in the warfarin group, but less common in the dabigatran group when compared with
previous studies[2],[8],[9],[10].
Dabigatran etexilate requires fewer medical appointments because it is not necessary
to monitor the INR, and previous studies have found that using 150 mg twice daily
reduced the risk of stroke[2] or systemic embolic events, compared with warfarin, thus reducing the hospitalization
cost. Due to these characteristics, lower total event costs, and lower long term follow-up
costs per patient, Clemens et al. concluded that dabigatran etexilate was cost-effective
when compared with warfarin in US patients with atrial fibrillation at any age[11].
Side effects were not common in this study, probably due to the small sample size.
Only dyspepsia was found in 16% of the dabigatran group, while the warfarin group
did not report any side effects, except minor bleeding. In the RE-LY trial by Connolly
et al., many adverse events were reported that were not found in our sample, but they
did find a smaller frequency of dyspepsia[2]. Minor bleeding happened in 17.7% of our warfarin group and 4% in the dabigatran
group. Major bleeding did not happen in our sample. Our results are consistent with
a recent meta-analysis that showed that dabigatran etexilate use is not associated
with bleeding issues in atrial fibrillation patients[12]. However, interruption due to cost was very significant in our sample, with 22%
of patients changing treatment.
In a retrospective cohort of patients with atrial fibrillation using dabigatran (n
= 1,302) or warfarin (8,102), dabigatran use was associated with a higher risk of
any bleeding (hazard ratio (HR): 1.30, IC 95% 1.20-1.41) and major bleeding (HR: 1.85,
IC 95% 1.64-1.41), but with a lower risk for intracranial hemorrhage (HR: 0.32, IC
95% 0.20-0.50). These risks were greater in African Americans and patients with chronic
kidney disease[13]. In our sample, the risk for minor bleeding was higher in warfarin patients, with
no reports of major bleeding. Despite the small sample and a reduced statistical power
in this study, contradictory results may have been due to the characteristics of the
Brazilian population.
Our results show similarities to previous studies regarding the follow-up period,
minor bleeding and less frequent medical appointments. Some disagreements, such as
the absence of major bleeding and only one death, were possibly due to the small sample
size in our study. Another limitation was the impossibility of standardizing anticoagulation
treatment among patients, which can create concerns about the potential source of
confounders. Nevertheless, our results showed that dabigatran etexilate can be used
in the Brazilian population in nonvalvular atrial fibrillation and atrial flutter,
with a lower frequency of minor bleeding, compared with warfarin, and a rare occurrence
of major bleeding, hospitalization and death. Another important result is the less
frequent medical appointments, which leads to lower long-term follow-up costs per
patient—especially important in the public health system.
This study was not adequately designed to show dabigatran's efficacy and safety and
more studies in the Brazilian population are needed. Among the patients taking warfarin,
there was a higher frequency of women, heart failure and Chagas disease than those
taking dabigatran. We believe this higher percentage of women was due to the small
sample and the impossibility of adjusting the protocol before use. The frequency of
heart failure can be explained by the higher incidence of Chagas disease in the warfarin
group. The lack of studies within this population may explain the lower indication
for dabigatran in this subgroup of patients, which generates selection bias. We did
not carry out an adjusted analysis due to the fact that the data model presented important
limitations for using a multivariate analysis with continuous outcomes, which would
have led to dubious results.
In conclusion, patients using dabigatran etexilate had a lower frequency of minor
bleeding and number of medical appointments than those in the warfarin group. There
was no difference in major bleeding, hospitalization and deaths between the groups
during follow-up.
