Keywords
direct oral anticoagulant - atrial fibrillation - surgery - bleeding - thromboembolism
Introduction
The perioperative management of patients who are receiving a direct oral anticoagulant
(DOAC) for atrial fibrillation is becoming an increasingly common clinical problem.
Approximately one in six patients per year receiving a DOAC long-term will be assessed
for perioperative management.[1]
[2] This is an especially high-risk period for patients where a DOAC interruption interval
that is too long may place patients at risk for thrombosis and a DOAC interruption
interval that is too short may place patients at risk for bleeding. The development
of these complications may be related to the timing and duration of DOAC interruption,
the inherent bleeding risk of the surgery or procedure being undertaken, the use of
perioperative heparin bridging, and patient-specific factors including advanced age
and comorbid conditions. In clinical practice, the periprocedural management of DOACs
varies widely,[3] which places many patients at risk for these complications. The Perioperative Anticoagulation
Use for Surgery Evaluation (PAUSE) study was the first to prospectively assess a standardized
perioperative management strategy in three cohorts of DOAC-treated patients on apixaban,
dabigatran, or rivaroxaban who needed an elective surgery.[4] The study's principal finding was that in the combined study population of 3,007
patients, the 30-day perioperative rates of major bleeding (MB) were low (1.4%), as
were rates of arterial thromboembolism (ATE) (0.33%).[4]
Despite these encouraging findings, DOAC use involves multiple agents and dose regimens,
with the potential for between-DOAC differences in pharmacologic and pharmacokinetic
properties, and perioperative management involves a spectrum of surgery and procedure
types. These factors, along with patient-specific factors, such as renal function
and age, may affect rates of perioperative bleeding and thromboembolism. It is clinically
relevant, therefore, to examine the safety of the PAUSE management strategy across
different patient subgroups, according to DOAC type and dose regimen used, surgery/procedure-related
bleed risk, and according to patient renal function and age.
Against this background, we undertook a prespecified subgroup analysis of the PAUSE
study database. Our primary aim was to compare rates of MB and ATE according to DOAC
type, DOAC dose, surgery/procedure-related bleed risk, patient renal function, and
patient age. Our secondary aim was to assess any clinically important bleeding and
any thromboembolism across these patient subgroups.
Methods
Patient Population and Perioperative Management
The PAUSE cohort study was conducted at 23 clinical sites in Canada, the United States,
and Europe. The study involved DOAC-treated patients with atrial fibrillation who
required anticoagulant therapy interruption for an elective surgery/procedure. Participants
were ≥18 years old, were receiving apixaban, dabigatran, or rivaroxaban (edoxaban
was not universally available for clinical use during PAUSE), and were scheduled for
an elective (i.e., planned) surgery or procedure.
Patients were separated into three cohorts according to the DOAC used and were managed
with a standardized perioperative DOAC interruption and resumption strategy based
on DOAC pharmacokinetic properties, surgery/procedure-related bleed risk ([Table 1]), estimated creatinine clearance (CrCl), and patient age. Patients were classified
as undergoing a high- or low bleed risk surgery or procedure according to an empiric
classification scheme that was adopted from another perioperative anticoagulant management
study, the BRIDGE trial.[5] DOACs were withheld for 1 day before and after a low bleed risk surgery/procedure
and for 2 days before and 2 to 3 days after a high bleed risk surgery/procedure. The
exception to this management was patients on dabigatran with a CrCl of 30 to <50 mL/min
in whom 1 to 2 additional days of interruption was done to account for dabigatran's
primary dependence on the kidney for elimination. Low-dose low-molecular weight heparin
was permitted postoperatively in patients at risk for venous thromboembolism until
the DOAC was resumed.
Table 1
Surgery/procedure classification based on bleed risk
|
High bleed risk
|
Low bleed risk
|
|
Any surgery requiring neuraxial anesthesia
• Neuraxial anesthesia/injection—epidural anesthesia/injection.
|
Gastrointestinal procedures
• Colonoscopy, gastroscopy, sigmoidoscopy—endoscopic retrograde pancreaticocholangiography—capsule
endoscopy—push enteroscopy—Barrett's esophagus ablation.
|
|
Major intracranial or neuraxial surgery
• Brain cancer resection—laminectomy or neuraxial tumor resection—intracranial (subdural,
epidural) bleed evacuation.
|
Cardiac procedures:
• Permanent pacemaker implantation or battery change.
• Internal cardiac defibrillator implantation or battery change—artrioventricular
node ablation—coronary artery angiography (radial approach).
|
|
Major thoracic surgery
• Lobectomy, pneumonectomy, esophagectomy.
|
Dental procedures
• Tooth extraction (up to two extractions) —endodontic (root canal) procedure.
|
|
Major cardiac surgery
• Coronary artery bypass—valve replacement or repair.
|
Skin procedures and skin biopsy
|
|
Major vascular surgery
• Aortic aneurysm repair—aorto-bifemoral bypass, popliteal bypass—carotid endarterectomy.
|
Eye procedures and phacoemulsification (cataract)
|
|
Major abdominopelvic surgery
• Hepatobiliary cancer resection—pancreatic cancer or pseudocyst resection—colorectal
and gastric cancer resection—diverticular disease resection.
• Inflammatory bowel disease resection—renal cancer resection—bladder cancer resection—endometrial
cancer resection—ovarian cancer resection—radical prostatectomy.
|
|
|
Major orthopaedic surgery
• Hip arthroplasty or hip fracture repair—knee arthroplasty or tibial osteotomy—shoulder
arthroplasty—metatarsal osteotomy.
|
|
|
Other major cancer or reconstructive surgery
• Head and neck cancer surgery—reconstructive facial, abdominal, limb surgery.
|
|
Clinical Outcomes
The primary clinical outcomes in PAUSE and in this subgroup analysis were MB, defined
by standardized criteria for surgery-related bleeding, and ATE, defined as an ischemic
stroke, transient ischemic attack, or systemic embolism.[6] The secondary clinical outcomes for this analysis were clinically important bleeding,
which was a composite of MB and clinically relevant nonmajor bleeding (CRNMB), and
any thromboembolism, which was a composite of ATE, myocardial infarction, deep vein
thrombosis, pulmonary embolism, and catheter-associated venous or arterial embolism.
These clinical outcomes were assessed from the time of the first preoperative DOAC
dose interruption until 30 days after the surgery/procedure and were adjudicated by
an independent committee blinded to the DOAC the patients were receiving and their
perioperative management.
We assessed clinical outcomes in the following patient subgroups according to: DOAC
type (apixaban, dabigatran, and rivaroxaban); DOAC dose regimen (standard- or low-dose
regimen); surgery/procedure-related bleed risk (high or low bleed risk); patient renal
function (CrCl <50 mL/min or ≥50 mL/min); and patient age (age < 75 years and age ≥ 75
years). Patient who were taking apixaban with CrCl <25 mL/min and those taking rivaroxaban
or dabigatran with a CrCl <30 mL/min were excluded from the PAUSE study and this subgroup
analysis.
Statistical Analysis
We used descriptive statistics to summarize the clinical outcomes, where the frequency,
proportion, and associated 95% confidence intervals (CIs) are reported. Fisher's exact
test was used for testing the null hypothesis of independence between the clinical
outcome and patient characteristic. A p-value <0.05 was considered as statistically significant of rejecting the null hypothesis,
that is, an association between the outcome and patient characteristic.
Results
In the PAUSE study, 3,007 patients were enrolled and included in the primary efficacy
analysis, out of which 1,257 patients (41.8%) were in the apixaban cohort, 668 (22.2%)
were in the dabigatran cohort, and 1,082 patients (36.0%) were in the rivaroxaban
cohort. A low-dose regimen was taken by 20.0% (n = 252) of apixaban-treated patients (2.5-mg twice daily), by 37.1% (n = 248) of dabigatran-treated patients (110 mg twice daily), and by 16.7% (n = 181) of rivaroxaban-treated patients (15 mg daily). One-third (33.2%) of all patients
underwent a high bleed risk surgery/procedure. Moderately impaired renal function
(CrCl: 30–50 mL/min) was seen in 18.6% (n = 234) of patients on apixaban, 12.0% (n = 80) of patients on dabigatran, and 14.3% (n = 155) of patients on rivaroxaban. Finally, 46.3% (n = 582) of patients on apixaban, 44.0% (n = 294) of patients on dabigatran, and 42.9% (n = 464) of patients on rivaroxaban were greater than or equal to the age of 75 years.
DOAC Type and Dose Regimen and Risk for Bleeding and Thromboembolism
As shown in [Table 2], there was no effect of the DOAC type (apixaban, dabigatran, rivaroxaban) on the
outcomes of MB, ATE, any bleeding, or any thromboembolism. Similarly, as shown in
[Table 3], there was no effect of the DOAC dose regimen (apixaban 5 vs. 2.5 mg, dabigatran
150 vs. 110 mg, rivaroxaban 20 vs. 15 mg) on MB, ATE, any bleeding, or any thromboembolism.
Table 2
Effect of DOAC type of clinical outcomes
|
Clinical outcome
|
DOAC
|
|
Apixaban (N = 1,257)
|
Dabigatran (N = 668)
|
Rivaroxaban (N = 1,082)
|
|
Major bleeding
|
|
No. % (95% CI)
|
17, 1.35 (0.85–2.16)
|
6, 0.90 (0.41–1.95)
|
20, 1.85 (1.2–2.84)
|
|
p-Value
|
p = 0.25
|
|
Arterial thromboembolism
|
|
No. % (95% CI)
|
2, 0.16 (0.04–0.58)
|
4, 0.60 (0.23–1.53)
|
4, 0.37 (0.14–0.95)
|
|
p-Value
|
p = 0.25
|
|
Any bleeding (MB and CRNMB)
|
|
No. % (95% CI)
|
38, 3.02 (2.21–4.12)
|
19, 2.84 (1.83–4.4)
|
45, 4.16 (3.12–5.52)
|
|
p-Value
|
p = 0.22
|
|
Any thromboembolism
|
|
No. % (95% CI)
|
9, 0.72 (0.38–1.36)
|
7, 1.05 (0.51–2.15)
|
5, 0.46 (0.2–1.08)
|
|
p-Value
|
p = 0.34
|
Abbreviations: CI, confidence interval; CRNMB, clinically relevant nonmajor bleeding;
DOAC, direct oral anticoagulant; MB, major bleeding.
Note: Bold values represent the percentage of patients that experienced that clinical
outcome.
Table 3
Effect of DOAC dose regimen on clinical outcomes
|
Clinical outcome
|
DOAC dose regimen
|
|
Apixaban
|
Dabigatran
|
Rivaroxaban
|
|
2.5 mg (n = 252)
|
5 mg (n = 1,005)
|
110 mg (n = 248)
|
150 mg (n = 420)
|
15 mg (n = 181)
|
20 mg (n = 901)
|
|
Major bleeding
|
|
No. % (95% CI)
|
3, 1.2 (0.41–3.4)
|
14, 1.4 (0.83–2.3)
|
2, 0.81 (0.22–2.9)
|
4, 0.95 (0.37–2.4)
|
6, 3.3 (1.53–7.0)
|
14, 1.5 (0.93–2.6)
|
|
p-Value
|
p = 1.0
|
p = 1.0
|
p = 0.13
|
|
Arterial thromboembolism
|
|
No. % (95% CI)
|
1, 0.40 (0.07–2.2)
|
1, 0.10 (0.02–0.56)
|
1, 0.40 (0.07–2.2)
|
3, 0.71 (0.24–2.1)
|
1, 0.55 (0.1–3.1)
|
3, 0.33 (0.11–0.97)
|
|
p-Value
|
p = 0.36
|
p = 1.0
|
p = 0.52
|
|
Any bleeding (MB and CRNMB)
|
|
No. % (95% CI)
|
10, 4.0 (2.2–7.1)
|
28, 2.8 (1.9–4.0)
|
8, 3.2 (1.6–6.2)
|
11, 2.6 (1.5–4.6)
|
8, 4.4 (2.3–8.5)
|
37, 4.1 (3.0–5.6)
|
|
p-Value
|
p = 0.31
|
p = 0.64
|
p = 0.84
|
|
Any thromboembolism
|
|
No., % (95% CI)
|
3, 1.2 (0.41–3.4)
|
6, 0.60 (0.27–1.3)
|
2, 0.81 (0.22–2.9)
|
5, 1.2 (0.51–2.8)
|
1, 0.55 (0.10–3.1)
|
4, 0.44 (0.17–1.1)
|
|
p-Value
|
p = 0.39
|
p = 1.0
|
p = 1.0
|
Abbreviations: CI, confidence interval; CRNMB, clinically relevant nonmajor bleeding;
DOAC, direct oral anticoagulant; MB, major bleeding.
Note: Bold values represent the percentage of patients that experienced that clinical
outcome.
Surgery/Procedure Type and Risk for Bleeding and Thromboembolism
As shown in [Table 4], the incidence of MB was low overall (<2%) but higher in patients having a high
bleed risk surgery/procedure. In apixaban-treated patients, the rate of MB was significantly
higher in the high bleed risk group (2.9%; 95% CI: 1.7–5.1) than in the low bleed
risk group (0.59%; 95% CI: 0.25–1.4) (p < 0.01). In dabigatran-treated patients, the rate of MB was not significantly different
between the high bleed risk group (0.88%; 95% CI: 0.24–3.1) and low bleed risk group
(0.91%; 95% CI: 0.35–2.3) (p = 1.0). In rivaroxaban-treated patients, the rate of MB was nominally but not significantly
higher in the high bleed risk group (2.9%; 95% CI: 1.6–5.2) than in the low bleed
risk group (1.3%; 95% CI: 0.67–2.4) (p = 0.06). Regardless of whether patients were having a high or low bleed risk surgery/procedure,
the rate of ATE was low in apixaban-treated, dabigatran-treated, and rivaroxaban-treated
patients.
Table 4
Effect of surgery/procedure-related bleed risk on clinical outcomes
|
Outcome
|
DOAC type and surgery/procedure-related bleed risk
|
|
Apixaban
|
Dabigatran
|
Rivaroxaban
|
|
High bleed risk (n = 406)
|
Low bleed risk (n = 851)
|
High bleed risk (n = 228)
|
Low bleed risk (n = 440)
|
High bleed risk (n = 373)
|
Low bleed risk (n = 709)
|
|
Major bleeding
|
|
No., % (95% CI)
|
12, 2.9 (1.7–5.1)
|
5, 0.59 (0.25–1.4)
|
2, 0.88 (0.24–3.1)
|
4, 0.91 (0.35–2.3)
|
11, 2.9 (1.6–5.2)
|
9, 1.3 (0.67–2.4)
|
|
p-Value
|
p < 0.01
|
p = 1.0
|
p = 0.06
|
|
Arterial thromboembolism
|
|
No. % (95% CI)
|
1, 0.25 (0.04–1.4)
|
1, 0.12 (0.02–0.66)
|
1, 0.44 (0.08–2.4)
|
3, 0.68 (0.23–2.0)
|
2, 0.54 (0.15–1.9)
|
2, 0.28 (0.08–1.0)
|
|
p-Value
|
p = 0.54
|
p = 1.0
|
p = 0.61
|
|
Any bleed (MB + CRNMB)
|
|
No. % (95% CI)
|
23, 5.7 (3.8–8.4)
|
15, 1.8 (1.1–2.9)
|
7, 3.1 (1.5–6.2)
|
12, 2.7 (1.6–4.7)
|
25, 6.7 (4.9–9.7)
|
20, 2.8 (1.8–4.3)
|
|
p-Value
|
p < 0.01
|
p = 0.81
|
p < 0.01
|
|
Any thromboembolism
|
|
No. % (95% CI)
|
7, 1.7 (0.84–3.5)
|
2, 0.24 (0.06–0.85)
|
3, 1.3 (0.45–3.8)
|
4, 0.91 (0.3–2.3)
|
3, 0.80 (0.27–2.3)
|
2, 0.28 (0.08–1.0)
|
|
p-Value
|
p < 0.01
|
p = 0.69
|
p = 0.35
|
Abbreviations: CI, confidence interval; CRNMB, clinically relevant nonmajor bleeding;
DOAC, direct oral anticoagulant; MB, major bleeding.
Note: Bold values represent the percentage of patients that experienced that clinical
outcome.
The rate of any (major and clinically relevant nonmajor) bleeding, remained low overall.
When classified according to bleeding risk, the high bleed risk procedures had a higher
rate of any bleeding. In apixaban-treated patients, the rate of any bleeding was significantly
higher in the high bleed risk group (5.7%; 95% CI: 3.8–8.4) than low bleed risk group
(1.8%; 95% CI: 1.1–2.9) (p < 0.01). In dabigatran-treated patients, the rate of any bleeding was not significantly
different between the high bleed risk group (3.1%; 95% CI: 1.5–6.2) and low bleed
risk group (2.7%; 95% CI: 1.6–4.7) (p = 0.81). In rivaroxaban-treated patients, the rate of any bleeding was significantly
higher in the high bleed risk group (6.7%; 95% CI: 4.9–9.7) than the low bleed risk
group (2.8%; 95% CI: 1.8–4.3) (p < 0.01).
Finally, the rate of any thromboembolism was infrequent. It was significantly higher
in high bleed risk (1.7%; 95% CI: 0.84–3.5) than low bleed risk procedures (0.24%;
95% CI: 0.06–0.85) in apixaban-treated patients (p < 0.01), and did not differ in high bleed risk (1.3%; 95% CI: 0.45–3.8) and low bleed
risk procedures (0.91%; 95% CI: 0.3–2.3) in dabigatran-treated patients (p = 0.69), or in high bleed risk (0.80%; 95% CI: 0.27–2.3) and low bleed risk procedures
(0.28%; 95% CI: 0.08–1.0) in rivaroxaban-treated patients (p = 0.35).
Renal Function and Risk for Bleeding and Thromboembolism
As shown in [Table 5], when categorizing patients based on renal function, there was no significant difference
in MB, ATE, any bleeding, or any thromboembolism according to patient renal function
(CrCl 25–50 mL/min vs. CrCl > 50 mL/min for apixaban, and CrCl 30–50 mL/min vs. ≥ 50 mL/min
for dabigatran and rivaroxaban). Patients were excluded from the initial PAUSE study
with CrCl <25 mL/min for apixaban, and <30 mL/min for dabigatran or rivaroxaban.
Table 5
Effect of renal function on clinical outcomes
|
Outcome
|
DOAC cohort and creatinine clearance[a]
|
|
Apixaban
|
Dabigatran etexilate
|
Rivaroxaban
|
|
25–50 mL/min (n = 234)
|
>50 mL/min (n = 1023)
|
30–50 mL/min (n = 80)
|
>50 mL/min (n = 588)
|
30–50 mL/min (n = 155)
|
>50 mL/min (n = 927)
|
|
Major bleeding
|
|
No. % (95% CI)
|
1, 0.43 (0.08–2.4)
|
16, 1.6 (0.96–2.5)
|
1, 1.2 (0.22–6.7)
|
5, 0.85 (0.36–2.0)
|
5, 3.2 (1.4–7.3)
|
15, 1.6 (0.98–2.6)
|
|
p-Value
|
p = 0.22
|
p = 0.54
|
p = 0.19
|
|
Arterial thromboembolism
|
|
No. % (95% CI)
|
1, 0.43 (0.08–2.4)
|
1, 0.10 (0.02–0.55)
|
0, 0.0 (0–4.6)
|
4, 0.68 (0.26–1.7)
|
1, 0.65 (0.11–3.6)
|
3, 0.32 (0.11–0.95)
|
|
p-Value
|
p = 0.34
|
p = 1.0
|
p = 0.46
|
|
Any bleed (MB + CRNMB)
|
|
No. % (95% CI)
|
6, 2.6 (1.2–5.5)
|
32, 3.1 (2.2–4.4)
|
3, 3.7 (1.3–10.4)
|
16, 2.7 (1.7–4.4)
|
6, 3.9 (1.8–8.2)
|
39, 4.2 (3.1–5.7)
|
|
p-Value
|
p = 0.83
|
p = 0.49
|
p = 1.0
|
|
Any thromboembolism
|
|
No., % (95% CI)
|
3, 1.3 (0.44–3.7)
|
6, 0.59 (0.27–1.3)
|
0, 0.0 (0–4.6)
|
7, 1.2 (0.58–2.4)
|
1, 0.65 (0.11–3.6)
|
4, 0.43 (0.17–1.1)
|
|
p-Value
|
p = 0.38
|
p = 1.0
|
p = 0.54
|
Abbreviations: CI, confidence interval; CRNMB, clinically relevant nonmajor bleeding;
DOAC, direct oral anticoagulant; MB, major bleeding.
a Patients were excluded from the PAUSE study with CrCl <25 mL/min for apixaban, and
<30 mL/min for dabigatran or rivaroxaban.
Note: Bold values represent the percentage of patients that experienced that clinical
outcome.
Patient Age and Risk for Bleeding and Thromboembolism
As shown in [Table 6], when categorizing patients based on patient age, there was no significant difference
in MB, ATE, any bleeding, or any thromboembolism according to patient age (age < 75
years and age ≥ 75 years).
Table 6
Effect of patient age on clinical outcomes
|
Outcome
|
DOAC cohort and patient age
|
|
Apixaban
|
Dabigatran etexilate
|
Rivaroxaban
|
|
Age < 75 y
(n = 675)
|
Age ≥ 75 y
(n = 582)
|
Age < 75 y
(n = 374)
|
Age ≥ 75 y
(n = 294)
|
Age < 75 y
(n = 618)
|
Age ≥ 75 y
(n = 464)
|
|
Major bleeding
|
|
No. % (95% CI)
|
6, 0.89
(0.41–1.93)
|
11, 1.89
(1.06–3.35)
|
3, 0.80
(0.27–2.33)
|
3, 1.02
(0.35–2.96)
|
11, 1.78
(1–3.16)
|
9, 1.94
(1.02–3.64)
|
|
p-Value
|
p = 0.15
|
p = 1.0
|
p = 1.0
|
|
Arterial thromboembolism
|
|
No. % (95% CI)
|
1, 0.15
(0.03–0.83)
|
1, 0.17
(0.03–0.97)
|
2, 0.53
(0.15–1.93)
|
2, 0.68
(0.19–2.45)
|
3, 0.49
(0.17–1.42)
|
1, 0.22
(0.04–1.21)
|
|
p-Value
|
p = 1.0
|
p = 1.0
|
p = 0.64
|
|
Any bleed (MB + CRNMB)
|
|
No. % (95% CI)
|
15, 2.22
(1.35–3.63)
|
23, 3.95
(2.65–5.86)
|
12, 3.21
(1.84–5.52)
|
7, 2.38
(1.16–4.83)
|
23, 3.72
(2.49–5.52)
|
22, 4.74
(3.15–7.07)
|
|
p-Value
|
p = 0.10
|
p = 0.64
|
p = 0.44
|
|
Any thromboembolism
|
|
No. % (95% CI)
|
6, 0.89
(0.41–1.93)
|
3, 0.52
(0.18–1.5)
|
3, 0.80
(0.27–2.33)
|
4, 1.36
(0.53–3.45)
|
4, 0.65
(0.25–1.65)
|
1, 0.22
(0.04–1.21)
|
|
p-Value
|
p = 0.52
|
p = 0.71
|
p = 0.40
|
Abbreviations: CI, confidence interval; CRNMB, clinically relevant nonmajor bleeding;
DOAC, direct oral anticoagulant; MB, major bleeding.
Discussion
This study aimed to assess the effect of a standardized perioperative DOAC management
strategy on bleeding and thromboembolic outcomes when considered according to DOAC
type and dose regimen, surgery/procedure bleed risk, patient renal function, and patient
age. There are two main findings from this subgroup analysis of the PAUSE study. First,
there was no significant difference in perioperative MB and ATE in patients who were
receiving apixaban, dabigatran, or rivaroxaban and there was no significant difference
in these outcomes among patients who were receiving a standard or lower dose DOAC
regimen, according to patient renal function and age. Second, patients having a high
bleed risk surgery/procedure appeared to be at an increased risk for MB, but this
finding was not consistent across DOACs. While surgical bleed risk was found to be
an important determinant of bleeding, it had minimal effect on thromboembolic outcomes.
The incidence of any thromboembolism was significantly higher in high bleed risk (1.7%;
95% CI: 0.8–3.5) than low bleed risk (0.24%; 95% CI: 0.06–0.85) in apixaban-treated
patients (p < 0.01), but this was not the case for patients treated with dabigatran or rivaroxaban.
Taken together, these findings suggest that the PAUSE perioperative management is
comparable in terms of safety irrespective of the type and dose of DOAC patients were
receiving and patient renal function.
It is reassuring that the PAUSE management strategy is applicable to the three DOACs
and DOAC dose regimens studied. Although this analysis was prespecified, the PAUSE
study was not powered to detect across-DOAC group differences in bleeding and thromboembolic
outcomes. However, in a companion multivariable regression analysis of the PAUSE database,
DOAC type was not an independent predictor of perioperative MB. The lack of an association
between renal function and bleeding outcomes may be because patients on dabigatran
with a CrCl <50 mL/min had a longer preoperative interruption interval whereas most
patients taking apixaban or rivaroxaban may have had dose reductions with a CrCl <50 mL/min
or lower; in either case, these adjustments would have minimized residual DOAC levels
at the time of a surgery/procedure. In the aforementioned multivariable regression
analysis of the PAUSE database, patient CrCl was not predictive of perioperative bleeding.
There were numerically more bleeding events in patients having a high than low bleed
risk surgery/procedure, but the absolute risk for high bleed risk procedures was low:
approximately 2 to 3% for MB and approximately 5 to 7% for any (major and clinically
relevant nonmajor) bleeding. Rates of perioperative MB in the overall PAUSE study
population are comparable or lower than those observed in other perioperative antithrombotic
management trials, with overall rates of MB of 2 to 3%,[5]
[7]
[8] despite accounting for different definitions of bleeding. This finding is also in
line with a recent meta-analysis of periprocedural outcomes of DOACs of the large
atrial fibrillation trials, which found an overall MB rate of 2.1% with a periprocedural
strategy requiring DOAC interruption.[9] This is an expected finding as, intuitively, patients undergoing high bleed risk
surgery, such as cardiac, vascular, major orthopaedic or cancer surgery, are expected
to have more bleeding and transfusion requirements than patients having less extensive
surgery or procedures. As to whether a high bleed risk surgery or procedure confers
an increased risk for bleeding, there was a nonsignificant increase in MB (odds ratio
[OR] 2.7; 95% CI: 1.5–5.1) and any bleeding (OR 2.3; 95% CI: 1.6–3.4) on univariate
analysis of the PAUSE database independent of other factors such as increasing age
and comorbidities, but surgery/procedure bleed risk was not a significant determinant
with multivariate modeling.[10] The increased risk of MB in high bleed risk procedures in our analysis was comparable
to a further analysis of the BRIDGE trial, which found a nearly threefold increased
risk of MB (OR 2.9, 95% CI 1.4–5.9) when comparing high versus low bleed risk procedures
during interruption of chronic oral anticoagulant therapy.[11] Further study is needed, to determine if specific surgery types are more susceptible
to an increase in perioperative bleeding.
We acknowledge limitations in this subgroup analysis of the PAUSE database, most important
of which is that the PAUSE study was not designed to have sufficient power to assess
differences in bleeding and thromboembolic outcomes between patient subgroups distinguished
by DOAC used, surgery type, renal function, and patient age. However, our analysis
reassuringly did not find any important signal across DOACs in the subgroups studied.
Our study found that when categorizing patients based on renal function, there was
no significant difference in MB, ATE, any bleeding, or any thromboembolism. However,
patients were categorized to either a CrCl of >50 mL/min, which was considered normal,
or a CrCl <50 mL/min, which was considered reduced. Patients with CrCl less than 25 mL/min
for apixaban or less than 30 mL/min for dabigatran or rivaroxaban, were excluded from
the initial study design. As more patients with end-stage renal disease start using
apixaban,[12] this variable may have more importance and may require further study. In the original
PAUSE study, there were few patients who received neuraxial anesthesia (n = 230), for whom there is a concern about increased bleeding risk associated with
an excessive residual anticoagulant level.[4] Further study is required to fully characterize this high-risk surgical procedure
and determine the best way to manage these patients to minimize perioperative risk.
A randomized clinical trial was considered during design of the original PAUSE study
but was not adopted because no alternative strategy existed that would be suitable
as a control. Instead, a prospective management study was adopted. Comparison of outcomes
across DOACs was therefore limited because random allocation of DOACs was not feasible
within the context of perioperative management. Finally, the event rate for ATE events
was extremely low which prevented meaningful analysis and limited the power to undertake
comparisons. Our findings should thus be considered exploratory and hypothesis generating.
Additional studies are needed, possibly using large, population-based linked databases,
to corroborate the findings in this study and to assess determinants of perioperative
bleeding and thromboembolism for specific DOACs. Finally, these findings may not be
applicable to patients taking edoxaban, as this DOAC was not available for clinical
use during development of the PAUSE study protocols and, thus, edoxaban-treated patients
were excluded from PAUSE.
To summarize, among DOAC-treated patients who received standardized perioperative
management, we found no significant differences in bleeding and thromboembolic outcomes
according to DOAC type, DOAC dose regimen, patient renal function, and patient age.
The empiric classification of surgical bleeding risk initially defined in the BRIDGE
trial appears to appropriately discriminate DOAC-related perioperative bleeding risk.
