Keywords
anticoagulant - dabigatran etexilate - apixaban - rivaroxaban - perioperative period
Introduction
Direct oral anticoagulants (DOACs) are a group of agents acting against specific coagulation
targets IIa (dabigatran etexilate) and Xa (apixaban, edoxaban, and rivaroxaban).[1]
[2] The perioperative management of anticoagulant drugs is always challenging. For decades,
the protocol for patients on vitamin K antagonists (VKA) has included a bridging therapy,
mostly a low-molecular weight heparin (LMWH), but current guidelines recommend against
bridging in low to moderate thrombotic-risk patients.[3]
[4]
[5]
During the first years of DOAC management, due to the lack of experience and unsuitable
standardized monitoring, dissimilar recommendations were made, and some of them (such
as the Spanish ones) proposed bridging therapy for selected patients at high thrombotic
risk.[6]
[7]
[8] However, pharmacokinetic characteristics of DOACs seem to favor discontinuing the
drug for some days (depending on the DOAC, the hemorrhagic risk, and renal function)
without bridging, which has been included in the latest proposals.[5]
[9]
[10]
In a recent meta-analysis,[11] including the Phase III studies of each drug,[12]
[13]
[14]
[15] the rate of 30-day postoperative arterial thromboembolic events (all causing ischemic
stroke) was 0.41 and 1.81% for major bleeding events, but the meta-analysis does not
differentiate the outcome in relation to perioperative DOAC withdrawal. A previous
large real-world study,[16] based on 863 procedures, reported major cardiovascular events at 1.0%, up to 4.6%
when considering only the 10.1% major surgeries. Similarly, major bleeding events
were more common after major procedures (8.0% compared with 1.2% in the pooled data).
The PAUSE study,[17] using a standardized perioperative DOAC management, based on DOAC pharmacokinetic
properties, procedure-associated bleeding risk, and renal function, without bridging
therapy, showed low rate of major bleeding and arterial thrombotic events. But none
of these studies has linked complications in periprocedural DOAC management with drug-free
time or bridging use.
In order to know real-world management and outcomes, we conducted an open, prospective,
observational nonintervention registry.
Methods
The RA-ACOD is a prospective, observational, Spanish multicenter registry of adult
patients under DOAC treatment requiring either scheduled or urgent surgery or an invasive
procedure. No specific DOAC management protocol was standardized. The present study
analyses perioperative DOAC management for scheduled procedures.
Ethics Approval/License
The Clinic Hospital of València Ethics Committee first approved the RA-ACOD study
on February 27, 2014 and it was registered at ClinicalTrials.gov (NCT03182218). Each
hospital local committee also approved the study. All patients provided written informed
consent, including a data protection waiver, before enrolment.
Patient Population
The RA-ACOD registry was open to all the Anesthesiology Departments of Spanish hospitals.
Consecutive patients were eligible if the inclusion criteria were met: age: 18 years
or older; chronic treatment with any DOAC (at least 3 months); scheduled surgery or
invasive procedure; signed and dated informed consent form; availability for follow-up
by telephone call. No exclusion criteria were applied.
Aim and Outcomes
The aim of the study was to evaluate current practice in scheduled perioperative DOACs
management to elaborate future safety and efficacy recommendations based on the hemorrhagic
and thrombotic events found.
The primary outcomes were the cumulative incidence of periprocedural thrombotic (arterial
or venous thrombotic events) or hemorrhagic (major and minor bleeding events) complications.
The secondary outcomes were the relationship between events incidence and the use
of bridging therapy and to obtain information on current DOACs management in clinical
practice.
Data Reporting
Reported variables and definitions are summarized in [Supplementary Material S1] and [Table S1]. For the statistical analysis, two groups of thrombotic risk were made according
to clinical relevance: low-moderate and high thrombotic risk. Taking into account
the type of surgeries, patients were divided into two groups: low and moderate-high
bleeding risk. In addition, we analyzed the interruption of DOAC based on estimated
glomerular filtration rate (eGFR), and we divided all patients into two groups according
to eGFR more or less and equal than 50 mL kg 1.73 m−2.
About the perioperative DOAC management both the time of DOAC withdrawal (preoperative)
and the time to DOAC restart (postoperative) have been considered. Furthermore, taking
these two times together, that is, the total time without DOAC, has been named as
DOAC-free time.
Arterial and venous thrombotic events were diagnosed by physicians not related to
the study. The anesthesiologist and the surgeon in charge assessed whether the intraoperative
bleeding in the operating room was “more than normal.” Bleeding events were classified
as major (any fatal hemorrhage, or related to a decrease in hemoglobin >2 g/dL, or requiring
reintervention) or minor (any hemorrhagic event not classified as major).[18] The cause of death was recorded and its association with hemorrhagic or thrombotic
etiology when applicable.
There were two follow-up frames: the immediate postoperative period (24–48 hours)
and up to 30 days postoperatively. For the 30-day assessment, a double system was
established: telephone interview and clinical history review. The information was
obtained by a member of the local research team. To prevent variability in data collection,
a centralized database with quality-control algorithms was developed. All the investigators
were trained to fill in the electronic case report form and to collect data to uniform
criteria, especially regarding definitions of the medical conditions.
Statistics
Categorical variables are expressed as absolute and relative frequencies, with 95%
confidence intervals (CIs) for proportions based on the binomial distribution. Quantitative
continuous variables (age, weight, and height) are shown as mean (standard deviations).
All other quantitative variables, due to their measure scale and strong asymmetry,
are studied using nonparametric techniques: median (interquartile range).
Chi-square test was performed to find possible associations of those variables with
the main outcome parameters (thrombosis, bleeding, and mortality). Bivariate odds
ratios (ORs) and 95% CIs were also calculated. Kruskal-Wallis and U Mann-Whitney test
were used to find possible associations with the main outcomes. Adjusted p-values are obtained using Holm multiple comparison procedure.
Logistic regression with stepwise (forward/backward) covariate selection was used
to study the possible relationship between the outcome parameters (thrombotic event,
minor and major bleeding event, and mortality) and DOAC type, thrombotic risk, hemorrhagic
risk, withdrawal time, DOAC-free time, and bridging therapy. Independent covariates
were entered into the model if a significant association was found (p < 0.05). Covariates were sequentially removed if this exclusion did not result in
a significant change in the log-likelihood ratio test. The cutoff for variable removal
was set at a significance level of 0.1. We then calculated the adjusted ORs and the
corresponding 95% CI values. The calibration of the logistic regression model was
assessed by the Hosmer–Lemeshow goodness-of-fit statistic.
A result was considered statistically significant when the p-value (or adjusted p-value, in case of multiple comparisons) was less than 0.05. The statistical analysis
was performed with the statistical package R (version 3.2.2; R: A language and environment
for statistical computing, https://www.r-project.org/).
Results
Cohort Characteristics
RA-ACOD registry enrolled 1,066 patients in 26 Spanish hospitals ([Supplementary Table S2]) from November 2014 till December 2017. Nine hundred forty-one of them who underwent
scheduled surgery, were included in the present study, 40 were excluded because of
a form filling error. Thus, we analyzed data obtained from 901 patients ([Fig. 1]). Among the patients included, 322 (35.7%) were on apixaban, 304 (33.7%) on rivaroxaban,
267 (29.6%) on dabigatran, and 8 (0.9%) on edoxaban. The clinical characteristics
of these patients are given in [Table 1] and [Supplementary Table S3]. Types of surgery included in the study are listed in [Supplementary Table S4].
Fig. 1 Recruitment flowchart.
Table 1
Patients and procedures characteristics
|
Total subjects (n)
|
|
901
|
|
Demographic data
|
Gender, male [n (%)]
|
553 (61.4)
|
|
Age [y, median (25–75%)]
|
75 (69–81)
|
|
Weight [kg, median (25–75%)]
|
79 (70–89)
|
|
Height [cm, median (25–75%)]
|
165 (159–172)
|
|
eGFR [median (25–75%)]
|
77.9 (58.4–101.3)
|
|
Comorbidity [n (%)]
|
History of heart failure
|
81 (9.0)
|
|
Hypertension
|
731 (81.1)
|
|
Diabetes mellitus
|
284 (31.5)
|
|
Stroke
|
200 (22.2)
|
|
Pulmonary embolism
|
14 (1.6)
|
|
Deep vein thrombosis
|
33 (3.7)
|
|
Peripheral artery disease
|
178 (19.8)
|
|
Active oncologic disease
|
173 (19.2)
|
|
Thrombophilia
|
8 (0.9)
|
|
Liver disease
|
36 (4.0)
|
|
Alcohol abuse
|
73 (8.2)
|
|
Street drug addiction
|
3 (0.3)
|
|
DOAC indication [n (%)]
|
Subjects (n)
|
901
|
|
Atrial fibrillation
|
874 (97.0)
|
|
Venous thromboembolism
|
15 (1.7)
|
|
Recurrent venous thromboembolism
|
12 (1.3)
|
|
Concomitant treatment [n (%)]
|
Aspirin
|
77 (8.5)
|
|
Clopidogrel
|
11 (1.2)
|
|
NSAID
|
13 (1.4)
|
|
Amiodarone
|
80 (8.9)
|
|
Verapamil
|
7 (0.8)
|
|
Ketoconazole
|
1 (0.1)
|
|
Dronedarone
|
7 (0.8)
|
|
Other p-glycoprotein inhibitors
|
54 (6.0)
|
|
CHA2DS2-VASc
|
Subjects (n)a
|
874
|
|
0–4
|
613 (70.1)
|
|
5–6
|
212 (24.3)
|
|
7–9
|
49 (5.6)
|
|
Patient thrombotic riskb [n (%)]
|
Subjects (n)
|
901
|
|
Low
|
619 (68.7)
|
|
Moderate
|
227 (25.2)
|
|
High
|
55 (6.1)
|
|
Bleeding risk of procedureb [n (%)]
|
Subjects (n)
|
901
|
|
Low
|
412 (45.7)
|
|
Moderate
|
427 (47.4)
|
|
High
|
62 (6.9)
|
|
Type of surgery [n (%)]
|
Subjects (n)
|
901
|
|
Minor
|
235 (26.1)
|
|
Major nonorthopaedic
|
304 (33.7)
|
|
Major orthopaedic
|
178 (19.8)
|
|
Endoscopy
|
51 (5.7)
|
|
Ophthalmologic
|
96 (10.7)
|
|
Others
|
37 (4.1)
|
|
Type of anaesthesia [n (%)]
|
Subjects (n)
|
901
|
|
General
|
515 (57.0)
|
|
Neuraxial block
|
229 (25.5)
|
|
Nerve block
|
72 (8.0)
|
|
Local
|
85 (9.5)
|
Abbreviations: CHA2DS2-VASc score,1 point for congestive heart failure, hypertension, diabetes mellitus,
female, age 65–74 y and vascular disease (peripheral artery disease, myocardial infarction,
aortic plaque); 2 points for age ≥75 y, prior stroke or transient ischemic attack
or thromboembolism; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration
rate; NSAID, nonsteroidal anti-inflammatory drug.
a Only patients with atrial fibrillation.
b See [Supplementary Material S1].
Perioperative DOAC Management
[Table 2] summarizes perioperative DOAC management, considering the type of DOAC and the use
of bridging therapy. The (median [25th–75th percentile]) time of preoperative DOAC
withdrawal was 2 days (2–3 days). The dabigatran withdrawal time was significantly
longer by 1 day (p = 0.013).
Table 2
Perioperative DOAC management
|
All DOAC
n = 901
(n [%])
|
Dabigatran
n = 267
(n [%])
|
Apixaban
n = 322
(n [%])
|
Rivaroxaban
n = 304
(n [%])
|
Edoxaban
n = 8
(n [%])
|
|
Preoperative DOAC management
|
|
Withdrawal time
|
|
1 d
|
121 (13.4)
|
33 (12.4)
|
43 (13.4)
|
44 (14.5)
|
1 (12.5)
|
|
2 d
|
367 (40.7)
|
94 (35.2)
|
126 (39.1)
|
141 (46.4)
|
6 (75.0)
|
|
3 d
|
208 (23.1)
|
61 (22.8)
|
87 (27.0)
|
60 (19.7)
|
0
|
|
4 d
|
59 (6.5)
|
28 (10.5)
|
16 (5.0)
|
15 (4.9)
|
0
|
|
5 d
|
109 (12.1)
|
40 (15.0)
|
34 (10.6)
|
34 (11.2)
|
1 (12.5)
|
|
> 5 d
|
37 (4.1)
|
11 (4.1)
|
16 (5.0)
|
10 (3.3)
|
0
|
|
Bridging therapy
|
|
No
|
586 (65.0)
|
167 (62.8)
|
219 (68.0)
|
191 (62.8)
|
8 (100.0)
|
|
Yes
|
315 (35.0)
|
99 (37.2)
|
103 (32.0)
|
113 (37.2)
|
0
|
|
LMWH prophylactic dose
|
261 (82.9)
|
78 (78.8)
|
91 (88.3)
|
92 (81.4)
|
0
|
|
LMWH therapeutic dose
|
54 (17.1)
|
21 (21.2)
|
12 (11.7)
|
21 (18.6)
|
0
|
|
Start 24 h after ACOD stop
|
286 (91.1)
|
89 (89.9)
|
91 (89.2)
|
106 (93.8)
|
0
|
|
Start 48 h after ACOD stop
|
28 (8.9)
|
10 (10.1)
|
11 (10.8)
|
7 (6.2)
|
0
|
|
Last dose 12 h before surgery
|
199 (63.8)
|
65 (66.3)
|
68 (67.3)
|
66 (58.4)
|
0
|
|
Last dose 24 h before surgery
|
113 (36.2)
|
33 (33.7)
|
33 (32.7)
|
47 (41.6)
|
0
|
|
Postoperative DOAC management
|
|
Postoperative restart time
|
|
< 24 h
|
210 (23.3)
|
60 (22.5)
|
95 (29.5)
|
53 (17.4)
|
2 (25.0)
|
|
= 24–48 h
|
295 (32.7)
|
85 (31.8)
|
96 (29.8)
|
109 (35.9)
|
5 (62.5)
|
|
= 3–30 d
|
319 (35.4)
|
107 (40.1)
|
94 (29.2)
|
118 (38.8)
|
0
|
|
No restart in 30 d
|
77 (8.5)
|
15 (5.6)
|
37 (11.5)
|
24 (7.9)
|
1 (12.5)
|
|
Bridging therapy
|
|
No
|
403 (44.7)
|
107 (39.8)
|
167 (51.9)
|
123 (40.5)
|
6 (75.0)
|
|
Yes
|
498 (55.3)
|
160 (60.0)
|
155 (48.1)
|
181 (59.5)
|
2 (25.0)
|
|
LMWH prophylaxis dose
|
407 (45.2)
|
131 (49.2)
|
124 (38.5)
|
151 (49.7)
|
1 (12.5)
|
|
LMWH therapeutic dose
|
91 (10.1)
|
29 (10.9)
|
31 (9.6)
|
30 (9.9)
|
1 (12.5)
|
|
Perioperative DOAC management
|
|
DOAC-free time (d)[a]
|
5 (3–8)
|
6 (4–9)
|
5 (3–7)
|
5 (3–8)
|
3.5 (3–4)
|
Abbreviations: DOAC, direct oral anticoagulant; DOAC-free time, time since preoperative
withdrawal till postoperative restart; LMWH, low-molecular weight heparin.
a Median (25th–75th percentile).
We also analyzed the withdrawal time related to the eGFR and the bleeding risk of
the surgery ([Table 3]). No statistically significant differences were found among the four DOACs (p = 0.767) when eGFR was ≥50 mL kg 1.73 m−2. Nevertheless, for an eGFR <50 mL kg 1.73 m−2, dabigatran was interrupted 1 day more than the other DOACs (4 days [3–5 days]).
Table 3
Preoperative DOAC-withdrawal time related to estimated glomerular filtration rate
(eGFR) and bleeding risk of surgery
|
DOAC
|
Anti-Xa
|
Anti-II
|
|
n
|
634
|
267
|
|
eGFR (mL min 1.73 m−2)
|
≥50
|
<50
|
≥50
|
<50
|
|
n
|
528
|
106
|
244
|
23
|
|
Preop. bridging therapy [n (%)]
|
176 (33.3)
|
40 (37.7)
|
85 (35.7)
|
12 (52.2)
|
|
Low bleeding risk of surgery
|
n = 247
|
n = 47
|
n = 110
|
n = 8
|
|
Withdrawal-time (d)a
|
2 (1–3)
|
2 (2–3)
|
2.5 (1.3–4.5)
|
|
Moderate/high bleeding risk of surgery
|
n = 281
|
n = 59
|
n = 134
|
n = 15
|
|
Withdrawal-time (d)a rate (eGFR) and bleeding risk of surgery
|
2 (2–3)
|
3 (2–4)
|
4 (3–5)
|
Abbreviations: DOAC, direct oral anticoagulant; AntiXa, apixaban, rivaroxaban, edoxaban;
Anti II, dabigatran; Preop, preoperative.
a Median (25th–75th percentile).
Preoperative bridging therapy with LMWH was used in 315 (35%) of the patients, 261
(82.7%) of them with prophylactic dose. Bridging therapy was more frequently used
in patients who withdrew DOAC treatment more than 2 days (61% [252/413]), compared
with patients who withdrew DOAC 2 days or less before surgery (12.9% [63/488]). However,
bridging therapy indication was not related to the DOAC type (p = 0.382), or thrombotic risk (p = 0.103; 32.8% [203/619], 38.8% [88/227] and 43.6% [24/55] of low, moderate, and
high-risk patients, respectively).
In the postoperative period, 56% (505/901) of the patients restarted DOAC in the first
48 hours and at least 75% of patients had done so within 5 days after surgery (2 days
[1–5 days]). Postoperative thromboprophylaxis was used in 498 (55.3%) patients and,
similar to the preoperative period, in most cases with prophylactic dose ([Table 2]). Mechanical prophylaxis devices were used in 163 (18.1%) patients. Mechanical and
pharmacological prophylaxis were used regardless of the time of DOAC restart.
During the 30-day follow-up, DOAC was not restarted in 77 (8.5%) patients. Postoperative
thromboprophylaxis was prescribed in 68 of them; prophylactic LMWH in 46, and therapeutic
in 22. There are several postoperative complications related to the delay in DOAC
reinitiating ([Supplementary Material S2] for details).
Periprocedural Events
The occurrences of thrombotic and bleeding events within the 30 days after surgery
are shown in [Table 4] ([Supplementary Tables S5] and [S6]). A thrombotic event was observed in 14 (1.6%, [0.9–2.6%]) patients: ischemic stroke
in five (0.6%), acute coronary syndrome in six (0.7%), and venous thromboembolism
(VTE) in three (0.3%) patients. Thrombotic events were not statistically related to
the thrombotic risk classification. Also, the use of bridging therapy was not associated
with a lower rate of thrombotic events. However, preoperative DOAC withdrawal time
(OR: 1.57 [1.03–2.4]) and DOAC-free time longer than 6 days (OR: 1.9 [1.43–2.5]) were
independent risk factors for thrombotic event. A preoperative DOAC withdrawal longer
than 3 days and 4 days was statistically related to thrombotic event with an OR: 3.5
(1.2–10) and OR: 4 (1.3–11.7), respectively. The final model of the multivariate binary
regression analysis showed that higher prevalence of thrombotic events was associated
with a DOAC-free time longer than 6 days (OR: 5.42 [1.18–26]).
Table 4
Perioperative thrombotic and bleeding risk events (bivariate analysis)
|
Total Patients
|
Thrombotic events
|
Minor bleeding events
|
Major bleeding events
|
|
n
|
n (%)
|
OR (95% CI)
|
p-Value
|
n (%)
|
OR (95% CI)
|
p-Value
|
n (%)
|
OR (95% CI)
|
p-Value
|
|
Bleeding risk
Low
Moderate/high
|
412
489
|
3 (0.7)
11 (2.3)
|
3.1 (0.9–11.3)
|
0.117
|
25 (6.1)
51 (10.4)
|
1.8 (1.1–3.0)
|
0.026
|
5 (1.2)
12 (2.5)
|
2.0 (0.7–5.9)
|
0.264
|
|
Thrombotic risk
Low/moderate
High
|
846
55
|
12 (1.4)
2 (3.6)
|
3.3 (0.4–16.7)
|
0.178
|
70 (8.3)
6 (10.9)
|
1.0 (0.4–2.5)
|
0.963
|
14 (1.7)
3 (5.5)
|
4.4 (0.9–18.6)
|
0.051
|
|
Preoperative withdrawal time (d)
|
|
All DOAC
3
>3
|
696
205
|
7 (1)
7 (3.4)
|
3.5 (1.2–10)
|
0.033
|
48 (6.9)
28 (13.7)
|
2.1 (1.3–3.5)
|
0.004
|
12 (1.7)
5 (2.4)
|
1.42 (0.5–4)
|
0.136
|
|
Dabigatran
3
>3
|
188
79
|
2 (1.1)
3 (3.8)
|
3.7 (0.6–22.4)
|
0.313
|
18 (9.6)
16 (20.3)
|
2.4 (1.2–5.0)
|
0.029
|
1 (0.5)
2 (2.5)
|
4.9 (0.4–54.4)
|
0.436
|
|
Apixaban
3
>3
|
256
66
|
2 (0.8)
2 (3)
|
2.5 (0.9–6.8)
|
0.397
|
21 (8.2)
4 (6.1)
|
0.76 (0.3–1.9)
|
0.747
|
6 (2.3)
1 (1.5)
|
0.7 (0.1–4.3)
|
1
|
|
Rivaroxaban
3
>3
|
244
60
|
3(1.2)
2 (3.3)
|
2 (0.69–6.2)
|
0.555
|
9 (3.7)
8 (13.3)
|
2.6 (1.5–4.6)
|
0.009
|
5 (2)
2 (3.3)
|
1.5 (0.4–4.8)
|
0.9
|
|
Preoperative bridging therapy
|
|
No
Yes
|
586
315
|
7 (1.2)
7 (2.2)
|
1.9 (0.7–5.4)
|
0.366
|
37 (6.3)
39 (12.4)
|
2.1 (1.3–3.4)
|
0.003
|
5 (0.9)
12 (3.8)
|
4.6 (1.6–13.2)
|
0.004
|
|
LMWH prophylactic dose
LMWH therapeutic dose
|
261
54
|
4 (1.5)
3 (5.6)
|
3.8 (0.8–17.4)
|
0.187
|
27 (10.3)
12 (22.2)
|
2.5 (1.2–5.3)
|
0.029
|
7 (2.7)
5 (9.3)
|
3.7 (1.1–12.1)
|
0.056
|
|
Postoperative restart DOAC (d)
|
|
All DOAC
3
>3
|
561
340
|
5 (0.9)
9 (2.6)
|
3 (1.005–9)
|
0.07
|
32 (5.7)
44 (12.9)
|
2.4 (1.5–4)
|
0.000
|
5 (0.9)
12 (3.5)
|
4 (1.4–11.6)
|
0.01
|
|
Dabigatran
3
>3
|
158
107
|
2 (1.3)
1 (1.1)
|
2.3 (0.4–13.7)
|
0.658
|
12 (7.6)
22 (20.5)
|
3 (1.5–6.7)
|
0.004
|
1 (0.6)
2 (1.8)
|
3.5 (0.3–33)
|
0.733
|
|
Apixaban
3
>3
|
216
106
|
1 (0.5)
3 (2.8)
|
6.3 (0.6–61)
|
0.205
|
13 (6)
12 (11.3)
|
2 (0.87–4.5)
|
0.147
|
2 (0.9)
5 (4.7)
|
5.3 (1.01–27)
|
0.074
|
|
Rivaroxaban
3
>3
|
180
126
|
2 (1.1)
3 (2.3)
|
2.2 (0.3–13)
|
0.686
|
7 (3.9)
10 (7.9)
|
2 (0.8–5.7)
|
0.205
|
2 (1–1)
5 (3.9)
|
3.7 (0.7–19)
|
0.209
|
|
Postoperative thromboprophylaxis
No
Yes
|
403
498
|
3 (0.7)
11 (2.2)
|
3.0 (0.8–10.8)
|
0.136
|
15 (3.7)
61 (12.2)
|
3.6 (2.0–6.4)
|
0.000
|
5 (1.2)
12 (2.4)
|
2.0 (0.7–5.6)
|
0.303
|
|
LMWH prophylactic dose
LMWH therapeutic dose
|
407
91
|
6 (1.5)
5 (5.5)
|
3.9 (1.2–13.0)
|
0.049
|
45 (11.1)
16 (17.6)
|
1.7 (0.9–3.2)
|
0.124
|
9 (2.2)
3 (3.3)
|
1.5 (0.4–5.7)
|
0.816
|
|
DOAC-free time (d)
|
|
6
>6
|
525
376
|
3 (0.6)
11 (2.9)
|
1.9 (1.43–2.5)
|
0.006
|
26 (5)
50 (13.3)
|
1.66 (1.4–2)
|
0.000
|
6 (1.1)
11 (2.9)
|
1.56 (1.1–2.2)
|
0.08
|
Abbreviations: CI, confidence interval; DOAC, direct oral anticoagulant; LMWH, low-molecular
weight; OR, odds ratio.
Intraoperative bleeding was assessed by the physician in charge in 899 patients and
was considered higher than normal in 49 (5.5%) patients. This fact was well predicted
by bleeding risk classification, showing an OR: 4.7 (2.2–10.2) in procedures of the
moderate/high bleeding risk group compared with the low risk one. Patients with a
higher bleeding assessment also had a statistically significant higher DOAC free time
(p < 0.001). Only five patients (0.6%) needed a surgical re-operation due to bleeding.
The surgical procedures classified as moderate/high bleeding risk were associated
with a statistically significant higher incidence of minor bleeding events (OR 1.8
[1.1–3.0]), but they were not associated with major bleeding events ([Table 4]). Dabigatran showed a higher rate of minor bleeding events compared with the other
type of DOAC (OR: 2.3 [1.3–4.1]). There was a statistically significant relationship
between the use of preoperative bridging therapy and bleeding events, minor (OR: 2.1
[1.3–3.4]) and major (OR: 4.6 [1.6–13.2]). Likewise, there was an association between
the longer preoperative withdrawal time and the incidence of minor bleeding events
(p < 0.001), finding a statistical interaction between DOAC withdrawal time and the
use of bridging therapy (OR: 4.3 [2.2–8.7]). Among patients who suffered some minor
bleeding event, the DOAC was restarted significantly later (p < 0.001), especially in the case of dabigatran (3.1 days [1.5–6.4], p = 0.004). Applying the final model of the multivariate binary regression analysis
the higher prevalence of major bleeding events was associated with bridging therapy
(OR: 4.2 [1.4–12.3]) and the risk of high bleeding at surgery (OR: 5.3 [1.78–15.8]).
If DOAC-free time longer than 6 days was added to the model, it was not significantly
associated with major bleeding events.
In the 30-day follow-up, 14 (1.6%) patients died ([Supplementary Table S7]). The death was considered of hemorrhagic etiology in three (21.4%) and thrombotic
in one (7.1%) patient. Other causes were infections in six cases, heart failure in
three cases, and a cerebral tumor in one case. Death was related to the bridging therapy
(OR:3.3 [1.1–9.9]).
Discussion
This study offers real-world data on periprocedural DOAC management and outcomes in
901 patients (53.5% major surgery). It has shown low complication rates (1.6% of thrombotic
events and 1.9% of major bleeding events), even in patients who underwent moderate
to high bleeding risk procedures.
Recommendations on DOAC management during the perioperative period (time of interruption
before surgery and resumption afterward) are mainly based on their pharmacokinetics,
renal function, and periprocedural-associated bleeding and thrombotic risk.[2]
[3]
[4]
[5]
[9]
[10] It has been shown that using a structured simple management approach to DOACs as
proposed in PAUSE trial[17] can decrease variability and periprocedural adverse events. But DOAC regimens from
real-world experience are scarce, mainly in patients undergoing major surgery procedures.
As in other safety and efficacy studies,[19]
[20] it is necessary to know real-world data to better define perioperative recommendations.
Short-term DOAC perioperative interruption was the most common practice in the registry,
being the interval longer for dabigatran (3–5 days) than for anti-Xa (2–4 days) in
patients with eGFR <50 mL min 1.73 m−2, as it is mostly proposed. The perioperative management is more homogeneous than
the anticoagulant reintroduction, which showed a high variability, maybe related to
bleeding risk assessment during the postoperative period. In our study, this wide
range of days for reintroduction of DOAC was linked to bleeding events, highlighting
that 8.4% of patients were without anticoagulation 30 days after the procedure. Another
possible reason for some patients could be the absence of indication.
Preoperative bridging therapy was still used in 35% of the patients (82.9% as a prophylactic
dose) with similar rates compared with the Dresden Study (29.8%),[16] reflecting the difficulties to implement the guidelines, since nowadays there is
a general agreement about not bridging. Our results agree with the guidelines on the
lack of thrombotic protection of bridging and on its increasing risk of periprocedural
hemorrhage.
Patient-specific thrombotic risk was calculated with the CHA2DS2-VASc score in the case of atrial fibrillation (AF). Pooled incidence of thrombotic
events was 1.6%, slightly higher than the rates previously described in a real-world
setting (1% in the Dresden registry).[16] Nevertheless, considering only the ischemic stroke incidence (0.6%), our results
agree with the ones described in phase III DOAC studies (0.31–0.49%). They also agree
with the recently published PAUSE study, with an incidence between 0.16 and 0.6 depending
on the cohort.[17] Recommendations made in 2018 to 2019 propose a 1 to 3 days DOAC withdrawal time,
mainly depending on DOAC type, renal function, and periprocedural hemorrhagic risk.[2]
[9]
[21] This is the first study that shows an association between preoperative DOAC withdrawal
time longer than 3 days and thrombotic events, increasing as this time is longer.
Interestingly, not only preoperative DOAC withdrawal time was an independent factor
for thrombotic events, but also DOAC-free time longer than 6 days. Both underlie the
importance of an adequate and no-long window without anticoagulation, before and after
surgery. Certainly, many patients received thromboprophylaxis with LMWH (55.3%) till
the DOAC restart, but this does not mean to start over anticoagulation.
Our results showed that dabigatran was associated with a significantly higher rate
of minor bleeding (12.8%) than that related to the other DOACs (apixaban 7.8%, rivaroxaban
5.7%, p = 0.008). It was higher but not comparable with the results of the RELY trial subanalysis
(8.5% of minor bleeding events),[12] in which less than 10% of patients underwent high-bleeding risk procedures.
Pooled rate of bleeding events was 10.4%, with 8.5% of the events considered as minor
and 1.9% (17/901) considered as major bleeding, but the comparison with other reports
is difficult. In a recent meta-analysis, Shaw et al[11] published data on the safety in DOACs management in the perioperative period, with
few data related to high bleeding risk procedures, thus, not reflecting real world.[22] A standardized protocol, as used in the PAUSE study, implied a major bleeding event
rate of 0.9to 1.35 to 1.85% (dabigatran–apixaban–rivaroxaban cohort, respectively)
considering less than 35% of high bleeding risk procedures.[17]
No spinal bleeding was found. Nevertheless, having performed 229/901 neuraxial techniques,
there is not enough statistical power to draw any real conclusion or recommendation
related to the preoperative withdrawal time of the DOAC to perform a safe neuraxial
puncture.
An important result to consider is that minor (OR: 2.1) and major (OR: 4.68) bleeding
events were related to the use of preoperative bridging therapy. Our data collection
began in late 2014, when its use was recommended in high thrombotic risk patients,[6]
[7]
[8] but bridging was also registered in the last recruitment year, against current guidelines
recommendation.[5]
[9]
[21]
[22]
[23] These results are similar to the Dresden registry. In 2015, the BRIDGE trial related
bridging to a higher rate of bleeding in patients receiving VKAs,[24] but the recommendations at that time were not conclusive for DOACs.[25] In any case, our results support recommendations against the use of bridging therapy
in periprocedural DOACs management, agreeing that it is overprescribed.[21]
One patient died during the 30-day follow-up from complications of a thrombotic etiology
and three patients from bleeding causes. When considering all deaths, again bridging
therapy and DOAC-free time had a significant impact on risk of death. Nevertheless,
the mortality rate is too small to draw conclusions and these data should be confirmed
in larger studies.
Weaknesses in the Study
The main real-world study limitations are due to its observational characteristics
and lack of randomization. Nevertheless, before performing statistics, we checked
each group basal characteristics, finding that there was no significant difference
related to baseline characteristics.
Most of the patients included in the study had AF (97%). Nevertheless, patients with
VTE were not excluded, since we considered they are value for general measurements.
But further studies are necessary to confirm the results in patients on DOAC without
FA. In the same line, we did not exclude patients on edoxaban, although they could
not be studied as a different drug.
The assessment of the thrombotic risk was not related to the procedure, nor was the
Caprini score collected. However, considering that the patients in the study are on
chronic anticoagulant treatment, that is secondary prophylaxis, the recommendation
would be pharmacologic prophylaxis for all of them.[26]
In line with other studies results we have found low number of events (thrombotic,
major bleeding, death). But, given the observational nature of the study, there is
a chance that variables not considered in the study could have influenced some of
the results, such as the postoperative LMWH therapy. Besides, minor bleeding assessment,
as defined in the study, can be a concern since it may be considered as subjective.
This study was performed in a wide variety of hospitals with different periprocedural
DOACs management. Furthermore, thrombotic and bleeding events were needed to be clinically
relevant to be considered. Despite this, we believe that the remote continuous auditing
and training of the investigators, support the quality of the data collected.
Future Studies
Although a randomized controlled trial (RCT) could be recommended to standardized
practice, the PAUSE trial results represent good data in the field of periprocedural
DOACs, and an RCT is unlikely to take place if the results of PAUSE are well adopted.
Conclusion
RA-ACOD is a real-world registry performed with the aim of evaluating periprocedural
thrombotic and bleeding events in unselected patients on DOAC chronic anticoagulation,
scheduled for surgery or invasive procedures. Our results, with a pooled rate of all
thrombotic (1.6%) and major bleeding events (1.9%), showed that the perioperative
DOACs management in current clinical practice is associated with a low complication
rate.
Since a long preoperative DOAC withdrawal and DOAC-free time were related to a higher
incidence of thrombotic events, and the use of bridging therapy to a higher incidence
of bleeding events, we would suggest a short preprocedural DOAC interruption, without
bridging therapy and a reduced DOAC-free time, as a safe and suitable practice.
