e604 March 7, 2017 Circulation. 2017;135:e604–e633. DOI: 10.1161/CIR.0000000000000477ABSTRACT: Non–vitamin K oral anticoagulants (NOACs) are now… [609505]

e604 March 7, 2017 Circulation. 2017;135:e604–e633. DOI: 10.1161/CIR.0000000000000477ABSTRACT: Non–vitamin K oral anticoagulants (NOACs) are now widely
used as alternatives to warfarin for stroke prevention in atrial fibrillation and management of venous thromboembolism. In clinical practice, there is still widespread uncertainty on how to manage patients on NOACs who
bleed or who are at risk for bleeding. Clinical trial data related to NOAC
reversal for bleeding and perioperative management are sparse, and recommendations are largely derived from expert opinion. Knowledge of time of last ingestion of the NOAC and renal function is critical to managing these patients given that laboratory measurement is challenging because of the lack of commercially available assays in the United States. Idarucizumab is available as an antidote to rapidly reverse the effects of dabigatran. At present, there is no specific antidote available in the United
States for the oral factor Xa inhibitors. Prothrombin concentrate may be
considered in life-threatening bleeding. Healthcare institutions should adopt a NOAC reversal and perioperative management protocol developed with multidisciplinary input.
As the US population ages, the burden of atrial fibrillation (AF) and venous throm-
boembolic disease is expected to increase, and prescriptions for long-term anticoagulation will climb. Anticoagulated patients are vulnerable to spontane-
ous, traumatic and perioperative bleeding. Warfarin is a vitamin K antagonist (VKA)
that has been used for decades to prevent and treat arterial and venous thromboem-bolism (VTE). More recently, 4 non–vitamin K antagonist oral anticoagulants (NOACs) have been approved in the United States as alternatives to warfarin for prevention of stroke resulting from nonvalvular AF (NVAF), and prevention and treatment of VTE. These are dabigatran etexilate (Pradaxa, Boehringer Ingelheim, Germany); rivaroxa-ban (Xarelto, Bayer HealthCare AG, Leverkusen, Germany), apixaban (Eliquis, Pfizer and Bristol-Myers Squibb, New York, NY) and edoxaban (Savaysa, Daiichi Sankyo,
Tokyo, Japan). Direct oral anticoagulants has been proposed as alternative nomen-clature for these class of agents.
1 NOACs are associated with comparable or lower
risk of stroke, systemic embolism, major bleeding, and death compared with warfa-rin for NVAF.
2–5 In contrast with warfarin, NOACs have a more predictable therapeutic
effect, do not require routine monitoring, have fewer potential drug-drug interactions and no restriction on dietary consumption of vitamin K–containing food. However, universal adoption of NOACs has been stunted by the lack of specific antidotes and measurement assays. This scientific statement reviews the literature and offers practical suggestions for providers who manage patients who are actively bleeding and who are at risk for bleeding in the acute care and periprocedural setting. This statement focuses on interpreting available data rather than providing specific man-Amish N. Raval, MD,
FAHA, Chair
Joaquin E. Cigarroa, MD
Mina K. Chung, MD, FAHALarry J. Diaz-Sandoval,
MD, FAHA
Deborah Diercks, MDJonathan P . Piccini, MD,
MHS, FAHA
Hee Soo Jung, MDJeffrey B. Washam,
PharmD, FAHA
Babu G. Welch, MDAllyson R. Zazulia, MD,
FAHA
Sean P . Collins, MD, MSc,
FAHA, Co-Chair
On behalf of the Ameri
–
can Heart Association Clinical Pharmacology Subcommittee of the Acute Cardiac Care and General Cardiology Committee of the Coun
–
cil on Clinical Cardiol –
ogy; Council on Car –
diovascular Disease in the Young; and Council on Quality of Care and Outcomes ResearchManagement of Patients on Non–Vitamin K
Antagonist Oral Anticoagulants in the Acute Care
and Periprocedural Setting
A Scientific Statement From the American Heart Association
© 2017 American Heart
Association, Inc.Key Words: AHA Scientific
Statements ◼ acute care
◼ anticoagulants ◼ non–vitamin K antagonist ◼ periproceduralAHA SCIENTIFIC STATEMENT
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Management of Patients on NOACs in the Acute Care and Periprocedural Setting
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e605
CLINICAL STATEMENTS
AND GUIDELINESagement recommendations in under-studied populations
such as oncology patients.
Members of this American Heart Association (AHA)
writing group were selected for their diverse expertise in cardiovascular medicine, emergency medicine, critical
care, neurology, surgery, and pharmacology. A system-
atic search of the literature for each subtopic was per-formed in PubMed and Ovid and was supplemented by review of bibliographies as well as manual searches of key articles. Each of the following search terms were in-
cluded individually and in combination: dabigatran, apix-
aban, rivaroxaban, edoxaban, anticoagulation, reversal,
antidote, atrial fibrillation, venous thromboembolism,
bleeding, intracranial, cardioversion, catheterization,
cardiac implantable devices, kidney injury, transition,
switching, pharmacology, andexanet alfa, idarucizumab,
ciraparantag, gastrointestinal, trauma, surgery, percu-
taneous coronary intervention, neuraxial anesthesia,
stroke, and overdose. Writing group members were instructed to write subtopic sections aligned with their
experience. Members were instructed to cite contempo-rary guidelines and scientific statements where appropri-ate. The writing group did not assign formal classes of recommendation/level of evidence per the AHA Scien-
tific Document Development Process recommendation
that went into effect September 1, 2015. Sections were then reviewed by another writing group member. Sec-tion drafts were submitted to the writing group chair and co-chair and compiled into a single document. Web and
teleconferences were convened to review and edit the
full draft. The final document was submitted for indepen-dent peer review and approved for publication by the AHA Manuscript Oversight Committee on April 29, 2016.PHARMACOLOGY OF NOACS
NOACs act through direct inhibition of thrombin or inhi-
bition of factor Xa (Figure 1). Dabigatran etexilate me-sylate is a competitive direct thrombin inhibitor. Rivar-
oxaban, apixaban, and edoxaban inhibit factor Xa and
prothrombinase activity, thus inhibiting the conversion of
prothrombin to thrombin. Thrombin catalyzes the con-
version of fibrinogen to fibrin; activates factors V, VIII,
XI, and XIII; and activates platelets. Therefore, inhibiting
thrombin decreases thrombus formation. In contrast
with warfarin, NOACs have a rapid onset of action, a
shorter half-life, and more predictable pharmacokinet-
ics. Routine therapeutic monitoring was not done in the major NOAC efficacy trials and is at present not recom-mended in usual clinical practice. Information pertaining to NOAC dose, time to peak effect, and time to offset of effect is outlined in Table 1.
NOACs are substrates for P-glycoprotein (P-gp) trans-
port and apixaban and rivaroxaban are substrates for CYP 3A4 metabolism. Therefore, concomitant medica-tions that are inducers or inhibitors of these pathways should be evaluated for the potential to interact (Table 2). Macrolides and nondihydropyridine calcium channel blockers are 2 commonly prescribed classes of medica-tions that impact therapeutic levels of NOACs, although a post hoc analysis of 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) showed no evidence of differential
outcomes between rivaroxaban and warfarin in patients treated with ≥1 combined P-gp and CYP 3A4 inhibitors.
6
Edoxaban exists in a predominantly unchanged form
Figure 1. Clotting cascade
and anticoagulants.
VKA indicates vitamin K
antagonist.
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March 7, 2017 Circulation. 2017;135:e604–e633. DOI: 10.1161/CIR.0000000000000477 e606
Table 1. Comparison Among NOACs
Dabigatran Rivaroxaban Apixaban Edoxaban
Approved indications Nonvalular AF
↓ Risk of stroke and
systemic embolismNonvalular AF
↓ Risk of stroke and
systemic embolismNonvalular AF
↓ Risk of stroke and
systemic embolismNonvalular AF
↓ Risk of stroke and
systemic embolism.
Limitation: should not
use in patients with
CrCl >95 mL/min
as a result of ↑ risk of ischemic stroke compared with
warfarin at 60 mg
DVT, PE
Treatment after 5–10 d
parenteral AC
↓ Recurrence Prophylaxis after hip
replacementDVT, PE
Treatment ↓ Recurrence
Prophylaxis after hip or knee replacementDVT, PE
Treatment ↓ Recurrence
Prophylaxis after hip replacementDVT, PE
↓ Recurrence
Treatment after 5–10
d initial parenteral AC
Mechanism of action Direct thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor
Time to peak 1 h; delayed to 2 h
with food2–4 h 3–4 h 1–2 h
Bioavailability 3%–7% 10-mg dose: 80%–100% ~50% 62%
20-mg dose: 66%
↑ With food
Plasma protein binding 35% 92%–95% ~87% 55%
Volume of distribution 50–70 L 50 L 21 L 107 L
Plasma t
1/212–17 h 5–9 h ~12 h (8–15 h) 10–14 h
Elderly 14–17 h Elderly 11–13 h
Mild to moderate renal
impairment 15–18 h
Severe renal impairment 28 h
Metabolism Hepatic and plasma
hydrolysis to active
dabigatranHepatic: oxidation by
CYP3A4/5, CYP2J2;
hydrolysis to inactive
metabolites (51%)Hepatic: 25% mainly by CYP3A4/5; lesser by CYP1A2,
CYP2C8, CYP2C9, CYP2C19,
CYP2J2; O-demethylation and hydroxylationMinimal CYP3A4 hydrolysis, conjugation,
oxidation
Hepatic glucuronidation to active metabolites (<10%)P-gp substrate No active circulating metabolitesActive metabolite (M-4, <10% of parent)
P-gp substrate No major or active
circulating metabolitesSubstrate of CYP3A4, P-gp, BCRPP-gp substrate
Substrate of P-gp and ABCG2 (BCRP)
Excretion Renal (~80%) after IV
administrationRenal (66%): 36% active, 30% inactive metabolitesRenal (27%) Renal (~50%): primarily as unchanged drug
After oral, 7% recovered in
urine, 86% in fecesFeces (28%): 7% active, 21% inactive metabolitesBiliary and direct intestinal excretionMetabolism and biliary/intestinal excretion accounts for the rest
(Continued )
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CLINICAL STATEMENTS
AND GUIDELINESDosing
Nonvalvular AF CrCl >30 mL/min: 150 mg
BIDCrCl >50 mL/min: 20 mg daily with evening meal5 mg BID CrCl >50 to ≤95 mL/min: 60 mg daily
CrCl 15–30 mL/min: 75 mg BIDCrCl 15–50 mL/min: 15 mg daily with evening meal2.5 mg BID, if 2 of 3 characteristics: Cr ≥ 1.5 mg/dL,
age ≥80 y, weight ≤ 60 kgCrCl 15–50 mL/min: 30 mg daily
CrCl <15 mL/min or on
dialysis: Not recommendedNot recommended for CrCl <15 mL/min or on
dialysis in patients with AF NOT recommended for
CrCl >95 mL/min
CrCl 30–50 mL/min with
concomitant P-gp inhibitors: 75 mg BID
CrCl <30 mL/min with
concomitant P-gp inhibitors:
Avoid coadministration
DVT or PE
treatmentCrCl >30 mL/min: 150 mg BID after 5-10 d parenteral anticoagulation15 mg BID with food first 21 d for initial treatment, then 20 mg once daily
with food10 mg BID x 7 d, then 5 mg
BID60 mg once daily
CrCl ≤30 mL/min or on dialysis: Not recommendedNot recommended for CrCl <30 mL/min in
patients with DVT or PE CrCl 15–50 mL/min or
weight ≤60 kg or on
certain P-gp inhibitors:
30 mg once daily
↓ in recurrent DVT/PECrCl >30 mL/min: 150 mg
BID after 5–10 d parenteral
anticoagulation20 mg daily with food 2.5 mg BID
CrCl ≤30 mL/min or on
dialysis: Not recommended
DVT, PE
prophylaxis after hip or knee
replacementAfter hip replacement surgery:
CrCl >30 mL/min after
achievement of hemostasis: If given day of surgery,
110 mg 1–4 h postop; after
day of surgery 220 mg
once daily x 28–35 d
CrCl ≤30 mL/min or on
dialysis: Not recommended
CrCl <50 mL/min with concomitant P-gp inhibitors: Avoid
coadministrationInitial dose 6–10 h
after surgery provided
hemostasis established2.5 mg BID x 35 d after hip
replacement surgery or x 12 d
after knee replacement surgery
10 mg daily with or
without food x 35 d for
hip replacement, x 12 d
for knee replacement
Additional dosing
commentsAvoid use with patients with moderate-severe hepatic impairment (Child-
Pugh class B/C) or hepatic
disease with coagulopathyNot recommended in patients with severe hepatic impairment (Child-Pugh
class C)Not recommended with
CrCl <15 mL/min
15-20 mg taken with
food; 10 mg with or
without foodNot recommended
in patients with
moderate-severe hepatic impairment (Child-Pugh class B/C)Table 1. Continued
Dabigatran Rivaroxaban Apixaban Edoxaban
(Continued )
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in plasma with minimal metabolism through hydrolysis,
conjugation, and oxidation by CYP 3A4.
LABORATORY MEASUREMENT OF NOAC
EFFECT
One advantage of NOACs over warfarin is more rapid on-
set and offset of action with predictable pharmacokinet-ics and anticoagulant effect. This eliminates the necessi-
ty for routine therapeutic monitoring except for periodic
assessment of renal function.
7 Laboratory measurement
of NOAC level or effect may be necessary in certain acute care or perioperative settings, particularly when
there is uncertainty about the timing of last ingestion,
renal function, and gastrointestinal absorption. However,
the lack of US Food and Drug Administration–approved
NOAC laboratory assays complicates the management of NOAC overdose, NOAC-associated life-threatening bleeding, and the scheduling of urgent surgical proce-
dures.
8 All NOAC agents affect routine coagulation tests
but not in a manner that allows for a predictable and
quantitative measurement of anticoagulation effect. Spe-
cific NOAC agents are subsequently discussed.
Dabigatran
This agent is known to prolong the activated partial
thromboplastin time, prothrombin time, and thrombin
time. The package insert recommends using partial
thromboplastin time for measurement; however, there is no defined partial thromboplastin time therapeutic range
for dabigatran and the assay is relatively insensitive to
different plasma concentrations of direct thrombin inhibi-tors. Furthermore, the partial thromboplastin time can-not be used in patients with lupus anticoagulant or an
intrinsic clotting factor deficiency because its prolonga-
tion from these conditions would mask the anticoagulant
effect of dabigatran. Thrombin time is far more sensi-tive, and prothrombin time is less sensitive to dabigatran.
A normal partial thromboplastin time or thrombin time most likely excludes therapeutic levels of dabigatran, whereas a normal prothrombin time may not. Quantita-tive assessments of dabigatran levels can be obtained with the dilute thrombin time, the ecarin clotting time, or the ecarin chromogenic assay. Thrombin time and ecarin-
based assays show excellent linearity across on-therapy
drug concentrations and may be used for drug quantifica-tion. However, the US Food and Drug Administration has not approved these latter assays for measuring levels of dabigatran or other direct thrombin inhibitors.
8
Rivaroxaban, Apixaban, Edoxaban
At present, there are no US Food and Drug Administra-tion–approved assays or calibration reagents to measure the effect of direct oral factor Xa inhibitors. Rivaroxaban and apixaban affect activated clotting time and chro-mogenic anti–factor Xa assay; however, no therapeutic
range exists. Prothrombin time is less sensitive (espe-
cially for apixaban), and a normal prothrombin time may not exclude clinically relevant levels. Partial thromboplas-tin time demonstrates insufficient sensitivity and linearity for quantification.
9 Studies using spiked plasma samples
suggest using prothrombin time for a qualitative assess-ment of direct oral factor Xa inhibitors or chromogenic anti–factor Xa assay for a quantitative assessment of
direct oral factor Xa inhibitors.
8–10 Anti-Xa activity is linear
over a wide range of drug levels and may be used for
drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations.
In summary, although routine NOAC monitoring is
unnecessary, measurement of NOAC effect may assist
clinical management in certain acute care and peripro-
cedural settings. In most situations, the time of last drug ingestion combined with a recent assessment of creati-nine clearance (CrCl) should enable appropriate clinical decision making.Therapeutic measurement Routine not required Routine not required Routine not required Routine not required
To detect presence: aPTT,
ECT (if available), TTTo detect presence: PT, aPTT, antifactor Xa
activityTo detect presence: PT, aPTT,
antifactor Xa activityProlongs PT, aPTT, antifactor Xa activity
aPTT >2.5 times control may indicate overanticoagulationRenal function, CBC periodically, at least annually; hepatic functionRenal function, CBC periodically, at least annuallyRenal function, CBC periodically, at least annually
Renal function, CBC periodically, at least annually
AC indicates anticoagulant; AF, atrial fibrillation; aPTT, activated partial thromboplastin time; BID, twice daily; CBC, complete blood count; CrCl, creatinine
clearance; DVT, deep vein thrombosis; ECT, ecarin clotting time; IV, intravenous; NOACs, non–vitamin K antagonist oral anticoagulants; PE, pulmonary embolism; P-gp, P-glycoprotein; PT, prothrombin time; and TT, thrombin time.Table 1. Continued
Dabigatran Rivaroxaban Apixaban Edoxaban
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CLINICAL STATEMENTS
AND GUIDELINESTable 2. NOAC Drug Interactions
NOAC Interacting Medications Effect on NOAC Labeled Guidance; Comments
Dabigatran P-gp inducer: rifampin ↓ Dabigatran exposure Concomitant use should generally be
avoided.
P-gp inhibitors: ketoconazole, dronedarone ↑ Dabigatran exposure if concomitant moderate renal
impairmentIf moderate renal impairment (CrCl
30–50 mL/min) ↓ to 75 mg BID during concomitant use
P-gp inhibitors: ketoconazole, dronedarone, verapamil, amiodarone, quinidine, clarithromycin, ticagrelor↑ Dabigatran exposure if concomitant severe renal
impairmentIf severe renal impairment (CrCl 15–30 mL/
min) avoid concomitant use
Apixaban Strong dual P-gp and CYP3A4 inducers: rifampin, carbamazepine, phenytoin, St. John’s wort↓ Apixaban exposure Avoid concomitant use
Strong dual P-gp and CYP3A4 inhibitors:
ketoconazole, itraconazole, ritonavir,
clarithromycin↑ Apixaban exposure In patients on 5 mg or 10 mg BID, ↓ dose by 50% when coadministered
Avoid coadministration on 2.5 mg BID
Rivaroxaban Combined P-gp and strong CYP3A4
inducers: rifampin, carbamazepine, phenytoin, St. John’s wort↓ Rivaroxaban exposure Avoid concomitant use; may decrease rivaroxaban efficacy
Combined P-gp and strong CYP3A4 inhibitors: ketoconazole, itraconazole, HIV protease inhibitors (ritonavir, lopinavir/ritonavir, indinavir), conivaptan↑ Rivaroxaban exposure Avoid concomitant use
Combined P-gp and moderate CYP3A4 inhibitors: diltiazem, verapamil, amiodarone, dronedarone, erythromycin↑ Rivaroxaban exposure in patients with renal impairmentIn patients with CrCl 15 to <80 mL/min, rivaroxaban should not be used concomitantly unless the potential benefit
justifies the potential risks
No evidence of interaction observed in
ROCKET AF between treatment assignment
and outcomes in patients using ≥1
combined P-gp and moderate 3A4 inhibitors (including amiodarone, diltiazem, and verapamil)
6
Edoxaban P-gp inducer: rifampin ↓ Edoxaban exposure Avoid concomitant use
Strong P-gp inhibitors: ritonavir, nelfinavir, saquinavir, indinavir, cyclosporine↑ Edoxaban exposure Avoid concomitant use in patients taking edoxaban for treatment of VTE
P-gp inhibitors: verapamil, quinidine,
azithromycin, clarithromycin, itraconazole,
ketoconazole↑ Edoxaban exposure ↓ to 30 mg daily during concomitant administration for patients taking edoxaban for the treatment of VTE
Dose reduction is not recommended for AF
indications
In ENGAGE AF, a ↓ dose of edoxaban as
a result of concomitant P-gp inhibitor use
(verapamil, quinidine, dronedarone) was associated with ↓ edoxaban exposure and a relative ↑ in risk of stroke or systemic
embolism with edoxaban relative to
warfarin
176
AF, atrial fibrillation; BID, twice daily; CrCl, creatinine clearance; ENGAGE AF, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation
trial; NOAC, non–vitamin K antagonist oral anticoagulant; P-gp, P-glycoprotein; 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 VTE, venous thromboembolism.
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March 7, 2017 Circulation. 2017;135:e604–e633. DOI: 10.1161/CIR.0000000000000477
e610NOAC REVERSAL
This AHA writing group suggests hospital systems adopt
anticoagulation reversal protocols with multidisciplinary
representation from emergency medicine, critical care, cardiology, hematology, gastroenterology, neurology,
neurosurgery, trauma, acute care surgery, cardiotho-racic surgery, vascular surgery, pharmacy, and nursing.
An example of a NOAC reversal protocol is shown in Figure 2.
Dabigatran
For minor bleeding, supportive care and careful obser-vation are suggested. For major bleeding, intravenous
idarucizumab (Praxbind, Boehringer-Ingelheim, Germa-
ny) at a dose of 5 grams (2 consecutive intravenous infu-
sions of 2.5 g each) will reverse the anticoagulant effect
of dabigatran within minutes.
11 Idarucizumab is a mono-
clonal antibody fragment that binds dabigatran with an affinity 350 times that of thrombin. The RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran)
was a prospective cohort study that showed that ida-
rucizumab administration reversed anticoagulation as
evidenced by the normalization of the dilute thrombin
time and ecarin clotting time within minutes among sub-
jects suffering a serious hemorrhage or who required
an urgent procedure.
11 Early hemostasis was achieved
in bleeding subjects, and a low rate of perioperative
bleeding events was observed in subjects undergoing
urgent surgery. However, the strength of these clinical
observations is limited by the nonrandomized nature of
this study.Several studies have investigated the efficacy of pro-
thrombin complex concentrates (PCCs), recombinant fac-
tor VII activated, and fresh frozen plasma (FFP) in animal models; however, human data are mixed. One random-ized, placebo-controlled trial in healthy men treated with dabigatran showed that 4-factor PCC did not reverse the dabigatran effect on partial thromboplastin time, endoge-nous thrombin potential lag time, thrombin time, or ecarin clotting time.
12 Case reports of patients with life-threat-
ening bleeding associated with dabigatran therapy have demonstrated mixed results with the use of FFP, recombi-nant factor VII activated, PCCs, fibrinogen, and platelets.
8
Hemodialysis may remove 49% to 57% of dabigatran
within 4 hours given that the drug is only 35% bound to plasma proteins.
13,14 Hemodialysis may be considered
if the CrCl is chronically below 30 mL/min or in acute kidney injury. For major ingestion, there is some evi-dence to support the use of activated charcoal therapy if dabigatran was consumed within 1 to 2 hours; however, care must be taken to prevent aspiration in patients with decreased level of consciousness.
7,8 Furthermore, acti-
vated charcoal induced vomiting could have deleterious effects by increasing intracranial pressure in patients with intracranial hemorrhage (ICH).
In summary, the AHA writing group suggests com-
pression when possible, supportive measures, and up-front idarucizumab in the event of dabigatran-associated major bleeding.
Rivaroxaban and Apixaban
Similar to dabigatran, activated charcoal may prevent absorption of rivaroxaban and apixaban if administered
Figure 2. Example of a “Serious
Bleeding on a NOAC” protocol.
BUN indicates blood urea nitrogen;
CBC, complete blood count; IU, international units; IV, intravenous;
NOAC, non–vitamin K antagonist oral
anticoagulants; PCC, prothrombin complex concentrate; PRBC, packed red blood cells; PTT, partial thrombo-
plastin time; and TT, thrombin time.
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e611
CLINICAL STATEMENTS
AND GUIDELINESwithin 1 to 2 hours after NOAC ingestion. Rivaroxaban
and apixaban are highly bound to plasma proteins;
therefore, dialysis is ineffective in clearing these drugs.
Andexanet alfa is a recombinant modified human fac-tor Xa decoy protein that serves as a specific reversal agent to neutralize the anticoagulant effects of direct and indirect factor Xa inhibitors. This drug is admin-istered as an initial intravenous bolus followed by an infusion for up to 2 hours. A recent study revealed that andexanet alpha reversed the laboratory assessed
anticoagulant activity of rivaroxaban and apixaban in
older healthy individuals within minutes of administra-tion.
15 At present, the single arm, open-label ANNEXA-4
(Andexanet Alfa for Acute Major Bleeding Associated
with Factor Xa Inhibitors) trial is under way to confirm
the clinical benefit of this drug in patients on apixaban, rivaroxaban, edoxaban, or enoxaparin who present with
an acute major hemorrhage. An interim analysis of 67 patients revealed an 89% and 93% reduction in anti–factor Xa activity for those on rivaroxaban and apixaban respectively.
16 Of the entire cohort, 47 patients were
followed for clinical hemostasis. Of these, 37 (79%; 95% confidence interval [CI], 64–89) were adjudicated as having excellent or good clinical hemostasis. The
dosing protocol in this study was as follows: (1) for
patients who had taken apixaban, or rivaroxaban >7 hours prior, andexanet alfa was given as a bolus dose of 400 mg followed by an infusion of 480 mg over 2 hours; and (2) for patients who had enoxaparin, edoxa-ban, or rivaroxaban <7 hours prior or at an unknown time, the bolus dose and infusion dose amount was doubled (800-mg bolus, 960-mg infusion over 2 hours). At present, andexanet alfa is not approved in the United
States or elsewhere.
A randomized placebo-controlled study of young,
healthy volunteers treated with 20 mg of rivaroxaban
dosed twice daily found that administration of a 4-factor PCC led to normalization of the prothrombin time and the endogenous thrombin potential.
12 In contrast, an in
vitro study using human plasma obtained from healthy donors found that recombinant factor VII activated was
superior to a 4-factor PCC at normalizing laboratory co-
agulation studies.
17 Case reports of using FFP or PCC
to treat excess rivaroxaban ingestion have shown mod-est success in improving laboratory coagulation param-eters.
18–20 However, the correction of coagulation tests
by PCC, FFP, or recombinant factor VII activated does
not imply the reversal of the clinical anticoagulation ef-
fect of the drug. There is no evidence that FFP or PCC
controls NOAC-associated bleeding in humans.
Edoxaban
Four-factor PCC showed dose-dependent reversal of
edoxaban effect with complete reversal of bleeding duration after skin punch biopsy in volunteers and par-tial reversal of prothrombin time after a 50-IU/kg dose
administration.21 However, the clinical relevance of this
finding is uncertain.
Ciraparantag (PER977) is a small synthetic, water-
soluble, cationic molecule designed to specifically bind to unfractionated heparin and low-molecular-weight hep-arin through noncovalent hydrogen bonding and charge-charge interactions. It also binds in a similar way to di-rect Xa inhibitors and direct thrombin inhibitors. It has been shown to normalize whole blood clot time within 10 to 30 minutes of administration.
22,23 Ciraparantag is still
being investigated in early clinical trials as an antidote for edoxaban associated bleeding. It remains unknown whether andexanet alfa will have greater, equal, or less-er clinical efficacy for edoxaban reversal compared with ciraparantag.
MANAGEMENT OF LIFE-THREATENING
BLEEDING
All patients with life-threatening bleeding should be man-
aged with similar basic resuscitation principals, irrespec-tive of what type of anticoagulant they may be on. Imme-diate management of the patient’s airway, breathing, and circulation with attempts to control hemorrhage is vital. When life-threatening bleeding occurs in a compressible area of the body, direct pressure along with selective use of tourniquets can be life-saving. Similarly, immedi-ate resuscitation and stabilization with intravenous flu-ids, packed red blood cells and plasma may be required in the unstable patient. NOAC reversal as indicated in NOAC Reversal should be considered. These concepts apply to blunt and penetrating trauma, massive gastro-intestinal, retroperitoneal, pericardial hemorrhage, and other forms of major bleeding.
Specific Scenario: ICH
A meta-analysis of studies that have tested NOACs for ischemic stroke prevention in NVAF have estimated a pooled incidence of hemorrhagic stroke of 0.4%.
2–5,24
Overall, this represents a >50% relative reduction in ICH rate from the 0.9% observed with warfarin. Past VKA studies suggest that ICH is 11 times more likely to result in mortality compared with extracranial hemorrhage.
25
The reduction in ICH rate coupled with consistent non-inferiority compared with VKAs in preventing thrombotic events has produced a steady increase in the use of NOACs to prevent stroke in patients with NVAF.
Uniform recommendations do not exist regarding man-
agement of patients on NOACs who suffer ICH primarily because no consistent approach to their management was undertaken in the NOAC trials. Factors to consider include availability of reversal agents, the timing of urgent neurosur-gery, risk of thromboembolic events during the period off
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e612the anticoagulant, and reinstitution of anticoagulant therapy
after the ICH event or after surgery. The presence of ICH
creates a unique circumstance because of the noncom-
pressible location of the hemorrhage and poor tolerance of the brain to continued bleeding. The AHA/American Stroke Association “Guidelines for the Management of Spontane-ous Intracerebral Hemorrhage” recommends prompt cre-ation of a hemostatic environment to limit extension of the
hemorrhage and before surgical treatment.
26
Any acute neurological change in a patient on NOAC
therapy should be presumed to be vascular in origin.
A baseline severity score should be performed as part of the initial evaluation.
26,27 Computed tomography (CT)
is widely available, detects acute hemorrhage with high sensitivity, and defines the extent of the injury on the sur-
rounding parenchyma. Contrast-enhanced CT may iden-
tify patients at high risk of ICH expansion on the basis of the presence of contrast within the hematoma, also known as the spot sign.
28,29 Detailed vascular imaging
may identify predisposing vascular lesions such as an-eurysm, arteriovenous malformation, and dural fistula.
Concurrent with reversing the NOAC effect, blood
pressure needs to be intensively managed. Many studies associate elevated systolic blood pressure with greater hematoma expansion, neurological deterioration, and death and dependency after ICH.
30,31 The INTERACT2 tri-
al (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2) showed that acute blood pressure reduction to <140 mm Hg systolic was safe and resulted
in a trend toward improvement in functional recovery de-spite no significant reduction in the rate of hematoma growth.
32 No patients with NOAC use were included in
this trial. However, recent results from ATACH-2 (Antihy-pertensive Treatment of Acute Cerebral Hemorrhage-II) suggest aggressive lowering of systolic blood pressure
to 110 to 139 mm Hg may not confer benefit.
32a
The safety of resuming a NOAC regimen after ICH is
a common clinical dilemma. Decisions about whether to resume anticoagulation after ICH must take into account
the patient’s underlying thromboembolic risk and the risk for ICH recurrence. Embolic stroke risk versus bleeding risk stratification schemes such as the CHA
2DS2-VASc
and HAS-BLED scores may help guide treatment after ICH.
30,31 The HAS-BLED score has been validated in a
wide range of patients (AF and non-AF, VKA and non-VKA) and is the only bleeding risk scheme that is predictive
of ICH.
33 However, a high HAS-BLED score should not
be the sole consideration in clinical management. The
presence of a recent ICH should prompt closer evalua-
tion of other factors related to ICH reoccurrence.24,34,35
Factors that are suggested to increase ICH risk include
older age, poor blood pressure control, lobar ICH loca-tion, presence of microbleeds on gradient echo magnetic
resonance imaging, concurrent aspirin use, and the pres-
ence of apolipoprotein E ε 2 or ε 4 alleles. AHA/American
Stroke Association guidelines provide a class IIb recom-mendation for anticoagulation to be considered only after
nonlobar ICH; however, this recommendation is based on
warfarin-associated ICH data.
34 Whether NOACs can be
safely administered in this population is still unknown.
There is no clinical trial evidence to guide the man-
agement of patients with traumatic brain injury while on anticoagulants. An initial head CT is typical; however, the role of repeated CT or inpatient observation with neuro-logical assessment remains controversial when the initial
head CT is negative. Until further data become available,
NOAC reversal for traumatic ICH should be considered similar to nontraumatic ICH.
In summary, the AHA writing group suggests that trau –
matic and nontraumatic ICH patients on dabigatran who re –
quire NOAC reversal receive idarucizumab. ICH patients on rivaroxaban, apixaban, or edoxaban should receive PCC until more specific antidotes become available.
Specific Scenario: Trauma
The prevalence of NOAC use in the trauma population is unknown. To compare, the prevalence of warfarin use
in the trauma population in 2006 was 4% with a 1.7%
absolute rate increase over the previous 4 years.
36 Pa-
tients should be encouraged to carry information cards
or bracelets that would alert emergency medical provid-
ers regarding oral anticoagulation use.
Apart from a few case reports, there are limited data
to guide the management of NOACs in the setting of trauma.
37–42 The American College of Surgeons Advance
Trauma Life Support course43 recommends obtaining
a brief, focused history during the initial evaluation of
traumatically injured patients. This should include iden-
tifying the specific NOAC, timing of last ingestion, and the underlying reason for NOAC use. Laboratory testing
of renal function and coagulation parameters described
in Laboratory Measurement of NOAC Effect may help
with treatment decisions. Thromboelastography and
rotational thromboelastometry to detect NOAC activity in isolated trauma cases has been reported; however,
routine use cannot be recommended until further data
becomes available.
44,45
NOACs may be held during the period of clinic as-
sessment or until hemostasis has been achieved in trauma patients without bleeding and with mild bleeding, or bleeding from easily controllable foci. Maintaining ade-
quate urine output and specific NOAC reversal strategies
(NOAC reversal) should be considered in trauma patients with moderate or severe bleeding, or suspected bleed-
ing that requires further evaluation.
Specific Scenario: Gastrointestinal Bleeding
In major trials, dabigatran 150 mg twice daily, rivaroxa-ban, and edoxaban 60 mg once daily were associated
with a 1.5-fold increased risk of gastrointestinal bleeding
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e613
CLINICAL STATEMENTS
AND GUIDELINEScompared with warfarin; apixaban and dabigatran 110
mg twice daily had similar gastrointestinal bleeding risk; and edoxaban 30 mg once daily had significantly lower risk.
2,3,5 Factors associated with gastrointestinal bleed-
ing with NOAC use are anemia, previous gastrointestinal bleeding, long term aspirin use or baseline nonaspirin antiplatelet use, age, diastolic hypertension, smoking, sleep apnea, chronic obstructive pulmonary disease, pre-vious proton pump inhibitor use, renal dysfunction, and male sex.
46 Although gastrointestinal bleeding accounts
for nearly 90% of major extracranial hemorrhages in NVAF patients on therapeutic anticoagulation,
47 clinical
data specifically pertaining to NOAC reversal are lacking. Of the 3.3% of patients in the Dresden registry who expe-rienced major bleeding while on rivaroxaban, the majority of patients were managed conservatively without requir-ing surgery.
48 As in the case of trauma, general resuscita-
tion principles of airway, intravenous fluid, blood transfu-sion, and maintaining adequate urine output should be applied. A Blakemore tube for bleeding from esophageal varices may be considered. Immediate NOAC reversal should be considered in the unstable patient.
Reinitiating NOAC therapy after gastrointestinal bleed-
ing should take into account the patient’s underlying risk of bleeding and thrombosis risk. In a retrospective study of >4600 patients with NVAF who suffered gastrointes-tinal bleeding on anticoagulation (primarily warfarin), re-sumption of a single anticoagulant was associated with the lowest risk of mortality and thromboembolism com-pared with nonresumption of antithrombotic treatment. The risk of recurrent gastrointestinal bleeding was also low in the anticoagulated patients. Patients on NOACs comprised a very small subset of the entire cohort; therefore, it remains uncertain whether NOAC resump-tion after gastrointestinal bleeding would be similarly linked to these favorable outcomes.
49
MANAGEMENT OF PATIENTS ON NOACS WHO
ARE AT RISK FOR BLEEDING
Management of Patients Who Overdose on
NOACs
Data regarding the prevalence of overdoses or unpre-
scribed exposures to NOACs are largely based on ob-servational data from poison control centers and case reports.
13,14,18,19,50–61 Stevenson et al reported that be-
tween January 2011 and July 2013, there were 49 calls to a single poison control center regarding dabigatran and rivaroxaban.
18 Of these, only 4 cases were a result
of self-harm, and only mild bleeding was reported in 1 case. The majority of bleeding events were noted in pa-tients on long-term treatment and not acute ingestions, and there was no association with coagulation abnor-malities and risk of bleeding. Conway et al reported dab-igatran exposures from a national poison control center and noted that adverse outcomes occurred in only 5% of all calls, and only 1.3% were considered intentional.
50
An observational study from poison control centers in 9 states showed that among 223 NOAC exposure calls related to rivaroxaban and apixaban ingestions, 42% had abnormal coagulation studies and no patient had bleeding.
51 Unfortunately, there is limited information
to guide management of patients with NOAC overdose with and without bleeding. Collection of information on the type of NOAC, the ingested dose, time of ingestion, concomitant renal/liver disease, and relevant medica-tion coingestion is critically important in the acute pe-riod. Therapeutic management strategies in the acute care setting have largely been developed on the basis of clinical experience and an understanding of the phar-macology rather than trial data.
Management of Patients With Acute Kidney
Injury on NOACs
The risk of acute kidney injury is high in the patient pop-
ulation who are frequently prescribed NOACs. Andreu-Cayuelas et al performed an observational study of 162 patients with NVAF after hospitalization for acute heart failure. Creatinine was measured during follow-up to de-termine the need for dose adjustment of the hypotheti-cal NOACs.
62 The investigators reported 44% of patients
would have needed dabigatran dosage adjustment, 35% would have needed rivaroxaban adjustment, and 29% would have needed apixaban dosage adjustment. The patients with a baseline CrCl of <60 mL/min or age >75 years were at greatest risk of needing a dose adjust-ment during follow-up.
62
VKA-associated nephropathy has recently been de-
scribed as acute kidney injury with supratherapeutic in-ternational normalized ratio (INR) values with and without hematuria.
63–65 Alternatively, NOACs do not appear to be
associated with kidney injury. In a meta-analysis conduct-ed by Caldeira et al, NOACs did not increase the risk of renal failure (relative risk [RR], 0.96; 95% CI, 0.87–1.07; I
2= 17.8%; 6 randomized controlled trials) when com-
pared with a VKA.63 A recent analysis of ROCKET AF re-
vealed a small but statistically significant decline in mean CrCl± standard deviation among patients receiving war-farin (−4.3±14.6 mL/min) compared with patients re-ceiving rivaroxaban (−3.5±15.1 mL/min; P<0.001).
66 A
post hoc analysis of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial similarly re-vealed greater declines in CrCl with warfarin compared with dabigatran.
67
Administering a NOAC in a patient with acute kidney
injury increases the risk of bleeding. All NOACs should be used with caution in patients on hemodialysis, given the limited data available. Although a dosing recommen-dation for apixaban is provided for such patients in the product monograph, this recommendation is based on
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e614pharmacokinetic data in fewer than 20 patients. There
are no efficacy or safety data in this patient population.
Until these data become available, close measurement
or switching to an alternative anticoagulant is suggested
for patients who develop acute kidney injury as a result
of acute illness or injury.
Management of Patients With Ischemic Stroke
on NOACs
Whereas NOACs represent a major advance in stroke
prevention, it is still anticipated that acute ischemic
stroke (AIS) will occur in 1% to 2% of individuals with
NVAF treated with these agents each year.2–5 Their use
presents a number of challenges for clinicians managing
patients with AIS, including appropriate measurement of
anticoagulant activity in neurovascular emergencies, the
role of thrombolysis and endovascular therapy in AIS,
and timing of reinstitution of oral anticoagulation after
AIS. Thrombolytic therapy with intravenous recombinant
tissue-type plasminogen activator within 4.5 hours of
symptom onset is an established treatment in AIS68,69
but is associated with a >5-fold increase in the rate of ICH.
70 Because of the danger of further increasing ICH,
therapeutic anticoagulation is considered a contraindica-tion to thrombolytic therapy in AIS. AHA guidelines and
observational data support intravenous thrombolysis in
warfarin-treated patients provided the INR is no greater
than 1.7.
71,72 The data on safety of thrombolysis in the
presence of low levels of anticoagulation with warfarin
raises hope that the same may apply to NOACs.
Determining appropriate treatment for AIS patients re-
ceiving NOACs must balance the anticoagulant effect of
these agents and the ICH risk associated with reperfusion
strategies. As has been mentioned previously, routinely
performed blood coagulation studies do not reliably ex-
clude a significant plasma concentration of the NOACs.
Another difficulty in a time-sensitive setting is that the
more sensitive blood tests are either not routinely avail-
able or have an unacceptably long delay to results. In
experimental studies, pretreatment with dabigatran or
rivaroxaban did not increase the rate of thrombolysis-
associated ICH.72,73 Data on the safety and efficacy of
intravenous thrombolysis in AIS patients receiving NO-ACs are limited to approximately 2 dozen case reports
and a retrospective multicenter cohort study. Among the
case reports, ICH and poor outcome were rarely report-
ed when recombinant tissue-type plasminogen activator
was administered minutes to 24 hours after the last an-
ticoagulant dose.
74,75 The cohort study76 comprised 78
NOAC-treated patients undergoing intravenous throm-
bolysis or intra-arterial therapy a median of 13 hours
after the last NOAC dose compared with 441 warfarin-
treated patients and 8938 on no anticoagulants. After
propensity score matching, there was no significant dif-
ference in rate of any ICH, symptomatic ICH, or death among the groups. In the absence of immediately avail-
able blood tests sensitive to the presence of NOACs,
determining which patients taking these agents might be
appropriate candidates for thrombolysis requires con-
sideration of time from last dose, half-life of the agent
used, and presence of impaired renal function that may reduce drug clearance. A new recommendation in the AHA “Guidelines for the Early Management of Patients With Acute Ischemic Stroke” is that recombinant tissue-
type plasminogen activator should not be administered
to patients who take NOACs unless sensitive laboratory tests are normal or the patient has not received a dose of these agents for >48 hours.
71
Data guiding the use of endovascular therapy in AIS
patients who take NOACs are even more limited. Among the pivotal trials that established the safety and efficacy
of mechanical thrombectomy in patients with AIS and
large vessel occlusion, patients receiving NOACs were either excluded
77 or not specifically reported.78–81 A
handful of case reports suggest safety of endovascular therapy in patients on dabigatran and rivaroxaban even in the setting of abnormal coagulation studies.
82–87 In the
previously described cohort study, none of the 33 pa-tients who underwent endovascular therapy with or with-out intravenous thrombolysis experienced a symptom-
atic ICH. Reflecting the paucity of data in this area, the
AHA’s guidelines provide no recommendations regarding mechanical thrombectomy in patients whose use of anti-coagulant medications excludes them from intravenous thrombolysis.
88
The optimal timing of restarting anticoagulation after
AIS presents another challenge to healthcare profession-
als managing this population. Meta-analysis of 7 trials
of parenteral anticoagulation started within 48 hours of cardioembolic ischemic stroke
89 and systematic review
of 24 trials involving 23 748 participants with AIS90 test-
ing various parenteral and oral anticoagulants each con-cluded that while early anticoagulation is associated with
a reduced risk of recurrent ischemic stroke, this benefit
is entirely offset by an increased risk of symptomatic ICH with no reduction in risk of death or dependency.
The decision of when to restart oral anticoagulation
must balance the competing risks of recurrent thrombo-
embolic events and of hemorrhagic transformation. Con-
sideration is given to the type of event (transient isch-
emic attack versus cerebral infarct), time from stroke onset, and presence of factors associated with increased hemorrhage risk (large infarct size, uncontrolled blood pressure, hyperglycemia, thrombocytopenia, previous
hemorrhagic stroke, and thrombolytic treatment).
70,91
Hemorrhagic transformation of ischemic brain tissue
is a relatively common occurrence that is often asymp-tomatic or minimally symptomatic and uncommonly pro-
gresses in extent in the absence of predisposing fac-
tors.
92,93 Assuming the hemorrhagic transformation is
asymptomatic and remains stable, case series support
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CLINICAL STATEMENTS
AND GUIDELINESthe safety of starting or continuing warfarin in carefully
selected patients with a compelling indication.94 Whether
optimal timing of resumption of oral anticoagulation with NOACs should follow similar recommendations is un-
known. Differences in the pharmacological properties of
warfarin and the NOAC must be considered, notably the
more rapid time to anticoagulant effect with the NOACs
(a few hours compared with 4 to 5 days for warfarin). In
experimental models of ischemic stroke, neither dabiga-
tran pretreatment nor continued administration of dabi-
gatran after stroke onset significantly increased the risk
or volume of hemorrhagic transformation after middle
cerebral artery occlusion.
95,96 Clinical data are anecdotal
only. The phase III trials establishing the role of NOACs for stroke prevention in NVAF excluded patients within 7 to 30 days of stroke.
2–5,97 In general, guidelines support
withholding oral anticoagulation until 1 to 2 weeks after
stroke among individuals with NVAF, with shorter times
for those with transient ischemic attack or small, nondis-
abling strokes and longer times for moderate to severe
strokes.98–100 In NOAC-treated patients who have an AIS,
compliance with NOAC therapy should be established and alternative causes for the stroke investigated. There are no data to indicate that increasing the intensity of
anticoagulation, adding an antiplatelet agent, or switch-
ing to another oral anticoagulant provides additional pro-
tection against future ischemic events. Because of the
short half-lives of NOACs and rapid decline of protective
anticoagulation that occurs with missed doses, patients
with poor compliance might be more appropriately man-
aged with the longer-acting warfarin.
TRANSITIONING BETWEEN NOACS AND OTHER
ANTICOAGULANTS IN THE ACUTE CARE SETTING
Indications that require considerations for the transition-
ing of anticoagulants in the acute care setting include
the occurrence of a new clinical event (eg, myocardial
infarction) in patients on established oral anticoagulant
regimens, the development of a new or worsening co-
morbid medical condition (eg, renal failure) that neces-
sitates an anticoagulant transition and the need for an
invasive procedure. In the United States, the current la-beled prescribing information for each NOAC provides
guidance for the transition to and from NOAC agents
to other anticoagulants; however, these suggestions
are not specific for patients in the acute care setting (Table 3).
33,43,101,102
Temporary interruptions in oral anticoagulation are
commonly encountered in the acute care setting. On the
basis of trial observations from NOAC agents in patients with AF, approximately one third of AF patients will ex-
perience the need for a temporary interruption over the
course of 2 years.
103–105 The association of temporary interruptions in oral anticoagulant therapy with the risk
for clinical events has been reported in 3 of the clinical
trials comparing NOAC agents to VKAs in patients with
AF.103–105 In addition, a meta-analysis using data from
trials comparing the risk of thromboembolic events as-
sociated with temporary discontinuation found no sta-
tistically significant differences in the NOAC versus VKA
randomized groups (RR, 1.01; 95% CI, 0.68–1.49).106
Whereas the majority of the temporary interruptions in
the trials were around procedures, the use of peripro-
cedural bridging regimens varied on the basis of pa-tient characteristics and trial protocols. Only 6% and 11.7% of patients with temporary oral anticoagulation interruption received bridging in ROCKET AF and the ARISTOTLE trial (Apixaban for Reduction in Stroke and
Other Thromboembolic Events in Atrial Fibrillation), re-
spectively.
104,105
Much of the clinical outcome data regarding the
switching or transitioning between NOAC agents and
other anticoagulants comes from the clinical trials in pa-
tients with NVAF. Observations from trials reported the risk of embolic and bleeding events in the NOAC and VKA treatment groups associated with the transitions at the beginning and end of the trials have been published. A post hoc analysis of ROCKET AF reported an increased
risk of stroke in the rivaroxaban treatment group during
the end-of-study transition to the open-label therapy pe-riod.
107 Patients who received rivaroxaban compared with
those who received warfarin were observed to have an increased incidence of stroke during the period of transi-tion (3 to 30 days after the end of the study) to open-
label therapy (n=22 versus n=6; hazard ratio [HR], 3.72;
95% CI, 1.51–9.16) as well as a greater proportion of major bleeding events (n=25 versus n=7; HR, 3.62; 95% CI, 1.56–8.36).
107,108 In addition, during the end-of-study
transition period, the median time to first therapeutic INR was 3 days in the warfarin treatment group compared with 13 days in the rivaroxaban treatment group.
108 Simi-
lar observations of an increased risk of clinical events
in those assigned to NOAC therapy have been reported
from the ARISTOTLE trial end-of-study open-label transi-tion period.
109 At the end of ARISTOTLE, a 2-day bridging
period with apixaban or apixaban placebo was recom-mended during the initiation of open-label VKAs. During
the first 30 days after stopping blinded study drug, 21
stroke or systemic embolism events were noted in the apixaban group versus 5 in the warfarin group (adjust-ed HR, 4.10; 95% CI, 1.54–10.86). An excess in major bleeding events was also observed during this period in
the apixaban versus warfarin groups (n=26 versus n=10;
adjusted HR, 2.56; 95% CI, 1.23–5.30). On the basis of these observations, an end-of-study transition plan was designed for patients enrolled in the ENGAGE AF (Effec-tive Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation) trial.
110 In brief, for patients who were
planned to transition to open-label NOAC therapy, mea-
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surement of INR was conducted and the open-label NOAC
was initiated when the INR was <2.0. For patients transi-
tioning to a VKA, a 14-day kit was provided that included
a VKA algorithm and a modified dose of edoxaban, which
was to be continued until day 14 or an open-label INR ≥2.0, whichever occurred first. Within 30 days of study
drug discontinuation, strokes were observed to occur
in 7 patients in each of the 3 study treatment groups
with major bleeding events noted in 11 patients in the warfarin group, 10 patients in the edoxaban high-dose Table 3. Overview of US-Labeled Guidance for NOAC Anticoagulant Transitions
NOAC VKA Intravenous Anticoagulant LMWH/Other NOAC
Apixaban Apixaban→warfarin: Discontinue apixaban
and begin a parenteral anticoagulant and warfarin at the time the next scheduled
apixaban dose would have been takenApixaban→parenteral anticoagulant:
Discontinue apixaban and begin the new anticoagulant at the usual time of the next
dose of apixabanApixaban→LMWH/other NOAC:
Discontinue apixaban and begin the LMWH/other NOAC at the usual time of
the next dose of apixaban
Warfarin→apixaban: Discontinue warfarin
and start apixaban when INR <2.0LMWH/other NOAC→apixaban: Discontinue current NOAC/LMWH and
begin apixaban at the usual time of the
next dose of the other NOAC/LMWH
Dabigatran Dabigatran→warfarin:
For CrCl ≥50 mL/min, start warfarin 3 d
before discontinuing dabigatran
For CrCl 30–50 mL/min, start warfarin
2 d before discontinuing dabigatran
For CrCl 15–30 mL/min, start warfarin
1 d before discontinuing dabigatranDabigatran→parenteral anticoagulant:
Wait 12 h (CrCl ≥30 mL/min) or 24 h (CrCl
<30 mL/min) after last dabigatran dose before initiating a parenteral anticoagulantDabigatran→LMWH: Wait 12 h (CrCl >30 mL/min) or 24 h (CrCl <30 mL/min) after
last dabigatran dose before initiating a
parenteral anticoagulant
Warfarin→dabigatran: Discontinue warfarin and start dabigatran when INR
<2.0UFH→dabigatran: Start dabigatran at the
time of continuous infusion discontinuationLMWH→dabigatran: Start dabigatran 0–2 h before the time that the next LMWH
dose would have been given
Edoxaban Edoxaban→warfarin:
Oral option: Reduce daily edoxaban
dose by 50% and begin taking warfarin concomitantly. Measure INR at least weekly just before daily edoxaban dose.
Once a stable INR ≥2.0 is achieved,
discontinue edoxaban and continue warfarin
Parenteral option: Discontinue edoxaban and administer a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose.Edoxaban→parenteral anticoagulant: Discontinue edoxaban and start the
parenteral anticoagulant at the time of the
next scheduled dose of edoxabanEdoxaban→LMWH/other NOAC: Discontinue edoxaban and start the
LMWH/other NOAC at the time of the next
scheduled dose of edoxaban
Warfarin→edoxaban: Discontinue warfarin and start edoxaban when the INR is <2.5UFH→edoxaban: Discontinue UFH infusion and start edoxaban 4 h laterLMWH/other NOAC→edoxaban: Discontinue current NOAC/LMWH and start edoxaban at the time of the next scheduled other NOAC/LMWH dose
Rivaroxaban Rivaroxaban→warfarin: Discontinue rivaroxaban and begin a parenteral anticoagulant and warfarin at the time the next scheduled rivaroxaban dose would
have been takenRivaroxaban→UFH: Discontinue
rivaroxaban and initiate the parenteral anticoagulant at the time the next rivaroxaban dose would have been takenRivaroxaban→LMWH/other NOAC: Discontinue rivaroxaban and start the LMWH/other NOAC at the time of the next scheduled dose of rivaroxaban
Warfarin→rivaroxaban: Discontinue warfarin and start rivaroxaban as soon as INR <3.0UFH→rivaroxaban: Stop UFH infusion and administer rivaroxaban at the same timeLMWH/other NOAC→rivaroxaban: Start rivaroxaban 0–2 h before the next scheduled evening LMWH/other NOAC
dose and omit administration of the
LMWH/other NOAC
CrCl indicates creatinine clearance; INR, international normalized ratio; LMWH, low-molecular-weight heparin; NOAC, non–vitamin K antagonist oral
anticoagulant; UFH, unfractionated heparin; and VKA, vitamin K antagonist.
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CLINICAL STATEMENTS
AND GUIDELINESgroup, and 18 patients in the edoxaban low-dose group.
No statistically significant differences were observed in
primary efficacy or safety events among the 3 treatment groups in patients transitioning to open-label VKAs or in
those transitioning to open-label NOACs.
110 It is notable
that in patients transitioning to open-label VKAs, 85% had
at least 1 INR ≥ 2 by day 14.
Registry data on the outcomes of ambulatory AF pa-
tients transitioning from a VKA to a NOAC (dabigatran or rivaroxaban) have also been published.
111,112 In a
matched-cohort study of AF patients, there was no as-
sociation of transitioning from a VKA to either dabigatran
or rivaroxaban compared with remaining on VKA therapy
for embolic or bleeding events at a median follow-up of
10 months.112 Data from a large regional prospective
registry showed clinical events were relatively infrequent in the 30-day period after VKA to NOAC transitions de-spite only 75% of patients having an INR measurement
before NOAC initiation.
Although clinical decisions regarding the transition
between anticoagulants in the acute care setting are
likely to be affected by a number of factors, careful consideration should be given to strategies that mini-
mize prolonged durations of both subtherapeutic and
excessive anticoagulation during the transition periods.
Given the relatively infrequent use of periprocedural bridging strategies during temporary interruptions in
the clinical trials, clinical consideration should be given to managing patients experiencing temporary inter-
ruptions without bridging, as outlined in the individual
NOAC trials.PERIPROCEDURAL MANAGEMENT OF
PATIENTS WHO TAKE NOACS
Each year, ≈ 10% of patients on any long-term oral antico-
agulation require surgery or other invasive procedures.113
Approximately 20% of patients on warfarin undergo sur-
gery that has an extremely low risk of bleeding such as mi-
nor dental, dermatologic, or ophthalmologic procedures
where anticoagulation may be safely continued without
interruption.114 It is recommended that warfarin be held
for 5 days before surgery when significant bleeding is
anticipated and then reinitiated postoperatively when he-
mostasis is secured.115 Pre- and postoperative bridging
using low-molecular-weight heparin is recommended for
those patients with high thrombosis risk, such as those with certain mechanical valve prostheses or recent pul-monary embolism. In patients at low to intermediate risk
of thrombosis, bridging low-molecular-weight heparin
does not prevent thrombotic events and increases bleed-ing events
116 (Figure 3). Therefore, bridging anticoagula-
tion is not necessary in this subgroup of patients.
The limited data available pertaining to patients on
NOAC therapy who require surgery suggest that the perioperative bleeding risk is low for nonurgent sur-gery. The Dresden NOAC registry prospectively evalu-ated 2179 patients taking NOACs, of which 595 pa-
tients (27.3%) underwent 863 invasive procedures;
most were not urgent.
48 Invasive procedures were cat-
egorized as major or minor, and a bleeding event was categorized as major, clinically relevant nonmajor, or
minor per the International Society of Thrombosis and
Figure 3. Periprocedural management of patients on NOACs (non–vitamin K antagonist oral anticoagulants).
CrCl indicates creatinine clearance; ICD, implantable cardioverter-defibrillator; PT, prothrombin time; SVT, supraventricular tachy-
cardia; TE, thromboembolic event; TIA, transient ischemic attack; and VTE, venous thromboembolism.*Bridging may be considered in patients with a history of systemic embolus in the last 6 weeks.
110a
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e618Haemostasis definition.117 Of the entire cohort, only 46
patients (5.3%) experienced any bleeding complication
up to 30±5 days after the procedure. Major bleeding occurred in 10 of 863 (1.2%) procedures. Clinically
relevant nonmajor bleeding occurred in 29 patients
(3.4%) and minor bleeding occurred in only 7 patients
(0.8%). Periprocedural bleeding was studied in a sub-group analysis of the RELY trial which compared war-
farin to dabigatran for stroke prevention in NVAF.
103
Procedures were classified as being associated with
a low (coronary angiography, defibrillator implantation) or high risk of bleeding (cardiac, abdominal, and neu-rosurgery, or procedures requiring spinal anesthesia). There was no significant difference in the rates of peri-procedural major bleeding between patients who re-ceived dabigatran 110 mg (3.8%), dabigatran 150 mg (5.1%), or warfarin (4.6%); dabigatran 110 mg versus warfarin: RR, 0.83; 95% CI, 0.59 to 1.17; P =0.28;
dabigatran 150 mg versus warfarin: RR, 1.09; 95% CI, 0.80 to 1.49; P =0.58. Among patients who had ur-
gent surgery, major bleeding was increased, occurring in 17.8% with dabigatran 110 mg, 17.7% with dabi-gatran 150 mg, and 21.6% with warfarin: dabigatran 110 mg: RR, 0.82; 95% CI, 0.48 to 1.41; P =0.47;
dabigatran 150 mg: RR, 0.82; 95% CI, 0.50 to 1.35; P=0.44. Tailoring periprocedural NOAC management
to the type of invasive procedure may mitigate against bleeding. Common clinical scenarios are subsequently discussed.
Cardiac Catheterization and Percutaneous
Coronary Intervention
Patients with AF commonly have coexisting coronary
artery disease with an estimated 20% requiring per-cutaneous coronary intervention (PCI).
118 The 2012
American College of Cardiology/Society for Cardovas-cular Angiography and Interventions consensus docu-ment recommends that elective coronary angiography for patients on long-term warfarin be deferred until the INR is 1.8 for femoral artery access or <2.2 for radial artery access.
119 Unfortunately, there are very limited
data that address the management of patients on a NOAC who require cardiac catheterization or PCI. Pre-,
peri-, and postprocedural considerations are subse-quently discussed.
Preprocedural Considerations
Patients with stable ischemic heart disease with ischemic symptoms despite medical therapy or with intermediate- or
high-risk features on stress testing are often referred for coronary angiography and possible PCI. Patients with stable ischemic heart disease on a NOAC and who are not at high thrombosis risk should have the NOAC held until the antico-agulation effect is dissipated before undergoing coronary angiography and PCI. From the prescribing information, dabigatran should be held for at least 24 hours if CrCl ≥ 50
mL/min; for at least 72 hours if CrCL <50 mL/min; rivar-
oxaban, apixaban and edoxaban should be held for at least
24 hours.
33,43,101,102
In the absence of high risk features, patients should
not be bridged with a heparin before or after the proce-
dure.116 The decision to resume antithrombotic therapy
after the procedure should be guided by the throm-
boembolic risk as assessed by the CHA2DS2-VASc
score.120 Clinicians need to consider which antithrom-
botic and antiplatelet agents to resume and the du-ration of antiplatelet therapy, balancing ischemic and thrombotic events while minimizing the hemorrhagic
complications.
Patients presenting with an acute coronary syn-
drome (ACS) often undergo coronary angiography
and revascularization to reduce their risk of recurrent events, especially if they have an elevated Thromboly-sis in Myocardial Infarction (TIMI) risk score.
121 Where-
as patients with unstable angina or a non–ST-segment elevation myocardial infarction do not require im-mediate angiography, patients presenting with a ST-segment elevation myocardial infarction require emer-gency coronary angiography and revascularization of the infarct related artery.
122 For the unstable angina/
non–ST-segment elevation myocardial infarction pa-tient, appropriate dual antiplatelet therapy (DAPT) and heparin therapy should be started upstream, the
NOAC should be discontinued and the patient should
be scheduled for an urgent catheterization. In the ab-sence of electrical or hemodynamic instability, it is reasonable to wait for the effects of the NOAC to dissi-pate and then perform the procedure through a radial artery approach.
Periprocedural Considerations
Patients on NOACs undergoing coronary angiography or PCI will have an increased risk of hemorrhagic com-plications, and therefore, careful attention should be made to choice of vascular access site and use of ad-
junctive anticoagulants. Patients should undergo radial
artery access, unless there is a contraindication, be-cause the risk of bleeding and vascular complications
is reduced as compared with a femoral approach.
123 If
a femoral approach is required, one should consider using ultrasonography and fluoroscopy to guide vas-cular access. A micropuncture needle technique may
decrease the probability of a retroperitoneal bleed.
Although no data exist, it may be reasonable to use a vascular closure device to assist with postproce-dure hemostasis if the patient has amenable vascular anatomy. Venous access should be avoided unless
absolutely required. All patients undergoing PCI re-
quire antiplatelet therapy coupled with either heparin
or bivalirudin to reduce the periprocedural thrombotic complication rates, irrespective of background use of
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CLINICAL STATEMENTS
AND GUIDELINESVKAs or NOACs.124 The use of intravenous glycoprotein
agents should be discouraged and reserved for bailout
scenarios. For patients who receive intravenous hepa-
rin, one should use low-dose heparin regimens with an
activated clotting time goal of ≈ 250 seconds to re-
duce hemorrhagic complications.125
Postprocedural Considerations
The clinician should consider the patient’s risk of recur-
rent myocardial infarction, stent thrombosis, thromboem-
bolic risk, and hemorrhagic complications when selecting
anticoagulants. It is helpful to use the CHA2DS2-VASc risk
score to estimate the thromboembolic risk and the HAS-
BLED risk score to estimate the hemorrhagic risk and in-
clude the patient in a shared decision regarding the selec-
tion of DAPT versus triple therapy as well as the duration
of therapy. Several themes have emerged. The standard
of care to reduce coronary ischemic events post-PCI and
post-ACS is DAPT. The duration of DAPT is directly impact-
ed by the stent type (bare metal stent versus drug-eluting stent) and whether the patient underwent PCI for stable
ischemic heart disease or ACS.
126 However, oral anti-
thrombotic agents (not antiplatelet agents) are required to
prevent NVAF related stroke or VTE. Therefore, the clini-cian is faced with the consideration of DAPT, DAPT plus
warfarin (triple therapy), DAPT plus a NOAC (triple therapy)
or warfarin plus single antiplatelet therapy.
In a phase II study, triple therapy with dabigatran in
patients with ACS was associated with an increased risk of bleeding complications and planned phase III
trials were not pursued.
127 In a randomized clinical
trial of patients with ACS, apixaban increased bleeding
without reducing ischemic event in patients on either DAPT or aspirin alone. Intracranial bleed rates were in-
creased in patients treated with apixaban. Because of
concerns regarding safety without a signal of efficacy,
the trial was terminated.
128 Rivaroxaban was studied
in the ATLAS ACS-TIMI 51 (Anti-Xa Therapy to Lower
Cardiovascular Events in Addition to Aspirin With or
Without Thienopyridine Therapy in Subjects With Acute
Coronary Syndrome—Thrombolysis in Myocardial In-
farction) trial, which compared rivaroxaban or placebo
in addition to standard ACS therapies. Compared with
placebo, rivaroxaban (2.5 mg twice daily and 5.0 mg twice daily) decreased the rates of the composite pri-
mary end point including cardiovascular death, myo-
cardial infarction or stroke (10.7% versus 8.9%) while
increasing the rates of bleeding (non–coronary artery
bypass graft surgery) and ICH.
129 Only rivaroxaban cou-
pled with DAPT has been demonstrated to reduce isch-emic events at a cost of increased bleeding. However, the studied doses of rivaroxaban are not the doses proven to reduce the risk of thromboembolic events
secondary to AF.
European and Canadian guidelines suggest NOACs
are preferred over warfarin when it comes to triple ther-apy. However, these recommendations are based on
observational data and post hoc analysis of warfarin vs.
NOAC studies with limited number of patients. For ex-
ample, in ROCKET AF, only 1% of patients underwent PCI
during the trial.
130 Until further prospective, randomized
trial data become available on the subject, the AHA writ-
ing group suggests that clinicians use good judgment, weighing the risk/benefits of NOACs in the context of
triple therapy for their patients.
Proton pump inhibitors decrease the rates of upper
gastrointestinal bleeding in patients with DAPT and in pa-
tients with DAPT and antithrombotic therapy.
131 Patients
should be advised to avoid nonsteroidal anti-inflammato-ry medications as the risks of myocardial infarction and hemorrhagic complications are increased. Ongoing ran-
domized trials (Pioneer AF-PCI [Open-Label, Randomized,
Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vi-tamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary
Intervention],
132 RE-DUAL PCI [Evaluation of Dual Therapy
With Dabigatran vs. Triple Therapy With Warfarin in Pa-
tients With AF That Undergo a PCI With Stenting], RT-AF [Rivaroxaban in Patients With Atrial Fibrillation and Coro-
nary Artery Disease Undergoing Percutaneous Coronary
Intervention],
133 SAFE-A [Safety and Effectiveness Trial of
Apixaban Use in Association With Dual Antiplatelet Thera-py in Patients With Atrial Fibrillation Undergoing Percuta-neous Coronary Intervention]
134 and AUGUSTUS [A Study
of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombo-
sis (Blood Clots) Due to Having Had a Recent Coronary
Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart]) will assess the efficacy of a NOAC coupled with antiplatelet therapy in patients undergoing PCI. Until these trials are completed and published, the writing group makes the following suggestions:
1. For patients with a CHA
2DS2-VASc score of 0 or 1
treated with PCI, it is reasonable to omit anticoagu-
lant therapy and treat with DAPT.
2. For patients who require DAPT or triple therapy,
use low-dose aspirin, 81 mg daily.
3. For stable ischemic heart disease patients who require anticoagulant therapy and treatment with
PCI, discontinuation of P2Y
12 inhibitor therapy after
3 months may be reasonable.126
4. For ACS patients requiring anticoagulant therapy
and treatment with PCI (bare metal stent or drug-eluting stent), continuation of aspirin 81 mg daily
for 1 year and discontinuation of P2Y
12 therapy
after 6 months may be reasonable.126
5. For patients with a moderate to high risk of
bleeding, as assessed by the HAS-BLED score, a shortened duration of triple therapy or warfarin plus clopidogrel may be considered based on the
exploratory WOEST (What Is the Optimal Antiplatelet
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e620and Anticoagulant Therapy in Patients With Oral
Anticoagulation and Coronary Stenting) trial.135
6. Prasugrel and ticagrelor should not be used in conjunction with NOACs, as a result of excessive bleeding risk.
7. At present, there are limited data to recommend
the routine use of NOACs, coupled with clopidogrel
alone or DAPT after PCI. Of note, in clinical prac-tice, it can be challenging to reach and maintain therapeutic warfarin levels in certain patients. In these patients, it may be reasonable to combine a NOAC and clopidogrel after PCI.
Cardioversion of AF
Post hoc analyses from pivotal NOAC clinical trials have not shown significant differences in outcomes after car-dioversion in those treated with NOACs compared with warfarin.
136–138 Meta-analysis of events across random-
ized trials appears to confirm these results, finding no significant difference in stroke/systemic embolism
(odds ratio, 0.73; 95% CI, 0.31–1.72) or major/non-
major clinical relevant International Society on Throm-bosis and Haemostasis bleeding events (odds ratio, 1.41; 95% CI, 0.87–2.28) after cardioversion.
139,140
Moreover, there is 1 randomized clinical trial of car-dioversion in patients treated with a factor Xa inhibitor versus warfarin. More than 1500 patients undergoing
early (target period of 1 to 5 days after randomiza-
tion with transesophageal echocardiography [TEE]) or delayed (3 to 8 weeks) cardioversion were random-ized in a 2:1 fashion to rivaroxaban or warfarin. The primary efficacy end point (composite of stroke, tran-sient ischemic attack, peripheral embolism, myocardial infarction, and cardiovascular death) occurred in 0.51% of the rivaroxaban patients versus 1.02% of the VKA-treated patients (RR, 0.50; 95% CI, 0.15–1.73) with no
significant difference in bleeding observed.
141
Observational data from clinical practice demonstrate
similar findings. Data from a large nationwide cohort study
demonstrated no difference between outcomes in those
treated with dabigatran versus warfarin. In 1230 patients un-
dergoing cardioversion, the cumulative incidence of stroke, bleeding or death at 30 weeks was 2.0% in those treated with warfarin and 1.0% in those treated with dabigatran (ad-justed HR, 1.33; 95% CI, 0.33–5.42).
142 High-volume single-
center data (>4600 cardioversions) have also failed to iden-tify any difference in postcardioversion thromboembolic or bleeding events across warfarin and NOAC agents.
143
The ENSURE-AF trial (Edoxaban Versus Enoxaparin-
Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation) randomized 2199 patients to either edoxaban or enoxaparin/warfarin during TEE or non-TEE guided
electrical cardioversion.
144 For TEE-guided cardioversion,
randomization occurred <3 days from cardioversion and
study treatment was continued for at least 28 days. For non–TEE-guided cardioversion, study treatment was initiat-ed at least 21 days before cardioversion and extended for at least 28 days. The primary efficacy end point (compos-
ite of stroke, systemic embolic event, myocardial infarc-
tion, and cardiovascular mortality) and the primary safety
end point (major and clinically relevant nonmajor bleeding)
occurred at a statistically similar frequency. Edoxaban may be an effective and safe alternative to enoxaparin/warfarin for patients with NVAF requiring cardioversion.
Several practical considerations must be weighed when
cardioverting patients on NOAC therapy with AF duration
>24 hours. Similar to recommendations with warfarin, pa-
tients should be anticoagulated for a minimum of 3 weeks
before elective cardioversion. If not, then a TEE should be
performed to exclude the presence of left atrial append-age or left atrial thrombus. Similarly, if a given patient’s adherence to therapy is suboptimal (≥ 2 missed doses)
or in question, then a TEE should be considered. If a pa-tient has been on a properly dosed NOAC with 3 weeks of therapy and is found to have left atrial appendage or
left atrial thrombus, then consideration should be given to
switching to an alternate anticoagulant with special atten-tion to consistent anticoagulant use during the transition.
Catheter Ablation of AF
Catheter ablation is an increasingly used treatment option for rhythm control in NVAF. Because of the risks of peri-procedural thromboembolism, anticoagulation is required during the procedure. However, the presence of anticoag-
ulation can make the management of bleeding complica-
tions more difficult. Before the advent of NOAC therapy, observational
145,146 and randomized147 studies suggested
that uninterrupted VKA therapy was associated with su-perior outcomes compared with VKA interruption with intraprocedural heparin. In particular, the COMPARE (Role of Coumadin in Preventing Thromboembolism in Atrial Fi-
brillation [AF] Patients Undergoing Catheter Ablation) clini-
cal trial randomized 1584 patients to interrupted warfarin with bridging anticoagulation (n=790) versus continuous warfarin (n=794). Bleeding events were less common in the continuous warfarin arm with no significant difference in stroke or transient ischemic attack (0.4% versus 0.8% major bleeding, 0.5% versus 0.9% pericardial effusion, and 4% versus 22% minor bleeding).
147
How interrupted/continuous NOAC therapy compares
to continuous warfarin has been the subject of intense study over the past 5 years. Multiple systematic assess-ments and meta-analyses have demonstrated similar
outcomes in patients treated with NOACs (interrupted
or continuous) versus continuous warfarin.
148–152 One
randomized study compared uninterrupted rivaroxaban
and VKA in 248 patients. The occurrence of any throm-
boembolic events (0 versus 2) and bleeding events (21 versus 18) was similar in the uninterrupted rivaroxa-ban and VKA arms. Although the study was relatively
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CLINICAL STATEMENTS
AND GUIDELINESsmall with limited power, the results were largely in line
with previous observational data that have suggested
similar outcomes with NOAC and VKA therapy. Another
randomized study compared uninterrupted apixaban versus continuous warfarin in 200 subjects with drug-refractory AF undergoing ablation and found no differ-ence in thromboembolic or bleeding outcomes.
153 There
are several ongoing larger randomized clinical trials of interrupted versus uninterrupted NOAC therapy and con-tinuous warfarin versus continuous NOAC therapy.
The recommendation to use TEE to exclude the pres-
ence of left atrial appendage/left atrial thrombus should be similar regardless of whether VKA or NOAC therapy is used.
154 If the patient has not had 3 to 4 weeks of pre-
procedural anticoagulation or if the patient is considered at increased risk for stroke, the use of TEE is mandatory. However, many laboratories conduct a TEE in all patients
before ablation since thrombus can be observed even in
low-risk patients with paroxysmal AF.
155
Regardless of whether continuous or interrupted NOAC
therapy is used, on the basis of current consensus recom-
mendations, patients should be heparinized with 100-U/
kg bolus followed by an infusion of 10 U/kg/hour before or immediately after puncture. The activated clotting time should be checked every 10 to 15 minutes until target and then every 30 minutes thereafter. The activated clot-ting time target should be at least 300 to 350 seconds or 350 to 400 seconds in the case of spontaneous echocar-diographic contrast (“smoke”) or severe left atrial enlarge-ment.
154 Heparinization before transeptal access may be
associated with a lower risk of asymptomatic microembol-ic events as detected by brain magnetic resonance imag-ing.
156 It is important to note that the use of NOAC therapy
before and during the procedure results in the need for an increased dose of heparin to achieve target activated
clotting times during the ablation procedure.
157 After the
procedure, NOAC therapy is generally reintroduced within
4 to 8 hours after sheath removal if access site hemo-stasis has been achieved. Consistent with consensus rec-
ommendations, NOAC therapy should be continued for a
minimum of 2 to 3 months after ablation. Thereafter, oral anticoagulation should be based on the patient’s underly-ing risk for stroke (CHA
2DS2-VASc score) rather than the
current rhythm.
Electronic Device Implantation
Management of oral anticoagulation surrounding cardiac implantable electronic device insertion presents several
challenges. Oral anticoagulation increases the risk of
bleeding and hematoma formation after device implan-
tation. Furthermore, hematoma formation increases the
risk of postoperative infection. Based upon the results from randomized clinical trials, uninterrupted warfarin has been shown to lead to less bleeding and superior outcomes compared with interrupted warfarin and par-enteral bridging therapy.
158,159 These findings are also
consistent with the BRIDGE (Perioperative Bridging Anti-
coagulation in Patients With Atrial Fibrillation) trial, which
found no significant benefit to bridging for general inter-ruption of oral anticoagulation for invasive procedures in patients with NVAF.
116 However, the optimal manage-
ment of NOAC therapy surrounding cardiac implantable electronic device implantation remains unknown.
In general, discontinuation of NOAC therapy before
cardiac implantable electronic device implantation in a manner consistent with the elimination half-life is the most common practice pattern. For apixaban, edoxa-ban, and rivaroxaban, this would include discontinuation
24 hours in advance of the procedure. In the case of
dabigatran, discontinuation is recommended 24 hours before in patients with a CrCl ≥ 80 mL/min, 36 hours be-
fore in those with CrCl 50 to 79 mL/min, and 48 hours before in those with a CrCl <50 mL/min.
160 Survey data
from implanting physicians suggest wide variation in practice patterns reflecting the uncertainly over optimal management.
161 However, the majority of physicians
discontinue NOAC therapy at the time of implantation (82%).
161 Although uninterrupted warfarin has the best
evidence base (>1 randomized trial), an increasing num-ber of cardiac implantable electronic device patients are
taking NOAC therapy. Whether NOAC therapy can be
continued through cardiac implantable electronic de-vice implantation remains debated and is the subject of a large clinical trial (BRUISE CONTROL-2 [Strategy of Continued vs Interrupted Novel Oral Anticoagulant at Time of Device Surgery in Patients With Moderate to
High Risk of Arterial Thromboembolic Events] study) in
which perioperative management will be randomized to a strategy of continued versus interrupted NOAC thera-py. The few available observational data are limited by their small cohort size but have not identified significant
risks of bleeding with uninterrupted NOAC therapy.
162,163
When a decision is made to interrupt NOAC therapy for cardiac implantable electronic device implantation,
the implanting physician must decide when the NOAC therapy should be restarted. This decision is often influ-enced by patient characteristics, including risk factors for bleeding and the postimplantation physical examina-tion (eg, hematoma). Similar to discontinuation, prac-
tice patterns regarding resumption of NOAC therapy
after implantation are highly variable.
161 Typically, NOAC
therapy was restarted 24 to 48 hours after surgical pro-cedures in the pivotal NOAC trials. Patients with multiple
risk factors for bleeding, concomitant antiplatelet ther-
apy, or evidence of hematoma on their postoperative examination may benefit from a greater delay to NOAC resumption (3 to 5 days). However, given the lack of evidence to guide these decisions, management should
be approached on a patient-by-patient basis, weighing
the risks and benefits of earlier versus later resumption of NOAC therapy.
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e622Cardiovascular Surgery
There is limited information regarding the use of NOACs
in coronary artery bypass grafting or valve replacement
surgery. At present, information related to perioperative
NOAC use in cardiac surgery is anecdotal or based on
limited subset analyses.48,164,165 No significant bleeding
event differences were observed between rivaroxaban
and warfarin treated patients who underwent cardiac
surgery in ROCKET AF.110a The ATLAS ACS-2-TIMI-51 trial
tested rivaroxaban to lower cardiovascular events in
patients with ACS and reported 10 patients undergoing
coronary artery bypass grafting after ST-segment eleva-
tion myocardial infarction.129,166 Per the trial protocol, the
drug was stopped 12 hours before the procedure and
resumed 12 hours after the postprocedural drains were
removed or after the last dose of parenteral anticoagu-
lant therapy had been administered. The results specific
to this group were not reported; therefore, no conclu-sions regarding coronary artery bypass grafting–related
care can be made.
Established indications for NOACs in the pericardiac
surgery setting include stroke prevention in preoperative AF, prolonged or frequent postoperative AF, and VTE
treatment. NOAC use is contraindicated in patients with
mechanical valves; as the RE-ALIGN (The Randomized,
Phase II Study to Evaluate the Safety and Pharmacoki-
netics of Oral Dabigatran Etexilate in Patients After Heart
Valve Replacement) trial with dabigatran demonstrated,
there is an increased rate of thromboembolic and bleed-
ing complications compared with warfarin.
167 There are
case reports of dabigatran use after left ventricular
assist device placement168 and of rivaroxaban use for
heparin induced thrombocytopenia after coronary artery bypass grafting.
169 However, these off-label uses are not
supported by available clinical trial evidence.
For cardiac surgery, NOACs should be stopped in
the perioperative setting and restarted after clinical hemostasis has been established. As cardiac surgery
is considered a high-bleeding-risk procedure, surgery
should be postponed if at all possible until after the
appropriate interruption period. Bleeding after car-
diac surgery should be monitored via standard post-
procedure drains. Life-threatening bleeding should be
treated with supportive therapy, including transfusion
of blood products and administration of antifibrinolyt-
ics as indicated for hemorrhage resuscitation, and
return to the operating room. If contributing to an on-
going coagulopathy, administration of NOAC antidotes
as previously described (Laboratory Measurement of
NOAC Effect) could be considered. Mild bleeding may
be monitored, but NOACs should not be reinitiated until
there is bleeding control.
Similarly, the published experience of NOAC manage-
ment in patients undergoing vascular surgery is limited
to case reports and very small trial subsets.
48,164,165 In a subgroup analysis of ROCKET AF, patients with periph-
eral artery disease on rivaroxaban had a higher risk of major bleeding and nonmajor clinically relevant bleeding
compared with warfarin.
170
Noncardiovascular Surgery
Studies examining outcomes among NOAC users af-
ter noncardiovascular surgery largely grouped patients
into cohorts spanning minor to major high-risk sur-
gery.48,103,164,171 NOACs do not increase the rate of post-
operative bleeding events when compared with warfarin.
A pooled analysis of dabigatran phase III trial bleeding
data demonstrated no difference in postoperative bleed-ing events between patients on dabigatran and warfa-rin.
171 In the ARISTOTLE trial, there was no difference in
stroke, myocardial infarction, mortality, or bleeding for patients on apixaban versus warfarin for NVAF.
105 How-
ever, small differences may not have been detected as only 2.9% of procedures in this trial were considered emergent and only 10.2% of procedures were consid-
ered major.
Bridging therapy is not recommended during NOAC
therapy interruption for patients undergoing surgery.
The dabigatran RE-LY study demonstrated an increased risk for major bleeding with bridging therapy.
165 Non-
bridged patients had a thromboembolic event risk of 0.6%. Analysis of periprocedural dabigatran use in the
RE-LY trial demonstrated no difference in major bleed-
ing events between urgent versus elective surgery and major versus minor surgery.
103 There was also no
difference in fatal bleeding, reoperation as a result of bleeding, or transfusion requirements. There were few-er bleeding events in patients with shorter interruption periods, though this may not be a causal relationship
given that shorter interruptions may indicate patients
with characteristics of faster drug clearance. In con-trast, analysis of the Dresden NOAC registry demon-strated increased risk of bleeding in patients with major procedures.
48 Heparin bridging still did not reduce car-
diovascular events and did not statistically affect bleed-ing risk once the data were adjusted for major versus
minor procedures.
48 In the Canadian dabigatran cohort
study, none of the 541 patients received preoperative
bridging, and only 1.7% of patients received postopera-tive heparin or low-molecular-weight heparin. Despite this, there was only 1 transient ischemic attack event (0.2%) and no major arterial thromboembolic events. In
the ARISTOTLE study, 37.5% of procedures did not re-
quire NOAC interruption and 11.7% of patients received bridging anticoagulation.
105
In phase III trials of NOAC use for VTE prevention
in high-bleeding-risk orthopedic surgery, the first pro-
phylactic dose was administered 6 to 12 hours post-
operatively.172 Real-world registries of NOAC use after
orthopedic surgery suggest higher rates of bleeding
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CLINICAL STATEMENTS
AND GUIDELINEScompared with those observed in the trials. In the Dres-
den NOAC registry, 6 out of 42 patients undergoing
major orthopedic surgery developed major cardiovas-cular (n=2) or bleeding events (n=4).
48 In the Canadian
dabigatran cohort, 5 out of 19 patients undergoing
major orthopedic surgery developed major bleeding
complications.164 Caution should be exercised in man-
aging patients on NOACs who require major orthopedic
interventions.
Neuraxial Anesthesia
Spinal or epidural hematoma can be a devastating com-
plication of neuraxial anesthesia. There are limited data
pertaining to the interval between the discontinuation of
NOACs, the neuraxial anesthesia procedure itself, and
subsequent resumption of the NOAC. Rivaroxaban to
prevent VTE after total knee joint replacement or total hip arthroplasty with neuraxial anesthesia has also been
examined. In an analysis of 4 trials, neuraxial hematoma
occurred in only 1 of 4086 patients in the rivaroxaban
group and this occurred before drug administration.
173
Of the 2550 patients who underwent neuraxial anesthe-
sia in the rivaroxaban group in a phase IV cohort study, 1 patient developed intraspinal/hemorrhagic puncture.
174
These data suggest that the incidence of neuraxial he-matoma is low despite concurrent administration of therapeutic doses of a NOAC.
There are no robust clinical outcomes data to address
the timing and safety of NOAC discontinuation and rein-stitution. The American Society of Regional Anesthesia
and European Society of Regional Anesthesia and Pain
Therapy recommend stopping dabigatran 4 to 5 days
before neuraxial block.
175 For patients with end-stage
renal disease, 6 days off dabigatran is recommended.
For patients with high risk of VTE, dabigatran may be administered 12 hours after the pain intervention. This
group recommends stopping apixaban and rivaroxaban
3 to 5 days before neuroaxial block, and resuming either drug 12 hours after the pain intervention if the risk of
VTE is considered high. No guidance on edoxaban was
considered in this document. These recommendations
are controversial because discontinuation periods of ≥4
days are inconsistent with the return to hemostasis time
of these agents, which may expose patients to excess
thromboembolic risk.
CONCLUSION
NOACs are no longer novel and are now commonly used in day-to-day medical practice. Healthcare providers are
encouraged to use well-defined protocols established in
collaborations with multiple professional disciplines to
address NOAC dose and continuation or cessation when
invasive procedures are required. Such protocols should also be encouraged to assist acute care providers who
manage bleeding while patients take NOACs. Simple to
administer antidotes are either approved for use, such
as idarucizumab for dabigatran, or are currently under
investigation. Further studies that measure clinical out-
comes after NOAC reversal are needed to optimize pro-tocols for NOAC-associated bleeding and periprocedural
NOAC management.
ACKNOWLEDGMENTS
The AHA writing group thanks Taylor Klein for assistance in
reference formatting and Anne Leonard and Connie Land for administrative assistance.
FOOTNOTES
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or
business interest of a member of the writing panel. Specifically,
all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Asso-
ciation Science Advisory and Coordinating Committee on Octo-ber 10, 2016, and the American Heart Association Executive Committee on October 25, 2016. A copy of the document is
available at http://professional.heart.org/statements by using
either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 843-216-
2533 or e-mail kelle.ramsay@wolterskluwer.com.
The American Heart Association requests that this docu-
ment be cited as follows: Raval AN, Cigarroa JE, Chung MK,
Diaz-Sandoval LJ, Diercks D, Piccini JP, Jung HS, Washam JB,
Welch BG, Zazulia AR, Collins SP; on behalf of the American
Heart Association Clinical Pharmacology Subcommittee of the Acute Cardiac Care and General Cardiology Committee of the Council on Clinical Cardiology; Council on Cardiovascu-lar Disease in the Young; and Council on Quality of Care and
Outcomes Research. Management of patients on non–vitamin
K antagonist oral anticoagulants in the acute care and peri-procedural setting: a scientific statement from the American Heart Association. Circulation. 2017;135:e604–e633. doi:
10.1161/CIR.0000000000000477.
Expert peer review of AHA Scientific Statements is conducted
by the AHA Office of Science Operations. For more on AHA state-ments and guidelines development, visit http://professional.
heart.org/statements. Select the “Guidelines & Statements” drop-down menu, then click “Publication Development.”
Permissions: Multiple copies, modification, alteration, en-
hancement, and/or distribution of this document are not permit-ted without the express permission of the American Heart Asso-ciation. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright-Permission-
Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Per-missions Request Form” appears on the right side of the page.
Circulation is available at http://circ.ahajournals.org.
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Raval et al
March 7, 2017 Circulation. 2017;135:e604–e633. DOI: 10.1161/CIR.0000000000000477 e624
Writing Group Disclosures
Writing Group
Member Employment Research GrantOther Research
SupportSpeakers’
Bureau/
HonorariaExpert
WitnessOwnership
InterestConsultant/
Advisory Board Other
Amish N. Raval University of
WisconsinNone None None None None None None
Sean P . Collins Vanderbilt University
College of MedicineNone None None None None None None
Mina K. Chung Cleveland Clinic None None None None None None None
Joaquin E. CigarroaOregon Health and
Science UniversityNone None None None None None None
Larry J. Diaz-SandovalMichigan State
UniversityNone None None None None None None
Deborah Diercks UT Southwestern
Emergency MedicineNone Johnson &
Johnson*
(Steering
Committee
member on a
study about the
treatment of PE
using NOACS)None None None None None
Hee Soo Jung University of
WisconsinNIH(National
Center for
Advancing
Translational
Sciences)*;
National Board
of Medical
Examiners*None None None None None None
Jonathan P .
PicciniDuke University Janssen
Pharmaceuticals†None None None None Janssen
Pharmaceuticals*;
Medtronic*; BMS
Pfizer*None
Jeffrey B.
WashamDuke University Heart
CenterNone None None None None None None
Babu G. Welch UT Southwestern
Medical CenterSt. Paul Medical
Foundation†None None None None Stryker
Neurovascular*;
Covidien*None
Allyson R. ZazuliaWashington
UniversityNone None None None None None None
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as
reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns
5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be
“modest” if it is less than “significant” under the preceding definition.
*Modest.
†Significant.DISCLOSURES
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Management of Patients on NOACs in the Acute Care and Periprocedural Setting
Circulation. 2017;135:e604–e633. DOI: 10.1161/CIR.0000000000000477 March 7, 2017
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Jeffrey I. WeitzThrombosis &
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This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the
Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or
share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant”
under the preceding definition.
*Modest.†Significant.
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