Perioperative management of patients receiving anticoagulants - UpToDate https://www.uptodate.com/contents/perioperative-management-of-patient...

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Perioperative management of patients receiving anticoagulants

Authors: Gregory YH Lip, MD, FRCPE, FESC, FACC, James D Douketis, MD, FRCPC, FACP, FCCP
Section Editor: Lawrence LK Leung, MD
Deputy Editor: Jennifer S Tirnauer, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2018. | This topic last updated: Jun 11, 2018.

INTRODUCTION — The management of anticoagulation in patients undergoing surgical procedures is

challenging because interrupting anticoagulation for a procedure transiently increases the risk of
thromboembolism. At the same time, surgery and invasive procedures have associated bleeding risks that are
increased by the anticoagulant(s) administered for thromboembolism prevention. If the patient bleeds from
the procedure, their anticoagulant may need to be discontinued for a longer period, resulting in a longer
period of increased thromboembolic risk. A balance between reducing the risk of thromboembolism and
preventing excessive bleeding must be reached for each patient.

Additional issues relate to the specific anticoagulant used. For those taking a vitamin K antagonist (eg,
warfarin), it takes several days until the anticoagulant effect is reduced and then reestablished perioperatively;
the risks and benefits of "bridging" with a shorter acting agent, such as heparin, during this time are unclear.
The newer direct oral anticoagulants (eg, direct thrombin inhibitor dabigatran, factor Xa inhibitors rivaroxaban,
apixaban, edoxaban) have shorter half-lives, making them easier to discontinue and resume rapidly, but the
direct factor Xa inhibitors lack an approved drug-specific antidote, which raises concerns about treatment of
bleeding and management of patients who require an urgent surgery or invasive procedure.

Our approach to managing ongoing anticoagulation in patients undergoing surgery or an invasive procedure
is discussed here. Additional details regarding the use of specific anticoagulants and antiplatelet agents are
presented separately.

● Vitamin K antagonists – (See "Warfarin and other VKAs: Dosing and adverse effects".)

● Heparins – (See "Heparin and LMW heparin: Dosing and adverse effects".)

● Direct thrombin inhibitors and direct factor Xa inhibitors – (See "Direct oral anticoagulants and parenteral
direct thrombin inhibitors: Dosing and adverse effects".)

● Antiplatelet agents – (See "Perioperative medication management", section on 'Medications affecting

hemostasis'.)

Specific recommendations for individuals with prosthetic heart valves are discussed separately. (See
"Antithrombotic therapy for prosthetic heart valves: Management of bleeding and invasive procedures".)

Perioperative venous thromboembolism prevention in patients not receiving ongoing anticoagulation is also
discussed separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical

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patients".)

OVERVIEW OF OUR APPROACH

General approach — Interruption of anticoagulation temporarily increases thromboembolic risk, and

continuing anticoagulation increases the risk of bleeding associated with invasive procedures; both of these
outcomes adversely affect mortality [1-6]. Our approach to perioperative management of anticoagulation
takes into account these risks, along with specific features of the anticoagulant the patient is taking [7].

Of note, much of our approach is based on expert opinion; thrombotic and bleeding risks may vary depending
on individual circumstances, and data from randomized trials or well-designed observational studies are not
available to guide practice in many settings. In addition, the best surrogate for complete resolution of
anticoagulant effect is not always known or available for the newer direct oral anticoagulants. Thus, this
approach should be used as clinical guidance and should not substitute for clinician judgment in decisions
about perioperative anticoagulant management for individual patients.

Our approach to decision making is outlined as follows:

● Estimate thromboembolic risk – A higher thromboembolic risk increases the importance of minimizing
the interval without anticoagulation (table 1). We estimate thromboembolic risk for patients with atrial
fibrillation based on age and comorbidities. For those with a recent deep vein thrombosis or pulmonary
embolism, we estimate the risk based on the interval since diagnosis.

If thromboembolic risk is transiently increased (eg, recent stroke, recent pulmonary embolism), we prefer
to delay surgery until the risk returns to baseline, if possible. (See 'Estimating thromboembolic risk'
below.)

For patients with more than one condition that predisposes to thromboembolism, the condition with the
highest thromboembolic risk takes precedence.

● Estimate bleeding risk – A higher bleeding risk confers a greater need for perioperative hemostasis,
and hence a longer period of anticoagulant interruption. Bleeding risk is dominated by the type and
urgency of surgery; some patient comorbidities also contribute. Procedures with a low bleeding risk (eg,
dental extractions, minor skin surgery) often can be performed without interruption of anticoagulation.
(See 'Estimating procedural bleeding risk' below and 'Deciding whether to interrupt anticoagulation'
below.)

● Determine the timing of anticoagulant interruption – The timing of anticoagulant interruption depends
on the specific agent the patient is receiving. As examples, warfarin requires earlier discontinuation than
the shorter-acting direct oral anticoagulants (eg, dabigatran, rivaroxaban, apixaban, edoxaban) (table 2).
(See 'Timing of anticoagulant interruption' below.)

● Determine whether to use bridging anticoagulation – For most patients, we do not use bridging
anticoagulation (use of a short-acting parenteral agent to reduce the interval without anticoagulation),
because it increases bleeding risk without reducing the rate of thromboembolism. However, some
patients on warfarin with an especially high thromboembolic risk (eg, mechanical heart valve, recent
stroke) may benefit from bridging with heparin or low molecular weight (LMW) heparin. (See 'Bridging
anticoagulation' below.)

Example cases — The following examples illustrate our decision-making process using this approach in
general terms; importantly, management of every case must be individualized based on the judgement of the

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treating clinicians:

● A 76-year-old female with non-valvular atrial fibrillation, hypertension, and prior stroke three months ago,
receiving warfarin, requires elective hip replacement with neuraxial anesthesia; renal function is normal,
and weight is 75 kg. This patient has a very high thromboembolic risk (table 1) and a high bleeding risk
(table 3).

• Stop warfarin five days before the procedure (last dose on preoperative day minus 6).

• Preoperative bridging with dose LMW heparin (eg, dalteparin, 100 units/kg [7500 units]
subcutaneously twice daily) starting on preoperative day minus 3, with last dose on the morning of
day minus 1.

• Resume warfarin within 24 hours after surgery (usual dose).

• Postoperative low dose LMW heparin for VTE prevention (eg, dalteparin 5000 units subcutaneously
once daily) within 24 hours after surgery until postoperative bridging is started.

• Postoperative bridging on postoperative day 2 or 3, when hemostasis is secured (eg, dalteparin, 100
units/kg [7500 units] subcutaneously twice daily; continue for at least four to five days, until the INR
is therapeutic.

● A 70-year-old male with non-valvular atrial fibrillation, diabetes, and hypertension (CHA2DS2-VASc score
= 3) receiving dabigatran who requires a colon resection for cancer; renal function is normal. This patient
has a high thrombotic risk (table 1) and a high bleeding risk (table 3).

• Stop dabigatran three days before the procedure (off dabigatran for two days before the procedure
and the day of the procedure).

• No bridging.

• Resume dabigatran on day +2 or +3 after surgery, when patient is able to take medication by mouth.

• Use prophylactic dose LMW heparin for VTE prophylaxis for the first two to three postoperative days.

● A 55-year-old male with an unprovoked deep vein thrombosis (DVT) four months ago, receiving apixaban
5 mg twice daily, who requires a colonoscopy because of a personal history of premalignant colorectal
polyps; renal function is normal. This patient has a high thrombotic risk (table 1) and a low bleeding risk
(table 3).

• Stop apixaban two days before the procedure (off apixaban for one day before the procedure and
the day of the procedure).

• No bridging.

• Resume apixaban the day after the procedure, after at least 24 hours have elapsed when
hemostasis secured. If the patient requires polyp removal, delay resumption of apixaban for one to
two more days.

● A 68-year-old female with non-valvular atrial fibrillation, hypertension, and congestive heart failure
(CHA2DS2-VASc score = 4), receiving rivaroxaban 15 mg daily in the morning, requires a dental cleaning
and two dental extractions; creatinine clearance is 35 mL/min. This patient has a high thrombotic risk
(table 1) and a low bleeding risk (table 3).

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• Do not take rivaroxaban on the day of the procedure.

• Use oral tranexamic acid mouthwash just before the procedure and two to three times that day after
the procedure.

• Resume rivaroxaban the day after the procedure, after at least 24 hours have elapsed (assuming the
dental extractions were uneventful).

ESTIMATING THROMBOEMBOLIC RISK — The major factors that increase thromboembolic risk are atrial
fibrillation, prosthetic heart valves, and recent venous or arterial thromboembolism (eg, within the preceding
three months).

Atrial fibrillation — Atrial fibrillation accounts for the highest percentage of patients for whom perioperative
anticoagulation questions arise. Importantly, patients with atrial fibrillation are a heterogeneous group; risk can
be further classified according to clinical variables such as age, hypertension, congestive heart failure,
diabetes, prior stroke, and other vascular disease (table 1) [2,8]. The CHA2DS2-VASc score (table 4)
(calculator 1), which incorporates these variables, is discussed in detail separately; of note, use of risk scores
has not been prospectively validated in the perioperative setting. (See "Atrial fibrillation: Risk of
embolization".)

The magnitude of this issue was illustrated in three large trials: RE-LY (Randomized Evaluation of Long-Term
Anticoagulant Therapy), ROCKET AF (Rivaroxaban Once daily, oral direct factor Xa inhibition Compared with
vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), and ARISTOTLE
(Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) [9-11]. These trials
of each randomly assigned 15,000 to 20,000 patients to warfarin versus another oral anticoagulant
(dabigatran, rivaroxaban, or apixaban, respectively). Surgical or other invasive procedures were required in
one-fourth of patients in RE-LY and one-third of patients in ROCKET AF and ARISTOTLE.

● RE-LY (dabigatran versus warfarin) – Of the 4591 patients who underwent elective procedures or surgery
in the RE-LY trial, the perioperative thromboembolic risk was 1.2 percent, based on a composite endpoint
of stroke, cardiovascular death, and pulmonary embolus [9]. There were no differences in
thromboembolic risk with dabigatran versus warfarin, or with the high versus the low dabigatran dose.
However, urgent surgery was associated with a higher risk of ischemic stroke or systemic embolism than
elective surgery (warfarin: 1.8 versus 0.4 percent; dabigatran 150 mg twice daily: 1.4 versus 0.4 percent;
dabigatran 110 mg twice daily: 2.8 versus 0.3 percent).

● ROCKET AF (rivaroxaban versus warfarin) – Of the 4692 anticoagulant interruptions in this trial, 40
percent were for surgery or invasive procedures [11]. The thromboembolic risk during anticoagulant
interruption was similar for rivaroxaban and warfarin (0.3 and 0.4 percent).

● ARISTOTLE (apixaban versus warfarin) – During 9260 procedures performed on patients in the
ARISTOTLE trial, the perioperative thromboembolic risk was 0.57 percent for warfarin and 0.35 percent
for apixaban [10].

Bleeding risk in these trials and registries are presented below. (See 'Overview of whether to interrupt' below.)

Prosthetic heart valve — The risks of thromboembolism and perioperative management of patients with
prosthetic heart valves are discussed separately. (See "Antithrombotic therapy for prosthetic heart valves:
Management of bleeding and invasive procedures", section on 'Management of antithrombotic therapy for
invasive procedures' and "Diagnosis of mechanical prosthetic valve thrombosis or obstruction".)

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Recent thromboembolism — Thromboembolic risk is greater in the immediate period following a

thromboembolic event and declines over time. Individuals with a recent thromboembolic event are likely to
benefit from delaying surgery, if possible. If emergency surgery is required (eg, acute cholecystectomy),
bridging anticoagulation may be used to reduce the interval without an anticoagulant. (See 'Bridging
anticoagulation' below.)

Venous — The perioperative risk of venous thromboembolism (VTE) is greatest in individuals with an
event (eg, deep vein thrombosis, pulmonary embolus) within the prior three months and those with a history
of VTE associated with a high-risk inherited thrombophilia (table 1). However, many patients with VTE do not
require thrombophilia testing, and we do not perform this testing specifically to evaluate perioperative
thrombotic risk in patients who otherwise do not warrant screening. Appropriate use of thrombophilia
screening is discussed separately. (See "Clinical presentation and diagnosis of the nonpregnant adult with
suspected deep vein thrombosis of the lower extremity".)

Individuals with cancer have a moderate risk, and those with an event more than one year ago have a low risk
of VTE complications.

Thus, patients who require surgery within the first three months following an episode of VTE are likely to
benefit from delaying elective surgery, even if the delay is only for a few weeks. This approach is supported
by data showing that the recurrence risk for individuals with a recent VTE is highest within the initial three to
four weeks and diminishes over the following two months [12-14]. Without anticoagulation, the early risk of
recurrent VTE was approximately 50 percent; treatment with warfarin for one month reduced this risk to 8 to
10 percent, and after three months of warfarin therapy the risk declined to 4 to 5 percent [14-16].

Arterial — The risk of recurrent arterial embolism from any cardiac source is approximately 0.5 percent
per day in the first month after an acute event [17]. The vast majority of cases are due to atrial fibrillation;
other less common cardiac sources include paradoxical embolism, non-bacterial thrombotic endocarditis in a
patient with malignancy, dilated or poorly contractile left ventricle, or left ventricular aneurysm (table 5)
[18-20].

Thus, patients with a recent arterial embolism are likely to benefit from delaying elective surgery, if such a
delay is possible.

ESTIMATING PROCEDURAL BLEEDING RISK — The risk of bleeding is dominated by the type of surgery
or invasive procedure. Patient comorbidities (eg, older age, decreased renal function) and medications that
affect hemostasis (eg, aspirin) may also contribute [3,21,22].

As a general guideline, we divide procedures into high and low bleeding risk (two-day risk of major bleeding 2
to 4 percent or 0 to 2 percent, respectively); examples of high bleeding risk procedures include coronary
artery bypass surgery, kidney biopsy, and any procedure lasting >45 minutes; low bleeding risk procedures
include cholecystectomy, carpal tunnel repair, and abdominal hysterectomy (table 3) [2]. Importantly, these
categories do not substitute for clinical judgement or consultation between the surgeon and other treating
clinicians. Neuraxial, intracranial, and cardiac procedures are especially concerning because the location of
potential bleeding increases the risk of serious complications. (See "Neuraxial anesthesia/analgesia
techniques in the patient receiving anticoagulant or antiplatelet medication".)

Major bleeding is generally defined as bleeding that is fatal, involves a critical anatomic site (eg, intracranial,
pericardial), requires surgery to correct, lowers the hemoglobin by ≥2 g/dL, or requires transfusion of ≥2 units
packed red cells; however, there is heterogeneity in definitions used by different clinicians [23].

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The risks of some specific types of procedures are also discussed in detail separately in the following topic
reviews, along with management issues specific to those procedures:

● Neuraxial anesthesia – (see "Neuraxial anesthesia/analgesia techniques in the patient receiving

anticoagulant or antiplatelet medication")

● Gastrointestinal procedures – (see "Management of anticoagulants in patients undergoing endoscopic

procedures", section on 'Elective procedures in anticoagulated patients')

● Percutaneous coronary intervention (eg, angioplasty, atherectomy, stenting) – (see "Periprocedural

management of antithrombotic therapy in patients receiving long-term oral anticoagulation undergoing
percutaneous coronary intervention", section on 'Elective patients' and "Coronary artery disease patients
requiring combined anticoagulant and antiplatelet therapy", section on 'Prevention')

● Ophthalmologic procedures – (see "Diabetic retinopathy: Prevention and treatment", section on

'Patients taking antiplatelet or anticoagulant medication' and "Age-related macular degeneration:
Treatment and prevention", section on 'Safety in patients taking anticoagulants or antiplatelet drugs' and
"Cataract in adults", section on 'Antithrombotic agents')

Dental and cutaneous procedures are generally associated with a low risk of bleeding. (See 'Settings in which
continuing the anticoagulant may be preferable' below.)

Patient factors can also contribute to bleeding risk; these patient-related risks can be quantified using
bleeding risk scores. An example is the HAS-BLED score (calculator 2), which was used in the BNK Online
Bridging Registry (BORDER), an observational registry that assessed perioperative outcomes in outpatients
undergoing invasive cardiac procedures (eg, cardiac catheterization, pacemaker implantation, cardiac
surgery) [24]. Nearly all of the patients were receiving a vitamin K antagonist, which was interrupted for the
procedure and replaced with a bridging agent, usually a low molecular weight (LMW) heparin. There were 35
clinically relevant bleeding episodes during 1000 procedures (3.5 percent). A HAS-BLED bleeding risk score
≥3 was the most predictive variable for bleeding (HR 11.8, 95% CI 5.6-24.9). The HAS-BLED score assigns
one point each for hypertension, abnormal renal or liver function (two points for both), stroke, bleeding
tendency, labile INRs, elderly age, and antiplatelet drugs or alcohol (table 6).

DECIDING WHETHER TO INTERRUPT ANTICOAGULATION

Overview of whether to interrupt — Once the thromboembolic and bleeding risks have been estimated, a
decision can be made about whether the anticoagulant should be interrupted or continued. Data comparing
the relative benefits of continuing anticoagulation versus interrupting an anticoagulant are limited, and
decisions that balance thromboembolic and bleeding risks must be made on a case-by-case basis. No
scoring system can substitute for clinical judgment in this decision making.

● In general, the anticoagulant must be discontinued if the surgical bleeding risk is high. Those at very high
or high thromboembolic risk should limit the period without anticoagulation to the shortest possible
interval; in some cases this involves the use of a bridging agent. (See 'Settings requiring anticoagulant
interruption' below and 'Whether to use bridging' below.)

● In contrast, individuals undergoing selected low bleeding risk surgery often can continue their
anticoagulant; in certain cases, continuation of the anticoagulant may preferable. (See 'Settings in which
continuing the anticoagulant may be preferable' below.)

Practices to reduce bleeding and thromboembolic risks should be employed regardless of whether the

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patient's anticoagulant is interrupted or continued. Examples include the following:

● Agents that interfere with platelet function should be avoided for routine analgesia (eg, nonsteroidal anti-
inflammatory drugs [NSAIDs], aspirin) unless the benefit outweighs the increased risk of bleeding, and
routine perioperative use of aspirin should be avoided due to an increased risk of bleeding and lack of
benefit. By contrast, if these agents are administered for a separate indication (eg, recent stroke, acute
coronary syndromes, implanted coronary stent) they can (and generally should) be continued [25]. Issues
associated with perioperative aspirin use are discussed in detail separately. (See "Perioperative
medication management", section on 'Medications affecting hemostasis' and "Periprocedural
management of antithrombotic therapy in patients receiving long-term oral anticoagulation undergoing
percutaneous coronary intervention".)

● For those not receiving an anticoagulant in the immediate postoperative period, thromboprophylaxis to
reduce the risk of venous thromboembolism should be used when appropriate. (See "Prevention of
venous thromboembolic disease in adult nonorthopedic surgical patients".)

Settings requiring anticoagulant interruption — Individuals undergoing surgery with a high risk of bleeding
will require interruption of their usual anticoagulant perioperatively, putting them at higher risk of
thromboembolic complications related to their underlying condition.

● If the very high risk of thromboembolism is transient (eg, ischemic stroke within the previous month),
attempts should be made to delay elective surgery, if possible, until the thromboembolic risk has returned
to baseline.

It may also be advisable to delay elective surgery in a patient with atrial fibrillation who has had
inadequate anticoagulation in the preceding month. This is based on the observation that among patients
with nonvalvular atrial fibrillation, over 85 percent of thrombi resolve after four weeks of warfarin therapy
[26]. (See "Atrial fibrillation: Risk of embolization", section on 'Imaging predictors'.)

● Individuals with a temporarily very high or high thromboembolic risk in whom surgery cannot be delayed
(eg, potentially curative cancer surgery in a patient who just had an acute VTE) should limit the interval
without an anticoagulant to minimize the risk of thromboembolism. This generally involves stopping the
usual anticoagulant as close to surgery as possible, restarting it as soon as possible, and using a
bridging agent before and/or after surgery while the usual anticoagulant is not therapeutic, especially for
those on warfarin. A temporary inferior vena cava filter may also be appropriate in selected individuals
(See 'Timing of anticoagulant interruption' below and 'Bridging anticoagulation' below and 'Temporary
vena cava filters' below.)

● For individuals with a chronically elevated thromboembolic risk, we often use bridging anticoagulation to
minimize the period when anticoagulation is not being used. (See 'Appropriate settings for bridging'
below.)

● Individuals with a moderate thromboembolic risk generally can interrupt their anticoagulant for surgery
without bridging. The bleeding risk from bridging may outweigh any potential benefit, especially in those
with low-risk nonvalvular atrial fibrillation [27,28].

Temporary vena cava filters — Placement of a temporary inferior vena caval (IVC) filter indicated in patients
with a recent (within the prior three to four weeks) acute VTE who require interruption of anticoagulation for a
surgery or major procedure in which it is anticipated that therapeutic-dose anticoagulation will need to be
delayed for more than 12 hours postoperatively. As an example, most patients who require surgery using

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general or neuraxial anesthesia that must be performed within three to four weeks of an acute VTE would
require placement of an IVC filter. Further information about the placement of IVC filters is presented
separately. (See "Placement of vena cava filters and their complications".)

In contrast, patients who require temporary interruption of anticoagulation for a minor procedure such as
central venous catheter placement, which may be performed with omission of one dose of an anticoagulant,
would not require an IVC filter. Individuals with a VTE more than four weeks prior to the intended surgery do
not require placement of an IVC filter, and other clinical situations such as prior perioperative VTE or high-risk
thrombophilia are not routine indications for perioperative placement of an IVC filter.

Settings in which continuing the anticoagulant may be preferable — For individuals undergoing selected
surgery that confers a low risk of bleeding (eg, cataract extraction) it may be preferable for them to continue
their anticoagulant, depending on patient factors and the judgement of the treating clinician. Continuing the
anticoagulant likely reduces the risk of thromboembolism, and in some settings (eg, cardiac implantable
electronic device) it actually reduces the risk of bleeding as well. For those receiving warfarin or another
vitamin K antagonist, it is important to confirm that the INR is not above the therapeutic range at the time of
the procedure.

● Dental procedures – Dental procedures are generally considered to confer a low risk of bleeding, and
anticoagulation can be continued in most patients during these procedures. The evidence for the safety
of continuing anticoagulation comes from patients receiving warfarin with an INR in the therapeutic range
[29-35]. In the ARISTOTLE trial, which included patients anticoagulated with warfarin versus apixaban for
atrial fibrillation, perioperative bleeding rates were approximately 1 percent in patients undergoing dental
and other low bleeding risk procedures. Bleeding can be further reduced with the use of topical
hemostatic agents (eg, tranexamic acid mouthwash, used three to four times daily for one to two days)
[8,34,36-39].

An exception is multiple tooth extractions, which we consider high bleeding risk. (See 'Settings requiring
anticoagulant interruption' above.)

● Cutaneous procedures – Cutaneous procedures (eg, skin biopsy, tumor excision) are also generally
considered to confer a low risk of bleeding; the potential for local control measures further reduces
concerns about bleeding risk.

● Selected cardiac procedures – For certain cardiac procedures, there is evidence that continuing
anticoagulation is safe (and in some cases associated with better outcomes) compared with stopping and
restarting the anticoagulant.

• Cardiac implantable devices – We agree with a position document from the European Heart
Rhythm Association (EHRA) that states the majority of patients undergoing implantation of a cardiac
electronic device (eg, pacemaker, cardioverter-defibrillator) should continue their anticoagulant
perioperatively [40]. This is based on data from the BRUISE CONTROL trial, which randomly
assigned patients on warfarin undergoing implantation of a cardiac implantable electronic device to
continuation of warfarin or heparin bridging, as well as other smaller trials [41]. This trial found a
lower risk of bleeding in patients who continued warfarin. Potential explanations for the increased
bleeding in the heparin bridging arm include initiation of postprocedure bridging too early (eg, within
24 hours after the procedure) or better identification of surgical bleeding sites that could be
addressed during the procedure in patients receiving continued warfarin.

An exception is a patient with a low risk of thromboembolic events, in whom warfarin may be

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discontinued, or a patient receiving a direct oral anticoagulant, for whom temporary discontinuation is
likely to be appropriate; bridging anticoagulation is not recommended in such individuals [40]. In an
analysis of 611 patients from the RE-LY trial (dabigatran versus warfarin in atrial fibrillation) who
underwent implantable device surgery, pocket hematomas occurred at a similar frequency in those
who had interruption of dabigatran and those who had interruption of warfarin without bridging [42]. It
is not clear whether uninterrupted dabigatran would be associated with lower risks of bleeding and/or
thrombosis. (See "Cardiac implantable electronic devices: Peri-procedural complications".)

• Endovascular procedures and catheter ablation – Endovascular procedures include a variety of

venous and arterial interventions such as angioplasty, catheter ablation, and atherectomy. In a meta-
analysis of randomized trials involving over 20,000 patients undergoing these procedures,
uninterrupted warfarin therapy was associated with equivalent or lower rates of complications
compared with interruption of warfarin [43]. As an example, a benefit of warfarin continuation rather
than discontinuation with bridging was reported in the COMPARE trial, which randomly assigned
patients with atrial fibrillation undergoing catheter ablation to continued warfarin or discontinuation of
warfarin with bridging [44]. In this trial, patients randomized to continue warfarin had a lower risk of
stroke and less bleeding.

We also agree with the EHRA position document statement that all patients undergoing catheter
ablation for atrial fibrillation should receive full anticoagulation with heparin in addition to continuing
their oral anticoagulant [40].

If a decision is made to discontinue the anticoagulant (eg, patient with renal insufficiency), bridging is
reserved for those with a high-very high thromboembolic risk, and not used for those with a moderate
thromboembolic risk. (See 'Appropriate settings for bridging' below.)

TIMING OF ANTICOAGULANT INTERRUPTION — If a decision has been made to interrupt the

anticoagulant for surgery with high or moderate bleeding risk, the agent should be stopped in sufficient time to
allow anticoagulation to resolve. For some agents, laboratory testing is a reliable indicator that the
anticoagulant effect has resolved after discontinuation (eg, warfarin); for others, well-validated and easily
accessible testing is not always available (eg, direct oral anticoagulants [DOACs]). If a moderate or high
bleeding risk surgery is required urgently or immediately, reversal of the anticoagulant may also be required.
(See 'Urgent/emergency invasive procedure' below.)

Data to guide the timing of anticoagulant interruption are evolving, especially for DOACs, and much of our
practice is based on expert opinion and observational studies as we await results from ongoing trials [45].
Risks of bleeding with neuraxial anesthesia and risks of thrombosis in patients with prosthetic heart valves are
especially concerning; these issues are discussed in detail separately. (See "Neuraxial anesthesia/analgesia
techniques in the patient receiving anticoagulant or antiplatelet medication" and "Antithrombotic therapy for
prosthetic heart valves: Indications".)

Typical durations of anticoagulant interruption are illustrated by the RE-LY trial, which randomized individuals
with nonvalvular atrial fibrillation to warfarin or dabigatran for prevention of thromboembolism [9]. In this trial,
nearly half of patients treated with dabigatran had surgery within 48 hours of stopping the drug, whereas only
approximately 1 in 10 patients treated with warfarin had surgery within 48 hours of drug discontinuation. The
incidence of thromboembolism was low (<1 percent), and bleeding rates were similar for those receiving
warfarin or either dabigatran dose. (See 'Atrial fibrillation' above.)

Warfarin — Warfarin blocks a vitamin K-dependent step in clotting factor production; it impairs coagulation by
preventing synthesis of factors II (prothrombin), VII, IX, and X. Resolution of warfarin effect is determined by

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measurement of the prothrombin time (PT), which is standardized across institutions using an international
normalized ratio (INR).

● Discontinuation – If it has been determined that warfarin discontinuation is appropriate, we typically

discontinue warfarin five days before elective surgery (ie, last dose of warfarin is given on day minus 6)
and, when possible, check the PT/INR on the day before surgery [8,14,46,47]. If the INR is >1.5, we
administer low dose oral vitamin K (eg, 1 to 2 mg) to hasten normalization of the PT/INR and recheck the
following day. We proceed with surgery when the INR is ≤1.4. An INR in the normal range is especially
important in patients undergoing surgery associated with a high bleeding risk (eg, intracranial, spinal,
urologic) or if neuraxial anesthesia is to be used. (See 'Estimating procedural bleeding risk' above and
'Neuraxial anesthesia' below.)

This timing of warfarin discontinuation is based on the biological half-life of warfarin (36 to 42 hours) and
the observed time for the PT/INR to return to normal after stopping warfarin (eg, two to three days for the
INR to fall to below 2.0; four to six days to normalize) [46]. Normalization of the INR may take longer in
patients receiving higher-intensity anticoagulation (INR 2.5 to 3.5), and in elderly individuals [48]. Half-
lives of other vitamin K antagonists also differ (eg, 8 to 11 hours for acenocoumarol; approximately ten for
phenprocoumon [49]; approximately three days for fluindione). (See "Warfarin and other VKAs: Dosing
and adverse effects", section on 'Warfarin administration'.)

For a procedure that requires more rapid normalization of the INR, additional interventions may be
needed to actively reverse the anticoagulant. (See 'Urgent/emergency invasive procedure' below.)

This discontinuation schedule will produce a period of several days with subtherapeutic anticoagulation.
As an example, it is estimated that if warfarin is withheld for five days before surgery and is restarted as
soon as possible afterwards, patients would have a subtherapeutic INR for approximately eight days (four
days before and four days after surgery) [14]. Thus, for patients at very high or high thromboembolic risk,
bridging may be appropriate.

● Use of bridging preoperatively – We generally reserve bridging for individuals considered at very high
or high risk of thromboembolism (eg, recent stroke, mechanical heart valve, CHA2DS2-VASc score of 7 or
8 (table 4) (calculator 1), CHADS2 score of 5 or 6) if they require interruption of warfarin. In these cases,
the bridging agent (eg, therapeutic dose subcutaneous low molecular weight [LMW] heparin) is started
three days before surgery. (See 'Bridging anticoagulation' below.)

A bridging agent may also be appropriate if there is a prolonged period during which the patient cannot
take oral medications (eg, postoperative ileus).

● Restarting warfarin and postoperative bridging – We resume warfarin 12 to 24 hours after surgery,
typically the evening of the day of surgery or the evening of the day after surgery, assuming there were
no unexpected surgical issues that would increase bleeding risk and the patient is taking adequate oral
fluids [8]. We use the same dose the patient was receiving preoperatively.

After warfarin is restarted in the perioperative setting, it takes 5 to 10 days to attain a full anticoagulant
effect as measured by an INR above 2.0. Thus, we generally treat individuals at very high risk and some
individuals with a high risk of thromboembolism with a heparin bridging agent during this period. (See
'Bridging anticoagulation' below.)

Dabigatran — Dabigatran is a direct thrombin inhibitor; it reversibly blocks the enzymatic function of thrombin
in converting fibrinogen to fibrin (factor IIa).

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● Discontinuation – Dabigatran can be discontinued two to three days before a surgical procedure in
patients with normal or mildly impaired renal function (ie, creatinine clearance >50 mL/minute), and two
to four days before the procedure in those with more severe renal insufficiency (eg, creatinine clearance
between 30 and 50 mL/minute), with the longer intervals used for higher bleeding risk procedures and
the shorter interval for surgeries with less bleeding risk.

As an example, in a patient on dabigatran with a creatinine clearance >50 mL/min undergoing a high
bleeding risk procedure, the patient will skip four doses of dabigatran (no drug on surgical day minus 2
and day minus 1) and no drug on the day of surgery (table 2). In dabigatran-treated patients with a
creatinine clearance 30 to 50 mL/min undergoing a high bleeding risk procedure such as neuraxial
anesthesia, a longer interval for interruption is required. (See 'Neuraxial anesthesia' below.)

The last preoperative day on which dabigatran is administered can be more closely estimated based on
the elimination half-life of dabigatran, which varies according to renal function (eg, 12 to 14 hours in
patients with normal renal function) [2,50-53]. A protocol incorporating bleeding risk and creatinine
clearance was tested in a prospective cohort of 541 dabigatran-treated patients undergoing surgery and
was found to be effective in minimizing bleeding and thrombotic complications [53].

Unlike the PT/INR for warfarin, routine coagulation tests have not been validated for ensuring that
dabigatran effect has resolved. A normal or near-normal aPTT may be used in selected patients to
evaluate whether dabigatran has been adequately cleared from the circulation prior to surgery (eg,
patients at high risk of surgical bleeding) (table 7). Importantly, the reliability of aPTT testing may depend
on the specific assay used; if available, a diluted plasma thrombin time may be preferable [51,54,55].
(See "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects",
section on 'Dabigatran' and "Clinical use of coagulation tests".)

● Use of bridging – In general, the rapid offset and onset of dabigatran activity obviates the need for
bridging anticoagulation. We reserve bridging anticoagulation for selected individuals who are at very
high risk for postoperative thromboembolism and require extended interruption of dabigatran. Examples
include postoperative bridging in patients who are unable to take oral medications postoperatively due to
intestinal ileus from gastrointestinal surgery. (See 'Bridging anticoagulation' below.)

● Restarting dabigatran – Dabigatran should be resumed postoperatively when hemostasis has been
achieved, at the same dose the patient was receiving preoperatively. Since dabigatran has a rapid onset
of action, with peak effects occurring two to three hours after intake, caution should be used in patients
who have had major surgery or other procedures associated with a high bleeding risk.

We often delay resumption of dabigatran for two to three days after high bleeding risk procedures and, if
needed, administer a lower dabigatran dose for the initial two to three postoperative days (eg, 110 mg
once daily) or use prophylactic dose LMW heparin for this period. We generally restart dabigatran one
day after low bleeding risk surgery (if it was interrupted) and two to three days after high bleeding risk
surgery.

Rivaroxaban — Rivaroxaban is a direct factor Xa inhibitor; it reversibly blocks the enzymatic function of
factor Xa in converting prothrombin to thrombin.

● Discontinuation – Rivaroxaban can be discontinued approximately two to three days before a

procedure, with the longer interval for higher bleeding risk procedures and the shorter interval for lower
bleeding risk procedures (table 2). Thus, for high bleeding risk procedures, the patient will skip two doses
of rivaroxaban, and not receive any doses on surgical days minus 2, minus 1, or the day of surgery.

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These intervals are based on an elimination half-life of 7 to 11 hours and apply to individuals with normal
renal function or mild renal insufficiency (eg, creatinine clearance >50 mL/minute), who are likely to be
receiving the 20 mg once daily dose; and to those with moderate renal insufficiency (eg, creatinine
clearance between 30 and 50 mL/minute), who are likely to be receiving the 15 mg once daily dose.

Longer intervals for interruption may be required for situations in which the bleeding risk is very high,
such as neuraxial anesthesia. (See 'Neuraxial anesthesia' below.)

Rivaroxaban interacts with dual inhibitors of CYP-3A4 and P-glycoprotein (eg, systemic ketoconazole,
ritonavir); dose adjustment or substitution of heparin may be appropriate if these dual CYP-3A4 and
P-glycoprotein inhibitors are used perioperatively. Interactions with drugs that inhibit only one of these
enzymes do not seem to alter rivaroxaban anticoagulant effect.

Unlike the PT/INR for warfarin, routine coagulation tests have not been validated for ensuring that the
rivaroxaban anticoagulant effect has resolved. A normal or near-normal anti-factor Xa activity level may
be used in selected patients to evaluate whether rivaroxaban has been adequately cleared from the
circulation prior to surgery (eg, patients at high risk of surgical bleeding) (table 7) [2]. Of note, the
reliability of anti-factor Xa activity testing may depend on the specific assay used, and clinicians are
advised to speak with their clinical laboratory to determine whether this assay is available at their
institution and whether it has been validated for direct factor Xa inhibitors.

● Use of bridging – In general, the rapid offset and onset of rivaroxaban obviates the need for bridging
anticoagulation. In rare cases bridging may be required, such as the use of postoperative bridging in
individuals who have a very high thromboembolic risk and are unable to take oral medications
postoperatively due to intestinal ileus from gastrointestinal surgery. (See 'Bridging anticoagulation'
below.)

● Restarting rivaroxaban – Rivaroxaban can be resumed postoperatively when hemostasis has been
achieved, at the same dose the patient was receiving preoperatively. Since rivaroxaban has a rapid onset
of action, caution should be used in patients who have had major surgery or other procedures associated
with a high bleeding risk.

We often delay rivaroxaban for two to three days after high bleeding risk procedures and, if needed, use
prophylactic dose LMW heparin for this period. We generally restart rivaroxaban one day after low
bleeding risk surgery (if it was interrupted) and two to three days after high bleeding risk surgery.

Apixaban — Apixaban is a direct factor Xa inhibitor; it reversibly blocks the enzymatic function of factor Xa in
converting prothrombin to thrombin.

● Discontinuation – Apixaban can be discontinued approximately two to three days before a procedure,
with the longer interval for higher bleeding risk procedures and the shorter interval for lower bleeding risk
procedures (table 2). Thus, for high bleeding risk procedures, the patient will skip four doses of apixaban,
and not receive any doses on surgical days minus 2, minus 1, or the day of surgery. These intervals are
based on an apixaban elimination half-life of 8 to 12 hours. These intervals apply to individuals with
normal renal function or mild renal insufficiency (eg, creatinine clearance >50 mL/minute), who are likely
to be receiving the 5 mg twice daily dose; and to those with moderate to severe renal insufficiency (eg,
creatinine clearance between 30 and 50 mL/minute), who are likely to be receiving the 2.5 mg twice daily
dose.

Longer intervals for interruption may be required for situations in which the bleeding risk is very high,

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such as neuraxial anesthesia. (See 'Neuraxial anesthesia' below.)

Unlike the PT/INR for warfarin, routine coagulation tests have not been validated for ensuring that
apixaban effect has resolved. A normal or near-normal anti-factor Xa activity level may be used in
selected patients to evaluate whether apixaban has been adequately cleared from the circulation prior to
surgery (eg, patients at high risk of surgical bleeding) (table 7). Of note, the reliability of anti-factor Xa
activity testing may depend on the specific assay used, and clinicians are advised to speak with their
clinical laboratory to determine whether this assay is available at their institution and whether it has been
validated for direct factor Xa inhibitors.

● Use of bridging – In general, the rapid offset and onset of apixaban obviates the need for bridging
anticoagulation. In rare cases, bridging may be required, such as the use of postoperative bridging in
individuals who have a very high thromboembolic risk and are unable to take oral medications
postoperatively due to intestinal ileus from gastrointestinal surgery. (See 'Bridging anticoagulation'
below.)

● Restarting apixaban – Apixaban can be resumed postoperatively when hemostasis has been achieved,
at the same dose the patient was receiving preoperatively. Since apixaban has a rapid onset of action,
caution should be used in patients who have had major surgery or other procedures associated with a
high bleeding risk.

We often delay apixaban for two to three days after high bleeding risk procedures, and if needed use
prophylactic dose LMW heparin for this period. We generally restart apixaban one day after low bleeding
risk surgery (if it was interrupted).

Edoxaban — Edoxaban is a direct factor Xa inhibitor; it reversibly blocks the enzymatic function of factor Xa
in converting prothrombin to thrombin.

● Discontinuation – Edoxaban can be discontinued approximately two to three days before a procedure,
with the longer interval for higher bleeding risk procedures and the shorter interval for lower bleeding risk
procedures (table 2). Thus, for high bleeding risk procedures, the patient will skip two doses of edoxaban,
and not receive any doses on surgical days minus 2, minus 1, or the day of surgery. These intervals are
based on an edoxaban elimination half-life of 10 to 14 hours. These intervals apply to individuals with
normal renal function or mild renal insufficiency (eg, creatinine clearance >50 mL/minute) and those with
moderate renal insufficiency (eg, creatinine clearance between 30 and 50 mL/minute), who are likely to
be receiving the 60 mg once daily or the 30 mg once daily doses, respectively.

Longer intervals for interruption may be considered for those undergoing major surgery, neuraxial
anesthesia or manipulation, or other situations in which complete hemostatic function may be required.
(See 'Neuraxial anesthesia' below.)

Unlike the PT/INR for warfarin, routine coagulation tests have not been validated for ensuring that
edoxaban effect has resolved. A normal or near-normal anti-factor Xa activity level may be used in
selected patients to evaluate whether edoxaban has been adequately cleared from the circulation prior to
surgery (eg, patients at high risk of surgical bleeding) (table 7). Of note, the reliability of anti-factor Xa
activity testing may depend on the specific assay used, and clinicians are advised to speak with their
clinical laboratory to determine whether this assay is available at their institution and whether it has been
validated for direct factor Xa inhibitors.

● Use of bridging – In general, the rapid offset and onset of edoxaban obviates the need for bridging

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anticoagulation. In rare cases, bridging may be required, such as the use of postoperative bridging in
individuals who have a very high thromboembolic risk and are unable to take oral medications
postoperatively due to intestinal ileus from gastrointestinal surgery. (See 'Bridging anticoagulation'
below.)

● Restarting edoxaban – Edoxaban can be resumed postoperatively when hemostasis has been
achieved, at the same dose the patient was receiving preoperatively. Since edoxaban has a rapid onset
of action, caution should be used in patients who have had major surgery or other procedures associated
with a high bleeding risk.

We often delay edoxaban for two to three days after high bleeding risk procedures, and if needed use
prophylactic dose LMW heparin for this period. We generally restart edoxaban one day after low bleeding
risk surgery (if it was interrupted).

BRIDGING ANTICOAGULATION — Bridging anticoagulation involves the administration of a short-acting

anticoagulant, typically a low molecular weight (LMW) heparin, during the interruption of a longer-acting
agent, typically warfarin. There are no data on using the newer direct oral anticoagulants (eg, direct thrombin
inhibitors, direct factor Xa inhibitors) as bridging agents; further, the direct factor Xa inhibitor agents lack a
specific reversal strategy should bleeding occur. Thus, we use LMW heparin or unfractionated heparin when
bridging is required. (See 'Heparin product and dose' below.)

Appropriate settings for bridging

Whether to use bridging — The intent of bridging is to minimize the time the patient is not
anticoagulated, thereby minimizing the risk for perioperative thromboembolism. However, this needs to be
balanced with the importance of mitigating the risk of postoperative bleeding. A slight delay in resumption of
postoperative anticoagulation is preferable to premature initiation of postoperative bridging that results in
bleeding, which ultimately will lengthen the period without an anticoagulant and thus increase thromboembolic
risk.

The clinician needs to decide whether bridging is appropriate and, if so, whether the benefit applies
preoperatively, postoperatively, or both.

Bridging anticoagulation may be appropriate in patients who will have a very high thromboembolic risk with
prolonged interruption of their anticoagulant (generally a vitamin K antagonist [VKA]). Individual patient
comorbidities that increase bleeding risk may also need to be considered because an increased
postoperative bleeding risk may be a reason to avoid bridging. We suggest the use of bridging in individuals
taking warfarin for one of the following conditions [1]:

● Embolic stroke or systemic embolic event within the previous three months

● Mechanical mitral valve (see "Antithrombotic therapy for prosthetic heart valves: Management of bleeding
and invasive procedures", section on 'Our approach')

● Mechanical aortic valve and additional stroke risk factors (see "Antithrombotic therapy for prosthetic heart
valves: Management of bleeding and invasive procedures", section on 'Our approach')

● Atrial fibrillation and very high risk of stroke (eg, CHADS2 score of 5 or 6, stroke or systemic embolism
within the previous 12 weeks)

● Venous thromboembolism (VTE) within the previous three months (preoperative and postoperative

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bridging) (see 'When to bridge: Preoperative, postoperative, or both' below)

● Recent coronary stenting (eg, within the previous 12 weeks) (see "Periprocedural management of
antithrombotic therapy in patients receiving long-term oral anticoagulation undergoing percutaneous
coronary intervention")

● Previous thromboembolism during interruption of chronic anticoagulation

For most other patients on warfarin with atrial fibrillation (ie, for most individuals not included in the list of
examples above), we suggest not using bridging anticoagulation. We feel more strongly about avoiding
bridging the lower the patient’s baseline thromboembolic risk (eg, lower CHADS2 or CHA2DS2-VASc score
(table 8)) and the higher the risk of bleeding. This practice is supported by the BRIDGE trial (Bridging
Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive
Procedure or Surgery), which randomly assigned 1884 patients with atrial fibrillation who required interruption
of warfarin for an invasive procedure to receive bridging anticoagulation with the LMW heparin dalteparin
versus placebo [56]. The incidence of arterial thromboembolic events 30 days after the procedure was similar
in those who received dalteparin or placebo (0.3 versus 0.4 percent). The incidence of major bleeding (a
secondary outcome) was higher in those who received dalteparin (3.2 versus 1.3 percent), although none of
the bleeds were fatal. Patients were excluded from the trial if they had a mechanical heart valve, or a recent
(within previous 12 weeks) stroke, embolism, or transient ischemic attack.

Results of a randomized trial comparing postoperative bridging versus no bridging in patients with a
mechanical heart valve (PERIOP-2), where all patients receive preoperative bridging, are eagerly awaited
[6,57].

Additional evidence to support our practice comes from a systematic review and meta-analysis of 34 studies
in patients undergoing elective surgery or procedures [58]. All of the studies were observational except for
one randomized trial in patients undergoing dental extraction. Bridging was used in 7118 patients; most
received LMW heparin, at several dose levels. The large range of heparin doses and inclusion of procedures
with varied bleeding risks led to a high degree of heterogeneity. There was no significant difference in the rate
of thromboembolism in patients who received bridging compared with patients who did not (odds ratio [OR]:
0.80; 95% CI 0.42-1.54). Bridging was associated with a threefold increase in major bleeding compared with
no bridging (OR: 3.60; 95% CI 1.52-8.50); full-dose heparin was associated with an increase in overall
bleeding compared with lower heparin doses (OR: 2.28; 95% CI 1.27-4.08) (see 'Heparin product and dose'
below). Bridging versus no bridging did not affect major outcomes in patients who required a major procedure
during participation in large anticoagulation trials for atrial fibrillation, including the RE-LY (warfarin versus
dabigatran), ROCKET-AF (warfarin versus rivaroxaban), and ARISTOTLE (warfarin versus apixaban) trials
[9-11]. In the RE-LY trial patients receiving warfarin had more thromboembolic events associated with bridging
than with non-use of bridging (1.8 versus 0.3 percent); patients who received bridging also had a higher risk
of major bleeding (warfarin: 6.8 percent with bridging, 1.6 percent without; dabigatran: 6.5 percent with
bridging, 1.8 percent without) [59].

Additional "real world" data comes from the ORBIT-AF and Dresden registries. ORBIT-AF (Outcomes
Registry for Better Informed Treatment of Atrial Fibrillation) is a community-based registry of outpatients with
atrial fibrillation receiving any oral anticoagulant; in this study, 2200 of 7372 individuals (30 percent) had
interruption of anticoagulation for a procedure [60]. Bridging was used in 24 percent of these interruptions,
especially in patients with a history of stroke or a mechanical heart valve and/or receiving warfarin; bleeding
events were more common in individuals who received bridging compared with those who did not receive
bridging (5.0 versus 1.3 percent). A composite endpoint that included major bleeding, myocardial infarction,

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stroke, systemic embolism, hospitalization, or death within 30 days was also higher in those who received
bridging (13 versus 6.3 percent). In the Dresden NOAC registry, over 800 patients who were receiving
dabigatran, rivaroxaban, or apixaban for any indication and underwent an invasive procedure had similar
rates of major cardiovascular events if they received bridging, no bridging, or no anticoagulant discontinuation
[61]. Bridging was not an independent risk factor for major bleeding; however, individuals undergoing major
procedures were more likely to receive bridging and to have major bleeding.

A potential role for bridging in reducing the risk of "rebound hypercoagulability" has also been proposed;
however, this premise is not supported by data from the BRIDGE trial discussed above [56].

Of note, management of perioperative anticoagulation in patients with mechanical heart valves is discussed in
detail separately. (See "Antithrombotic therapy for prosthetic heart valves: Management of bleeding and
invasive procedures", section on 'Management of antithrombotic therapy for invasive procedures'.)

Bridging is generally not used for the shorter-acting direct oral thrombin inhibitors or factor Xa inhibitors.
However, bridging may be appropriate for individuals on these agents who have a very high thromboembolic
risk and a more prolonged interruption of their anticoagulant (eg, due to postoperative intestinal ileus that
prevents oral intake). (See 'Dabigatran' above and 'Rivaroxaban' above and 'Apixaban' above and 'Edoxaban'
above.)

When to bridge: Preoperative, postoperative, or both — Once a decision to use bridging has been
made, the next decision is whether to use bridging before the procedure, after the procedure, or both (table
9).

● Atrial fibrillation – As noted above, we suggest not using bridging for most patients with atrial fibrillation.
(See 'Whether to use bridging' above.)

However, for those for individuals for whom bridging is used due to a very high risk of thromboembolism,
we use bridging both preoperatively and postoperatively [14]. Warfarin is usually resumed 12 to 24 hours
after surgery, typically the evening of the day of surgery or the evening of the day after surgery, as long
as adequate hemostasis has been achieved. (See 'Warfarin' above.)

● Venous thromboembolism

• First three months – For individuals within the first three months after an acute episode of VTE, we
use bridging both preoperatively and postoperatively, typically with therapeutic-dose LMW heparin
(eg, enoxaparin 1 mg/kg twice daily) [14]. This practice is based on the high incidence of recurrence
without anticoagulation. While postoperative intravenous heparin doubles the rate of bleeding, there
is a net reduction in serious morbidity in such patients because the risk of postoperative recurrent
VTE is high (see 'Preoperative timing of bridging' below and 'Postoperative timing of bridging' below)
In selected patients in whom surgery cannot be delayed beyond the first month after the diagnosis of
an acute VTE, it may be appropriate to use a temporary inferior vena cava (IVC) filter, especially if
bridging anticoagulation cannot be used postoperatively due to high bleeding risk. (See "Overview of
the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Patients with
contraindications to anticoagulation' and "Treatment, prognosis, and follow-up of acute pulmonary
embolism in adults", section on 'Inferior vena cava filters'.)

• Greater than three months – For individuals greater than three months after an acute episode of
VTE, we generally use postoperative bridging, typically with a low dose LMW heparin regimen (eg,
enoxaparin 40 mg daily), but not preoperative bridging [62]. For patients who are undergoing a minor

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procedure or day surgery, bridging is probably not justified. This practice is based on the significantly
reduced risk of VTE recurrence after the first month [63,64]. (See 'Postoperative timing of bridging'
below.)

Heparin product and dose — Two types of heparin products are available: LMW heparins and
unfractionated heparin. LMW heparins have similar efficacy compared with unfractionated heparin, are more
convenient to use, and generally do not require monitoring. Intravenous unfractionated heparin is less costly
and can be reversed more rapidly than subcutaneous LMW heparin; it may be a reasonable alternative in
some individuals.

● We prefer LMW heparin for bridging anticoagulation in individuals with a very high risk of arterial
thromboembolism (eg, rheumatic heart disease, atrial fibrillation with recent embolic stroke, high-risk
mechanical heart valve) and those with a moderate risk of thromboembolism (eg, active cancer)
[27,28,65].

Perioperative anticoagulation management in individuals with prosthetic heart valves is discussed in

detail separately. (See "Antithrombotic therapy for prosthetic heart valves: Management of bleeding and
invasive procedures", section on 'Management of antithrombotic therapy for invasive procedures'.)

● For individuals with renal insufficiency and/or those requiring hemodialysis, intravenous or subcutaneous
unfractionated heparin can be used more easily because dosing is unaffected by renal clearance [66].
(See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Dosing'.)

We do not use any of the newer direct oral anticoagulants (eg, dabigatran, rivaroxaban, apixaban, edoxaban)
for bridging, as there are no data on the safety or efficacy of these agents for perioperative bridging.

Heparins can be dosed at prophylactic doses, therapeutic doses, or doses intermediate between the two. Of
note, the term "therapeutic dose" refers to doses typically used for treatment of thromboembolic disease,
despite the fact that in this case it is being used prophylactically (ie, to prevent thromboembolism). There are
no clinical trial data or practice standards to guide dosing, and clinical judgment is required to determine the
appropriate dose for each patient [58,67,68].

● Therapeutic dosing – Therapeutic dosing (also called "full dose") is appropriate for bridging
anticoagulation for individuals with a potential arterial thromboembolic source (eg, atrial fibrillation,
mechanical heart valve) or VTE within the preceding month. Typical regimens include enoxaparin, 1
mg/kg subcutaneously twice daily or dalteparin, 100 units /kg subcutaneously twice daily.

● Intermediate dosing – Intermediate dose anticoagulation may be appropriate for individuals with atrial
fibrillation or VTE within the preceding month when bridging is needed but concerns about bleeding are
greater. Typical regimens include enoxaparin, 40 mg twice daily, or dalteparin, 5000 units subcutaneously
twice daily.

● Prophylactic dosing – Prophylactic dose anticoagulation (also called "low dose") generally is not used
for bridging in patients with atrial fibrillation, because there is no evidence that prophylactic dose heparin
prevents stroke in this setting. This dose level may be reasonable in patients who have had a VTE event
between within the preceding 3 to 12 months. Typical prophylactic regimens include enoxaparin, 40 mg
once daily, or dalteparin 5000 units subcutaneously once daily.

The use of prophylactic dose heparin for postoperative VTE prevention in patients not receiving ongoing
anticoagulation is discussed separately. (See "Prevention of venous thromboembolic disease in adult
nonorthopedic surgical patients".)

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Additional details regarding heparin products, including dose adjustments for obesity and renal impairment
are provided separately. (See "Heparin and LMW heparin: Dosing and adverse effects".)

Timing of bridging

Preoperative timing of bridging — We generally initiate heparin bridging three days before a planned
procedure (ie, two days after stopping warfarin), when the PT/INR has started to drop below the therapeutic
range.

● LMW heparin – We discontinue LMW heparin 24 hours before the planned surgery or procedure, based
on a biologic half-life of most subcutaneous LMW heparins of approximately three to five hours [8,65,69].
If a twice-daily LMW heparin regimen is given, the evening dose the night before surgery is omitted,
whereas if a once-daily regimen is given (eg, dalteparin 200 international units/kg), one-half of the total
daily dose is given on the morning of the day before surgery. This ensures that no significant residual
anticoagulant will be present at the time of surgery, based on studies that have shown a residual
anticoagulant effect at 24 hours after stopping therapeutic-dose LMW heparin, and it is consistent with
the 2012 ACCP Guidelines [8,12,70,71].

● Unfractionated heparin – For therapeutic dose unfractionated heparin, we continue the intravenous
infusion until four to five hours before the procedure, based on the biologic half-life of intravenous
unfractionated heparin of approximately 45 minutes [8,69,70]. If subcutaneous unfractionated heparin is
used, typically with a dose of approximately 250 international units/kg twice daily, the last dose can be
given the evening before the procedure.

Postoperative timing of bridging — Postoperative resumption of unfractionated heparin and LMW

heparin is similar, based on the onset of anticoagulation at approximately one hour after administration for
both forms of heparin, and peak anticoagulant activity at approximately three to five hours.

● The resumption of bridging, especially when given as a therapeutic-dose regimen, should be delayed
until there is adequate hemostasis based on a clinical assessment of the wound site, drainage fluid
amount, and expected postoperative bleeding; coupled, where appropriate, with hemoglobin levels [72].
This assessment will vary depending on the surgery type and individual patient considerations, and it
may be difficult for surgery where ongoing bleeding is not readily apparent (eg, cardiac, intracranial).

● For those undergoing major surgery or those with a high bleeding risk procedure, therapeutic-dose
unfractionated heparin or LMW heparin should be delayed for 48 to 72 hours after hemostasis has been
secured [8].

● For most minor procedures associated with a low bleeding risk in which bridging is used (eg,
laparoscopic hernia repair), therapeutic-dose unfractionated heparin or LMW heparin can usually be
resumed 24 hours after the procedure.

Resumption of bridging anticoagulation too early, especially the use of therapeutic dose heparin within 24
hours after surgery, is associated with a two- to fourfold increased risk for major bleeding compared with no
bridging or prophylactic dose heparin. The increased bleeding risk was demonstrated in the Prospective peri-
operative enoxaparin cohort trial (PROSPECT), which evaluated bleeding risk in a cohort of 260 patients
undergoing major surgery whose treating physicians used bridging anticoagulation [73]. In this trial, nine
patients had major postoperative bleeding (3.5 percent), most on postoperative day 0, and 19 (7.3 percent)
had minor bleeding.

Postoperatively, warfarin is generally resumed on the same postoperative day as the heparin. Heparin can be

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discontinued when the INR reaches the therapeutic range for individuals at moderate thromboembolism risk.

Individuals with heparin-induced thrombocytopenia — Heparin-induced thrombocytopenia (HIT) is a

potentially life-threatening condition in which heparin-induced antibodies to platelets can cause
thrombocytopenia and/or venous or arterial thrombosis. (See "Clinical presentation and diagnosis of heparin-
induced thrombocytopenia".)

Patients with HIT should not receive any heparin (eg, they should not receive heparin flushes, unfractionated
heparin, or LMW heparin). Non-heparin anticoagulants that can be used in patients with HIT are discussed
separately. (See "Management of heparin-induced thrombocytopenia", section on 'Anticoagulation'.)

URGENT/EMERGENCY INVASIVE PROCEDURE — Reversal of the patient's usual anticoagulant may be

required for more urgent or emergency surgery or procedures, or to treat perioperative bleeding. Agents with
a potential prothrombotic effect (eg, prothrombin complex concentrates [PCCs], plasma products, immediate
reversal agents) should be reserved for the treatment of severe, life-threatening bleeding or anticipated
severe bleeding (eg, intracranial hemorrhage, emergency major surgery with elevated prothrombin
time/international normalized ratio [PT/INR]). Agent-specific strategies include the following:

● Warfarin – For individuals who require reversal of warfarin or other vitamin K antagonists, the appropriate
reversal strategy is determined by the degree of anticoagulation (eg, PT/INR, clinical bleeding), urgency
of the procedure, and degree of bleeding risk (table 10).

• If semi-urgent reversal of warfarin is required (eg, within one to two days), warfarin should be
withheld and vitamin K administered (eg, 2.5 to 5.0 mg of oral or intravenous vitamin K). (See
"Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Urgent
surgery/procedure'.)

• If immediate reversal is required (eg, for emergency surgery or active bleeding), this can be
achieved via the use of prothrombin complex concentrates (PCCs) or plasma products (eg, Fresh
Frozen Plasma [FFP]; Plasma Frozen Within 24 Hours After Phlebotomy [PF24]) along with vitamin
K (table 11) [74,75]. The 4-factor PCCs contain adequate amounts of all vitamin K-dependent
clotting factors, whereas 3-factor PCCs may require supplementation with FFP for adequate factor
VII (table 12). Of note, there is a thrombotic risk associated with these products, and they should be
used only if there is life-threatening bleeding and prolongation of the INR by a vitamin K antagonist
[75]. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on
'Serious/life-threatening bleeding'.)

● Dabigatran – Dabigatran is an oral direct thrombin inhibitor; it can be reversed by idarucizumab (table
13). In an open-label study involving 503 patients who had bleeding or required emergency surgery,
idarucizumab effectively reversed the anticoagulant effect of dabigatran [76]. The use of this agent as
well as other potential strategies for individuals receiving dabigatran who are at great risk of serious
bleeding with an emergency procedure are presented separately. (See "Management of bleeding in
patients receiving direct oral anticoagulants".)

● Rivaroxaban, apixaban, and edoxaban – Rivaroxaban, apixaban, and edoxaban are oral direct factor Xa
inhibitors; these anticoagulants can be reversed by andexanet alfa, approved in May of 2018. PCCs have
been used in cases of potentially life-threatening bleeding, but this is not based on high-quality evidence
(table 13). These and other potential strategies for individuals receiving these agents who are at great
risk of serious bleeding with an urgent/emergency procedure are presented separately. (See
"Management of bleeding in patients receiving direct oral anticoagulants".)

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Algorithms for anticoagulant reversal depending on the severity of bleeding are provided by various societies
and groups such as Thrombosis Canada.

Additional discussions of postoperative bleeding are presented separately. (See "Postoperative complications
among patients undergoing cardiac surgery", section on 'Hematologic dysfunction'.)

NEURAXIAL ANESTHESIA — Neuraxial (ie, spinal or epidural) anesthesia should not be used in
anticoagulated individuals, due to the risk of potentially catastrophic bleeding into the epidural space. The
increased risk of bleeding applies both at the time of catheter placement and the time of removal.

If neuraxial anesthesia is considered for surgical anesthesia or postoperative pain control, the timing of
anesthesia and anticoagulant administration should be coordinated to optimize the safe use of both. Early
consultation with the anesthesiologist is advised. This subject is discussed in detail separately. (See
"Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication".)

The timing of anticoagulant use in patients receiving neuraxial anesthesia is illustrated by evidence-based
guidelines from the American Society of Regional Anesthesia (ASRA), which suggest the following [77,78]:

● Prophylactic dose LMW heparin (eg, enoxaparin 40 mg once daily):

• Before surgery, wait at least 10 to 12 hours after the last dose of LMW heparin is administered
before a spinal/epidural catheter is placed.

• After surgery, when there is adequate surgical site hemostasis, wait at least six to eight hours after
catheter removal before resuming treatment with LMW heparins.

● Therapeutic dose LMW heparin (eg, enoxaparin, 1 mg/kg twice daily):

• Before surgery, wait at least 24 hours after the last dose of LMW heparin is administered before a
spinal/epidural catheter is placed.

• After surgery, when there is adequate surgical site hemostasis, for twice daily dosing, wait at least 24
hours after catheter removal before resuming therapeutic-dose LMW heparin. For once daily dosing,
wait at least six to eight hours after catheter removal before the first dose; the second postoperative
dose should occur no sooner than 24 hours after the first dose.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links:
Anticoagulation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics"
and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)

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● Basics topics (see "Patient education: Anti-clotting medicines: Direct oral anticoagulants (The Basics)"
and "Patient education: Anti-clotting medicines: Warfarin (Coumadin) (The Basics)")

● Beyond the Basics topics (see "Patient education: Warfarin (Coumadin) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Interruption of anticoagulation temporarily increases thromboembolic risk, and continuing anticoagulation

increases the risk of bleeding associated with invasive procedures; both of these outcomes adversely
affect mortality. We take into account these risks, along with specific features of the anticoagulant the
patient is taking. Case examples are provided above. (See 'Overview of our approach' above.)

● Thromboembolic risk – Those at very high or high thromboembolic risk should limit the period without
anticoagulation to the shortest possible interval. The major factors that increase thromboembolic risk are
atrial fibrillation, prosthetic heart valves, and recent venous or arterial thromboembolism (eg, within the
preceding three months) (table 1). If thromboembolic risk is transiently increased (eg, recent stroke,
recent pulmonary embolism), we prefer to delay surgery until the risk returns to baseline, if possible. (See
'Estimating thromboembolic risk' above.)

• Atrial fibrillation – In the RE-LY trial, the perioperative thromboembolic risk was 1.2 percent based
on a composite endpoint of stroke, cardiovascular death, and pulmonary embolus. We estimate
thromboembolic risk for patients with atrial fibrillation based on clinical variables including age and
comorbidities. (See 'Atrial fibrillation' above and "Atrial fibrillation: Anticoagulant therapy to prevent
embolization".)

• Prosthetic heart valve – The risks of thromboembolism and perioperative management of patients
with bioprosthetic and mechanical heart valves are discussed separately. (See "Antithrombotic
therapy for prosthetic heart valves: Management of bleeding and invasive procedures", section on
'Management of antithrombotic therapy for invasive procedures' and "Diagnosis of mechanical
prosthetic valve thrombosis or obstruction".)

• Recent thromboembolism – The perioperative risk of venous thromboembolism (VTE) is greatest

in individuals with an event within the prior three months, and those with a history of VTE associated
with a high-risk inherited thrombophilia. Patients who require surgery within the first three months
following an episode of VTE are likely to benefit from delaying elective surgery, even if the delay is
only for a few weeks. The risk of recurrent arterial embolism from any cardiac source is
approximately 0.5 percent per day in the first month after an acute event. (See 'Recent
thromboembolism' above.)

● Bleeding risk – A higher bleeding risk confers a greater need for perioperative hemostasis, and hence a
longer period of anticoagulant interruption. Bleeding risk is dominated by the type and urgency of surgery
(table 3); some patient comorbidities (eg, older age, decreased renal function) and medications that
affect hemostasis also contribute. (See 'Estimating procedural bleeding risk' above and 'Deciding whether
to interrupt anticoagulation' above.)

• High risk – High bleeding risk procedures include coronary artery bypass surgery, kidney biopsy,
and any procedure lasting >45 minutes. In general, the anticoagulant must be discontinued if the
surgical bleeding risk is high. (See 'Settings requiring anticoagulant interruption' above.)

• Low risk – Low bleeding risk procedures include dental extractions, minor skin surgery,
cholecystectomy, carpal tunnel repair, and abdominal hysterectomy. Individuals undergoing selected

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low bleeding risk surgery often can continue their anticoagulant. (See 'Settings in which continuing
the anticoagulant may be preferable' above.)

• Cardiac implantable device or catheter ablation for atrial fibrillation – Continuing warfarin was
associated with a lower risk of bleeding in patients on the BRUISE CONTROL trial who were
undergoing implantation of a cardiac implantable electronic device (eg, pacemaker, implantable
cardioverter-defibrillator) and patients on the COMPARE trial who were undergoing catheter ablation
for atrial fibrillation. (See 'Overview of whether to interrupt' above and "Cardiac implantable
electronic devices: Peri-procedural complications".)

● Timing of interruption – If a decision has been made to interrupt the anticoagulant, the timing of
discontinuation and reinitiation depends on the specific agent used (table 2). (See 'Timing of
anticoagulant interruption' above and 'Warfarin' above and 'Dabigatran' above and 'Rivaroxaban' above
and 'Apixaban' above and 'Edoxaban' above.)

● Bridging – Bridging anticoagulation involves the administration of a short-acting anticoagulant, typically a

low molecular weight (LMW) heparin, during the interruption of a longer-acting agent, typically warfarin.
The intent is to minimize the risk of perioperative thromboembolism.

For selected patients on warfarin (eg, mechanical mitral valve; stroke, systemic embolism, or transient
ischemic attack within the previous 12 weeks; mechanical aortic valve and additional stroke risk factors;
atrial fibrillation and very high risk of stroke [eg, CHADS2 score of 5 or 6]; venous thromboembolism
within the previous 12 weeks; recent coronary stenting; previous thromboembolism during interruption of
chronic anticoagulation), we suggest the use of bridging (Grade 2C).

For most other patients on warfarin with atrial fibrillation or VTE, we suggest not using bridging (Grade
2B). We feel more strongly about avoiding bridging the lower the baseline thromboembolic risk and the
higher the bleeding risk.

In contrast to individuals on warfarin, bridging usually is not required for individuals receiving a direct
thrombin inhibitor or factor Xa inhibitor, because these agents have shorter half-lives (table 2). (See
'Appropriate settings for bridging' above.)

• Agent – When bridging is used, we prefer LMW heparin for most patients. An exception is an
individual with renal insufficiency and/or hemodialysis requirement, for whom intravenous or
subcutaneous unfractionated heparin can be used more easily. We do not use dabigatran,
rivaroxaban, apixaban, or edoxaban for bridging. Non-heparin anticoagulants that can be used in
patients with heparin-induced thrombocytopenia are discussed separately. (See 'Heparin product
and dose' above.)

• Timing – Bridging can be used preoperatively, postoperatively, or both, depending on the underlying
condition for which the patient is being anticoagulated (table 9). The timing depends on the heparin
product used and the procedural bleeding risk. Importantly, resumption of bridging anticoagulation
too early is associated with an increased risk for major bleeding. (See 'When to bridge: Preoperative,
postoperative, or both' above and 'Timing of bridging' above.)

• Heart valve – Perioperative anticoagulation in individuals with prosthetic heart valves is presented
separately. (See "Antithrombotic therapy for prosthetic heart valves: Management of bleeding and
invasive procedures", section on 'Management of antithrombotic therapy for invasive procedures'.)

● Urgent/Emergency procedure – Reversal of the patient's usual anticoagulant may be required for more

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urgent or emergency procedures, or to treat perioperative bleeding. Agents with a potential prothrombotic
effect (eg, immediate reversal agents, prothrombin complex concentrates, plasma products) should be
reserved for the treatment of life-threatening, severe bleeding or anticipated severe bleeding (eg,
intracranial hemorrhage, emergency major surgery with elevated prothrombin time/international
normalized ratio [PT/INR]). (See 'Urgent/emergency invasive procedure' above and "Management of
bleeding in patients receiving direct oral anticoagulants".)

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68. Tafur AJ, McBane R 2nd, Wysokinski WE, et al. Predictors of major bleeding in peri-procedural

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anticoagulation management. J Thromb Haemost 2012; 10:261.

69. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:141S.
70. O'Donnell MJ, Kearon C, Johnson J, et al. Brief communication: Preoperative anticoagulant activity after
bridging low-molecular-weight heparin for temporary interruption of warfarin. Ann Intern Med 2007;
146:184.
71. Douketis JD, Woods K, Foster GA, Crowther MA. Bridging anticoagulation with low-molecular-weight
heparin after interruption of warfarin therapy is associated with a residual anticoagulant effect prior to
surgery. Thromb Haemost 2005; 94:528.
72. Strebel N, Prins M, Agnelli G, Büller HR. Preoperative or postoperative start of prophylaxis for venous
thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med 2002;
162:1451.
73. Dunn AS, Spyropoulos AC, Turpie AG. Bridging therapy in patients on long-term oral anticoagulants
who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). J Thromb
Haemost 2007; 5:2211.
74. Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients treated with vitamin
K antagonists. Anesthesiology 2008; 109:918.
75. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex
concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-
controlled, phase IIIb study. Circulation 2013; 128:1234.
76. Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.
N Engl J Med 2017; 377:431.
77. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J
Anaesth 2011; 107 Suppl 1:i96.
78. Horlocker TT, Vandermeuelen E, Kopp SL, et al. Regional Anesthesia in the Patient Receiving
Antithrombotic or Thrombolytic Therapy: American Society of Regional Anesthesia and Pain Medicine
Evidence-Based Guidelines (Fourth Edition). Reg Anesth Pain Med 2018; 43:263.

Topic 1312 Version 61.0

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GRAPHICS

Perioperative thrombotic risk

Indication for anticoagulant therapy

Risk stratum
Mechanical heart valve Atrial fibrillation VTE

Very high thrombotic risk* Any mitral valve prosthesis CHA 2 DS 2 -VASc score of Recent (within three
Any caged-ball or tilting ≥6 months) VTE
disc aortic valve prosthesis (or CHADS 2 score of 5-6) Severe thrombophilia (eg,
Recent (within six months) Recent (within three deficiency of protein C,
stroke or transient months) stroke or protein S, or antithrombin;
ischemic attack transient ischemic attack antiphospholipid
antibodies; multiple
Rheumatic valvular heart
abnormalities)
disease

High thrombotic risk Bileaflet aortic valve CHA 2 DS 2 -VASc score of VTE within the past 3 to 12
prosthesis and one or 4-5 or CHADS 2 score of months
more of the of following 3-4 Nonsevere thrombophilia
risk factors: atrial (eg, heterozygous factor V
fibrillation, prior stroke or Leiden or prothrombin
transient ischemic attack, gene mutation)
hypertension, diabetes,
Recurrent VTE
congestive heart failure,
age >75 years Active cancer (treated
within six months or
palliative)

Moderate thrombotic risk Bileaflet aortic valve CHA 2 DS 2 -VASc score of VTE >12 months previous
prosthesis without atrial 2-3 or CHADS 2 score of and no other risk factors
fibrillation and no other 0-2 (assuming no prior
risk factors for stroke stroke or transient
ischemic attack)

Refer to UpToDate topics on perioperative anticoagulation management for details.

VTE: venous thromboembolism; CHADS 2 : congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and
stroke or transient ischemic attack; CHA 2 DS 2 -VASc: congestive heart failure, hypertension, age ≥75 years (2 points),
diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (2 points), vascular disease (peripheral
artery disease, myocardial infarction, or aortic plaque), age 65-74 years, sex category female.
* Very high risk patients may also include those with a prior stroke or transient ischemic attack occurring >3 months
before the planned surgery and a CHA 2 DS 2 -VASc score <6 (or CHADS 2 score <5), those with prior thromboembolism
during temporary interruption of anticoagulation, or those undergoing certain types of surgery associated with an
increased risk for stroke or other thromboembolism (eg, cardiac valve replacement, carotid endarterectomy, major
vascular surgery).

Modified from Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy:
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines. Chest 2012; 141(2 Suppl):e326S. Copyright © 2012. Reproduced with permission from the
American College of Chest Physicians.

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Perioperative management of oral direct thrombin inhibitors and factor Xa

inhibitors

Interval between last dose

and procedure
Resumption after
Renal NOTE: No anticoagulant is
procedure
Anticoagulant function administered the day of
and dose the procedure

High bleeding Low bleeding High bleeding Low bleeding

risk risk risk risk

Dabigatran CrCl >50 Give last dose Give last dose

mL/minute three days two days before
Dose 150 mg before procedure (ie,
twice daily procedure (ie, skip two doses
skip four doses on the day
on the two days before the
before the procedure)
procedure)

CrCl 30 to 50 Give last dose Give last dose

mL/minute five days before three days
Dose 150 mg procedure (ie, before
twice daily skip eight doses procedure (ie,
on the four days skip four doses
before the on the two days
procedure) before the
procedure)

Rivaroxaban CrCl >50 Give last dose Give last dose

mL/minute three days two days before
Dose 20 mg before procedure (ie,
once daily procedure (ie, skip one dose on Resume 48 to 72 Resume 24
skip two doses the day before hours after hours after
CrCl 30 to 50 on the two days the procedure) surgery (ie, surgery (ie,
mL/minute before the postoperative postoperative
Dose 15 mg procedure) day 2 to 3) day 1)
once daily

Apixaban CrCl >50 Give last dose Give last dose

mL/minute three days two days before
Dose 5 mg twice before procedure (ie,
daily procedure (ie, skip two doses
skip four doses on the day
CrCl ≤50 on the two days before the
mL/minute before the procedure)
Dose 2.5 mg procedure)
twice daily

Edoxaban CrCl 50 to 95 Give the last Give the last

mL/minute dose three days dose two days
Dose 60 mg before the before the
once daily procedure (ie, procedure (ie,
skip two doses skip one dose on
CrCl ≤50 on the two days the day before
mL/minute* before the the procedure)
Dose 30 mg procedure)
once daily

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Bleeding risk is determined primarily by the type of surgery; patient comorbidities may also play a role. In patients
undergoing neuraxial anesthesia or a very high bleeding risk procedure, a longer period of interruption may be
warranted. In many low bleeding risk procedures, the anticoagulant does not need to be interrupted. Bridging
anticoagulation may be appropriate preoperatively in patients with a very high thromboembolic risk who require
more prolonged interruption of the anticoagulant (eg, for renal insufficiency) and/or postoperatively in patients
who are unable to resume the anticoagulant (eg, unable to take oral medication due to intestinal ileus). Refer to
the UpToDate topics on perioperative management of patients receiving anticoagulants for further details.

CrCl: creatinine clearance.

* Product information varies in different countries regarding a lower limit of CrCl below which the drug should not be used.

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Procedural bleeding risk

High bleeding risk procedure (two-day risk of major bleed 2 to 4%)

Any major operation of duration >45 minutes

Abdominal aortic aneurysm repair

Coronary artery bypass

Endoscopically guided fine-needle aspiration

Foot/hand/shoulder surgery

Heart valve replacement

Hip replacement

Kidney biopsy

Knee replacement

Laminectomy

Neurosurgical/urologic/head and neck/abdominal/breast cancer surgery

Polypectomy, variceal treatment, biliary sphincterectomy, pneumatic dilatation

Transurethral prostate resection

Vascular and general surgery

Low bleeding risk procedure (two-day risk of major bleed 0 to 2%)

Abdominal hernia repair

Abdominal hysterectomy

Arthroscopic surgery lasting <45 minutes

Axillary node dissection

Bronchoscopy with or without biopsy

Carpal tunnel repair

Cataract and noncataract eye surgery

Central venous catheter removal

Cholecystectomy

Cutaneous and bladder/prostate/thyroid/breast/lymph node biopsies

Dilatation and curettage

Gastrointestinal endoscopy ± biopsy, enteroscopy, biliary/pancreatic stent without sphincterotomy, endosonography

without fine-needle aspiration

Hemorrhoidal surgery

Hydrocele repair

Noncoronary angiography

Pacemaker and cardiac defibrillator insertion and electrophysiologic testing

Tooth extractions

This table is based on definitions derived from surgical/subspecialty societies in anticoagulant bridging or
anticoagulant bridging management studies. Refer to UpToDate content on management of anticoagulants in
patients undergoing gastrointestinal procedures for information on bleeding risks of additional gastrointestinal
procedures.

Adapted from research originally published in Blood. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients
undergoing an elective procedure or surgery. Blood 2012; 120:2954. Copyright © 2012 the American Society of

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Hematology.

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Clinical risk factors for stroke, transient ischemic attack, and systemic embolism
in the CHA 2 DS 2 -VASc score

(A) The risk factor-based approach expressed as a point based scoring system, with
the acronym CHA 2 DS 2 -VASc
(NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points)
CHA 2 DS 2 -VASc risk factor Points

Congestive heart failure +1

Signs/symptoms of heart failure or objective evidence of reduced
left-ventricular ejection fraction

Hypertension +1
Resting blood pressure >140/90 mmHg on at least two occasions or
current antihypertensive treatment

Age 75 years or older +2

Diabetes mellitus +1
Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral
hypoglycaemic agent and/or insulin

Previous stroke, transient ischaemic attack, or thromboembolism +2

Vascular disease +1
Previous myocardial infarction, peripheral artery disease, or aortic
plaque

Age 65-74 years +1

Sex category (female) +1

(B) Adjusted stroke rate according to CHA 2 DS 2 -VASc score

CHA 2 DS 2 -VASc score Patients Stroke and thromboembolism
(n = 73,538) event rate at one-year follow-up
(%)

0 6369 0.78

1 8203 2.01

2 12,771 3.71

3 17,371 5.92

4 13,887 9.27

5 8942 15.26

6 4244 19.74

7 1420 21.50

8 285 22.38

9 46 23.64

CHA 2 DS 2 -VASc: Congestive heart failure, Hypertension, Age (≥75) (doubled), Diabetes, Stroke (doubled), Vascular
disease, Age (65-74), Sex.

Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation
developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on
behalf of the European Society of Cardiology. Copyright © 2016 Oxford University Press. Available at: www.escardio.org/.

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Causes of acute arterial occlusion

Arterial thrombosis
Native arterial
Arterial embolus following Arterial injury
thrombosis
intervention

Cardiac source Atherosclerotic plaque Vein bypass graft Iatrogenic

Atrial fibrillation Aneurysm thrombosis Prosthetic bypass graft Thromboembolism
Myocardial infarction Arterial dissection Angioplasty site Closure devices
Endocarditis Arterial Stent/stent-graft site Device embolization
Valvular disease entrapment/compression Traumatic
Atrial myxoma Popliteal entrapment
Prosthetic valves Thoracic outlet
Arterial source syndrome

Aneurysm Thrombophilia

Atherosclerotic Low flow state

plaque
Paradoxical embolus

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Clinical characteristics comprising the HAS-BLED bleeding risk score

HAS-BLED
score Bleeds per 100
Letter Clinical characteristic* Points
(total patient-years ¶
points)

H Hypertension (ie, uncontrolled blood 1 0 1.13

pressure)

A Abnormal renal and liver function (1 point 1 or 2 1 1.02

each)

S Stroke 1 2 1.88

B Bleeding tendency or predisposition 1 3 3.74

L Labile INRs (for patients taking warfarin) 1 4 8.70

E Elderly (age greater than 65 years) 1 5 to 9 Insufficient data

D Drugs (concomittant aspirin or NSAIDs) or 1 or 2

excess alcohol use (1 point each)

Maximum 9
points

The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin.
Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for
further information and other bleeding risk scores and their performance relative to clinical judgement.

INR: international normalized ratio; NSAIDs: nonsteroidal anti-inflammatory drugs.

* Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of
chronic dialysis, renal transplantation, or serum creatinine ≥200 micromol/L. Abnormal liver function is defined as chronic
hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than two
times the upper limit of normal, plus one or more of aspartate transaminase, alanine transaminase, and/or alkaline
phosphatase more than three times the upper limit normal). Bleeding predisposition includes chronic bleeding disorder
or previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin includes unstable INRs,
excessively high INRs, or <60 percent time in therapeutic range.
¶ Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1-year risk of major
bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in
contemporary cohorts may vary from these estimates.

Original figure modified for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for
thromboprophylaxis in atrial fibrillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All
rights reserved.

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Expected effects of anticoagulant drugs on commonly used coagulation tests

Brand Anti-factor
Drug class Drug PT aPTT
name(s) Xa activity

Vitamin K Warfarin Coumadin, ↑ ↑/–* –

antagonists Jantoven

Acenocoumarol Sintrom ↑ ↑/–* –

Heparins Unfractionated –¶ ↑ ↑
heparin

LMW heparins – ↑/– ↑

Enoxaparin Lovenox
Dalteparin Fragmin
Nadroparin Fraxiparine

Fondaparinux Arixtra – ↑/– ↑

Direct thrombin Argatroban Acova ↑ ↑ –

inhibitors
Dabigatran Pradaxa ↑/– ↑ –

Direct factor Xa Rivaroxaban Xarelto ↑/– ↑/– ↑Δ

inhibitors
Apixaban Eliquis ↑/– ↑/– ↑Δ

Edoxaban Lixiana, Savaysa ↑Δ

Betrixaban Bevyxxa ↑Δ

PT and aPTT are measured in seconds; anti-factor Xa activity is measured in units/mL. Upward arrow (↑) signifies
an increase above normal due to the anticoagulant (prolongation of PT or aPTT; increase in anti-factor Xa activity).
The effect magnitude will vary depending on the reagent formulation and instrument used. Dash (–) signifies no
appreciable effect. Normal ranges for the PT, aPTT, and anti-factor Xa activity vary among laboratories and should
be reported from the testing laboratory along with the patient result. Refer to the UpToDate topic on coagulation
testing for details.

PT: prothrombin time; aPTT: activated partial thromboplastin time; LMW heparin: low molecular weight heparin.
* Warfarin has a weak effect on most aPTT reagents. However, warfarin use will increase the sensitivity of the aPTT to
heparin effect.
¶ While heparin, LMW heparin, and fondaparinux should, in theory, prolong the PT as indirect thrombin inhibitors, in
practice most PT reagents contain heparin-binding chemicals that block any heparin effect below a concentration of 1
unit/mL. Above concentrations of 1 unit/mL, heparin effect on the PT may be observed.
Δ Anti-factor Xa activity testing must be calibrated for the specific anticoagulant; this information should be verified with
the clinical laboratory. Data are not available for betrixaban but would be expected to be similar to other direct factor Xa
inhibitors.

Some of the data are from: Samuelson BT, Cuker A, Crowther M, Garcia DA. Laboratory assessment of the anticoagulant
activity of direct oral anticoagulants: A systematic review. Chest 2017; 151:127.

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Comparison of the CHADS2 and CHA2DS2-VASc risk stratification scores for

subjects with nonvalvular AF

Definition and scores for CHADS 2 and Stroke risk stratification with the
CHA 2 DS 2 -VASc CHADS 2 and CHA 2 DS 2 -VASc scores

CHADS 2 acronym Score CHADS 2 acronym Unadjusted ischemic stroke

rate (% per year)*
Congestive HF 1
0 0.6%
Hypertension 1
1 3.0%
Age ≥75 years 1
2 4.2%
Diabetes mellitus 1
3 7.1%
Stroke/TIA/TE 2
4 11.1%
Maximum score 6
5 12.5%
CHA 2 DS 2 -VASc acronym Score
6 13.0%
Congestive HF 1
CHA 2 DS 2 -VASc Unadjusted ischemic stroke
Hypertension 1
acronym rate (% per year)*
Age ≥75 years 2
0 0.2%
Diabetes mellitus 1
1 0.6%
Stroke/TIA/TE 2
2 2.2%
Vascular disease (prior MI, PAD, or aortic 1
3 3.2%
plaque)
4 4.8%
Age 65 to 74 years 1
5 7.2%
Sex category (ie, female sex) 1
6 9.7%
Maximum score 9
7 11.2%

8 10.8%

9 12.2%

AF: atrial fibrillation; CHADS 2 : Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Prior Stroke or
TIA or Thromboembolism (doubled); CHA 2 DS 2 -VASc: Congestive heart failure, Hypertension, Age ≥75 years (doubled),
Diabetes mellitus, Prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65-74 years, Sex category;
HF: heart failure; LV: left ventricular; MI: myocardial infarction; PAD: peripheral artery disease; TE: thromboembolic; TIA:
transient ischemic attack.
* These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 [1]. Actual rates of stroke
in contemporary cohorts might vary from these estimates.

Reference:
1. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182
678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500.
Original figure modified for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the
Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. DOI:
10.1016/j.jacc.2014.03.022. Table used with the permission of Elsevier Inc. All rights reserved.

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Recommendations for preoperative and postoperative anticoagulation in patients

on a vitamin K antagonist

Indication Before surgery After surgery

Venous thromboembolism

Within first month IV heparin or SQ IV heparin or SQ LMWH

LMWH

Second/third month No change* IV heparin or SQ LMWH

≥3 months No change* SQ heparin or LWMH

Arterial thromboembolism

Recent, within one month IV heparin or SQ IV heparin or SQ LMWH

LMWH

Prophylaxis (eg, non-valvular AF, mechanical heart No change* Resume oral

valve) anticoagulation ¶

NOTE: Warfarin should be withheld to allow the INR to fall spontaneously to 1.5 to 2 before surgery is performed.

IV: intravenous; SQ: subcutaneous; LMWH: low molecular weight heparin; AF: atrial fibrillation; INR: international
normalized ratio.
* If the patient is hospitalized, SQ heparin or LMWH should be administered, but hospitalization is not recommended
solely for this purpose.
¶ Can use SQ heparin or SQ LMWH if the surgery carries a high risk of postoperative thromboembolism.

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Reversing anticoagulation in warfarin-associated bleeding

Management
Time to anticoagulation reversal Comments and cautions
option

Discontinuing 5 to 14 days Five days is typical for patients with an INR

warfarin therapy in the therapeutic range

Vitamin K* 6 to 24 hours to correct the INR, longer to Recovery of factors X and II (prothrombin)
fully reverse anticoagulation takes longer than 24 hours
Risk of anaphylaxis with intravenous
injection
Impaired response to warfarin lasting up to
one week may occur after large doses (ie,
>5 mg)

Fresh frozen plasma Depends on the time it takes to complete the Effect is transient and concomitant vitamin K
infusion; typically 12 to 32 hours for must be administered
complete reversal Potential for volume overload (2 to 4 L to
normalize INR)
Potential for TRALI
Potential for viral transmission

Prothrombin complex 15 minutes after 10-minute to 1-hour Effect is transient, and concomitant vitamin
concentrate infusion K must be administered; limited availability
Cost
Variable factor VII content depending on the
product: a 4-factor PCC is preferred
Potentially prothrombotic

Recombinant factor 15 minutes after bolus infusion Effect is transient, and concomitant vitamin
VIIa K must be administered
Cost
Potentially prothrombotic

Please refer to the UpToDate topic on warfarin reversal in intracerebral hemorrhage for further details of
management.

INR: international normalized ratio; TRALI: transfusion-related acute lung injury; PCC: prothrombin complex concentrate.
* A total of 10 mg intravenously by slow infusion given over 10 minutes.

Adapted with permission from: Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intercerebral
hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007; 82:82. Copyright © 2007 Dowden Health Media.

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Emergent reversal of anticoagulation from warfarin for life-threatening

hemorrhage in adults: Suggested approaches based upon available resources

A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach):

1. Give 4F PCC* 1500 to 2000 units ¶ IV over 10 minutes. Check INR 15 minutes after completion of the infusion.
If INR is not ≤1.5, give additional 4F PCC (refer to topic or drug reference for details).

2. Give vitamin K 10 mg IV over 10 to 20 minutes.

B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available:

1. Give 3F PCC* 1500 to 2000 units ¶ IV over 10 minutes. Check INR 15 minutes after completion of the infusion.
If INR is not ≤1.5, give additional 3F PCC (refer to topic or drug reference for details).

2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume
overload is a concern.

3. Give vitamin K 10 mg IV over 10 to 20 minutes.

C. Neither 3F PCC nor 4F PCC is available:

1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR ≥1.5,
administer 2 additional units of FFP IV rapid infusion. Repeat process until INR ≤1.5. May wish to administer loop
diuretic between FFP infusions if volume overload is a concern.

2. Give vitamin K 10 mg IV over 10 to 20 minutes.

These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and
over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions
can occur.
It may be reasonable to thaw four units of FFP while awaiting the PT/INR. The transfusion service may substitute
other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are
considered clinically interchangeable. PCC will reverse anticoagulation within minutes of administration; FFP
administration can take hours due to the volume required; vitamin K effect takes 12 to 24 hours, but
administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the
PT/INR is needed to guide further therapy. Refer to topics on warfarin reversal in individual situations for further
management.

PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S
and protein C; 3F PCC: PCC containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT:
prothrombin time; INR: international normalized ratio; FEIBA: factor eight inhibitor bypassing agent.
* Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and
single-factor IX products (ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal.
¶ PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on
INR and patient weight if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based
dosing.

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PCC products available in the United States

Unactivated prothrombin complex concentrates (PCCs)

4 factor: Contain coagulation factors II, VII, IX, and X in inactive forms
Kcentra

3 factor: Contain factors II, IX, and X (little to no factor VII)

Bebulin VH
Profilnine SD

Activated prothrombin complex concentrates (aPCCs)

4 factor: Contain coagulation factors II, VII, IX, and X; factor VII is mostly activated*
FEIBA NF

The table lists 4- and 3-factor (which contain little to no factor VII) PCC products available in the United States.
PCCs also contain proteins C and S, and some contain heparin from the purification. Unactivated factors are
proenzymes (inactive precursor proteins). Activated factors have higher enzymatic activity. Refer to UpToDate
topics on warfarin reversal for use of these products. Kcentra is sold in Canada as Octaplex.

PCCs: prothrombin complex concentrates; FEIBA NF: factor eight inhibitor bypassing activity, nanofiltered.
* A single-factor product containing recombinant activated human factor VII (rFVIIa) is also available.

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Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent

risk of death from bleeding)

Anticoagulant Reversal agent

Dabigatran (Pradaxa) Idarucizumab (Praxbind); initial

dose: 5 grams

Apixaban (Eliquis) Andexanet alfa (AndexXa) if

available; initial dose depends on
the dose of the factor Xa inhibitor
Betrixaban (Bevyxxa)
and the interval since the last
dose.*
Edoxaban (Lixiana, Savaysa) OR

4-factor PCC (Kcentra, Octaplex)

Rivaroxaban (Xarelto) if andexanet alfa is not available;
initial dose: 50 units per kg

These agents have the potential to cause life-threatening thrombosis and should only be used under the direction
of a specialist with expertise in their use and/or in a patient at imminent risk of death from bleeding. Although
there are preclinical data that suggest PCCs may partially overcome the effects of a DOAC, there is no high-quality
evidence that establishes the benefit of PCCs in DOAC-treated patients who are bleeding. Refer to UpToDate topics
on treatment of bleeding in patients receiving a DOAC or perioperative management of patients receiving a DOAC
for information on additional risks and alternatives for treating bleeding.

DOAC: direct oral anticoagulant; PCC: prothrombin complex concentrate.

*High-dose andexanet is used if the patient received a higher dose of factor Xa inhibitor (eg, rivaroxaban >10 mg,
apixaban >5 mg, or dose unknown) within the previous eight hours; andexanet is given as an 800 mg bolus at 30
mg/minute followed by 960 mg infusion at 8 mg/minute.
Low-dose andexanet is used if the patient received a lower dose of factor Xa inhibitor (eg, rivaroxaban ≤10 mg, apixaban
≤5 mg) OR if ≥8 hours have elapsed since the last dose of factor Xa inhibitor; andexanet is given as a 400 mg bolus at 30
mg/minute followed by 480 mg infusion at 4 mg/minute

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Contributor Disclosures
Gregory YH Lip, MD, FRCPE, FESC, FACC Speaker's Bureau: Bayer [Atrial fibrillation and thrombosis
(rivaroxaban)]; BMS/Pfizer [Atrial fibrillation and thrombosis (apixaban)]; Boehringer Ingelheim [Atrial
fibrillation and thrombosis (dabigatran)]; Daiichi-Sankyo [Atrial fibrillation and thrombosis (edoxaban)];
Medtronic [Atrial fibrillation and thrombosis]; Sanofi Aventis [Atrial fibrillation and thrombosis].
Consultant/Advisory Boards: Bayer/Janssen [Atrial fibrillation and thrombosis (rivaroxaban)]; BMS/Pfizer
[Atrial fibrillation and thrombosis (apixaban)]; Boehringer Ingelheim [Atrial fibrillation and thrombosis
(dabigatran)]; Daiichi-Sankyo [Atrial fibrillation and thrombosis (edoxaban)]; Medtronic [Atrial fibrillation and
thrombosis]. James D Douketis, MD, FRCPC, FACP, FCCP Consultant/Advisory Boards: Bayer [Venous
thromboembolic disease, atrial fibrillation (Rivaroxaban)]; Sanofi [Venous thromboembolic disease
(Enoxaparin)]; Leo Pharma [Venous thromboembolic disease (Tinzaparin)]; Janssen [Venous thromboembolic
disease, atrial fibrillation (Rivaroxaban)]. Lawrence LK Leung, MD Nothing to disclose Jennifer S Tirnauer,
MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.

Conflict of interest policy

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