Keywords anticoagulation - edoxaban - bridging - heparin - major procedures
Introduction
Edoxaban is a direct-acting non-vitamin K-dependent oral anticoagulant (NOAC) approved
for stroke prevention in nonvalvular atrial fibrillation (SPAF) and for the treatment
of deep venous thrombosis (DVT) and pulmonary embolism (PE) as well as secondary prevention
of venous thromboembolism (VTE). In these indications, NOACs such as edoxaban feature
the standard anticoagulation strategy nowadays, widely replacing the former standard
vitamin K antagonists (VKAs).
A common clinical problem is the need to perform interventional procedures or surgery
in anticoagulated patients, with up to 25% of the patients requiring diagnostic or
therapeutic procedures within 2 years.[1 ]
[2 ] For these procedures, uninterrupted continuation of anticoagulation is often not
possible for bleeding risk, but interrupting anticoagulation may increase the periprocedural
risk of thromboembolic complications. A significant problem with VKA therapy was the
slow washout and slow onset of action if VKAs were interrupted for major surgical
procedures. The resulting gaps in oral anticoagulation were 2 to 3 weeks,[3 ]
[4 ]
[5 ] making interim heparin bridging mandatory in most cases. In contrast, NOACs such
as edoxaban exhibit a much shorter half-life (10–14 hours) and a rapid onset of action
after restart (maximum plasma levels within 2 hours after intake).[6 ] This pharmacokinetic profile potentially could help to reduce the periprocedural
duration of anticoagulation gaps, allowing for a preprocedural interruption of only
24 to 72 hours and a restart within hours or days after the procedure, as recommended
in current guidelines.[7 ] As a consequence, periprocedural heparin bridging may not be as important in NOAC
as in VKA patients.[8 ] Mounting evidence on this issue has led to several guidelines and expert consensus
statements especially in the field of periprocedural anticoagulation of SPAF patients.[7 ]
[9 ] However, data on management patterns and clinical outcomes following major surgical
procedures in edoxaban patients are scarce, since edoxaban was the latest NOAC to
be approved. Recently published data from the Edoxaban Management in Diagnostic and
Therapeutic Procedures (EMIT-AF/VTE) studies[10 ]
[11 ] provide some insights into this topic but less than 25% of the evaluated procedures
were high-risk procedures according to the European Heart Rhythm Association (EHRA)
classification[7 ] and complication rates in this subset of procedures were considerably higher than
in the minor and low-risk categories.
The objective of this analysis was to evaluate the baseline risk profiles for thromboembolic
and bleeding complications, management patterns, and clinical outcomes for edoxaban-anticoagulated
patients needing surgical or interventional therapies. With this in mind, we extracted
data on major surgical procedures in edoxaban patients treated for SPAF or VTE in
the prospective DRESDEN NOAC REGISTRY.
Methods
Patients
The DRESDEN NOAC REGISTRY (Clinical trials.gov: NCT01588119) is a large national prospective observation study
in the administrative district of Dresden (Saxony), Germany. An active recruiting
network of more than 230 registered physicians and hospitals from the out- and inpatients
sector enroll NOAC patients since 2011. Patients on all available NOAC drugs were
eligible to participate in the registry, starting from the day of each specific license
in Germany. For edoxaban, enrolment started with the license in 2015. All enrolled
patients give their written informed consent and are followed by the central registry
office with standardized protocols in a prospective manner. Adult patients with SPAF
and/or VTE and a planned anticoagulation duration of at least 3 months in a therapeutic
dose scheme of edoxaban are eligible. No exclusion criteria apply. Patients are interviewed
by telephone visits 30 days after baseline and in a quarterly sequence thereafter
to collect data of outcomes and management of NOAC therapy in daily care.
The registry protocol prespecified that all patients undergoing diagnostic or therapeutic
procedures were to be interviewed about the periprocedural management of anticoagulation
and supporting documents (reports, laboratory values, charts, discharge letters, death
certificates) were collected from the health care provider and submitted to central
adjudication by the registry office.
Surgical or Interventional Procedures
All interventional and surgical procedures were categorized according to the bleeding
risk categories published in the updated “2021 European Heart Rhythm Association Practical
Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants”[7 ] and in the chapter “Perioperative Management of Antithrombotic Therapy” of the 9th
American College of Chest Physicians consensus paper,[12 ] which consider periprocedural bleeding risk, frequency of bleeding, and severity
of tissue trauma. The present analyses focuses on major procedures only, defined as
procedures with relevant tissue trauma and high bleeding risk and including open pelvic,
abdominal and thoracic surgery; brain surgery and neuroinvasive procedures, i.e.,
spinal tap; major orthopaedic and trauma surgery; extensive wound revision surgery
and necrosectomy and vascular surgery.
In case that patients underwent more than one major procedure within the same edoxaban
interruption or bridging period, only the first procedure was counted for the 30-day
follow-up period and all outcomes during this period were assigned to this index procedure.
Data Collection and Outcome Evaluation
Data collection included procedure type and date, date and time of last edoxaban intake,
type and intensity of heparin bridging anticoagulation, and date and time of restarting
edoxaban or any other oral anticoagulant. To qualify for the analysis, edoxaban intake
had to be at least once within the last 7 days prior to the index procedure. Low-molecular-weight
heparin bridging scheme was classified as prophylactic dose (<100 IU per kg bodyweight
per day), intermediate dosage (100–150 IU per kg bodyweight per day), and therapeutic
dose regimen (>150 IU per kg bodyweight per day). Unfractionated heparin (UFH) was
considered prophylactic if it was administered subcutaneously for maximum of 15,000 IU
per day, whereas intravenous UFH infusion with a target activated partial thromboplastin
time (aPTT) <2-fold of normal was classified as intermediate dosage and with a target
aPTT >2-fold of normal was classified as therapeutic dosage. To evaluate the impact
of heparin bridging on clinical outcomes, the use of heparin was categorized into
“no heparin bridging (patients with no or low-dose heparin prophylaxis only) versus
“heparin bridging” (patients with intermediate or therapeutic dosages of heparin).
Clinical outcomes of interest consisted of major cardiovascular events, major bleeding,
and all-cause mortality, respectively.
Major cardiovascular events include acute coronary syndrome (comprising unstable angina, non-ST-elevation infarction,
and ST-elevation infarction) as well as stroke or transient ischemic attack and systemic
embolism complemented by VTE (DVT or PE).
Major bleedings were evaluated using the International Society of Thrombosis and Haemostasis (ISTH)
definition for major bleeding events[13 ] and for minor and clinically relevant nonmajor bleedings (CRNMs) with a standardized
bleeding assessment tool.[14 ] Additionally, evaluation of major bleeds was performed using the “Bleeding Academic
Research Consortium Definition for Bleeding” (BARC).[15 ] Of note, the use of the ISTH definition of major bleedings for surgical patients[16 ] was deemed inappropriate since this definition is to be used in randomized controlled
trials to assess efficacy of reversal agents. [Supplementary Table S1 ] (online only) provides an overview over the bleeding assessment and comparisons
with published results of the DRESDEN NOAC REGISTRY .[17 ]
The primary outcomes were a composite endpoint of fatal or nonfatal major cardiovascular events for efficacy
and the major bleeding rate for safety evaluation.
Secondary effectiveness and safety outcomes were death from cardiovascular disease as well as rates of CRNM bleeding or death
from any cause, respectively.
Rates of outcome events were evaluated until day 30 after procedure and data collection
included information on outcome severity level, medical approach to periprocedural
bleeding complications and to major cardiovascular events.
Statistical analyses were performed for all procedures, including several interventions
in the same patient, as well as for subtypes of major procedures.
Statistics
Demographic and outcome data are shown as absolute values, percentages, standard deviation,
and 95% confidence intervals (CIs) or median with 25th and 75th percentiles, when
appropriate. 95% CIs for proportions are given according to Clopper–Pearson interval.
A p -value of ≤0.05 is regarded to be statistically significant. Differences in baseline
variables or outcome event rates were compared using the Student's t -test, Mann–Whitney U-test, Fisher's exact test, or Chi-squared test, as appropriate.
All statistical analyses were performed using the IBM SPSS Statistics Version 28 and
MedCalc version 14.8.1.
Baseline Characteristics
Between November 1, 2011 and December 31, 2021, 5,197 patients receiving a NOAC for
SPAF or VTE treatment were enrolled. In total, 13,638 surgical or interventional procedures
in 3,583 patients were reported in the registry population. Of these, 3,448 procedures
were performed in patients who took edoxaban within the preceding 7 days, including
287 (8.3%) major procedures in 245 patients and 3,161 (91.7%) nonmajor procedures
in 1,124 patients ([Supplementary Fig. S1 ] [online only]). Overall, patient characteristics were comparable for major and nonmajor
procedures, but significant differences existed with regard to gender, concomitant
antiplatelet therapies, and the proportion of patients with an increased risk for
stroke or systemic embolism, defined by a CHA2 DS2 -VASc score ≥2 ([Table 1 ]).
Table 1
Patient characteristics at baseline of patients with edoxaban undergoing 3,448 surgical
or interventional procedures
All procedures, N = 3448
Major procedures, N = 287
Nonmajor procedures, N = 3,161
p -Value
Male, n (%)
2,057/3,448 (59.7)
144/287 (50.2)
1,913/3,161 (60.5)
0.0006
Median age (25–75th percentile), y
74.0 (67.0–79.0)
74.0 (67.0–80.0)
74.0 (67.0–79.0)
0.3989
Median BMI (25–75th percentile), kg/m2
28.1 (25.4–31.0)
28.4 (25.4–31.5)
28.1 (25.4–31.0)
0.4425
Indication for edoxaban
SPAF, n (%)
2,816/3,448 (81.7)
237/287 (82.6)
2,579/3,161 (81.6)
0.3764
VTE, n (%)
611/3,448 (17.7)
50/287 (17.4)
561/3,161 (17.7)
Off-label, n (%)
21/3,448 (0.6)
0
21/3,161 (0.7)
Concomitant antiplatelet therapy, n (%)
169/3,448 (4.9)
6/287 (2.1)
163/3,161 (5.2)
0.0212
Heart failure, n (%)
778/3,448 (22.6)
69/287 (24.0)
709/3,161 (22.4)
0.5316
Arterial hypertension, n (%)
2,864/3,448 (83.1)
234/287 (81.5)
2,630/3,161 (83.2)
0.4706
Diabetes, n (%)
1,012/3,448 (29.4)
81/287 (28.2)
931/3,161 (29.5)
0.6614
Prior TIA, stroke, or systemic embolism, n (%)
342/3,448 (9.9)
24/287 (8.4)
318/3,161 (10.1)
0.3569
PAD/CAD, n (%)
567/3,448 (16.4)
52/287 (18.1)
515/3,161 (16.3)
0.4242
Impaired renal function[a ], n (%)
484/3,448 (14.0)
47/287 (16.4)
437/3,161 (13.8)
0.2334
CHADS2 ≥ 2[b, ]
n (%)
2,126/3,448 (61.7)
179/287 (62.4)
1,947/3,161 (61.6)
0.7960
CHA2 DS2 -VASc ≥ 2[b ], n (%)
3,015/3,448 (87.4)
262/287 (91.3)
2,753/3,161 (87.1)
0.0400
CHA2 DS2 -VASc ≥ 4[b ], n (%)
1,508/3,448 (43.7)
138/287 (48.1)
1,370/3,161 (43.3)
0.1209
HAS-BLED score ≥ 2[c ], n (%)
1,824/3,448 (52.9)
152/287 (53.0)
1,672/3,161 (52.9)
0.9826
Abbreviations: BMI, body mass index; PAD/CAD, peripheral arterial occlusive disease/coronary
artery disease; SPAF, stroke prevention in atrial fibrillation; TIA, transient ischemic
attack; VTE, venous thromboembolism.
a Impaired renal function was defined as current or history of GFR <50 mL/min.
b CHADS2 and CHA2 DS2 -VASc scores are validated risk prediction scores for stroke/systemic embolism in
atrial fibrillation patients.
c HASBLED is a validated risk prediction score for major bleeding in anticoagulated
patients.
Major procedures consisted of orthopaedic/trauma surgery (44.3%); open pelvic, abdominal
or thoracic surgery (30.4%); central nervous system surgery and procedures (13.9%);
vascular surgery (9.1%); and extensive wound revision surgery (2.4%) ([Fig. 1 ]). Of all 287 procedures, only 3 (1%) were emergency procedures which did not allow
for a scheduled preprocedural edoxaban interruption ((intraabdominal abscess; acute
cholecystitis; amputation for acute limb ischemia).
Fig. 1 Types of major procedures.
In the subset of patients undergoing major procedures, SPAF (81.7%) was the most common
indication for edoxaban treatment, followed by VTE therapy and secondary prevention
(17.7%) and off-label indications (0.6%). Preprocedure edoxaban dosage was 60 mg once
daily in 195 procedures and 30 mg once daily in 92 procedures.
Patterns of Periprocedural Edoxaban and Bridging Management
Most of the major procedures were performed with a scheduled interruption of edoxaban
(284/287; 99%) with a median preprocedural interruption of 2 days (25–75th percentile:
2.0–3.3 days) and a median postprocedural interruption of 8.0 days (25–75th percentile:
2.8–5.0 days). This resulted in a total median edoxaban interruption time of 11.0
days (25–75th percentile: 5.0–18.0 days).
Patients with an eGFR <50 mL/min at baseline were managed with a comparable median
preprocedural interruption of 2 days (25–75th percentile: 1.0–3.0 days), but a longer
median postprocedural interruption of 13.5 days (25–75th percentile: 6.5–20.3 days).
In a total of 183/287 procedures (63.8%), heparin bridging was used to replace edoxaban
anticoagulation, with heparin dosages being prophylactic in 46/183 (25.1%); intermediate
in 111/183 (60.6%), or therapeutic in 26/183 (14.2%) of cases ([Supplementary Fig. S1 ] [online only]). Another 36 (12.5%) procedures were performed without heparin bridging.
In the remaining 65 cases, no data on the use and/or dosage of heparin bridging could
be obtained from the health care provider.
[Supplementary Table S2 ] (online only) demonstrates baseline characteristics of patients receiving heparin
bridging (i.e., intermediate or therapeutic heparin) or not (i.e., no anticoagulation
or low-dose heparin prophylaxis only). Both groups had comparable demographic profiles
but numerically more patients in the subgroup without heparin bridging had hypertension
and a history of stroke, resulting in a higher risk for thromboembolism (as indicated
by CHADS2 and CHA2 DS2 -VASc scores ≥2) and bleeding (as indicated by a HAS-BLED score ≥2).
Postprocedure, 237/271 (87.5%) patients with a temporarily edoxaban interruption restarted
edoxaban within the 30-day follow-up interval. Thirteen patients permanently discontinued
edoxaban, of whom 6/13 (46.2%) were switched to VKA, 4/13 (30.8%) remained on heparin
anticoagulation beyond day 30, and 3/13 (23.1%) stopped taking anticoagulants completely.
Effectiveness and Safety Endpoints
The effectiveness and safety outcomes within 30 days postprocedure are listed in [Table 2 ]. Overall, 7 (2.4%; 95% CI: 1.2–4.9%) major cardiovascular events were reported,
comprising 5 newly diagnosed venous thromboembolic events and 2 arterial thromboembolic
events (details in [Supplementary Table S3 ] [online only]). In total, 63 bleeding events were observed in 287 major procedures
(22.0%; 95% CI: 17.6–2.71%), comprising 38 ISTH major bleeding events (13.2%; 95%
CI: 9.8–17.7%, details in [Supplementary Table S4 ] [online only]) and 25 ISTH CRNM bleedings (8.7%; 95% CI: 6.0–12.5%). When criteria
within the ISTH major bleeding definition were assessed hierarchically, 1 case was
adjudicated as fatal bleeding, 4 cases had critical site bleeding, and 16 had transfusion
of ≥2 red blood cell units. The remaining 17 cases had a postprocedural drop in hemoglobin
≥2 g/dL without fulfilling any of the other three criteria. [Supplementary Fig. S2 ] (online only) depicts the distribution pattern over time as well as the BARC bleeding
severity within the 38 ISTH major bleeding events.
Table 2
Effectiveness and safety outcomes of 287 major procedures in edoxaban patients within
day 30 post procedure
Outcome at day 30 postprocedure
Major procedures, n = 287
Major CV events, n (%; 95% CI)
7 (2.4; 1.2–4.9)
ISTH major bleeding, n (%; 95% CI)
38 (13.2; 9.8–17.7)
ISTH nonmajor bleeding, n (%; 95% CI)
25 (8.7; 6.0–12.5)
BARC 1, n (%; 95% CI)
12 (4.2; 2.4–7.2)
BARC 2, n (%; 95% CI)
14 (4.9; 2.9–8.0)
BARC 3a, n (%; 95% CI)
22 (7.7; 5.1–11.3)
BARC 3b, n (%; 95% CI)
11 (3.8; 2.2–6.7)
BARC 3c, n (%; 95% CI)
2 (0.7; 0.2–2.5)
BARC 4, n (%; 95% CI)
1 (0.3; 0.1–1.9)
BARC 5a, n (%; 95% CI)
0
BARC 5b, n (%; 95% CI)
1 (0.3; 0.1–1.9)
All-cause death, n (%; 95% CI)
6 (2.1; 1.0–4.5)
Abbreviations: BARC, Bleeding Academic Research Consortium; CI, confidence interval;
CV, cardiovascular.
Within 30 days of follow-up, six patients died (2.1%; 95% CI: 1.0–4.5%) with causes
of death being a ruptured truncus coeliacus following palliative angioplasty for an
infiltrating pancreas cancer (ruled as fatal bleeding), septic organ failure, pneumocystis
jirovecii pneumonia, COVID-19-pneumonia, septic complications following clipping of
a ruptured cerebrovascular aneurism, or terminal malignant disease. No fatal cardiovascular
event occurred.
The distribution patterns of major cardiovascular outcomes, ISTH major bleeding, and
death in relation to periprocedural edoxaban management are depicted in [Fig. 2 ] (according to type of surgical procedure) and [Fig. 3 ] (according to heparin bridging).
Fig. 2 Time–frequency plot of major cardiovascular outcomes, ISTH major bleeding and death
in relation to periprocedural edoxaban management, and type of surgery. Of note, the
figure depicts only patients who developed clinical outcomes of interest. ISTH, International
Society of Thrombosis and Haemostasis.
Fig. 3 Time–frequency plot of major cardiovascular outcomes, ISTH major bleeding and death
in relation to periprocedural edoxaban management, and heparin bridging. Of note,
the figure depicts only patients who developed clinical outcomes of interest. ISTH,
International Society of Thrombosis and Haemostasis.
As depicted in [Figs. 2 ] and [3 ] and in [Supplementary Table S3 ] (online only), all seven major cardiovascular events occurred within 2 weeks after
procedure, and in 6/7 cases the event was diagnosed during edoxaban interruption or
within 24 hours after restarting edoxaban. The remaining major cardiovascular event
(partial thrombus in jugular vein at central venous catheter insertion site) was diagnosed
on day 8 postsurgery in a patient who restarted edoxaban 30 mg once daily 4 days after
hemicolectomy.
The majority of ISTH major bleeding events (20/38; 52.6%) occurred within the first
24 hours after procedure and 37/38 occurred within 8 days (of note, one patient experienced
a recurrent major bleeding event on day 27, following an initial major bleeding on
the day of surgery). None of the major bleeding events occurred after a restart of
edoxaban ([Supplementary Table S4 ] [online only]).
The use or intensity of heparin bridging did not seem to reduce the risk of major
cardiovascular events, which occurred in 4/137 (2.9%; 95% CI: 1.1–7.3%) with heparin
bridging versus 3/82 (3.7%; 95% CI: 1.3–10.2%) without ([Table 3 ]).
Table 3
Effectiveness and safety outcomes of 287 major procedures in edoxaban patients within
day 30 postprocedure, according to heparin bridging
Outcome at day 30 after procedure
Edoxaban continued,
Edoxaban interrupted, no heparin bridging (prophylactic low-dose heparin allowed),
Edoxaban interrupted, heparin bridging (intermediate or therapeutic dosages),
Edoxaban interrupted, no information about bridging available,
n = 3
n = 82
n = 137
n = 65
Net clinical benefit (major cardiovascular and major bleeding events), n (%; 95% CI)
1(33.3; 6.1–79.2)
12 (14.6; 8.6–23.9)
27 (19.7; 13.9–27.2)
5 (7.7; 3.3–16.8)
Major CV events, n (%; 95% CI)
0
3 (3.7; 1.3–10.2)
4 (2.9; 1.1–7.3)
0
Major bleeding, n (%; 95% CI)
1 (33.3; 6.1–79.2)
9 (11.0; 5.9–19.6)
23 (16.8; 11.5–23.9)
5 (7.7; 3.3–16.8)
Nonmajor bleeding, n (%; 95% CI)
0
4 (4.9; 1.9–11.9)
12 (8.8; 5.1–14.7)
9 (13.8; 7.5–24.3)
BARC 1, n (%; 95% CI)
0
2 (2.4; 0.7–8.5)
6 (4.4; 2.0–9.2)
4 (6.2; 2.4–14.8)
BARC 2, n (%; 95% CI)
0
1 (1.2; 0.2–6.7)
8 (5.8; 3.0–11.1)
5 (7.7; 3.3–16.8)
BARC 3a, n (%; 95% CI)
0
5 (6.1; 2.6–13.5)
13 (9.5; 5.6–15.6)
4 (6.2; 2.4–14.8)
BARC 3b, n (%; 95% CI)
1 (33.3; 6.1–79.2)
3 (3.7; 12.5–10.2)
6 (4.4; 2.0–9.2)
1 (1.5; 0.3–8.2)
BARC 3c, n (%; 95% CI)
0
2 (2.4; 0.7–8.5)
0
0
BARC 4, n (%; 95% CI)
0
0
1 (0.7; 0.1–4.0)
0
BARC 5a, n (%; 95% CI)
0
0
0
0
BARC 5b, n (%; 95% CI)
0
0
1 (0.7; 0.1–4.0)
0
Death, n (%; 95% CI)
0
4 (4.9; 1.9–11.9)
2 (1.5; 0.4–5.2)
0
Abbreviations: BARC, Bleeding Academic Research Consortium; CI, confidence interval;
CV, cardiovascular.
With regard to major bleeding, safety outcomes trended to be more frequent in patients
undergoing procedures with heparin bridging (23/137; 16.8%; 95% CI: 11.5–23.9%) versus
procedures without heparin bridging (9/82; 11.0%; 95% CI: 5.9–19.6%; [Table 3 ]).
With regard to net clinical benefit (rates of major cardiovascular or major bleeding
events combined), [Table 3 ] indicates that event rates were lowest in the subgroup of patients receiving no
heparin bridging.
[Supplementary Table S5 ] (online only) demonstrates baseline characteristics of patient with or without major
outcome events. Patients experiencing major outcome events tended to be older (median:
77.0 vs. 74.0 years), were more often SPAF patients (88.4 vs. 81.6%), and more often
suffered from impaired renal function (23.3 vs. 15.2%), which translated in a higher
proportion of patients at higher risk for thromboembolism (as indicated by CHADS2 and CHA2 DS2 -VASc scores ≥2) and bleeding (as indicated by a HAS-BLED score ≥2) at baseline.
As indicated by [Supplementary Table S6 ] (online only), rates of major cardiovascular and bleeding events were considerably
higher in patients needing emergency procedures (major cardiovascular events: 9.3%;
ISTH major bleeding: 23.3%, and BARC class 3–5 major bleeding: 20.9%) compared with
patients after elective major surgery (1.2, 11.5, and 11.1%, respectively).
Discussion
The present analysis indicates that approximately 8% of all surgical or interventional
procedures performed in NOAC patients belong to the high-risk category according to
EHRA.[7 ] This indicates a need for optimal anticoagulant management, since these patients
are at increased risk for thromboembolism and bleeding. The thrombotic risk reflects
a combination of disposition (hence the indication for anticoagulation) and exposure
to major surgery. At the same time, the bleeding risk may be increased by patient-dependent
risk factors (such as impaired renal function and frailty), residual anticoagulant
activity from NOAC, overlapping anticoagulant activity from heparin bridging, and
from the surgical procedure itself. This complex situation indicates a medical need
to optimize the periprocedural anticoagulation management of SPAF and VTE patients.
Several studies have therefore addressed the periprocedural management of NOAC patients.
One of the largest studies in the field, the “Perioperative Anticoagulation Use for
Surgery Evaluation” (PAUSE) trial,[18 ] reported management patterns and outcomes in more than 3,000 SPAF patients but did
not recruit edoxaban patients. In contrast, EMIT-AF/VTE was designed to document the
risks of bleeding and thromboembolic events in more than 1,000 patients on edoxaban
undergoing diagnostic and therapeutic procedures in clinical practice, but more than
75% of the studied interventions carried a minor or low risk for complications only.[10 ]
Our study therefore provides valuable new insights into the management patterns and
outcomes of edoxaban patients undergoing major risk procedures.
Patient Characteristics
When we compared the patient characteristics of edoxaban patients undergoing major
surgical procedures to the profiles of patients undergoing nonmajor procedures, we
found that most characteristics were comparable with minor, but significant differences
only with regard to female sex, higher CHA2 DS2 -VASc scores (both more common in major procedures), and concomitant antiplatelet
therapy (less common in major procedures). However, advanced age (median 74 years)
and high proportion of patients with prior stroke (8–10%), impaired renal function
(15%), heart failure (22–24%), or CHA2 DS2 -VASc score ≥4 (48%) were frequently observed in both subgroups, indicating the high
baseline risk of the overall population, which needs to be taken into account when
the outcome event rates are discussed below. Overall, the baseline characteristics
of our cohort are very similar to those reported in PAUSE (mean age 72–73 years; mean
CHA2 DS2 -VASc score 3.5; prior stroke 7–10%; heart failure 13–19%)[18 ] and EMIT-AF/VTE (mean age 72 years; CHA2 DS2 -VASc score >3 41%; renal impairment 19%; heart failure 13%).[10 ]
Edoxaban Management Patterns
Guidance documents provide specific periprocedural management recommendations for
each NOAC and for each risk category of procedures. The EHRA[7 ] recommendation for edoxaban and major procedures suggests to stop edoxaban 2 days
prior without heparin bridging and a restart within 48 to 72 hours postprocedure with
a consideration of heparin in prophylactic dosages in between. A similar protocol
was prespecified in the PAUSE trial.[18 ] However, this recommendation is dedicated to SPAF patients and no similarly detailed
recommendations are available for VTE patients, who may have a higher thromboembolic
risk especially if procedures requiring edoxaban interruption are performed early
after VTE diagnosis.
The preprocedural edoxaban interruption in our dataset (median: 2 days, 25–75th percentile:
2.0–3.3 days) indicates a good adherence to the recommendations above. However, given
that 15.0% of the major procedures were unplanned events done on the same day of admission
and due to the heterogeneity and complexity of some of the observed major procedures,
the postprocedural time to the restart of edoxaban showed a wider range with a median
of 8 days (25–75th percentile: 2.8–15.0 days), which was even longer for patients
with a baseline eGFR <50 mL/min (13.5 days; 25–75th percentile: 6.5–20.3 days).
Colonna et al[10 ] and Unverdorben et al[11 ] recently reported on the periprocedural management of edoxaban patients in the EMIT
registries. Here, 123 of 280 cases (44%) undergoing high bleeding risk procedures
had a preprocedural interruption <48 hours and 30 (11%) had an interruption longer
than 72 hours. Unfortunately, no information on the median duration of interruption
before procedure or on the time until restart was provided, which limits comparisons
with our dataset.
When we compare the management patters for edoxaban with our previously reported mixed
NOAC cohort published in the early phase of NOAC use,[17 ] the management patterns are consistent. In this previous cohort of apixaban, dabigatran,
and rivaroxaban patients, the NOAC was stopped 2 days before procedure (interquartile
range: 2 days). However, data on the postprocedural NOAC resumption were lacking for
the subset of patients undergoing major procedures in this past analysis.
Efficacy and Safety Outcomes
In our cohort of 287 patients undergoing major surgical procedures, we observed 30-day
event rates of 2.4% (major cardiovascular events), 13.2% (ISTH major bleeding), and
2.1% (all-cause mortality), respectively. These numbers clearly reflect the aforementioned
fact that our cohort underwent major surgical procedures despite a high-risk profile
of baseline cardiovascular and bleeding risk factors. Overall, our outcome data are
comparable to those of a previous analysis from our group from the early NOAC era
which evaluated 863 procedures in a rivaroxaban cohort (87 major procedures) and reported
event rates of 4.6, 8.0, and 2.3% for major cardiovascular events, ISTH major bleeding,
and death, respectively.[17 ]
In PAUSE,[18 ] event rates are more difficult to compare, since three different NOACs were tested
in this trial, nearly 70% of procedures were nonmajor procedures and a strict protocol
for preprocedural interruption and postprocedural resumption was provided with patients
being excluded from the per-protocol analysis in case of protocol deviations. Still,
also PAUSE reported a rate of 3% major bleedings following major procedures in DOAC
recipients. Unfortunately, cardiovascular events and mortality were not reported separately
for patients undergoing major procedures.[18 ]
The observational EMIT registries[10 ]
[11 ] followed SPAF and VTE patients with edoxaban in routine clinical care in a multinational
setting and evaluated efficacy and safety in more than 1,000 patients undergoing a
wide range of different procedures, including 280 major procedures. Similar to PAUSE,
the EMIT registries showed higher rates of bleeding events in major compared with
minor procedures (5.7 vs. 3.1%), although only five major events bleeding were documented
in total (0.4% of all 1,155 procedures). Rates of arterial events (0.5%) and cardiovascular
deaths (0.2%) were also low. Unfortunately, neither major bleeding rates nor VTE event
rates can be directly compared with our dataset, since most procedures in EMIT were
nonmajor and event rates were not separately provided for the major procedures. However,
rates of arterial thromboembolism (1.4%), cardiovascular mortality (0.4%), and all-cause
mortality (0.7%) were separately reported for major procedures. Within our composite
endpoint of major cardiovascular events, we found two events of arterial thromboembolism
(0.7%) and zero cases of cardiovascular deaths, indicating consistency to EMIT. However,
our all-cause mortality rate (2.1%) was higher than in the EMIT registries, which
was likely unrelated to the edoxaban management and more related to the type of procedures
and patient risk profiles, since only one fatal bleeding and zero cardiovascular deaths
were contained in this signal.
Finally, when we compare the present outcome rates for edoxaban with our mixed NOAC
cohort event rates published in 2014,[17 ] the crude event rates in the current analysis trended toward lower cardiovascular
events (major cardiovascular events 4.6% in 2014 vs. 2.4%; cardiovascular death 2.3%
in 2014 vs. 0) but higher rates of major bleeding (8.0% in 2014 vs. 13.2%), although
all 95% CIs showed a large overlap.
The 13% rate of major bleeding deserves some further discussion. First of all, the
majority of all major bleeding events occurred within the first 48 hours after major
procedures and were very likely related to the extent of the surgical procedure itself
rather than the periprocedural management of anticoagulants. This consideration is
further supported by the fact that 33 of the 38 ISTH major bleeding events were adjudicated
based on a need for red blood cell transfusions or a drop in hemoglobin, which are
common scenarios also in major procedures in nonanticoagulated patients. This observation
further questions if the ITSH bleeding definition is the optimal outcome parameter
in this clinical setting. Because of this, all observed bleeding events were additionally
adjudicated according to the BARC bleeding definition. Not surprisingly, out of 38
ISTH major bleeding events, only 4 events fell into BARC categories 3c–5, resulting
in a crude event rate of 1.4% for immediately life-threatening bleeding. The remaining
events fell into categories BARC 3a (n = 22; any transfusion or drop in hemoglobin of 3–5 g/dL) or BARC 3b (drop in hemoglobin
>5 g/dL or cardiac tamponade or bleeding requiring surgery or vasopressor drugs).
Finally, we observed a lack of benefit from an intensified heparin bridging regimen.
Rates of cardiovascular events were not reduced, but bleeding complications were numerically
increased – a finding that is in line with previous observations.[8 ]
[17 ] According to our data, the best risk-benefit relation was observed in patients receiving
no heparin bridging or only prophylactic dosages of heparin, which confirms the above
mentioned EHRA guidance[7 ] to use not more than prophylactic heparin dosages if NOAC can be resumed within
days after major surgery.
Limitations
There are several limitations of our study. A selection bias is not negligible, because
edoxaban was the last NOAC approved and, as a consequence, the prescription pattern
may not be identical to those of other NOAC cohorts from the past. As with all observational
studies, missing data or underreporting of outcome events may also be confounders
in our registry. However, our methodology has been well standardized over more than
10 years; all patient interviews during follow-up are performed by well-trained study
nurses using standardized questionnaires. For the reported 287 procedures, no patient
was lost to follow-up (0%) or withdrew consent (0%). Although not part of our outcome
endpoint for the presented analysis, nonmajor bleeding events are routinely collected
in our registry, thus limiting the likelihood that major events were missed.
Furthermore, with only 45 major outcome events (7 major cardiovascular events, 38
major bleeding events) our study did not allow for adjusted comparisons of different
management strategies. It is in the nature of observational studies that the potential
for confounding prevents establishing causal relationships between prescribed treatments
and outcomes. For this, randomized comparisons for different treatment strategies
are needed. The value of observational studies in this field is to provide insights
into management patterns and to study outcomes within these patterns. As such, we
provide very granular data on the periprocedural edoxaban management, the intensity
of heparin treatments, and provide patterns for the timing of outcome events according
to type of procedures or heparin strategies. On the other hand, our sample size of
>3,000 procedures in edoxaban patients including 287 major procedures, the use of
clinically relevant endpoints, and the rigorous central event adjudication process
are important strengths of our registry and the presented analysis.
Conclusion
Our results indicate that adherence to bridging recommendations in edoxaban-treated
patients undergoing major surgical procedures is adequate. Given the high baseline
risk of the population and the increase of thrombotic and bleeding risks from major
surgery, the observed complication rates fell into a clinically acceptable range.
Edoxaban management patterns (stop 2 days before and resumption within days postsurgery)
follow existing guidelines and the best risk–benefit balance was achieved by guideline-recommended
low-dose heparin prophylaxis instead of therapeutic heparin bridging. Our results
therefore not only confirm previous studies in this field and guidance recommendations
in SPAF patients, but extend these to VTE patients and to patients receiving edoxaban—a
cohort for which real-world data are still scarce. Still, the observed high degree
of variance especially for using heparin bridging and for delaying restart of oral
anticoagulation postsurgery warrants further studies, investigating the reasons for
these clinical decisions and to evaluate optimized hospital-standard operating procedures
that aim to further improve standardization and patient outcomes.
