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Article history:
Received 16 August 2016
Accepted 6 November 2016
Available online xxxx
Keywords:
Anticoagulants
Major bleeding
Intracranial hemorrhage
Dabigatran
Rivaroxaban
Apixaban
a b s t r a c t
Background: Limited data are available on major bleeding (MB) occurring during treatment with vitamin K
(VKAs) or direct oral anticoagulants (DOACs) outside clinical trials.
Methods: Patients hospitalized for MB while on treatment with VKAs or DOACs were included in a multicenter
study to compare clinical presentation, management and outcome of bleeding. The primary study outcome
was death at 30 days.
Results: Between September 2013 and September 2015, 806 patients were included in the study, 76% on VKAs
and 24% on DOACs. MB was an intracranial hemorrhage in 51% and 21% patients on VKAs or DOACs, respectively
(Odds Ratio [OR] 3.79; 95% condence interval [CI] 2.595.54) a gastrointestinal bleeding in 46% and 25% patients
on DOACs and VKAs, respectively (OR 2.62; 95% CI 1.873.68). Death at 30 days occurred in 130 patients (16%),
18% and 9% of VKA and DOAC patients (HR 1.95; 95% CI 1.193.22, p = 0.008). The rate of death at 30 days was
similar in VKA and DOAC patients with intracranial hemorrhage (26% and 24%; HR 1.05, 95% CI 0.542.02) and
gastrointestinal bleeding (11% and 7%; HR 1.46, 95% CI 0.573.74) and higher in VKA than DOAC patients with
other MBs (10% and 3%; HR 3.42, 95% CI 0.7815.03).
Conclusions: Admission for ICH is less frequent for DOAC patients compared with VKA patients. Admission for
gastrointestinal MB is more frequent for DOAC as compared to VKA patients. Mortality seems lower in patients
with MBs while on DOACs than VKAs but this nding varies across different types of MBs.
2016 Published by Elsevier Ireland Ltd.
1. Background
Bleeding is the most feared complication of oral anticoagulant treatment. During treatment with vitamin K antagonists (VKA), the incidence of major bleeding (MB) and fatal bleeding is estimated to be 2
5% and 0.51% per year [1,2]. Direct oral anticoagulants (DOACs) were
evaluated in clinical trials and then introduced in clinical practice for
the prevention of stroke and systemic embolism in atrial brillation
and for the prophylaxis and treatment of venous thromboembolism.
Corresponding author.
E-mail address: cecilia.becattini@unipg.it (C. Becattini).
http://dx.doi.org/10.1016/j.ijcard.2016.11.117
0167-5273/ 2016 Published by Elsevier Ireland Ltd.
Please cite this article as: C. Becattini, et al., Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life, Int J Cardiol (2016),
http://dx.doi.org/10.1016/j.ijcard.2016.11.117
2. Methods
3. Results
- Chronic heart failure by the presence of signs and symptoms of either right or left ventricular failure or both, conrmed by non-invasive or invasive measurements demonstrating objective evidence of cardiac dysfunction.
- Vascular disease as the presence of peripheral vascular disease (any the following: intermittent claudication, previous surgery or percutaneous intervention on the abdominal aorta or the lower extremity vessels, vascular abdominal or thoracic
surgery, arterial and venous thrombosis) or coronary artery disease (prior myocardial
infarction, angina, percutaneous coronary interventions or coronary artery by-pass
surgery).
Please cite this article as: C. Becattini, et al., Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life, Int J Cardiol (2016),
http://dx.doi.org/10.1016/j.ijcard.2016.11.117
79 10
79 9
78 11
3699
448 (56)
3699
108 (56)
3794
340 (55)
602 (75)
93 (11)
87 (10)
24 (3)
591 (73)
154 (80)
33 (18)
3 (2)
142 (74)
448 (73)
60 (10)
87 (14)
21 (3)
449 (73)
184 (23)
60 (31)
124 (20)
Previous bleeding, n
(%)
Previous ICH, n (%)
174 (22)
80 (42)
94 (15)
27 (3)
4 (2)
23 (4)
226 (28)
31 (16)
195 (32)
40 (5)
3 (2)
37 (6)
Alcohol, n (%)
43 (5)
18 (9)
25 (4)
161 (20)
47 (25)
114 (18)
Malignancy, n (%)
92 (11)
29 (15)
63 (10)
49 (26)
168 (27)
Cardio-vascular
217 (27)
disease, n (%)
Chronic heart failure, 207 (26)
n (%)
Antiplatelet use, n (%) 77 (10)
60 (31)
147 (24)
13 (7)
64 (10)
8 (4)
25 (4)
33 (4)
107 (56)
255 (41)
1.79
1.292.49
b0.001
13 (7)
74 (12)
0.53
0.291.00
0.042
Fibrinogen
Prothrombin
complex
concentrates
Activated factor VII
1
268 (33)
1
35 (18)
0
233 (38)
0.37
0.250.55
b0.001
9 (1)
8 (1)
ns
Vitamin K
483 (60)
12 (6)
471 (77)
ns
Tranexamic acid
18 (2)
12 (6)
6 (1)
0.001
Endoscopy
231 (29)
88 (46)
143 (23)
b0.001
Angiography
49 (6)
5 (3)
44 (7)
ns
Other procedures
39 (5)
17 (9)
22 (4)
b0.001
Surgery
138 (17)
23 (12)
115 (19)
0.40
0.053,21
0.02
0.010.04
6.80
2.5218.39
2.82
2.013.96
0.35
0.140.89
2.63
1.375.07
0.59
0.370.96
b0.001
b0.001
b0.001
0.022
0.003
0.033
0.013
0.04
0.067
0.061
ns
0.038
ns
ns
The management of MBs is reported in Table 3. At admission, anticoagulant treatment was withdrawn in 89% of patients (97% and 62% of
VKA and DOAC patients, respectively; OR 21.76, 95% CI 12.3938.23,
p b 0.001).
Table 2
Sites of MB.
MBs
TOT
DOAC
VKA
OR
(N = 806) (N = 191) (N = 615) 95% CI
Intracranial, n (%)
354 (44)
41 (21)
313 (51)
b0.001
Gastrointestinal, n
(%)
Soft/muscle, n (%)
239 (30)
88 (46)
151 (25)
80 (10)
11 (6)
69 (11)
Retroperitoneal, n
(%)
Genito-urinary, n
(%)
Pleural/pericardial/
peritoneal, n (%)
Articular, n (%)
33 (4)
2 (1)
31 (5)
27 (3)
15 (8)
12 (2)
21 (3)
5 (3)
16 (3)
18 (2)
9 (5)
9 (1)
9 (5)
6 (1)
Ocular, n (%)
Spinal, n (%)
Other, n (%)
9 (5)
0
0
5 (1)
9 (1)
5 (1)
5 (1)
Patients
DOAC
Warfarin
OR
(N = 806) (N = 191) (N = 615) 95% CI
Transfusion 2units 362 (45)
units of red blood
cells
Fresh frozen plasma 87 (11)
ns
0.26
0.180.39
2.62
1.873.68
0.48
0.250.93
0.20
0.050.84
4.28
1.979.32
1.01
0.362.78
3.33
1.308.51
5.02
1.7614.29
Table 3
Management of major bleedings.
1.05
ns
0.761.46
1.07
0.741.55
1.81
1.262.61
3.99
2.785.74
0.55
0.191.61
0.42
0.270.63
0.25
0.080.82
2.45
1.314.61
1.43
0.972.11
1.57
0.982.52
0.92
0.631.33
1.46
1.022.08
0.63
0.341.17
1.03
0.462.33
b0.001
0.027
0.015
b0.001
ns
0.008
0.001
b0.001
ns
Transfusion of at least two units of red blood cells was given more
commonly in DOAC than in VKA patients. Overall, fresh frozen plasma
and prothrombin complex concentrates were used in 11% and 33% of
patients, respectively, both less commonly in DOAC than in VKA patients. More specically, prothrombin complex concentrates were
used in 160 and 14 patients with intracranial hemorrhage on VKAs
and DOACs, respectively (51 vs 34%, OR 2.02, 95% CI 1.023.99, p =
0.044), and in 73 and 21 patients with extracranial bleedings on VKA
and DOAC, respectively (24 vs 14%, OR 1.96, 95% CI 1.153.33, p =
0.013). Fibrinogen, activated factor VII and tranexamic acid were rarely
used in both patient groups (Table 3).
For the management of MBs, DOAC patients more frequently required endoscopy or other procedures (arthrocentesis, pleural drainage,
nasal packing, and other), while VKA patients more frequently required
angiography or surgery (Table 3). No patient received hemodialysis. In
91 patients, MB was managed only by transfusion of red blood cells.
3.3. Clinical outcome
During the hospital stay 134 patients died. Death at 30 days occurred
in 130 patients (16%), 112 VKA and 18 DOAC patients (18% and 9%, HR
1.95; 95% CI 1.193.22, p = 0.008) (Fig. 2). The increased risk for 30-day
mortality in VKA compared to DOAC patients was conrmed after
adjusting for differences on baseline clinical features (diabetes, previous
bleeding, renal and renal failure, chronic heart failure; HR 1.67, 95% CI
1.002.79, p = 0.05) and after exclusion of patients on anticoagulant
treatment for valvular diseases (HR 2.07, 95% CI 1.253.43, p = 0.04)
(Table 4).
Death at 30 days occurred in 26% and 24% of the VKA and DOAC patients with intracranial hemorrhage (81 and 10 patients, HR 1.05, 95% CI
0.542.02), respectively. The similar risk for 30-day mortality in VKA
compared to DOAC patients after intracranial hemorrhage was conrmed at adjusted analysis (HR 0.92, 95% CI 0.471.81). Among patients
with gastrointestinal bleedings, death at 30 days occurred in 11% and 7%
of the VKA and DOAC patients, respectively (16 and 6 patients, HR 1.46,
95% CI 0.573.74; adjusted HR 1.76, 95% CI 0.654.76). Concerning other
MBs, death at 30 days occurred in 10% and 3% of the VKA and DOAC patients (15 and 2 patients, HR 3.42, 95% CI 0.7815.03; adjusted HR 1.71,
95% CI 0.319.47), respectively (Table 4).
When the analysis was limited to MBs not associated with trauma,
death at 30 days occurred in 19% and 9% of VKA and DOAC patients,
Please cite this article as: C. Becattini, et al., Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life, Int J Cardiol (2016),
http://dx.doi.org/10.1016/j.ijcard.2016.11.117
Fig. 2. Kaplan Meier curves for cumulative risk of death at 30 days in DOAC and VKA
patients.
Table 4
Death at 30 days.
Death rates (%)
VKA
DOAC
18
26
7
10
19
19
31
9
24
11
3
9
9
39
HR (95% CI)
1.78 (1.082.93)
1.05 (0.542.02)
1.46 (0.573.74)
3.42 (0.7815.03)
2.07 (1.253.43)
2.13 (1.203.76)
1.05 (0.542.03)
1.67 (1.002.79)
0.92 (0.471.81)
1.76 (0.654.76)
1.71 (0.319.47)
1.84 (1.013.32)
1.08 (0.542.13)
Intracranial hemorrhage.
Adjusted analysis for differences on baseline clinical features (diabetes, previous bleeding, renal and liver failure, chronic heart failure).
Please cite this article as: C. Becattini, et al., Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life, Int J Cardiol (2016),
http://dx.doi.org/10.1016/j.ijcard.2016.11.117
patients, this could reect a lower prevalence of MB perceived as immediately life-threatening by the attending physician. It is conceivable that
the increased use of prothrombin complex concentrates in VKA patients
was driven by an increased severity of bleeding, as it was suggested in a
previous case series [37]. However, it should be considered that no consensus exists on the potential role of prothrombin complex concentrates in the treatment of DOACs-associated MB [38]. According to
current available evidences, mortality in patients with intracranial hemorrhage while on VKA treatment is still quite high despite warfarin reversal [3941]. Whether the availability in clinical practice of specic
DOAC antidotes will change management and clinical outcome of
DOAC-associated MBs remains to be dened [42].
Our study has some limitations. This is not a management study, and
thus all comparisons between DOACs and VKAs should be seen with
caution as all therapeutic decisions were left to the discretion of attending physicians. This cohort study included patients at time of MB and
thus it does not allow the assessment of predictors of MBs or a direct
comparison of the safety of DOACs and VKAs. In particular, as about
one third of the study patients were included in one tertiary hospital
with a Neurosurgery Department, a Stroke Unit and a large Intensive
Care Unit, the proportion of patients with ICH is considerable.
Patients on anticoagulant treatment for valvular diseases were only
represented in the VKA group and this could have accounted for a selection bias. However, the results obtained after exclusion of these patients
(n = 87) were consistent with those obtained in the overall study population. As further limitations, laboratory tests at admission (as coagulation tests, hemoglobin values or platelet count) and information on
anticoagulation resumption were not systematically reported. However, our study also has some strengths. We evaluated one of the largest
cohort of patients with MBs occurring on oral anticoagulant treatment
in real-life, with a considerable number of patients on treatment with
DOACs [15,17,4345]. This allowed the comparison of DOAC and VKA
MBs on clinically relevant issues. In this setting the multicenter design
should also be seen as a strength of the study.
In conclusion, admission for ICH is less frequent for DOAC patients
compared with VKA patients. Admission for gastrointestinal MB is
more frequent for DOAC as compared to VKA patients. Mortality
seems lower in patients with MBs while on DOACs than VKAs but this
nding varies across different types of MBs.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.ijcard.2016.11.117.
Disclosures
Cecilia Becattini reports lectures fees from Boehringer Ingelheim and
Bayer HealthCare.
Jan. Beyer-Westendorf has received honoraria and research support
from Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb,
and Pzer.
Sandra Marten has received honoraria from Bayer HealthCare.
Laura Franco, Luca Masotti, Cinzia Nitti, Simone Vanni, Giorgia
Manina, Sergio Cattinelli, Roberto Cappelli, Rodolfo Sbrojavacca and
Fulvio Pomero have nothing to disclose.
Giancarlo Agnelli reports lectures fees from Boehringer Ingelheim,
from Sano, from Bayer HealthCare, and from Daiichi-Sankyo.
Contributions of authors
Cecilia Becattini contributed to the interpretation of data, drafting
and critical revision of the manuscript as well as supervision of all statistical analyses and is the guarantor of the paper, taking responsibility for
the integrity of the work as a whole, from inception to published article;
Laura Franco contributed to the conception and design of the study, to
the interpretation of data, drafting and critical revision of the manuscript; Jan Beyer-Westendorf, Luca Masotti, Cinzia Nitti, Simone Vanni,
Giorgia Manina, Sergio Cattinelli, Roberto Cappelli, Rodolfo Sbrojavacca,
Please cite this article as: C. Becattini, et al., Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life, Int J Cardiol (2016),
http://dx.doi.org/10.1016/j.ijcard.2016.11.117
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Please cite this article as: C. Becattini, et al., Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life, Int J Cardiol (2016),
http://dx.doi.org/10.1016/j.ijcard.2016.11.117